Mono- and Disubstituted 3-Propyl Gamma-Aminobutyric Acids

专利摘要:
The present invention is directed to a series of novel monosubstituted and disubstituted 3-propyl gamma aminobutyric acids of the general formula (I) The compounds of the present invention are useful as therapeutic agents in the treatment of epilepsy, stroke, motor hypotonia, cranial diseases, neurodegenerative diseases, depression, anxiety, panic disorder, pain, neuropathological diseases, arthritis, sleep disorders, IBS and gastric injuries . Methods of making the compounds of the invention and useful intermediates are also part of the present invention. ≪ Formula 1 >
公开号:KR20020009631A
申请号:KR1020017015841
申请日:2000-05-31
公开日:2002-02-01
发明作者:토마스 리차드 벨리오티；저스틴 스티븐 브라이언스；아이호에조 빅터 에카토；오거스틴 토비 오슈마；로버트 마이클 스켈쿤；앤드류 존 쏘르프；로렌스 데이비드 와이즈；데이비드 쥐르겐 우스트로우；포-와이 옌；제이콥 브래들리 슈와르츠
申请人:로즈 암스트롱, 크리스틴 에이. 트러트웨인；워너-램버트 캄파니；
IPC主号:

专利说明:

Mono- and Disubstituted 3-Propyl Gamma-Aminobutyric Acids < RTI ID = 0.0 >
[1] Compounds of formula 1 are known from U.S. Pat. No. 4,024,175 and its divisional U.S. Pat. No. 4,087,544. The disclosed use has the protective effect against convulsions induced by thiosemicarbazide; Protection against cardiazole convulsions; Protective effects against brain diseases, epilepsy, stroke, hypokinesia and cranial trauma; And improvement of brain function. The following compounds are also useful in elderly patients. Such patents are incorporated herein by reference.
[2]
[3] Wherein R ₁ is hydrogen or a lower alkyl radical and n is 4, 5 or 6.
[4] Compounds of formula (2), or pharmaceutically acceptable salts thereof, are known from U.S. Patent No. 5,563,175 and its various various patents. The contents of these patents are incorporated herein by reference.
[5]
[6] Wherein R ₁ is a straight or branched chain alkyl group of 1 to 6 carbon atoms, phenyl or cycloalkyl of 3 to 6 carbon atoms, R ₂ is hydrogen or methyl, and R ₃ is hydrogen or carboxyl.
[7] SUMMARY OF THE INVENTION [
[8] The compounds of the present invention are those of formula (I) or a pharmaceutically acceptable salt thereof.
[9]
[10] Wherein R ¹ is hydrogen, straight or branched chain alkyl of 1 to 6 carbon atoms, or phenyl, and R ² is a straight or branched alkyl of 1 to 8 carbon atoms, a straight or branched alkyl of 2 to 8 carbon atoms, or Alkoxy, alkylcycloalkyl, alkylalkoxy, alkyl OH, alkylphenyl, alkylphenoxy, phenyl or substituted phenyl, and R < ² > If it is methyl R ¹ is a straight or branched chain alkyl of 1 to 6 carbon atoms.
[11] Preferred compounds are those compounds of formula I, wherein R < ¹ > is hydrogen and R < ² > is alkyl.
[12] Other preferred compounds are those compounds of formula I, wherein R < ¹ > is methyl and R < ² >
[13] More preferred compounds are those compounds of formula I, wherein R < ¹ > is methyl and R < ² > is methyl or ethyl.
[14] Particularly preferred compounds are 3-aminomethyl-5-methylheptanoic acid; 3-Aminomethyl-5-methyl-octanoic acid; 3-Aminomethyl-5-methyl-nonanoic acid; 3-Aminomethyl-5-methyl-decanoic acid; 3-Aminomethyl-5-methyl-undecanoic acid; 3-Aminomethyl-5-methyl-dodecanoic acid; 3-Aminomethyl-5-methyl-tridecanoic acid; 3-Aminomethyl-5-cyclopropyl-hexanoic acid; 3-Aminomethyl-5-cyclobutyl-hexanoic acid; 3-Aminomethyl-5-cyclopentyl-hexanoic acid; 3-Aminomethyl-5-cyclohexyl-hexanoic acid; 3-Aminomethyl-5-trifluoromethyl-hexanoic acid; 3-Aminomethyl-5-phenyl-hexanoic acid; 3-Aminomethyl-5- (2-chlorophenyl) -hexanoic acid; 3-Aminomethyl-5- (3-chlorophenyl) -hexanoic acid; 3-Aminomethyl-5- (4-chlorophenyl) -hexanoic acid; 3-Aminomethyl-5- (2-methoxyphenyl) -hexanoic acid; 3-Aminomethyl-5- (3-methoxyphenyl) -hexanoic acid; 3-Aminomethyl-5- (4-methoxyphenyl) -hexanoic acid; And 3-aminomethyl-5- (phenylmethyl) -hexanoic acid.
[15] Other particularly preferred compounds are (3R, 4S) -3-aminomethyl-4,5-dimethyl-hexanoic acid, 3-aminomethyl-4,5-dimethyl-hexanoic acid; (3R, 4S) -3-Aminomethyl-4,5-dimethyl-hexanoic acid MP; (3S, 4S) -3-Aminomethyl-4,5-dimethyl-hexanoic acid; (3R, 4R) -3-Aminomethyl-4,5-dimethyl-hexanoic acid MP; 3-Aminomethyl-4-isopropyl-hexanoic acid; 3-Aminomethyl-4-isopropyl-heptanoic acid; 3-Aminomethyl-4-isopropyl-octanoic acid; 3-Aminomethyl-4-isopropyl-nonanoic acid; 3-Aminomethyl-4-isopropyl-decanoic acid; And 3-aminomethyl-4-phenyl-5-methyl-hexanoic acid.
[16] Other preferred compounds include
[17] (3S, 5S) -3-Aminomethyl-5-methoxy-hexanoic acid;
[18] (3S, 5S) -3-Aminomethyl-5-ethoxy-hexanoic acid;
[19] (3S, 5S) -3-Aminomethyl-5-propoxy-hexanoic acid;
[20] (3S, 5S) -3-Aminomethyl-5-isopropoxy-hexanoic acid;
[21] (3S, 5S) -3-Aminomethyl-5-tert-butoxy-hexanoic acid;
[22] (3S, 5S) -3-Aminomethyl-5-fluoromethoxy-hexanoic acid;
[23] (3S, 5S) -3-Aminomethyl-5- (2-fluoro-ethoxy) -hexanoic acid;
[24] (3S, 5S) -3-Aminomethyl-5- (3,3,3-trifluoro-propoxy) -hexanoic acid;
[25] (3S, 5S) -3-Aminomethyl-5-phenoxy-hexanoic acid;
[26] (3S, 5S) -3-Aminomethyl-5- (4-chloro-phenoxy) -hexanoic acid;
[27] (3S, 5S) -3-Aminomethyl-5- (3-chloro-phenoxy) -hexanoic acid;
[28] (3S, 5S) -3-Aminomethyl-5- (2-chloro-phenoxy) -hexanoic acid;
[29] (3S, 5S) -3-Aminomethyl-5- (4-fluoro-phenoxy) -hexanoic acid;
[30] (3S, 5S) -3-Aminomethyl-5- (3-fluoro-phenoxy) -hexanoic acid;
[31] (3S, 5S) -3-Aminomethyl-5- (2-fluoro-phenoxy) -hexanoic acid;
[32] (3S, 5S) -3-Aminomethyl-5- (4-methoxy-phenoxy) -hexanoic acid;
[33] (3S, 5S) -3-Aminomethyl-5- (3-methoxy-phenoxy) -hexanoic acid;
[34] (3S, 5S) -3-Aminomethyl-5- (2-methoxy-phenoxy) -hexanoic acid;
[35] (3S, 5S) -3-Aminomethyl-5- (4-nitro-phenoxy) -hexanoic acid;
[36] (3S, 5S) -3-Aminomethyl-5- (3-nitro-phenoxy) -hexanoic acid;
[37] (3S, 5S) -3-Aminomethyl-5- (2-nitro-phenoxy) -hexanoic acid;
[38] (3S, 5S) -3-Aminomethyl-6-hydroxy-5-methyl-hexanoic acid;
[39] (3S, 5S) -3-Aminomethyl-6-methoxy-5-methyl-hexanoic acid;
[40] (3S, 5S) -3-Aminomethyl-6-ethoxy-5-methyl-hexanoic acid;
[41] (3S, 5S) -3-Aminomethyl-5-methyl-6-propoxy-hexanoic acid;
[42] (3S, 5S) -3-Aminomethyl-6-isopropoxy-5-methyl-hexanoic acid;
[43] (3S, 5S) -3-Aminomethyl-6-tert-butoxy-5-methyl-hexanoic acid;
[44] (3S, 5S) -3-Aminomethyl-6-fluoromethoxy-5-methyl-hexanoic acid;
[45] (3S, 5S) -3-Aminomethyl-6- (2-fluoro-ethoxy) -5-methyl-hexanoic acid;
[46] (3S, 5S) -3-Aminomethyl-5-methyl-6- (3,3,3-trifluoro-propoxy) -hexanoic acid;
[47] (3S, 5S) -3-Aminomethyl-5-methyl-6-phenoxy-hexanoic acid;
[48] (3S, 5S) -3-Aminomethyl-6- (4-chloro-phenoxy) -5-methyl-hexanoic acid;
[49] (3S, 5S) -3-Aminomethyl-6- (3-chloro-phenoxy) -5-methyl-hexanoic acid;
[50] (3S, 5S) -3-Aminomethyl-6- (2-chloro-phenoxy) -5-methyl-hexanoic acid;
[51] (3S, 5S) -3-Aminomethyl-6- (4-fluoro-phenoxy) -5-methyl-hexanoic acid;
[52] (3S, 5S) -3-Aminomethyl-6- (3-fluoro-phenoxy) -5-methyl-hexanoic acid;
[53] (3S, 5S) -3-Aminomethyl-6- (2-fluoro-phenoxy) -5-methyl-hexanoic acid;
[54] (3S, 5S) -3-Aminomethyl-6- (4-methoxy-phenoxy) -5-methyl-hexanoic acid;
[55] (3S, 5S) -3-Aminomethyl-6- (3-methoxy-phenoxy) -5-methyl-hexanoic acid;
[56] (3S, 5S) -3-Aminomethyl-6- (2-methoxy-phenoxy) -5-methyl-hexanoic acid;
[57] (3S, 5S) -3-Aminomethyl-5-methyl 6- (4-trifluoromethyl-phenoxy) -hexanoic acid;
[58] (3S, 5S) -3-Aminomethyl-5-methyl 6- (3-trifluoromethyl-phenoxy) -hexanoic acid;
[59] (3S, 5S) -3-Aminomethyl-5-methyl 6- (2-trifluoromethyl-phenoxy) -hexanoic acid;
[60] (3S, 5S) -3-Aminomethyl-5-methyl 6- (4-nitro-phenoxy) -hexanoic acid;
[61] (3S, 5S) -3-Aminomethyl-5-methyl 6- (3-nitro-phenoxy) -hexanoic acid;
[62] (3S, 5S) -3-Aminomethyl-5-methyl 6- (2-nitro-phenoxy) -hexanoic acid;
[63] (3S, 5S) -3-Aminomethyl-6-benzyloxy-5-methyl-hexanoic acid;
[64] (3S, 5S) -3-Aminomethyl-7-hydroxy-5-methyl-heptanoic acid;
[65] (3S, 5S) -3-Aminomethyl-7-methoxy-5-methyl-heptanoic acid;
[66] (3S, 5S) -3-Aminomethyl-7-ethoxy-5-methyl-heptanoic acid;
[67] (3S, 5S) -3-Aminomethyl-5-methyl-7-propoxy-heptanoic acid;
[68] (3S, 5S) -3-Aminomethyl-7-isopropoxy-5-methyl-heptanoic acid;
[69] (3S, 5S) -3-Aminomethyl-7-tert-butoxy-5-methyl-heptanoic acid;
[70] (3S, 5S) -3-Aminomethyl-7-fluoromethoxy-5-methyl-heptanoic acid;
[71] (3S, 5S) -3-Aminomethyl-7- (2-fluoro-ethoxy) -5-methyl-heptanoic acid;
[72] (3S, 5S) -3-Aminomethyl-5-methyl-7- (3,3,3-trifluoro-propoxy) -heptanoic acid;
[73] (3S, 5S) -3-Aminomethyl-7-benzyloxy-5-methyl-heptanoic acid;
[74] (3S, 5S) -3-Aminomethyl-5-methyl-7-phenoxy-heptanoic acid;
[75] (3S, 5S) -3-Aminomethyl-7- (4-chloro-phenoxy) -5-methyl-heptanoic acid;
[76] (3S, 5S) -3-Aminomethyl-7- (3-chloro-phenoxy) -5-methyl-heptanoic acid;
[77] (3S, 5S) -3-Aminomethyl-7- (2-chloro-phenoxy) -5-methyl-heptanoic acid;
[78] (3S, 5S) -3-Aminomethyl-7- (4-fluoro-phenoxy) -5-methyl-heptanoic acid;
[79] (3S, 5S) -3-Aminomethyl-7- (3-fluoro-phenoxy) -5-methyl-heptanoic acid;
[80] (3S, 5S) -3-Aminomethyl-7- (2-fluoro-phenoxy) -5-methyl-heptanoic acid;
[81] (3S, 5S) -3-Aminomethyl-7- (4-methoxy-phenoxy) -5-methyl-heptanoic acid;
[82] (3S, 5S) -3-Aminomethyl-7- (3-methoxy-phenoxy) -5-methyl-heptanoic acid;
[83] (3S, 5S) -3-Aminomethyl-7- (2-methoxy-phenoxy) -5-methyl-heptanoic acid;
[84] (3S, 5S) -3-Aminomethyl-5-methyl-7- (4-trifluoromethyl-phenoxy) -heptanoic acid;
[85] (3S, 5S) -3-Aminomethyl-5-methyl-7- (3-trifluoromethyl-phenoxy) -heptanoic acid;
[86] (3S, 5S) -3-Aminomethyl-5-methyl-7- (2-trifluoromethyl-phenoxy) -heptanoic acid;
[87] (3S, 5S) -3-Aminomethyl-5-methyl-7- (4-nitro-phenoxy) -heptanoic acid;
[88] (3S, 5S) -3-Aminomethyl-5-methyl-7- (3-nitro-phenoxy) -heptanoic acid;
[89] (3S, 5S) -3-Aminomethyl-5-methyl-7- (2-nitro-phenoxy) -heptanoic acid;
[90] (3S, 5S) -3-Aminomethyl-5-methyl-6-phenyl-hexanoic acid;
[91] (3S, 5S) -3-Aminomethyl-6- (4-chloro-phenyl) -5-methyl-hexanoic acid;
[92] (3S, 5S) -3-Aminomethyl-6- (3-chloro-phenyl) -5-methyl-hexanoic acid;
[93] (3S, 5S) -3-Aminomethyl-6- (2-chloro-phenyl) -5-methyl-hexanoic acid;
[94] (3S, 5S) -3-Aminomethyl-6- (4-methoxy-phenyl) -5-methyl-hexanoic acid;
[95] (3S, 5S) -3-Aminomethyl-6- (3-methoxy-phenyl) -5-methyl-hexanoic acid;
[96] (3S, 5S) -3-Aminomethyl-6- (2-methoxy-phenyl) -5-methyl-hexanoic acid;
[97] (3S, 5S) -3-Aminomethyl-6- (4-fluoro-phenyl) -5-methyl-hexanoic acid;
[98] (3S, 5S) -3-Aminomethyl-6- (3-fluoro-phenyl) -5-methyl-hexanoic acid;
[99] (3S, 5S) -3-Aminomethyl-6- (2-fluoro-phenyl) -5-methyl-hexanoic acid;
[100] (3S, 5R) -3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid;
[101] (3S, 5R) -3-Aminomethyl-7- (4-chloro-phenyl) -5-methyl-heptanoic acid;
[102] (3S, 5R) -3-Aminomethyl-7- (3-chloro-phenyl) -5-methyl-heptanoic acid;
[103] (3S, 5R) -3-Aminomethyl-7- (2-chloro-phenyl) -5-methyl-heptanoic acid;
[104] (3S, 5R) -3-Aminomethyl-7- (4-methoxy-phenyl) -5-methyl-heptanoic acid;
[105] (3S, 5R) -3-Aminomethyl-7- (3-methoxy-phenyl) -5-methyl-heptanoic acid;
[106] (3S, 5R) -3-Aminomethyl-7- (2-methoxy-phenyl) -5-methyl-heptanoic acid;
[107] (3S, 5R) -3-Aminomethyl-7- (4-fluoro-phenyl) -5-methyl-heptanoic acid;
[108] (3S, 5R) -3-Aminomethyl-7- (3-fluoro-phenyl) -5-methyl-heptanoic acid;
[109] (3S, 5R) -3-Aminomethyl-7- (2-fluoro-phenyl) -5-methyl-heptanoic acid;
[110] (3S, 5R) -3-Aminomethyl-5-methyl-oct-7-enoic acid;
[111] (3S, 5R) -3-Aminomethyl-5-methyl-non-8-enoic acid;
[112] (E) - (3S, 5S) -3-Aminomethyl-5-methyl-oct-6-enoic acid;
[113] (Z) - (3S, 5S) -3-Aminomethyl-5-methyl-oct-6-enoic acid;
[114] (Z) - (3S, 5S) -3-Aminomethyl-5-methyl-non-6-enoic acid;
[115] (E) - (3S, 5S) -3-Aminomethyl-5-methyl-non-6-enoic acid;
[116] (E) - (3S, 5R) -3-Aminomethyl-5-methyl-non-7-enoic acid;
[117] (Z) - (3S, 5R) -3-Aminomethyl-5-methyl-non-7-enoic acid;
[118] (Z) - (3S, 5R) -3-Aminomethyl-5-methyl-de-7-enoic acid;
[119] (E) - (3S, 5R) -3-Aminomethyl-5-methyl-undec-7-enoic acid;
[120] (3S, 5S) -3-Aminomethyl-5,6,6-trimethyl-heptanoic acid;
[121] (3S, 5S) -3-Aminomethyl-5, 6-dimethyl-heptanoic acid;
[122] (3S, 5S) -3-Aminomethyl-5-cyclopropyl-hexanoic acid;
[123] (3S, 5S) -3-Aminomethyl-5-cyclobutyl-hexanoic acid;
[124] (3S, 5S) -3-Aminomethyl-5-cyclopentyl-hexanoic acid; And
[125] (3S, 5S) -3-Aminomethyl-5-cyclohexyl-hexanoic acid
[126] .
[127] Other more preferred compounds include
[128] (3S, 5R) -3-Aminomethyl-5-methyl-heptanoic acid;
[129] (3S, 5R) -3-Aminomethyl-5-methyl-octanoic acid;
[130] (3S, 5R) -3-Aminomethyl-5-methyl-nonanoic acid;
[131] (3S, 5R) -3-Aminomethyl-5-methyl-decanoic acid;
[132] (3S, 5R) -3-Aminomethyl-5-methyl-undecanoic acid;
[133] (3S, 5R) -3-Aminomethyl-5-methyl-dodecanoic acid;
[134] (3S, 5R) -3-Aminomethyl-5,9-dimethyl-decanoic acid;
[135] (3S, 5R) -3-Aminomethyl-5,7-dimethyl-octanoic acid;
[136] (3S, 5R) -3-Aminomethyl-5,8-dimethyl-nonanoic acid;
[137] (3S, 5R) -3-Aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;
[138] (3S, 5R) -3-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;
[139] (3S, 5R) -3-Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;
[140] (3S, 5R) -3-Aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;
[141] (3S, 5R) -3-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;
[142] (3S, 5R) -3-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;
[143] (3S, 5R) -3-Aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;
[144] (3S, 5R) -3-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;
[145] (3S, SR) -3-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;
[146] (3S, 5R) -3-Aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;
[147] (3S, 5R) -3-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;
[148] (3S, 5R) -3-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;
[149] (3S, 5S) -3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid;
[150] (3S, 5S) -3-Aminomethyl-7-fluoro-5-methyl-heptanoic acid;
[151] (3S, 5R) -3-Aminomethyl-8-fluoro-5-methyl-octanoic acid;
[152] (3S, 5R) -3-Aminomethyl-9-fluoro-5-methyl-nonanoic acid;
[153] (3S, 5S) -3-Aminomethyl-7,7,7-trifluoro-5-methyl-heptanoic acid;
[154] (3S, 5R) -3-Aminomethyl-8,8,8-trifluoro-5-methyl-octanoic acid;
[155] (3S, 5R) -3-Aminomethyl-5-methyl-8-phenyl-octanoic acid;
[156] (3S, 5S) -3-Aminomethyl-5-methyl-6-phenyl-hexanoic acid; And
[157] (3S, 5R) -3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid
[158] .
[159] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of formula I and a pharmaceutically acceptable carrier.
[160] The compounds of the present invention are useful for the treatment of epilepsy, stroke, motor dysfunction and cranial diseases, neurodegenerative diseases, depression, anxiety, panic disorder, pain, neuropathological diseases, arthritis, sleep disorders, IBS and gastric injuries .
[161] The compounds of the present invention are monosubstituted and disubstituted 3-propyl gamma-aminobutyric acids as shown in Formula I above.
[162] The terms are as set forth below or are described herein.
[163] The term alkyl or alkenyl includes straight or branched chain alkyl groups of 1 to 8 or 2 to 8 carbon atoms inclusive, including but not limited to methyl, ethyl, propyl, n-propyl, isopropyl, butyl, Or a branched chain. Alkyl may be unsubstituted or substituted with 1 to 3 fluorine atoms. Preferred groups are methyl and ethyl.
[164] Cycloalkyl is a cyclic group having 3 to 7 carbon atoms.
[165] The benzyl and phenyl groups may be unsubstituted or substituted with one to three groups each independently selected from halogen, especially fluoro, alkoxy, alkyl and amino.
[166] Halogen includes fluorine, chlorine, bromine and iodine.
[167] Alkoxy is as defined above for alkyl.
[168] When R is hydrogen, pharmaceutically acceptable salts can be prepared from the corresponding salts with suitable inorganic or organic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, oxalic acid, lactic acid, citric acid, malic acid, salicylic acid, malonic acid, maleic acid , Succinic acid and ascorbic acid. Starting from the corresponding hydroxide or carbonate, a salt with an alkali or alkaline earth metal, for example sodium, potassium, magnesium or calcium, is formed. Salts with quaternary ammonium ions can also be prepared, for example, as tetramethyl-ammonium ions.
[169] Prodrugs of compounds I-VIII are included within the scope of the present invention. Aminoacyl-glycolic acid esters and aminoacyl-lactic acid esters are known as prodrugs of amino acids (Wermuth C. G., Chemistry and Industry, 1980: 433-435). The carbonyl group of the amino acid can be esterified by a known method. Prodrugs and soft drugs are known in the art (Palomino E., Drugs of the Future, 1990; 15 (4): 361368). Both of these documents are hereby incorporated herein by reference.
[170] The efficacy of orally administered drugs depends on the efficient delivery of the drug through the mucosal epithelium and its stability in the entero-hepatic circulation. Drugs that are effective after parenteral administration but less effective after oral administration or whose plasma half-life is considered too short may be chemically modified in the form of prodrugs.
[171] A prodrug is a drug that can be chemically modified to be biologically inactive at its site of action but can be degraded or modified by one or more enzymes or other in vivo metabolism to become a bioactive model.
[172] Such chemically modified drugs, or prodrugs, should be able to more easily penetrate the mucosal epithelium and be able to be absorbed, be a better salt preparation, or have their solubility and / Should be able to further improve systemic stability (e.g., increase in plasma half-life). These chemical transformations are as follows:
[173] 1) an ester or amide derivative which can be cleaved, for example, by esterase or lipase. In the case of an ester derivative, the ester is derived from the carboxylic acid residue of the drug molecule by a known method. In the case of an amide derivative, the amide can be derived from the carboxylic acid residue or amine residue of the drug molecule by known methods;
[174] 2) peptides that can be recognized by specific or non-specific proteases. The peptide can be coupled to the drug molecule via amide bond formation with an amine or carboxylic acid residue of the drug molecule by known methods;
[175] 3) a derivative that accumulates in the action site through membrane selection of a prodrug form or a modified prodrug form;
[176] 4) any combination of 1 to 3;
[177] Animal studies currently show that oral absorption of some drugs can be increased by the production of "soft" quaternary salts. Quaternary salts are referred to as "soft" Quaternary salts because, unlike conventional quaternary salts, such as RN ⁺ (CH ₃ ) ₃ , the soft quaternary salts can release the active drug upon hydrolysis .
[178] &Quot; Soft " quaternary salts have useful properties when compared to a basic drug or salt thereof. Water solubility can be increased as compared to other salts, such as hydrochloride, but more importantly, absorption of the drug from the intestines can be increased. Increased absorption is due to the fact that "soft" quaternary salts can form nonionizing pairs with micelles and bile acids that have surfactant properties and can more efficiently penetrate the intestinal epithelium same. After absorption, the prodrug is hydrolyzed rapidly, releasing the active parent drug.
[179] Some compounds of the present invention may exist in dissolved form as well as hydrated form, as well as in hydrated form. Generally, the dissolution profile including the hydration profile is the same as the dissolution profile and is included in the scope of the present invention.
[180] The compounds of the present invention include all enantiomeric and epimeric forms as well as suitable mixtures thereof. For example, the compound of Example 1 is a mixture of all four possible stereoisomers. The compound of Example 6 is one of the above isomers. When the structure can be defined, the structure of the cyclohexane ring carbon center may be R or S in these compounds.
[181] Radiation ligand binding assays using [ ³ H] gabapentin and α ₂ δ subunits derived from porcine brain tissue were used (Gee NS, Brown JP, Dissanayake VUK, Offord J., Thurlow R., Woodruff GN, Novel Anti-convulsant Drug, Gabapentin, Binds to the α ₂ δ Subunit of a Calcium Channel, "J. Biol Chem., 1996; 271: 5879-5776).
[182] <Table 1>
[183]
[184] Table 1 shows the binding affinities of the ₂ Subunit and the compound of the present invention.
[185] Compounds of the invention are compared to Neurontin (TM), a marketable drug useful for the treatment of diseases such as epilepsy. Neurotin (R) is 1- (aminomethyl) -cyclohexanoic acetic acid of the formula:
[186]
[187] Gabapentin (neuronal (TM)) is about 0.10 to 0.12 μM in this assay. Thus, the compounds of the invention are expected to exhibit pharmacological properties comparable to gabapentin or gabapentin, for example, as medicines for convulsions, anxiety and pain.
[188] The present invention also relates to the therapeutic use of the compounds of the present invention, which are similar to those for neurodegenerative diseases.
[189] Such neurodegenerative diseases are, for example, Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis.
[190] The present invention also encompasses treating neurodegenerative diseases called acute brain injury. These diseases include, but are not limited to, stroke, cranial trauma, and asphyxia.
[191] Stroke refers to cerebrovascular disease and can also be referred to as CVA (Cerebral Vascular Incident) and includes acute thromboembolic stroke. Calcane includes both focal ischemia and systemic ischemia. It also includes transient cerebral ischemic attacks and other cerebrovascular diseases accompanied by cerebral ischemia. The patient is specifically undergoing carotid endarterectomy, generally undergoing other cerebral or vascular procedures, or undergoing angiography, including cerebral angiography.
[192] Other diseases include head trauma, spinal trauma, or similar damage that occurs during the course of general anoxia, hypoxia, hypoglycemia, hypertension, as well as dislocation, hyperperfusion, and hypoxia.
[193] The present invention will be useful in various cases, such as during cardiac bypass, intracranial hemorrhage, prenatal vaginism, heart attack and epileptic persistence.
[194] Pain refers to acute pain as well as chronic pain.
[195] Acute pain is usually short-term pain and is associated with hyperactivity of the sympathetic nervous system. Examples include postoperative pain and allodynia.
[196] Chronic pain is defined as pain that usually lasts for three to six months and includes both chain pain and cardiogenic pain. Other pain is traumatic.
[197] Other pain is caused by injury or infection of the peripheral sensory nerve. This pain includes, but is not limited to, peripheral nerve trauma, herpes virus infection, diabetes mellitus, causalgia, plexus avulsion, neuroma, limb amputation and pain from vasculitis. Neuropathic pain is also caused by chronic alcoholism, human immunodeficiency virus infection, hypothyroidism, uremia, or nerve damage from vitamin deficiency. Neuropathic pain includes, but is not limited to, pain caused by nerve damage, such as pain caused by diabetes.
[198] Psychogenic pain is a pain not resulting from an organ such as back pain, irregular facial pain and chronic headache.
[199] Other forms of pain include, but are not limited to, inflammatory pain, osteoarthritic pain, trigeminal neuralgia, cancer pain, diabetic neuropathy, restless leg syndrome, herpetic neuralgia, postherpetic neuralgia, burning pain, brachial plexus excision, laryngeal pain, gout, Other forms of neuralgia, neuropathic and idiopathic pain syndrome.
[200] A skilled physician will be able to determine the conditions suitable for administering the compounds of the present invention to, for example, patients suffering from stroke, as well as patients susceptible to stroke or at risk for stroke.
[201] The compounds of the present invention are expected to be useful in the treatment of depression. The origin of depression can be the result of an institutional illness, a result of stress associated with personal loss, or idiopathic. Some forms of depression tend to occur on a family basis, suggesting that there is at least one causative mechanism for some form of depression. Depression is mainly diagnosed by quantifying changes in the mood of the ball. This assessment of mood is performed primarily by physicians or quantified by a neuropsychologist using proven evaluation criteria such as the Hamilton Depression Rating Scale or the Brief Psychiatric Rating Scale. A number of criteria have been developed to quantify and measure the degree of mood changes in patients with depression, such as insomnia, lack of concentration, lack of energy, feelings of lack of value, and guilt. The criteria for all psychiatric diagnoses, as well as the diagnosis of depression, are described in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, referred to as the DSM-IV-R (1994) manual published by the American Psychiatric Association.
[202] GABA is an inhibitory neurotransmitter of the central nervous system. Within the general context of inhibition, GABA-like mimics depression or depresses brain function, slowing brain function and reducing mood, resulting in depression.
[203] The compounds of the present invention can induce an anticonvulsant effect through an increase in the newly generated GABA at the synaptic boundary. If gabapentin actually increases the efficacy of GABA at the GABA level or at the synaptic interface, gabapentin may be classified as a GABA-like and will cause depression by slowing or depressing brain function, slowing brain function and reducing mood.
[204] The fact that a GABA agonist or GABA-like mimics the opposite action by elevating mood and thus is an anticonvulsant is a new concept different from the general opinion of the GABA activity.
[205] The compounds of the present invention are expected to be useful in the treatment of anxiety and panic, as evidenced by standard pharmacological procedures.
[206] In addition, the compounds of the present invention are expected to be useful in the treatment of sleep disorders. Sleep disorders are disorders that affect sleep ability and / or ability to maintain a sleep state, disorders that involve too much sleep, or abnormal behavior associated with sleep. Such disorders include, for example, insomnia, drug-related insomnia, sleep overload, sleep apnea, sleep apnea syndrome, and parasomnia.
[207] The compounds of the present invention are also useful in the treatment of arthritis.
[208] <Biological activity>
[209] <Table 2>
[210]
[211]
[212]
[213]
[214] The compounds of the present invention are useful as anxiolytics and anticonvulsants as described in Table 2 above. These are compared with isobutylglyba or pregabalin, which is (S) -3- (aminomethyl) -5-methylhexanoic acid of the formula:
[215]
[216] <Materials and Methods>
[217] Hyperalgesia induced by Carrageenin
[218] The Randall-Selitto method (Randall LO and Selitto JJ, "A method for measurement of analgesic activity on inflamed tissue," Arch. Int. Pharmacodyn., Vol. 1957; 4: 409-419). Male Sprague-Dawley rats (70-90 g) were trained in this apparatus prior to testing. The pressure was gently applied to the hind feet of each rat, and the perforation boundary was measured as the pressure (g) required to pull the foot back. A 250 g cut-off point was used to prevent any tissue damage to the foot. On the day of the test, baseline measurements were taken 2 to 3 times, and 100 μl of 2% carrageenin was administered into the right hind paw by intraplantar injection. In order to establish an animal with hyperalgesia, the intracoronary acceptance boundary was measured 3 hours after the administration of carrageenin. Animals were administered gabapentin (3 to 300 mg, subcutaneously), morphine (3 mg / kg, subcutaneously) or physiological water 3.5 hours after the administration of carrageenin, And 5 hours later.
[219] (R) -2-aza-spiro [4.5] decane-4-carboxylic acid hydrochloride was tested in the above carrageenin-induced hyperalgesia model. 30 mg / kg of the compound was orally administered and showed a maximum possible effect (MPE) of 53% after 1 hour of administration. Only 4.6% of MPE was seen 2 hours after administration.
[220] <Semicarbazide-induced tense seizures>
[221] Subcutaneous administration of semicarbazide (750 mg / kg) induced a tense seizure in mice. The latency period for stretching and extending forepaws was measured. Any mice that did not show convulsions within 2 hours after semicarbazide administration were considered protected mice and given a maximal incubation score of 120 min.
[222] <Animal>
[223] Male Hooded Lister rats (200-250 g) were purchased from Interfauna (Huntingdon, UK) and male TO mice (20-25 g) were purchased from Bantin and Kingman , UK). Two rodents were divided into six groups. A pair of 10 weight-bearing, double-calligraphy monkeys (Callithrix Jacchus) weighing 280 g to 360 g, raised at the Manchester University Metcalk School (Manch Ester, UK), were housed. All animals were placed in a light and dark place over a 12-hour period to provide sufficient food and water.
[224] &Lt; Drug administration >
[225] Prior to testing, the drug is administered intraperitoneally (IP) or subcutaneously (SC) at a volume of 1 ml / kg for rats and spiny monkeys, and at a volume of 10 ml / kg for mice.
[226] <Mouse light / arm box>
[227] The device is a box with an open top (length 45 cm, width 27 cm, height 27 cm), which is divided into small (2/5) and large (93/5) (Costall B., et al., "Exploration of mice in a black and white box: validation as a model of anxiety," Pharmacol. Biochem. Behav., 1989; 32: 777-785).
[228] There is a 7.5 x 7.5 cm opening in the center of the bottom of the floor. Small compartments are painted black and large compartments are painted white. The white block illuminates with a 60-W tungsten bulb. The laboratory illuminates with a red light. Each mouse is tested by placing each mouse in the center of the white area and letting the mouse explore the new environment for 5 minutes. Measures the time spent on the illuminated side (Kilfoil T., et al., "Effects of anxiolytic and anxiogenic drugs on exploratory activity in a simple model of anxiety inmice," Neuropharmacol., 1989; 28: 901-905).
[229] <Rat Rising X-maze>
[230] The standard elevated X-maze (Handley SL, et al., "Effects of alpha adrenoceptor agonists and antagonists in a maze-exploratory model of'fear'motivated behavior," Naunyn-Schiedeberg's Arch. Pharmacol., 1984; (Field, et al., &Quot; Automation of the rat elevated X-maze test of anxiety, " Br. J. Pharmacol., 1991; 102 (Suppl.): 304P). Place the animal in the center of the X-maze facing one of the open tubes. To measure the anxiolytic effect, the time spent in the distal half of the open tube is measured during a 5-minute test period (Costall, et al., "Use of the elevated plus maze to assess anxiolytic potential in the rat, &Quot; Br. J. Pharmacol., 1989; 96 (Suppl.): 312p).
[231] <Silkworm monkey human threat test>
[232] Record the total number of body postures the animal represents for a 2-minute trial period on a threat stimulus (a silkworm monkey standing about 0.5 cm away from us and staring at the eyes of a Silkworm monkey). The recorded body posture is an arching of glancing stare, tail posture, odor display of our / seated spot, hairy, retracted, and so on. Each animal is exposed twice to the challenge stimulus on the day before and after the drug treatment. The difference between the two scores is analyzed using Dunnett's t-test after unidirectional deviation analysis. All drug treatments are performed by subcutaneous administration at least 2 hours after the first (control) threat. The total treatment time for each compound is 40 minutes.
[233] &Lt;
[234] The rats are trained to press the lever for food compensation in the moving chamber. The training schedule is based on the assumption that a signal is delivered by digestion of the chamber, etc., without punishing four times over a period of 30 seconds at which the signal is delivered by the ignition of the chamber, And the bee is applied three times at a ratio of 3 for 3 minutes alternately. The degree of footshock for each rat is adjusted so as to obtain a reaction inhibition rate of approximately 80% to 90% as compared with the reaction when not subjected to bees. Give rats a menstrual cycle on the day of training.
[235] &Lt; DBA2 mouse model of anticonvulsant efficacy >
[236] All procedures were performed according to NIH guidelines for the care and use of laboratory animals under protocols approved by the Parke-Davis Animal Use Committee. Male DBA / 2 mice, 3 to 4 weeks old, were purchased from Jackson Laboratories, Bar Harbor, Maine. Immediately prior to the anticonvulsant test, the mice were placed on a wire mesh [10.16 cm ² (4 inch square)] floating from a steel rod. The mesh was slowly rotated 180 degrees and the mice were observed for 30 seconds. Any mouse away from the wire mesh was recorded as impaired (Coughenour LL, McLean JR, Parker RB, "A new device for impaired motor function in mice," Pharm. Biochem. Behav. 3): 351-3). The mice were confined within a closed acrylic plastic chamber (21 cm high, approximately 30 cm in diameter) with high frequency speakers (4 cm diameter) in the center of the top lid. A continuous S-shaped tone was generated that spread linearly at a frequency of 8 kHz to 16 kHz per 10 msec using an audio signal generator (Protek model B-810). The average sound pressure during stimulation was approximately 100 dB at the bottom of the chamber The mice were allowed to acclimate for 1 minute with the mouse in the chamber. The characteristic seizure sequence, consisting of a rigid extension following an intermittent seizure after a rough run in the vehicle-treated group DBA / 2 mice, and finally a respiratory arrest and death in more than 80% (Applied for up to 60 minutes, or for up to 60 sec.) In vehicle-treated mice, the seizure or respiratory arrest lasts for approximately 15 to 20 seconds Drug Treatment &lt; RTI ID = 0.0 &gt; recording the events of all ictal and pro-bit (probit) was analyzed by using the incidence of tonic seizures for calculating anticonvulsant ED ₅₀ (Litchfield JT, Wilcoxon F. "A simplified method for evaluating dose-effect experiments," J. Pharmacol., 1949, 96: 99-113.) The mice were used only once to test at each administration point. (N = 5 to 10 per administration) were tested for the two-hour seizure response (time of peak effect previously measured) induced by sound. And dissolved orally and administered orally at a volume of 10 ml / kg per kg of body weight The insoluble compound will be suspended in 1% carboxymethylcellulose The dosage is expressed as the weight of the active drug moiety.
[237] The compounds of the present invention are expected to be useful in the treatment of pain and phobias (Am. J. Pain Manag, 1995; 5: 7-9).
[238] In addition, the compounds of the present invention are expected to be useful in treating the symptoms of bipolar disorder, acute or chronic depression, single upside depression or recurrent depression. In addition, the compounds of the present invention are expected to be useful in the treatment and / or prevention of bipolar disorder (U.S. Patent No. 5,510,381).
[239] In addition, the compounds of the present invention are expected to be useful for sleep disorders. The prediction is as described in the literature (Drug Dev Res 1988; 14: 151-159).
[240] The compounds of the present invention can be manufactured and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the invention may be administered by injection, i. E., Intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally or intraperitoneally. In addition, the compounds of the invention may be administered by inhalation, for example, intranasally. In addition, the compounds of the present invention can be transdermally administered. It will be apparent to those skilled in the art that the following dosage forms may comprise as the active ingredient a compound of formula I or a corresponding pharmaceutically acceptable salt of a compound of formula I.
[241] Pharmaceutically acceptable carriers for the production of pharmaceutical compositions from the compounds of the present invention may be either solid or liquid. Solid formulations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier may be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials.
[242] In powders, the carrier is a finely divided solid mixed with the finely divided active component.
[243] In tablets, the active ingredient is mixed with the carrier having the necessary binding properties in suitable proportions and compacted to the desired shape and size.
[244] The powders and tablets preferably contain 5 or 10 to about 70% active ingredient. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter and the like. The term " preparation " is intended to encompass a preparation of the active compound, comprising as carrier a encapsulating material which provides a capsule in which the active ingredient, unmixed or unmixed with the other carrier, is surrounded by the carrier and bound to the carrier. Similarly, cachet and rosen map are included. Tablets, powders, capsules, pills, cachets and lozenges may be used in solid dosage forms suitable for oral administration.
[245] To prepare a suppository, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and stirred to homogeneously disperse the active ingredient in the molten wax. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.
[246] Liquid form preparations include solutions, suspensions, emulsions, for example, water or water propylene glycol solutions. The liquid formulation for parenteral administration may be formulated as a solution in aqueous polyethylene glycol solution.
[247] Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding the appropriate dye, flavoring, stabilizing and thickening agents as desired.
[248] Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active ingredient in water, including viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other known suspending agents.
[249] Also included are solid form preparations that can be converted to liquid preparations for oral administration immediately prior to use. Such liquid formers include solutions, suspensions and emulsions. These preparations may contain pigments, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers and the like in addition to the active ingredients.
[250] The pharmaceutical preparation is preferably in a single dosage form. In this form, the agent is subdivided into a single dose containing an appropriate amount of the active ingredient. Single dosage forms may be packaged preparations such as tablets, capsules and powders in vials or ampoules, and the package contains a quantity of the formulation. In addition, the unit dosage form may be a capsule, tablet, cachet, or lozenge itself, or it may be any suitable number of these formulations in packaged form.
[251] The amount of the active ingredient in the unit dosage form may vary depending on the specific use and efficacy of the active ingredient, or may be adjusted to 0.1 mg to 1 g. For medical use, the drug can be administered, for example, as a 100 or 300 mg capsule three times a day. If desired, the composition may contain other compatible therapeutic agents.
[252] For therapeutic use, the compounds used in the pharmaceutical methods of the present invention are administered at an initial dosage of from about 0.01 mg to about 100 mg / kg per day. A daily dose of about 0.01 mg to about 100 mg / kg is preferred. However, the dosage may vary depending on the patient's need, the severity of the condition to be treated and the compound used. Determination of the dosage appropriate for the particular condition is made by those skilled in the art. In general, the treatment is initiated at a lower dose than the optimal dose of the compound. Thereafter, the dose is gradually increased until the optimum effect is obtained under the specific conditions. For convenience, a total daily dose may be divided and administered in divided doses, if desired.
[253] The following examples illustrate the invention and are not intended to limit its scope.
[254] &Lt; General Synthetic Reaction Scheme &
[255] A comprehensive description
[256] Method 1
[257]
[258] a) LiAlH _4;
[259] b) pyridinium dichromate;
[260] c) triethylphosphonoacetate, NaH;
[261] d) Nitromethane DBU;
[262] e) i. H ₂ Pd / C; ii. HCl; iii. Ion exchange chromatography.
[263] Method 2
[264]
[265] X = OEt or a chiral oxazolidine adjuvant.
[266] a) triethylphosphonoacetate, NaH;
[267] b) i. NaOH, ii. Pivaloyl chloride, Et ₃ N, XH;
[268] c) R ¹ MgBr, CuBr ₂ DMS;
[269] _{d) NaHMDS, BrCH 2 CO 2} tBu;
[270] e) R = tBu i. LiOH, H ₂ 0 _2; ii. BH ₃ , iii. TsCl, ET ₃ N, iv. NaN ₃ , DMSO;
[271] f) R = Et i. LiOH, H ₂ 0 _2; ii. BH ₃ , iii. PTSA, THF; iv HBr EtOH, v. NaN ₃ DMSO;
[272] g) i. H ₂ Pd / C; ii. HCl, iii. Ion exchange chromatography.
[273] <Specific Embodiment>
[274] Synthesis of Example 1: 3-Aminomethyl-5-methylheptanoic acid
[275]
[276] _{a) PDC, CH 2 Cl 2} ;
[277] b) NaH, triethylphosphonoacetate;
[278] c) DBU, CH ₃ NO ₂ ;
[279] d) H ₂ , 10% Pd / C;
[280] e) 6N HCl, reflux, ion exchange resin (Dowex 50WX8, strong acidity).
[281] 3-methyl-1-pentanal 11
[282] 3-Methyl-1-pentanol 10 (15 g, 146.79 mmol) was added to a stirred suspension of pyridinium dichromate (112.17 g, 298.1 mmol) in 500 ml of dichloromethane. After stirring for 2.5 hours, 400 ml of ether was added and stirring was continued for 5 minutes. The filtrate from the mixture was concentrated to a small volume and loaded onto a column of Florisil. The compound was eluted with mineral oil ether and further chromatographed on a silica gel column using 10% ether in mineral oil ether as eluent to give 11 (6.5 g, 44%). _{^{1 H-NMR (CDCl 3)}} δ9.72, (d, -C H O), 2.38 (dd, 1H, -C H 2 CHO), 2.19 (dd, 1H, -C H 2 CHO), 1.95 (m _{, 1H, C 2 H 5 (} CH 3) C H CH 2 -), 1.4-1.0 (m), 0.9-0.8 (m).
[283] Ethyl 5-methyl-2-heptenoate 12
[284] Sodium hydride (60% dispersion, 2.4 g, 65 mmol) was washed with hexane and suspended in 60 ml of dimethoxyethane. Triethylphosphonoacetate was slowly added over about 5 minutes while cooling in an ice water bath. The reaction was stirred at 0 &lt; 0 &gt; C for 15 min and a solution of 3-methyl-1-pentanol 11 (6.5 g, 65 mmol) in 20 ml of methoxyethane was added. After refluxing overnight, the reaction was concentrated, water and hexane were added, the organic layer was separated and the aqueous layer was removed. The solution was washed twice with brine and dried over magnesium sulfate. Evaporation of the solvent gave 12 (6.75 g, 61%). _{^{1 H-NMR (CDCl 3)}} δ6.89 (m, 1H, -CH 2 C H: CHCOOEt), 5.77 (d, 1H, -CH 2 CH: C H COOEt), 4.16 (q, 2H, -COOC H ₂ CH _3), 2.15 and 1.98 (1H each, and _{multiple, -C H 2 CH: CHCOOEt)} , 1.48 (m, 1H, C 2 H 5 (CH 3) C H CH 2), 1. 30-1.10 (m ), And 0.83.
[285] Ethyl 5-methyl-3-nitromethylheptanoate 13
[286] To a solution of ethyl 5-methyl-2-heptanoate 12 (6.75 g, 39.70 mmol), DBU (6.0 g, 39.7 mmol) and nitromethane (21.97 g, 359.9 mmol) in 80 mL of acetonitrile was stirred at room temperature overnight Respectively. The mixture was concentrated to an oil. The oil solution in ether was washed with IN HCl, brine and dried. It was evaporated to give a bright oil which was chromatographed on silica gel eluting with 5% to 10% ether in mineral oil ether to give 13 (3.6 g, 42%). _{^{1 H-NMR (CDCl 3)}} δ4.49-4. 39 (m), 4.12-4.07 (m), 3.61 (m), 2.36 (m), 1.36-1.18 (m), 0.86-0.79.
[287] 3-Aminomethyl-5-methylheptanoic acid (Example 1)
[288] Ethyl 5-methyl-3-nitromethylheptanoate 13 (3.6 g) was hydrogenated in ethanol in the presence of 20% Pd / C and evaporated to 14. 30 ml of normal hydrochloric acid was added and refluxed overnight. The solvent was evaporated under reduced pressure and the residue azeotroped with toluene. The residual aqueous solution was added to the Dowex 50WX 8-100 ion exchange resin washed to neutral pH with HPLC grade water. The column was recovered with water until the pH of the eluate became neutral and then recovered with 0.5 N NH ₄ OH solution to give a fraction containing 3-aminomethyl-5-methylheptanoic acid. The fractions were collected and further chromatographed on a _C18 column. The compound was eluted with 40% water in methanol and crystallized from methanol-ether to give 630 mg of example 1 . ¹ H-NMR (CD ₃ OD) 2.83 (m, 1H), 2.75 (m, 1H), 2.35 m), 1.3-1.15 (m, 2H), 1.14-0.95 (m, 2H). 0.80 (m, 2CH _3). Molecular ions at (M + 1) 174 and other ions at 156,139 and 102 identified by MS. Calcd for C ₉ H ₁₉ NO ₂ : C, 62.39; H 11.05; N 8.08. Found C, 62.00; H, 10.83; N, 7.98.
[289] The following example can be prepared in a similar manner.
[290] 3-Aminomethyl-5-methyl-heptanoic acid;
[291] 3-Aminomethyl-5-methyl-octanoic acid;
[292] 3-Aminomethyl-5-methyl-nonanoic acid;
[293] 3-Aminomethyl-5-methyl-decanoic acid;
[294] 3-Aminomethyl-5-methyl-undecanoic acid;
[295] 3-Aminomethyl-5-methyl-dodecanoic acid;
[296] 3-Aminomethyl-5-methyl-tridecanoic acid;
[297] 3-Aminomethyl-5-cyclopropyl-hexanoic acid;
[298] 3-Aminomethyl-5-cyclobutyl-hexanoic acid;
[299] 3-Aminomethyl-5-cyclopentyl-hexanoic acid;
[300] 3-Aminomethyl-5-cyclohexyl-hexanoic acid;
[301] 3-Aminomethyl-5-trifluoromethyl-hexanoic acid;
[302] 3-Aminomethyl-5-phenyl-hexanoic acid;
[303] 3-Aminomethyl-5- (2-chlorophenyl) -hexanoic acid;
[304] 3-Aminomethyl-5- (3-chlorophenyl) -hexanoic acid;
[305] 3-Aminomethyl-5- (4-chlorophenyl) -hexanoic acid;
[306] 3-Aminomethyl-5- (2-methoxyphenyl) -hexanoic acid;
[307] 3-Aminomethyl-5- (3-methoxyphenyl) -hexanoic acid;
[308] 3-Aminomethyl-5- (4-methoxyphenyl) -hexanoic acid; And
[309] 3-Aminomethyl-5- (phenylmethyl) -hexanoic acid.
[310] Synthesis of Example 2: (3R, 4S) 3-Aminomethyl-4,5-dimethyl-hexanoic acid
[311]
[312] Reagents and conditions:
[313] a) (R) - (-) - 4-phenyl-2-oxazolidinone, (CH ₃ ) ₃ CCOCl, Et ₃ N, LiCl, THF, -20 to 23 ° C;
[314] _{b) MeMgCl, CuBrSMe 2, THF} , -35 ℃;
[315] c) NaHMDS, BrCH ₂ CO ₂ tBu, THF, -78 ° C to -40 ° C;
[316] _{d) LiOH, H 2 0 2} , THF, H 2 0, 25 ℃;
[317] e) BH ₃ SMe ₂ , THF, 0-25 ° C;
[318] f) pTsCl, pyridine, 25 &lt; 0 &gt;C;
[319] g) NaN ₃ , DMSO, 60 &lt; 0 &gt;C;
[320] h) Raney nickel, MeOH, H ₂ ; i) 3M HCl, reflux, ion exchange resin (Dowex 50WX8, strong acidity).
[321] [R- ( E)] 3- (4-methyl-pent-2-enoyl) -4-phenyl-oxazolidin-
[322] Trimethyl acetyl chloride (7.8 g, 0.065 mol) was added to acid 14 (6.9 g, 0.06 mol) and triethylamine (18 g, 0.187 mol) in THF (200 ml) at -20 < Lithium chloride (2.35 g, 0.55 mol) and (R) - (-) - 4-phenyl-2-oxazolidinone (8.15 g, 0.05 mol) were added after 1 hour and the thick suspension was warmed to room temperature. After 20 h, the suspension was filtered and the filtrate was concentrated. The resulting solid was recrystallized from hexane / ethyl acetate (5: 1) to give oxazolidinone 16 as a white solid (8.83 g, 68%). _{^{1 H NMR (CDCl 3) δ7.35}} (m, 5H), 7.18 (dd, 1H, J = 15.4 and 1.2 Hz), 7.02 (dd, 1H, J = 15.4 and 6.8 Hz), 5.45 (dd, 1H, J = 8.8 and 3.9 Hz), 4.68 (t, IH, J = 8.8 Hz), 4.22 (dd, Hz), 1.02 (d, 1H, J = 1.4 Hz). MS, m / z (relative intensity): 260 [M + H, 100%].
[323] (3R, 3R ^*) 3- (3,4-Dimethyl-pentanoyl) -4-phenyl-oxazolidin-2-one 17
[324] Methylmagnesium chloride (3 M solution in THF) was added to the copper (I) bromide-dimethyl sulfide complex in THF (45 mL) at -20 <0> C. After 20 minutes, oxazolidinone 16 (3.69 g, 0.014 mol) in THF (20 mL) was added dropwise over 10 minutes. After 2.5 hours, the reaction was quenched by the addition of saturated aqueous ammonium chloride solution. The resulting two layers were separated and the aqueous layer was extracted with ether. The combined organic layers were washed with 1M hydrochloric acid and then with 5% aqueous ammonium hydroxide. Dry the organic layer (MgSO ₄₎ and concentrated to a white solid to give the oxazolidinone 17 (3.39 g, 88%) . _{^{1 H NMR (CDCl 3) δ7.30}} (m, 1H), 5.40 (dd, 1H, J = 8.8 and 3.7 Hz), 4.63 (t, 1H, J = 8.8 Hz), 4.21 (dd, 1H, J = 1H, J = 16.1 and 8.5 Hz), 1.90 (m, 1H), 1.56 (m, 2H), 0.83 (d, d, 3H, J = 6.8 Hz), 0.78 (d, 3H, J = 6.8 Hz), 0.75 (d, 3H, J = 6.8 Hz). MS, m / z (relative intensity): 276 [M + H, 100%].
[325] [3R- (3R ^*(R ^*), 4S ^*)] - 4,5-dimethyl-3- (2-oxo-4-phenyl-oxazolidine-3- carbonyl) -hexanoic acid tert-butyl ester 18
[326] Sodium bis (trimethylsilyl) amide (14.4 mL, 0.014 mol of a 1 M solution in THF) was added to a solution of oxazolidinone 17 (3.37 g, 0.012 mol) in THF (35 mL) at -78 < After 35 minutes, tert-butyl bromoacetate (3.5 g, 0.018 mol) was added and the solution was immediately warmed to -40 &lt; 0 &gt; C. After 3 hours, the reaction was quenched by the addition of saturated aqueous ammonium chloride solution. The resulting two layers were separated and the aqueous layer was extracted with ether. The organic layer collected was concentrated and dried (MgSO _4). Flash chromatography (9: 1 to 5: 1 hexane / ethyl acetate concentration gradient) gave ester 18 (3.81 g, 82%) as a white solid. _{^{1 H NMR (CDCl 3) δ7.35}} (m, SH), 5.37 (dd, 1H, J = 8.4 and 3.1 Hz), 4.67 (t, 1H, J = 8.7 Hz), 4.41 (dt, 1H, J = (Dd, 1H, J = 16.9 and 3.5 Hz), 1.6 (dd, 1H, J = 16.9 and 12.0 Hz) 1H, J = 6.7Hz), 0.80 (d, IH, J), 1.45 (m, = 7.0 Hz). MS, m / z (relative _{intensity): 429 [MH + CH 3} CN, 100%], 388 [MH, 20%].
[327] (3R, 4S) -2- (l-Dimethyl-propyl) -succinic acid 4-tert-butyl ester 19
[328] A premix solution of lithium hydroxide (20 mL of 0.8 M aqueous solution, 0.016 mol) / H ₂ O ₂ (5.76 mL of 30% aqueous solution) was added to a solution of oxazolidinone 18 (3.62 g, 9.3 mmol) in THF (54 mL) ). After 7 h, the solution was diluted with water and sodium bisulfate (~ 10 g) was added. After stirring for a further 0.5 h, the two layers were separated and the aqueous layer was extracted with ether. The aqueous layer was then acidified again with 1M hydrochloric acid (pH 2) and extracted with ether. The organic layer collected was concentrated and dried (MgSO _4). Flash chromatography (5: 1 hexanes / ethyl acetate) gave the acid 19 (2.1 g, 95%) as a colorless oil. ¹ H NMR (CDCl ₃ ) 3.0 (m, 1H), 2.55 (dd, 1H, J = 16.6 and 11.2 Hz), 2.27 (dd, 1H, J = 16.6 and 3.4 Hz) 1H, J = 6.6Hz), 0.83 (d, 1H), 1.53 (m, 1H, J = 6.8 Hz). MS, m / z (relative intensity): 243 [MH, 100%].
[329] (3R, 4S) -3-hydroxymethyl-4,5-dimethyl-hexanoic acid tert-butyl ester 20
[330] A solution of borane-methyl sulfide complex (16 mL, 0.032 mol of a 2 M solution in THF) was added to a stirred solution of acid 19 (1.96 g, 8 mmol) in THF (20 mL) at 0 ° C. After 20 hours, methanol was added until foaming ceased and the solution was concentrated. Flash chromatography (5: 1 hexane / ethyl acetate concentration gradient) was performed to give alcohol 20 (1.29 g, 70%) as a colorless oil. ¹ H NMR (CDCl ₃ ) 3.62 (m, IH), 2.32 (m, IH), 2.14 , 0.93 (d, 1H, J = 6.8 Hz), 0.86 (d, 1H, J = 6.8 Hz). MS, m / z (relative intensity): 175 [M-tBu, 100%].
[331] (3R, 4S) -4,5-dimethyl-3- (toluene-4-sulfonyloxymethyl) -hexanoic acid tert-butyl ester 21
[332] toluenesulfonyl chloride (847 mg, 4.4 mmol) was added to a solution of alcohol 6 (850 mg, 3.7 mmol), DMAP (10 mg, 0.08 mmol) and triethylamine (1.23 mmol) in CH ₂ Cl ₂ mL, 8.88 mmol) and the solution was allowed to warm to room temperature. After 15 h, the solution was washed with 1N hydrochloric acid followed by brine. The organic layer collected was concentrated and dried (MgSO _4). Flash chromatography (100-92% hexane / ethyl acetate concentration gradient) was performed to give tosylate 7 (1.22 g, 86%) as a thick gum. _{^{1 H NMR (CDCl 3) δ7.80}} (d, 2H, J = 8.2 Hz), 7.25 (d, 2H, J = 8.2 Hz), 3.92 (m, 1H), 2.38 (s, 3H), 2.20 (m 2H), 1.95 (m, 1H), 1.40 (m, 1H), 1.32 (s, 9H), 1.27 J = 6.6 Hz), 0.63 (d, 1 H, J = 7.1 Hz). MS, m / z (relative intensity): 311 [85%], 198 [100%], 157 [95%].
[333] (3R, 4S) -3-azidomethyl-4,5-dimethyl-hexanoic acid tert-butyl ester 22
[334] A solution of tosylate 21 (1.19 g, 3.1 mmol) and sodium azide (402 mg, 6.2 mmol) in DMSO (15 mL) was warmed to 60 &lt; 0 &gt; C for 2.5 h. Water (100 mL) was added and the solution was extracted with ether. The organic layer collected was concentrated and dried (MgSO _4). Flash chromatography (9: 1 hexanes / ethyl acetate) provided azide 22 (628 mg, 80%) as a colorless oil. ¹ H NMR (CDCl ₃ ) 3.4 (dd, 1H, J = 12.21 and 6.11 Hz), 3.3 (dd, 1H, J = 21.11 and 6.59 Hz), 2.30 1H, J = 15.14 and 9.04 Hz), 1.55 (m, 1H), 1.45 (s, 9H), 1.35 = 6.59 Hz), 0.90 (d, 1H, J = 6.83 Hz), 0.80 (d, 1H, J = 7.08 Hz). MS (m / z): (relative intensity): 228 [MN ₂ , 35%], 172 [MN ₂ -tBu, 100%].
[335] (3R, 4S) -3-Aminomethyl-4,5-dimethyl-hexanoic acid tert-butyl ester 23 and [4R- [4R ^*(S ^*)]] - 4- (l-Dimethyl-propyl) -pyrrolidin-2-one 24
[336] The azide 8 (640 mg, 2.5 mmol) and Raney nickel (1 g) in methanol (50 mL) was shaken under a hydrogen atmosphere for 4 hours. The solution was filtered and the filtrate was concentrated to give a mixture of amine 23 and lactam 24 which was used in the next step without further purification.
[337] (3R, 4S) -3-Aminomethyl-4,5-dimethyl-hexanoic acid (Example 2)
[338] A solution of amine 23 and lactam 24 (500 mg) in 3 M hydrochloric acid was heated to reflux for 9 hours and then stirred at room temperature for 15 hours. The solution was concentrated and the resulting solid was purified sequentially by ion exchange chromatography, oxalate formation followed by ion exchange chromatography (Dowex 50WX8, strong acidity) to give Example 2 (343 mg) as a white solid Respectively. _{^{1 H NMR (D 2 O)}} δ2.87 (m, 2H), 2.22 (dd, 1H, J = 15.4 and 3.4 Hz), 2.12 (m, 1H), 1.93 (dd, 1H, J = 15.4 and 9.5 Hz 1H, J = 6.6 Hz), 0.74 (d, 1H, J = 6.6 Hz), 1.70 (d, ). MS, m / z (relative intensity): 174 [M + H, 100%].
[339] The following example can be prepared in a similar manner:
[340] 3-Aminomethyl-4,5-dimethyl-hexanoic acid;
[341] (3R, 4S) -3-Aminomethyl-4,5-dimethyl-hexanoic acid MP;
[342] (3S, 4S) -3-Aminomethyl-4,5-dimethyl-hexanoic acid;
[343] (3R, 4R) -3-Aminomethyl-4,5-dimethyl-hexanoic acid MP;
[344] 3-Aminomethyl-4-isopropyl-hexanoic acid;
[345] 3-Aminomethyl-4-isopropyl-heptanoic acid;
[346] 3-Aminomethyl-4-isopropyl-octanoic acid;
[347] 3-Aminomethyl-4-isopropyl-nonanoic acid;
[348] 3-Aminomethyl-4-isopropyl-decanoic acid; And
[349] 3-Aminomethyl-4-phenyl-5-methyl-hexanoic acid.
[350] <Method 3>
[351]
[352] Wherein R &lt; ₃ &gt; = OMe or H; R &lt; ₄ &gt; = Me, Et; n = 0 to 2
[353] The compound of formula 30 can be prepared from the compound of formula 29 by treatment with an aqueous acid such as hydrochloric acid at room temperature to reflux temperature. Alternatively, compounds of formula 30 can be prepared from compounds of formula 32 by treatment with trifluoroacetic acid in a solvent such as CH ₂ Cl ₂ or EtOAc. Compound 32 can be prepared by base-mediated hydrolysis of a Boc-protected lactam such as compound 31, which can be prepared from the compound of formula 29 by treatment with di-tert-butyl dicarbonate in a solvent such as THF, - Treatment of lactam 31 with aqueous sodium hydroxide gives acid 32.
[354] Compounds of formula 29 can be prepared from compounds of formula 28 (n = 0) by treatment with sodium or lithium metal in ammonia. Preferably, the reaction is carried out using sodium metal in ammonia. Alternatively, compounds of formula (29) can be prepared from compounds of formula (28) (n = 1 or 2) by treatment with seric ammonium nitrate in a mixture of acetonitrile and water. Other methods known in the literature for removing alkoxybenzyl groups substituted from nitrogen are described and available in Green et al., Green, Protective Groups in Organic Synthesis, Wiley, 2 ed, 1991.
[355] Compounds of formula 28 may be prepared from compounds of formula 27 wherein LG is a suitable leaving group such as a halide or alkyl sulphonate, preferably iodide, by a carbon-carbon bond forming reaction known in the art can do. Various methods described in the literature can be used to couple an organohalide or an organoalkylsulfonate and an organometallic reagent in the presence of various metal salts summarized in the literature (Comprehensive Organic Synthesis, volume 3: 413). For example, the compound of formula 28 can be treated with a suitable secondary halide (chloride or iodide) in the presence of magnesium metal, iodine and copper bromide dimethyl sulfide in a solvent such as tetrahydrofuran, And LG is an iodide. Alternatively, a method according to the literature (El Marini, Synthesis, 1992: 1104) can be used. Thus, the compound of formula 28 can be treated with a suitable methyl-substituted secondary halide, such as iodide, in the presence of magnesium, iodine and lithium tetrachlorocouphate in a solvent such as tetrahydrofuran, Iodide. &Lt; / RTI &gt;
[356] The compound of formula (27) introduces a suitable leaving group that can be nucleophilic substituted with a suitable nucleophile. Examples of such leaving groups include halides such as chloride, bromide or iodide; And sulfonate esters such as mesylate, tosylate, triflate, nosylate, and the like. Compounds of formula 27 wherein LG = iodide may be prepared from compounds of formula 26 by treatment with iodine, triphenylphosphine and imidazole in a solvent such as toluene.
[357] The compound of formula 26 may be prepared from the compound of formula 25 by treatment with a metal borohydride such as sodium borohydride in a solvent such as tetrahydrofuran or DME.
[358] Compound 25 was prepared in a manner similar to that of literature (Zoretic et al, J. Org Chem. 1980; 45: 810-814 or Nielsen et al J. Med. Chem., 1990; 33: 71-77) Such as, but not limited to, benzylamine or 2,4-dimethoxybenzylamine.
[359] Alternatively, the compound of formula 26 can be treated with sodium metal and ammonia to afford 4-hydroxymethyl-pyrrolidinone, and the resulting compound can be iodinated to give 4-iodomethyl-pyrrolidinone have. The 4-iodomethyl-pyrrolidinone can then be coupled with the organometallic reagent according to the above method without protection of the lactam nitrogen as follows.
[360]
[361] Thus, analogous to the above method, the lactam of formula 33 (see generally Nielsen et al., J. Med. Chem., 1990; 33: 71-77) Lt; RTI ID = 0.0 &gt; stereochemistry. &Lt; / RTI &gt;
[362]
[363] Compounds that can be prepared in this manner include the following compounds:
[364] 3-Aminomethyl-5-methyl-6-phenyl-hexanoic acid;
[365] 3-Aminomethyl-6- (4-chloro-phenyl) -5-methyl-hexanoic acid;
[366] 3-Aminomethyl-6- (3-chloro-phenyl) -5-methyl-hexanoic acid;
[367] 3-Aminomethyl-6- (2-chloro-phenyl) -5-methyl-hexanoic acid;
[368] 3-Aminomethyl-6- (4-fluoro-phenyl) -5-methyl-hexanoic acid;
[369] 3-Aminomethyl-6- (3-fluoro-phenyl) -5-methyl-hexanoic acid;
[370] 3-Aminomethyl-6- (2-fluoro-phenyl) -5-methyl-hexanoic acid;
[371] 3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid;
[372] 3-Aminomethyl-7- (4-chloro-phenyl) -5-methyl-heptanoic acid;
[373] 3-Aminomethyl-7- (3-chloro-phenyl) -5-methyl-heptanoic acid;
[374] 3-Aminomethyl-7- (2-chloro-phenyl) -5-methyl-heptanoic acid;
[375] 3-Aminomethyl-7- (4-fluoro-phenyl) -5-methyl-heptanoic acid;
[376] 3-Aminomethyl-7- (3-fluoro-phenyl) -5-methyl-heptanoic acid;
[377] 3-Aminomethyl-7- (2-fluoro-phenyl) -5-methyl-heptanoic acid;
[378] (3S) -3-Aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;
[379] (3S) -3-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;
[380] (3S) -3-Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;
[381] (3S) -3-Aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;
[382] (3S) -3-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;
[383] (3S) -3-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;
[384] (3S) -3-Aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;
[385] (3S) -3-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;
[386] (3S) -3-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;
[387] (3S) -3-Aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;
[388] (3S) -3-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;
[389] (3S) -3-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;
[390] (3S) -3-Aminomethyl-5-methyl-heptanoic acid;
[391] (3S) -3-Aminomethyl-5-methyl-octanoic acid;
[392] (3S) -3-Aminomethyl-5-methyl-nonanoic acid;
[393] (3S) -3-Aminomethyl-5-methyl-decanoic acid;
[394] (3S) -3-Aminomethyl-5-methyl-undecanoic acid;
[395] (3S) -3-Aminomethyl-5,7-dimethyl-octanoic acid;
[396] (3S) -3-Aminomethyl-5,8-dimethyl-nonanoic acid;
[397] (3S) -3-Aminomethyl-5,9-dimethyl-decanoic acid;
[398] (3S) -3-Aminomethyl-5, 6-dimethyl-heptanoic acid;
[399] (3S) -3-Aminomethyl-5,6,6-trimethyl-heptanoic acid;
[400] (3S) -3-Aminomethyl-5-cyclopropyl-hexanoic acid;
[401] (3S) -3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid;
[402] (3S) -3-Aminomethyl-7-fluoro-5-methyl-heptanoic acid;
[403] (3S) -3-Aminomethyl-8-fluoro-5-methyl-octanoic acid;
[404] (3S) -3-Aminomethyl-7,7,7-trifluoro-5-methyl-heptanoic acid;
[405] (3S) -3-Aminomethyl-8, 8, 8-trifluoro-5-methyl-octanoic acid;
[406] (3S) -3-Aminomethyl-5-methyl-hept-6-enoic acid;
[407] (3S) -3-Aminomethyl-5-methyl-oct-7-enoic acid;
[408] (3S) -3-Aminomethyl-5-methyl-non-8-enoic acid;
[409] (E) - (3S) -3-Aminomethyl-5-methyl-oct-6-enoic acid;
[410] (Z) - (3S) -3-Aminomethyl-5-methyl-oct-6-enoic acid;
[411] (E) - (3S) -3-Aminomethyl-5-methyl-non-6-enoic acid;
[412] (Z) - (3S) -3-Aminomethyl-5-methyl-non-6-enoic acid;
[413] (E) - (3S) -3-Aminomethyl-5-methyl-non-7-enoic acid;
[414] (Z) - (3S) -3-Aminomethyl-5-methyl-non-7-enoic acid;
[415] (E) - (3S) -3-Aminomethyl-5-methyl-de-7-enoic acid;
[416] (Z) - (3S) -3-Aminomethyl-5-methyl-de-7-enoic acid;
[417] 3-Aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;
[418] 3-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;
[419] 3-Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;
[420] 3-Aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;
[421] 3-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;
[422] 3-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;
[423] 3-Aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;
[424] 3-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;
[425] 3-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;
[426] 3-Aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;
[427] 3-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;
[428] 3-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;
[429] 3-Aminomethyl-5-methyl-heptanoic acid;
[430] 3-Aminomethyl-5-methyl-octanoic acid;
[431] 3-Aminomethyl-5-methyl-nonanoic acid;
[432] 3-Aminomethyl-5-methyl-decanoic acid;
[433] 3-Aminomethyl-5-methyl-undecanoic acid;
[434] 3-Aminomethyl-5,7-dimethyl-octanoic acid;
[435] 3-Aminomethyl-5,8-dimethyl-nonanoic acid;
[436] 3-Aminomethyl-5,9-dimethyl-decanoic acid;
[437] 3-Aminomethyl-5,6-dimethyl-heptanoic acid;
[438] 3-Aminomethyl-5,6,6-trimethyl-heptanoic acid;
[439] 3-Aminomethyl-5-cyclopropyl-hexanoic acid;
[440] 3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid;
[441] 3-Aminomethyl-7-fluoro-5-methyl-heptanoic acid;
[442] 3-Aminomethyl-8-fluoro-5-methyl-octanoic acid;
[443] 3-Aminomethyl-7,7,7-trifluoro-5-methyl-heptanoic acid;
[444] 3-Aminomethyl-8,8,8-trifluoro-5-methyl-octanoic acid;
[445] 3-Aminomethyl-5-methyl-hept-6-enoic acid;
[446] 3-Aminomethyl-5-methyl-oct-7-enoic acid;
[447] 3-Aminomethyl-5-methyl-non-8-enoic acid;
[448] (E) -3-Aminomethyl-5-methyl-oct-6-enoic acid;
[449] (Z) -3-Aminomethyl-5-methyl-oct-6-enoic acid;
[450] (E) -3-Aminomethyl-5-methyl-non-6-enoic acid;
[451] (Z) -3-aminomethyl-5-methyl-non-6-enoic acid;
[452] (E) -3-Aminomethyl-5-methyl-non-7-enoic acid;
[453] (Z) -3-Aminomethyl-5-methyl-non-7-enoic acid;
[454] (E) -3-Aminomethyl-5-methyl-de-7-enoic acid; And
[455] (Z) -3-Aminomethyl-5-methyl-de-7-enoic acid.
[456] <Method 4>
[457]
[458] Compounds of formula 40 can be prepared from compounds of formula 39 by treatment with diethylaminosulfurtrifluoride in a solvent such as methylene chloride at -78 [deg.] C to room temperature.
[459] Other methods for the fluorination of alcohols are known and are available as illustrated in the literature (Wilkinson, Chem. Rev. 1992; 92: 505-519). Compounds of formula 40 can be converted to the requisite gamma-amino acids as described in method 3 above.
[460] The compound of formula 39 can be prepared from the compound of formula 38 by treating with osmium tetroxide and sodium persodate in a solvent such as THF and water and reducing the resulting intermediate to sodium borohydride in a solvent such as ethanol.
[461] The compounds of formulas 38 and 34 may be prepared from compounds of formula 33 according to the principles described in method 3. [
[462] An alternative method for the synthesis of alcohol 39 (n = 0) is by treating the compound of formula 36 with a metal borohydride such as sodium borohydride in a solvent such as tetrahydrofuran or DME to give the compound of formula 37, Lt; RTI ID = 0.0 &gt; 37 &lt; / RTI &gt; in a manner analogous to the preparation of the compound. Compounds of formula 36 may be prepared from compounds of formula 35 by treatment with sodium chloride or lithium chloride in aqueous DMSO at room temperature to reflux temperature. Preferably, the reaction is carried out using sodium chloride in aqueous DMSO at reflux temperature. Compounds of formula 35 may be prepared from compounds of formula 34 by treatment with a suitable methylmalonic acid diester such as dimethylmethyl malonate, etc., with sodium hydride in a solvent such as DMSO or THF. Preferably, the reaction is carried out by adding NaH to a dimethyl methylmalonate solution in DMSO followed by addition of Lactam 34 (wherein LG is preferably iodide or as defined in Method 3) dissolved in DMSO do.
[463] Compounds 39 and 37 can be converted into a free amino acid having a hydroxyl group by the above method.
[464] The following compounds may be prepared in this manner:
[465] (3S) -3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid;
[466] (3S) -3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid;
[467] (3S) -3-Aminomethyl-7-fluoro-5-methyl-heptanoic acid;
[468] (3S) -3-Aminomethyl-8-fluoro-5-methyl-octanoic acid;
[469] (3S) -3-Aminomethyl-9-fluoro-5-methyl-nonanoic acid;
[470] (3S) -3-Aminomethyl-7-hydroxy-5-methyl-heptanoic acid; And
[471] (3S) -3-Aminomethyl-6-hydroxy-5-methyl-hexanoic acid.
[472] <Method 5>
[473]
[474] The compound of formula 41 can be prepared from the compound of formula 39 by treatment with a suitable base such as alkyl iodide (or alkylsulfonate) such as methyl iodide in a solvent such as DMSO or THF and the like, and n-butyl lithium or sodium hydride. Preferably, the reaction is carried out by adding NaH to the alcohol solution in DMSO followed by the addition of alkyl iodide and heating the reaction mixture at room temperature to reflux temperature. Conversion of the compound of formula 41 to a gamma-amino acid is described above.
[475] Alternatively, the compound of formula 41 may be treated with a suitable alkoxy anion in a solvent such as DMSO or THF to yield a compound of formula 42, wherein LG is iodide, bromide or sulfonate ester as illustrated in method 3, can do. The compound of formula 42 will also serve as a substrate for the carbon-carbon bond forming method described in method 3. [
[476] Compounds which can be prepared in this way are:
[477] (3S) -3-Aminomethyl-7-hydroxy-5-methyl-heptanoic acid;
[478] (3S) -3-Aminomethyl-7-methoxy-5-methyl-heptanoic acid;
[479] (3S) -3-Aminomethyl-7-ethoxy-5-methyl-heptanoic acid;
[480] (3S) -3-Aminomethyl-5-methyl-7-propoxy-heptanoic acid;
[481] (3S) -3-Aminomethyl-7-fluoromethoxy-5-methyl-heptanoic acid;
[482] (3S) -3-Aminomethyl-7- (2-fluoro-ethoxy) -5-methyl-heptanoic acid;
[483] (3S) -3-Aminomethyl-5-methyl-7- (3,3,3-trifluoro-propoxy) -heptanoic acid;
[484] (3S) -3-Aminomethyl-6-hydroxy-5-methyl-hexanoic acid;
[485] (3S) -3-Aminomethyl-6-methoxy-5-methyl-hexanoic acid;
[486] (3S) -3-Aminomethyl-6-ethoxy-5-methyl-hexanoic acid;
[487] (3S) -3-Aminomethyl-5-methyl-6-propoxy-hexanoic acid;
[488] (3S) -3-Aminomethyl-6-fluoromethoxy-5-methyl-hexanoic acid;
[489] (3S) -3-Aminomethyl-6- (2-fluoro-ethoxy) -5-methyl-hexanoic acid; And
[490] (3S) -3-Aminomethyl-5-methyl-6- (3,3,3-trifluoro-propoxy) -hexanoic acid.
[491] &Lt; Method 6 >
[492]
[493] Compounds of formula 53 may be prepared from compounds of formula 45 as shown above and may be prepared by the general methods described in Hoekstra et. Al., Organic Process Research and Development, 1997; 1: 26-38.
[494] The compound of formula 45 can be prepared from the compound of formula 44 by treatment with a solution of chromium trioxide in water / sulfuric acid. Alternatives for cleaving olefins in 44 can be utilized as detailed in Hudlicky, Oxidations in Organic Chemistry, ACS Monograph 186, ACS 1990: 77.
[495] The compound of formula 44, wherein R ₂ is alkyl, branched chain alkyl, cycloalkyl, alkyl-cycloalkyl, can be prepared by reacting (S) - Lt; RTI ID = 0.0 &gt; citronelly &lt; / RTI &gt; bromide. Substituting the halide in (S) -citronelyl bromide with an alkoxy anion can yield a compound of formula 44 wherein R is alkoxy or phenoxy ether (and its appropriate substituent according to formula 1). Alternatively, (S) -citronolol can be obtained by treating (S) citronellol with a base such as sodium hydride and treating the resulting alkoxide with an appropriate halogenated alkyl to give the compound of formula 44 Can be used. In another method, suitable sulfonic acid esters such as but not limited to (S) -citronelyl bromide [or (S) -3,7-dimethyl-oct-6-enyl ester methanesulfonate] (R) -2,6-dimethyl-oct-2-ene can be obtained by reduction with hydride or reduction with an aluminum hydride species such as LAH.
[496] One skilled in the art will appreciate that one of R- or S-citronellol or R- or S-citronellyl bromide is rationally selected to produce the requisite isomer at C5 of the final amino acid.
[497] Compounds which can be prepared in this way are:
[498] (3S, 5S) -3-Aminomethyl-7-methoxy-5-methyl-heptanoic acid;
[499] (3S, 5S) -3-Aminomethyl-7-ethoxy-5-methyl-heptanoic acid;
[500] (3S, 5S) -3-Aminomethyl-5-methyl-7-propoxy-heptanoic acid;
[501] (3S, 5S) -3-Aminomethyl-7-isopropoxy-5-methyl-heptanoic acid;
[502] (3S, 5S) -3-Aminomethyl-7-tert-butoxy-5-methyl-heptanoic acid;
[503] (3S, 5S) -3-Aminomethyl-7-fluoromethoxy-5-methyl-heptanoic acid;
[504] (3S, 5S) -3-Aminomethyl-7- (2-fluoro-ethoxy) -5-methyl-heptanoic acid;
[505] (3S, 5S) -3-Aminomethyl-5-methyl-7- (3,3,3-trifluoro-propoxy) -heptanoic acid;
[506] (3S, 5S) -3-Aminomethyl-7-benzyloxy-5-methyl-heptanoic acid;
[507] (3S, 5S) -3-Aminomethyl-5-methyl-7-phenoxy-heptanoic acid;
[508] (3S, 5S) -3-Aminomethyl-7- (4-chloro-phenoxy) -5-methyl-heptanoic acid;
[509] (3S, 5S) -3-Aminomethyl-7- (3-chloro-phenoxy) -5-methyl-heptanoic acid;
[510] (3S, 5S) -3-Aminomethyl-7- (2-chloro-phenoxy) -5-methyl-heptanoic acid;
[511] (3S, 5S) -3-Aminomethyl-7- (4-fluoro-phenoxy) -5-methyl-heptanoic acid;
[512] (3S, 5S) -3-Aminomethyl-7- (3-fluoro-phenoxy) -5-methyl-heptanoic acid;
[513] (3S, 5S) -3-Aminomethyl-7- (2-fluoro-phenoxy) -5-methyl-heptanoic acid;
[514] (3S, 5S) -3-Aminomethyl-7- (4-methoxy-phenoxy) -5-methyl-heptanoic acid;
[515] (3S, 5S) -3-Aminomethyl-7- (3-methoxy-phenoxy) -5-methyl-heptanoic acid;
[516] (3S, 5S) -3-Aminomethyl-7- (2-methoxy-phenoxy) -5-methyl-heptanoic acid;
[517] (3S, 5S) -3-Aminomethyl-5-methyl-7- (4-trifluoromethyl-phenoxy) heptanoic acid;
[518] (3S, 5S) -3-Aminomethyl-5-methyl-7- (3-trifluoromethyl-phenoxy) -heptanoic acid;
[519] (3S, 5S) -3-Aminomethyl-5-methyl-7- (2-trifluoromethyl-phenoxy) -heptanoic acid;
[520] (3S, 5S) -3-Aminomethyl-5-methyl-7- (4-nitro-phenoxy) -heptanoic acid;
[521] (3S, 5S) -3-Aminomethyl-5-methyl-7- (3-nitro-phenoxy) -heptanoic acid;
[522] (3S, 5S) -3-Aminomethyl-5-methyl-7- (2-nitro-phenoxy) -heptanoic acid;
[523] (3S, 5R) -3-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;
[524] (3S, 5R) -3-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;
[525] (3S, 5R) -3-Aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;
[526] (3S, 5R) -3-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;
[527] (3S, 5R) -3-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;
[528] (3S, 5R) -3-Aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;
[529] (3S, 5R) -3-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;
[530] (3S, 5R) -3-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;
[531] (3S, 5R) -3-Aminomethyl-5-methyl-heptanoic acid;
[532] (3S, 5R) -3-Aminomethyl-5-methyl-octanoic acid;
[533] (3S, 5R) -3-Aminomethyl-5-methyl-nonanoic acid;
[534] (3S, 5R) -3-Aminomethyl-5-methyl-decanoic acid;
[535] (3S, 5R) -3-Aminomethyl-5-methyl-undecanoic acid;
[536] (3S, 5R) -3-Aminomethyl-5,9-dimethyl-decanoic acid;
[537] (3S, 5R) -3-Aminomethyl-5,8-dimethyl-nonanoic acid;
[538] (3S, 5S) -3-Aminomethyl-7-fluoro-5-methyl-heptanoic acid;
[539] (3S, 5R) -3-Aminomethyl-8-fluoro-5-methyl-octanoic acid;
[540] (3S, 5R) -3-Aminomethyl-8,8,8-trifluoro-5-methyl-octanoic acid;
[541] (3S, 5R) -3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid;
[542] (3S, 5R) -3-Aminomethyl-7- (4-chloro-phenyl) -5-methyl-heptanoic acid;
[543] (3S, 5R) -3-Aminomethyl-7- (3-chloro-phenyl) -5-methyl-heptanoic acid;
[544] (3S, 5R) -3-Aminomethyl-7- (2-chloro-phenyl) -5-methyl-heptanoic acid;
[545] (3S, 5R) -3-Aminomethyl-7- (4-methoxy-phenyl) -5-methyl-heptanoic acid;
[546] (3S, 5R) -3-Aminomethyl-7- (3-methoxy-phenyl) -5-methyl-heptanoic acid;
[547] (3S, 5R) -3-Aminomethyl-7- (2-methoxy-phenyl) -5-methyl-heptanoic acid;
[548] (3S, 5R) -3-Aminomethyl-7- (4-fluoro-phenyl) -5-methyl-heptanoic acid;
[549] (3S, 5R) -3-Aminomethyl-7- (3-fluoro-phenyl) -5-methyl-heptanoic acid;
[550] (3S, 5R) -3-Aminomethyl-7- (2-fluoro-phenyl) -5-methyl-heptanoic acid; And
[551] (3S, 5R) -3-Aminomethyl-5,10-dimethyl-undecanoic acid.
[552] <Method 7>
[553]
[554] Compounds of formula 58 can be prepared from compounds of formula 57 by treatment with boron trifluoride diethyl etherate and triethylsilane in a solvent such as CH ₂ Cl ₂ . Thus, using an alternative method described in literature (Meyers, J. Org. Chem., 1993; 58: 36-42), sodium cyanoborohydride in a solvent such as THF / methanol with 3% The compound can be treated.
[555] The compound of formula 57 can be prepared from the compound of formula 56 by treatment with dimethylamine in a solvent such as DMF according to the method of Koot, Tetrahedron Lett., 1992; 33: 7969-7972.
[556] The compound of formula 56 is prepared by treating the appropriate primary halide 55 (iodide, bromide or chloride) with tBuLi under standard metal exchange conditions and treating the resulting organometallic reagent with a suitable copper salt such as copper bromide or copper iodide Lt; RTI ID = 0.0 &gt; (54). &Lt; / RTI &gt; The resulting organocuprate was added to a lactam in a solvent such as THF (see Koot et al, J. Org. Chem., 1992; 57: 1059-1061 for preparation of chiral lactam 54). This method is illustrated in the literature (Koot, Tetrahedron Lett., 1992; 33: 7969-7972).
[557] Those skilled in the art will appreciate that one of the R-1 halide or S-1 halide 55 can be rationally selected to produce the requisite isomer at C5 of the final amino acid.
[558] Compounds which can be prepared in this way are:
[559] (3S, 5S) -3-Aminomethyl-5-methoxy-hexanoic acid;
[560] (3S, 5S) -3-Aminomethyl-5-ethoxy-hexanoic acid;
[561] (3S, 5S) -3-Aminomethyl-5-propoxy-hexanoic acid;
[562] (3S, 5S) -3-Aminomethyl-5-isopropoxy-hexanoic acid;
[563] (3S, 5S) -3-Aminomethyl-5-tert-butoxy-hexanoic acid;
[564] (3S, 5S) -3-Aminomethyl-5-fluoromethoxy-hexanoic acid;
[565] (3S, 5S) -3-Aminomethyl-5- (2-fluoro-ethoxy) -hexanoic acid;
[566] (3S, 5S) -3-Aminomethyl-5- (trifluoro-propoxy) -hexanoic acid;
[567] (3S, 5S) -3-Aminomethyl-5-phenoxy-hexanoic acid;
[568] (3S, 5S) -3-Aminomethyl-5- (4-chloro-phenoxy) -hexanoic acid;
[569] (3S, 5S) -3-Aminomethyl-5- (3-chloro-phenoxy) -hexanoic acid;
[570] (3S, 5S) -3-Aminomethyl-5- (2-chloro-phenoxy) -hexanoic acid;
[571] (3S, 5S) -3-Aminomethyl-5- (4-fluoro-phenoxy) -hexanoic acid;
[572] (3S, 5S) -3-Aminomethyl-5- (3-fluoro-phenoxy) -hexanoic acid;
[573] (3S, 5S) -3-Aminomethyl-5- (2-fluoro-phenoxy) -hexanoic acid;
[574] (3S, 5S) -3-Aminomethyl-5- (4-methoxy-phenoxy) -hexanoic acid;
[575] (3S, 5S) -3-Aminomethyl-5- (3-methoxy-phenoxy) -hexanoic acid;
[576] (3S, 5S) -3-Aminomethyl-5- (2-methoxy-phenoxy) -hexanoic acid;
[577] (3S, 5S) -3-Aminomethyl-5- (4-nitro-phenoxy) -hexanoic acid;
[578] (3S, 5S) -3-Aminomethyl-5- (3-nitro-phenoxy) -hexanoic acid;
[579] (3S, 5S) -3-Aminomethyl-5- (2-nitro-phenoxy) -hexanoic acid;
[580] (3S, 5S) -3-Aminomethyl-6-methoxy-5-methyl-hexanoic acid;
[581] (3S, 5S) -3-Aminomethyl-6-ethoxy-5-methyl-hexanoic acid;
[582] (3S, 5S) -3-Aminomethyl-5-methyl-6-propoxy-hexanoic acid;
[583] (3S, 5S) -3-Aminomethyl-6-isopropoxy-5-methyl-hexanoic acid;
[584] (3S, 5S) -3-Aminomethyl-6-tert-butoxy-5-methyl-hexanoic acid;
[585] (3S, 5S) -3-Aminomethyl-6-fluoromethoxy-5-methyl-hexanoic acid;
[586] (3S, 5S) -3-Aminomethyl-6- (2-fluoro-ethoxy) -5-methyl-hexanoic acid;
[587] (3S, 5S) -3-Aminomethyl-5-methyl-6- (3,3,3-trifluoro-propoxy) -hexanoic acid;
[588] (3S, 5S) -3-Aminomethyl-5-methyl-6-phenoxy-hexanoic acid;
[589] (3S, 5S) -3-Aminomethyl-6- (4-chloro-phenoxy) -5-methyl-hexanoic acid;
[590] (3S, 5S) -3-Aminomethyl-6- (3-chloro-phenoxy) -5-methyl-hexanoic acid;
[591] (3S, 5S) -3-Aminomethyl-6- (2-chloro-phenoxy) -5-methyl-hexanoic acid;
[592] (3S, 5S) -3-Aminomethyl-6- (4-fluoro-phenoxy) -5-methyl-hexanoic acid;
[593] (3S, 5S) -3-Aminomethyl-6- (3-fluoro-phenoxy) -5-methyl-hexanoic acid;
[594] (3S, 5S) -3-Aminomethyl-6- (2-fluoro-phenoxy) -5-methyl-hexanoic acid;
[595] (3S, 5S) -3-Aminomethyl-6- (4-methoxy-phenoxy) -5-methyl-hexanoic acid;
[596] (3S, 5S) -3-Aminomethyl-6- (3-methoxy-phenoxy) -5-methyl-hexanoic acid;
[597] (3S, 5S) -3-Aminomethyl-6- (2-methoxy-phenoxy) -5-methyl-hexanoic acid;
[598] (3S, 5S) -3-Aminomethyl-5-methyl 6- (4-trifluoromethyl-phenoxy) -hexanoic acid;
[599] (3S, 5S) -3-Aminomethyl-5-methyl 6- (3-trifluoromethyl-phenoxy) -hexanoic acid;
[600] (3S, 5S) -3-Aminomethyl-5-methyl 6- (2-trifluoromethyl-phenoxy) -hexanoic acid;
[601] (3S, 5S) -3-Aminomethyl-5-methyl 6- (4-nitro-phenoxy) -hexanoic acid;
[602] (3S, 5S) -3-Aminomethyl-5-methyl 6- (3-nitro-phenoxy) -hexanoic acid;
[603] (3S, 5S) -3-Aminomethyl-5-methyl 6- (2-nitro-phenoxy) -hexanoic acid;
[604] (3S, 5S) -3-Aminomethyl-6-benzyloxy-5-methyl-hexanoic acid;
[605] (3S, 5R) -3-Aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;
[606] (3S, 5R) -3-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;
[607] (3S, 5R) -3-Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;
[608] (3S, 5R) -3-Aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;
[609] (3S, 5R) -3-Aminomethyl-5-methyl-heptanoic acid;
[610] (3S, SR) -3-Aminomethyl-5-methyl-octanoic acid;
[611] (3S, 5R) -3-Aminomethyl-5-methyl-nonanoic acid;
[612] (3S, 5R) -3-Aminomethyl-5-methyl-decanoic acid;
[613] (3S, 5R) -3-Aminomethyl-5-methyl-undecanoic acid;
[614] (3S, 5R) -3-Aminomethyl-5-methyl-dodecanoic acid;
[615] (3S, 5R) -3-Aminomethyl-5,7-dimethyl-octanoic acid;
[616] (3S, 5R) -3-Aminomethyl-5,8-dimethyl-nonanoic acid;
[617] (3S, 5R) -3-Aminomethyl-5,9-dimethyl-decanoic acid;
[618] (3S, 5R) -3-Aminomethyl-5,10-dimethyl-undecanoic acid;
[619] (3S, 5S) -3-Aminomethyl-5, 6-dimethyl-heptanoic acid;
[620] (3S, 5S) -3-Aminomethyl-5,6,6-trimethyl-heptanoic acid;
[621] (3S, 5S) -3-Aminomethyl-5-cyclopropyl-hexanoic acid;
[622] (3S, 5S) -3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid;
[623] (3S, 5S) -3-Aminomethyl-7-fluoro-5-methyl-heptanoic acid;
[624] (3S, 5R) -3-Aminomethyl-8-fluoro-5-methyl-octanoic acid;
[625] (3S, 5S) -3-Aminomethyl-7,7,7-trifluoro-5-methyl-heptanoic acid;
[626] (3S, 5R) -3-Aminomethyl-8,8,8-trifluoro-5-methyl-octanoic acid;
[627] (3S, 5S) -3-Aminomethyl-5-methyl-6-phenyl-hexanoic acid;
[628] (3S, 5S) -3-Aminomethyl-6- (4-chloro-phenyl) -5-methyl-hexanoic acid;
[629] (3S, 5S) -3-Aminomethyl-6- (3-chloro-phenyl) -5-methyl-hexanoic acid;
[630] (3S, 5S) -3-Aminomethyl-6- (2-chloro-phenyl) -5-methyl-hexanoic acid;
[631] (3S, 5S) -3-Aminomethyl-6- (4-methoxy-phenyl) -5-methyl-hexanoic acid;
[632] (3S, 5S) -3-Aminomethyl-6- (3-methoxy-phenyl) -5-methyl-hexanoic acid;
[633] (3S, 5S) -3-Aminomethyl-6- (2-methoxy-phenyl) -5-methyl-hexanoic acid;
[634] (3S, 5S) -3-Aminomethyl-6- (4-fluoro-phenyl) -5-methyl-hexanoic acid;
[635] (3S, 5S) -3-Aminomethyl-6- (3-fluoro-phenyl) -5-methyl-hexanoic acid;
[636] (3S, 5S) -3-Aminomethyl-6- (2-fluoro-phenyl) -5-methyl-hexanoic acid;
[637] (3S, 5R) -3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid;
[638] (3S, 5R) -3-Aminomethyl-7- (4-chloro-phenyl) -5-methyl-heptanoic acid;
[639] (3S, 5R) -3-Aminomethyl-7- (3-chloro-phenyl) -5-methyl-heptanoic acid;
[640] (3S, 5R) -3-Aminomethyl-7- (2-chloro-phenyl) -5-methyl-heptanoic acid;
[641] (3S, 5R) -3-Aminomethyl-7- (4-methoxy-phenyl) -5-methyl-heptanoic acid;
[642] (3S, 5R) -3-Aminomethyl-7- (3-methoxy-phenyl) -5-methyl-heptanoic acid;
[643] (3S, 5R) -3-Aminomethyl-7- (2-methoxy-phenyl) -5-methyl-heptanoic acid;
[644] (3S, 5R) -3-Aminomethyl-7- (4-fluoro-phenyl) -5-methyl-heptanoic acid;
[645] (3S, 5R) -3-Aminomethyl-7- (3-fluoro-phenyl) -5-methyl-heptanoic acid;
[646] (3S, 5R) -3-Aminomethyl-7- (2-fluoro-phenyl) -5-methyl-heptanoic acid;
[647] (3S, 5S) -3-Aminomethyl-5-methyl-hept-6-enoic acid;
[648] (3S, 5R) -3-Aminomethyl-5-methyl-oct-7-enoic acid;
[649] (3S, 5R) -3-Aminomethyl-5-methyl-non-8-enoic acid;
[650] (E) - (3S, 5S) -3-Aminomethyl-5-methyl-oct-6-enoic acid;
[651] (Z) - (3S, 5S) -3-Aminomethyl-5-methyl-oct-6-enoic acid;
[652] (Z) - (3S, 5S) -3-Aminomethyl-5-methyl-non-6-enoic acid;
[653] (E) - (3S, 5S) -3-Aminomethyl-5-methyl-non-6-enoic acid;
[654] (E) - (3S, 5R) -3-Aminomethyl-5-methyl-non-7-enoic acid;
[655] (Z) - (3S, 5R) -3-Aminomethyl-5-methyl-non-7-enoic acid;
[656] (Z) - (3S, 5R) -3-Aminomethyl-5-methyl-de-7-enoic acid; And
[657] (E) - (3S, 5R) -3-Aminomethyl-5-methyl-undec-7-enoic acid.
[658] <Method 8>
[659]
[660] The compound of formula 60 can be prepared from the compound of formula 59 by treatment with an appropriately substituted phenol (including phenol itself) under the conditions described in the literature (Mitsunobu, Synthesis, 1981: 1).
[661] The compound of formula 59 can be prepared from the compound of formula 39 by treatment with sodium or lithium metal in ammonia or the like. Preferably, the reaction is carried out using sodium metal in ammonia.
[662] Compound 60 can be directly hydrolyzed to produce a desired amino acid, or a method of hydrolyzing a Boc-protected lactam can be used.
[663] Compounds which can be prepared in this way are:
[664] (3S) -3-Aminomethyl-5-methyl-7-phenoxy-heptanoic acid;
[665] (3S) -3-Aminomethyl-7- (4-chloro-phenoxy) -5-methyl-heptanoic acid;
[666] (3S) -3-Aminomethyl-7- (3-chloro-phenoxy) -5-methyl-heptanoic acid;
[667] (3S) -3-Aminomethyl-7- (2-chloro-phenoxy) -5-methyl-heptanoic acid;
[668] (3S) -3-Aminomethyl-7- (4-fluoro-phenoxy) -5-methyl-heptanoic acid;
[669] (3S) -3-Aminomethyl-7- (3-fluoro-phenoxy) -5-methyl-heptanoic acid;
[670] (3S) -3-Aminomethyl-7- (2-fluoro-phenoxy) -5-methyl-heptanoic acid;
[671] (3S) -3-Aminomethyl-7- (4-methoxy-phenoxy) -5-methyl-heptanoic acid;
[672] (3S) -3-Aminomethyl-7- (3-methoxy-phenoxy) -5-methyl-heptanoic acid;
[673] (3S,) - 3-Aminomethyl-7- (2-methoxy-phenoxy) -5-methyl-heptanoic acid;
[674] (3S) -3-Aminomethyl-5-methyl-7- (4-trifluoromethyl-phenoxy) -heptanoic acid;
[675] (3S) -3-Aminomethyl-5-methyl-7- (3-trifluoromethyl-phenoxy) -heptanoic acid;
[676] (3S) -3-Aminomethyl-5-methyl-7- (2-trifluoromethyl-phenoxy) -heptanoic acid;
[677] (3S) -3-Aminomethyl-5-methyl-7- (4-nitro-phenoxy) -heptanoic acid;
[678] (3S) -3-Aminomethyl-5-methyl-7- (3-nitro-phenoxy) -heptanoic acid;
[679] (3S) -3-Aminomethyl-5-methyl-7- (2-nitro-phenoxy) -heptanoic acid;
[680] (3S) -3-Aminomethyl-6- (3-chloro-phenoxy) -5-methyl-hexanoic acid;
[681] (3S) -3-Aminomethyl-6- (2-chloro-phenoxy) -5-methyl-hexanoic acid;
[682] (3S) -3-Aminomethyl-6- (4-fluoro-phenoxy) -5-methyl-hexanoic acid;
[683] (3S) -3-Aminomethyl-6- (3-fluoro-phenoxy) -5-methyl-hexanoic acid;
[684] (3S) -3-Aminomethyl-6- (2-fluoro-phenoxy) -5-methyl-hexanoic acid;
[685] (3S) -3-Aminomethyl-6- (4-methoxy-phenoxy) -5-methyl-hexanoic acid;
[686] (3S) -3-Aminomethyl-6- (3-methoxy-phenoxy) -5-methyl-hexanoic acid;
[687] (3S) -3-Aminomethyl-6- (2-methoxy-phenoxy) -5-methyl-hexanoic acid;
[688] (3S) -3-Aminomethyl-5-methyl 6- (4-trifluoromethyl-phenoxy) -hexanoic acid;
[689] (3S) -3-Aminomethyl-5-methyl-6- (3-trifluoromethyl-phenoxy) -hexanoic acid;
[690] (3S) -3-Aminomethyl-5-methyl-6- (2-trifluoromethyl-phenoxy) -hexanoic acid;
[691] (3S) -3-Aminomethyl-5-methyl-6- (4-nitro-phenoxy) -hexanoic acid;
[692] (3S) -3-Aminomethyl-5-methyl-6- (3-nitro-phenoxy) -hexanoic acid;
[693] (3S) -3-Aminomethyl-5-methyl-6- (2-nitro-phenoxy) -hexanoic acid;
[694] (3S) -3-Aminomethyl-5-methyl-6-phenoxy-hexanoic acid; And
[695] (3S) -3-Aminomethyl-6- (4-chloro-phenoxy) -5-methyl-hexanoic acid.
[696] &Lt; Method 9 > Synthesis of C-4 substituted homologues
[697]
[698] The compound of formula 64 can be prepared from the compound of formula 63 by treating compound 63 with hydrogen at 50 psi in the presence of a catalyst such as Raney nickel in the presence of a base such as triethylamine in an organic solvent, . The product is then treated with an aqueous acid such as 6N HCl at room temperature to reflux temperature. The resulting mixture can be isolated by ion exchange chromatography.
[699] The compound of formula 63 is treated with an appropriate base such as, but not limited to, sodium hydride, n-butyllithium, and the like, and an alkylating agent such as t-butyl bromoacetate or benzyl bromoacetate in a solvent such as DMSO or THF, 62B. &Lt; / RTI &gt; Preferably, the reaction is carried out by treating a solution of the compound of formula 62B in THF with sodium hydride and alkylating the resulting anion with t-butyl bromoacetate.
[700] The compound of formula 62B may be prepared from the compound of formula 62A by treatment with sodium chloride in a solvent such as aqueous DMSO at 50 占 폚 to reflux temperature.
[701] The compound of formula 62A is treated with a suitable alkyl metal halide such as an alkyllithium reagent or an organomagnesium halide in a solvent such as THF or ether in the presence of a copper salt such as copper iodide, copper bromide dimethyl sulfide (not limited thereto) Lt; RTI ID = 0.0 &gt; (61). &Lt; / RTI &gt; Alternatively, the reaction can be carried out by treating the nitrile with alkyl magnesium chloride in a solvent such as ether at room temperature or below room temperature.
[702] Compound 61 can be prepared by condensing isobutylaldehyde and methylcyanoacetate according to known literature methods.
[703] &Lt; Method 10 >: C-4 substitution
[704]
[705] The double branched 3-substituted GABA analog 72 is prepared by hydrogenating azide 71 in the presence of a noble metal catalyst such as 5% palladium-on-carbon and hydrolyzing the resulting lactam to a strong acid such as 6N HCl at reflux temperature to yield azide 71 . The final product 72 can then be isolated using ion exchange chromatography.
[706] Compound 71 can be prepared in two steps by treating lactone 70 with HBr in a solvent such as ethanol at a temperature such as 0 ° C and reacting the resulting bromide with a sodium azide in a solvent such as dimethylsulfoxide at 10-80 ° C have.
[707] Lactone 70 is prepared by oxidizing compound 69 with an oxidizing agent such as sodium hypochlorite in the presence of a catalytic amount of ruthenium trichloride in a solvent such as acetonitrile at 0-100 C and treating the resulting compound with potassium carbonate in methanol at 25-70 & Followed by treatment with an acid such as p-toluenesulfonic acid in a solvent such as THF at reflux temperature or by treatment with aqueous acid such as HCl in water at ambient temperature.
[708] Compound 69 is prepared by reducing compound 68 with a hydride reducing agent such as lithium aluminum hydride in a solvent such as ether or THF and reacting the resulting alcohol with an alkylating agent such as acetic anhydride in the presence of a base such as triethylamine or pyridine .
[709] The compound of formula 68 can be prepared by reacting the compound of formula 67 with hydrogen at approximately 50 psi in the presence of a noble metal catalyst such as palladium on carbon 5% in the presence of a solvent such as ethanol. The compound of formula 67 can be prepared by reacting the compound of formula 66 with an ethanol solution saturated with hydrogen bromide gas. The compound of formula 66 is prepared by treating a compound of formula 65 with a strong base such as lithium diisopropylamine in a solvent such as THF at -78 &lt; 0 &gt; C and reacting the resulting anion with a compound such as benzyl bromide or benzyl iodide to give Can be manufactured.
[710] Compounds of formula 66 (R = H or lower alkyl) can be prepared according to the method of Davies, J. Org Chem., 1999; 64 (23): 8501-8508; Koch J. Org. Chem., 1993; 58 (10): 2725 Bertus, Tetrahedron, Asymmetry 1999; 10 (7): 1369-1380; Yamamoto, J. Am. Chem. Soc., 1992; 114 (20) ): 7652-60). &Lt; / RTI &gt;
[711] <Specific Embodiment>
[712] Example 3: Synthesis of 3-aminomethyl-5-methyl-octanoic acid
[713]
[714] l-Benzyl-4-hydroxymethyl-pyrrolidin-2-one 74
[715] Sodium borohydride (8.0 g, 0.211 mol) was added to a solution of methyl-1-benzyl-5-oxo-3-pyrrolidinecarboxylate 73 in 600 ml of 1,2-dimethoxyethane See Zoretic et al., J. Org. Chem., 1980; 45: 810-814) (32.0 g, 0.137 mol) and refluxed for 19 hours. The reaction was cooled to room temperature and 200 ml of water were added. The reaction was quenched with 1 M citric acid and concentrated under reduced pressure. The residue was extracted with dichloromethane, dried over magnesium sulphate and evaporated to dryness to give alcohol 74 (17.47 g, 62%) as a clear oil. ¹ H NMR (CDCl ₃ ) 7.30 (m, 5H), 4.38 (d, IH, J = 14.7), 4.46 ), 3.10 (m, 1H), 2.52 (m, 2H), 2.26 (m, 1H). MS, m / z (relative intensity): 207 [M + 2H, 66%]. IR (KBr) 3345, 2946, 2866, 1651, 1445, 1025, 737 and 698 cm ^-1 .
[716] l-Benzyl-4-iodomethyl-pyrrolidin-2-one 75
[717] (20.0 g, 0.076 mol), imidazole (10.8 g, 0.159 mol) and iodine (19.0 g, 0.075 mol) were sequentially added to the alcohol lactam 74 (11.18 g, 0.056 mol) in 210 ml toluene . After stirring the suspension for 1.5 hours, the supernatant was poured into another flask. The sticky yellow residue was washed twice with ether and the solution was collected. The solvent was evaporated and the residue was purified by chromatography on silica eluting with 1: 1 acetone / hexane to give iodolactam 75 (7.92 g, 46%) as a yellow oil. _{^{1 H NMR (CDCl 3) δ7.25}} (m, SH), 4.38 (d, 1H, J = 14.6), 4.46 (d, 1H, J = 14.6), 3.38 (dd, 1H, J = 7.8 and 2.2) , 3.20 (dd, 1H, J = 5.6 and 4.4), 3.12 (dd, 1H, J = 7.3 and 2.4), 2.96 (dd, 1H, J = 5.8 and 4.4), 2.60 , &Lt; / RTI &gt; 1H, J = 10.5 and 9.7). MS, m / z (relative intensity): 224 [MH-Bn, 94%], 317 [M + 2H, 64%]. IR 3027, 2917, 1688, 1438, 1267, and 701 cm ^-1 .
[718] l-Benzyl-4- (2-methyl-pentyl) -pyrrolidin-2-one 76
[719] One iodine crystal and 2-bromopentane (2.88 g, 0.019 mol) were added to a suspension of magnesium turnings in 15 ml of anhydrous THF under nitrogen. After an exothermic reaction that was periodically cooled in an ice bath, the reaction was stirred at room temperature for 2 hours. After addition of 8 ml of Li ₂ CuCl ₄ (prepared from 84 mg of LiCl and 134 mg of CuCl ₂ in 10 ml of anhydrous THF) at 0 ° C, 1-benzyl-4-iodomethylpyrrole 2-one 75 is added dropwise and the resulting suspension is stirred at 0 &lt; 0 &gt; C for 3 hours. Stirring was continued at room temperature for 1 hour and then quenched with saturated ammonium chloride solution. Water was added to dissolve the precipitate formed and the solution was then extracted with ether and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by chromatography on silica eluting with 1: 1 acetone / hexanes to give 1-benzyl-4- (2-methyl-pentyl) -pyrrolidin- , 69%). _{^{1 H NMR (CDCl 3) δ7.30}} (m, 5H), 4.44 (m, 2H), 3. 32 (m, 1H), 2.86 (m, 1H), 2.56 (m, 1H), 2.40 (m, 1H), 2.10 (m, 1H), 1.30 (m, 6H), 1.10 (m, 1H), 0.90 (m, 6H). MS, m / z (relative intensity): 261 [M + 2H, 100%], 301 [M-H + CH 3 CN, 82%], 260 [M + H, 72%].
[720] 4- (2-Methyl-pentyl) -pyrrolidin-2-one 77
[721] A 250 ml 3-necked flask equipped with a dry ice condenser was cooled to -78 &lt; 0 &gt; C. Ammonia (80 ml) was condensed into the flask and l-benzyl-4- (2-methyl-pentyl) -pyrrolidin-2-one 76 (1.67 g, 0.006 mol) in 15 ml THF was added. Freshly cut sodium beads were added until the deep blue persists. The cooling bath was removed and the reaction was stirred at reflux temperature (-33 [deg.] C) for 1 hour. The reaction was quenched with ammonium chloride and excess ammonia was evaporated. The resulting residue was diluted with water, extracted with dichloromethane, and dried over magnesium sulfate. The solvent was evaporated and then purified by chromatography on silica eluting with 1: 1 acetone / hexanes to give 4- (2-methyl-pentyl) -pyrrolidin-2-one 77 (0.94 g, 86%). _{^{1 H NMR (CDCl 3) δ6.25}} (br, 1H), 3.44 (m, 1H), 2.95 (m, 1H), 2.54 (m, 1H), 2.40 (m, 1H), 1.98 (m, 1H) , 1.30 (m, 6H), 0.80 (m, 6H). MS, m / z (relative intensity): 212 [M + 2H + CH 3 CN, 100%], 171 [M + 2H, 72%], 170 [M + 1H, 65%].
[722] 3-Aminomethyl-5-methyl-octanoic acid (Example 3)
[723] Pyridin-2-one 77 (0.94 g, 0.007 mol) was dissolved in 70 ml of 6N HCl and refluxed for 20 hours. The solution was evaporated in vacuo and the aqueous solution of the residue was added to Dowex 50WX 8-100 (strong acidic) ion exchange resin washed with HPLC grade water. The column was washed first with water and then with 5% ammonium hydroxide solution until the pH of the eluate was constant. The ammonium hydroxide fraction was evaporated and azeotroped with toluene. The white solid was washed with acetone, filtered and dried in a vacuum oven for 24 h to yield amino acid (0.61 g, 59%). _{^{1 H NMR (CD 3 0D)}} δ3.00 (m, 1H), 2.85 (m, 1H), 2.48 (m, 1H), 2.30 (m, 1H), 2.14 (brm, 1H), 1.60 (brm, 1H ), 1.38 (m, 4H), 1.18 (m, 2H), 0.60 (m, 6H). MS, m / z (relative intensity): 188 [M + H, 100%].
[724] Example 4: Synthesis of 3-aminomethyl-5,7-dimethyl-octanoic acid
[725]
[726] 1- (4-Methoxy-benzyl) -5-oxo-pyrrolidine-3-carboxylic acid methyl ester 79
[727] Dimethyl itaconate (48 g, 0.306 mol) in methanol (13 mL) was added to 4-methoxybenzylamine (42 g, 0.306 mol) in methanol (40 mL) at 0 ° C. The solution was stirred at room temperature for 4 days. 1N HCl was added to the solution followed by the addition of ether. The two layers were separated and the aqueous layer was extracted with ether. The organic layer was collected and dried (MgSO _4). The solution was pooled, dried in vacuo and the drying agent was filtered to precipitate the desired material 79 (23.26 g, 29%). MS, m / z (relative intensity): 264 [M + H, 100%]. Calcd for _{C 14 H l7 N l O 4} : C, 63.87; H, 6.51; N, 5.32. Found: C, 63.96; H, 6.55; N, 5.29.
[728] 4-Hydroxymethyl-l- (4-methoxy-benzyl) -pyrrolidin-2-one 80
[729] Of _{NaBH 4 (15 g, 0.081 mol} ) at room temperature it was added in the ester 79 in ethanol (600 ml). After 4.5 h, water (~ 200 ml) was carefully added to the reaction and the solution was stirred overnight at room temperature. The resulting solid was filtered off and the filtrate was concentrated to give alcohol 80 as an oil (15.33 g, 81%). MS, m / z (relative intensity): 235 [M + H, 100%].
[730] 4-Iodomethyl-l- (4-methoxy-benzyl) -pyrrolidin-2-one 81
[731] Triphenylphosphine (20 g, 0.077 mol), imidazole (10.8 g, 0.16 mol) and iodine (19 g, 0.075 mol) were added to alcohol 80 (12.9 g, 0.055 mol) in PhMe. The suspension was stirred at room temperature for 5 hours. A saturated aqueous solution of sodium thiosulfate was added and the two layers were separated. The aqueous layer was extracted with ether and the combined organic layers were washed with brine, dried (MgSO ₄ ) and concentrated. The residue was purified by flash chromatography (6: 1 to 4: 1 toluene / acetone) to give iodide 81 as an oil (11.9 g, 63%). MS, m / z (relative intensity): 346 [M + H, 100%].
[732] 4- (2,4-Dimethyl-pentyl) -l- (4-methoxy-benzyl) -pyrrolidin-
[733] The title compound was prepared from 4- (2,4-dimethyl-pentyl) -1- (4-methoxy-pyridin- -Benzyl) -pyrrolidin-2-one (1.22 g, 29%). MS, m / z (relative intensity): 304 [M + H, 100%].
[734] 4- (2,4-Dimethyl-pentyl) -pyrrolidin-2-one 83
[735] (4.2 g, 7.7 mmol) in H ₂ O (10 mL) was added to the lactam (1.17 g, 3.86 mmol) in MeCN (20 mL) at 0 ° C. After 50 min additional addition of ceric ammonium nitrate (2.1 g, 3.86 mmol) and after 1 h the mixture was adsorbed onto silica and purified by flash chromatography to give an oil. MS, m / z (relative intensity): 183 [M + H, 100%].
[736] 3-Aminomethyl-5,7-dimethyl-octanoic acid (Example 4)
[737] Amino acid was obtained as a solid using a method analogous to the preparation of 3-aminomethyl-5-methyl-octanoic acid (Example 3). MS, m / z (relative intensity): 202 [M + H, 100%].
[738] Example 5: Synthesis of (S) -3-aminomethyl-5-methyl-octanoic acid
[739]
[740] (S) -4-Hydroxymethyl-1 - ((S) -l-phenyl- ethyl) -pyrrolidin-
[741] Sodium borohydride (22 g, 0.595 mol) was added to ester 33 (49 g, 0.198 mol) in ethanol (600 mL). After 7 hours, 1 M citric acid was carefully added or the reaction was completely quenched by the addition of water after the foaming had ceased. The ethanol was removed under reduced pressure and ethyl acetate was added. The two layers were separated and the resulting aqueous layer is extracted with EtOAc, to afford the the combined organic layers were dried (MgS0 ₄₎ and concentrated to give sticky oil. MS, m / z (relative intensity): [M + H, 100%].
[742] (S) -4-Iodomethyl-l - ((S) -l-phenyl- ethyl) -pyrrolidin-
[743] Iodide 85 was obtained as an oil (35.2 g, 56%) using a method analogous to iodination of compound 80. Calcd for _{C 13 H l6 I l N l} O l: C, 47.43; H, 4.90; N, 4.25. Found: C, 47.41; H, 4.83; N, 4.17.
[744] 4- (2-Methyl-pentyl) -l - ((S) -l-phenyl- ethyl) -pyrrolidin-
[745] Compound 86 (2.71 g, 81.0%) was obtained as an oil using a method analogous to the preparation of 1-benzyl-4- (2-methyl-pentyl) -pyrrolidin- MS, m / z (relative intensity): 274 [M + 1H, 100%], 315 [M + H + CH 3 CN, 65%].
[746] (S) -4- (2-methyl-pentyl) -pyrrolidin-2-one 87
[747] Compound 87 (1.14 g, 72.8%) was obtained as an oil using a similar method to the preparation of 4- (2-methyl-pentyl) -pyrrolidin- MS, m / z (relative intensity): 170 [M + 1H, 10%], 211 [M + 1H + CH 3 CN, 90%].
[748] (S) -3-Aminomethyl-5-methyl-octanoic acid (Example 5)
[749] Amino acid (Example 5; 0.88 g, 74.3%) was obtained in a manner similar to the preparation of 3-aminomethyl-5-methyl-octanoic acid (Example 3). _{^{1 H NMR (CD 3 0D)}} δ2.95 (m, 1H), 2.80 (m, 1H), 2.40 (m, 1H), 2.25 (m, 1H), 2.05 (brm, 1H), 1.50 (brm, 1H ), 1.30 (m, 4H), 1.10 (m, 2H), 0.90 (m, 6H). MS, m / z (relative intensity): 188 [M + 1H, 100%], 186 [M-1H, 100%], 229 [M + 1H + CH 3 CN, 30%].
[750] Example 6: Synthesis of (S) -3-aminomethyl-7-methoxy-5-methyl-heptanoic acid
[751]
[752] (S) -l-phenyl-ethyl) -pyrrolidin-2-one 88 &lt; RTI ID = 0.0 &
[753] The adduct 88 (6 g, 74%) was obtained as an oil using a similar method to the preparation of l-benzyl-4- (2-methyl-pentyl) -pyrrolidin- MS, m / z (relative intensity): 272 [M + H, 100%].
[754] (S) -l-phenyl-ethyl) -pyrrolidin-2-one 89 &lt; RTI ID = 0.0 &
[755] OsO ₄ (2 mL of a 4 wt% solution in t-BuOH) was added to the alkene 88 (5.8 g, 0.021 mol) in THF / H ₂ O (3: 1, 100 mL). After 1 hour, sodium peroxoate (11.4 g, 0.053 mol) was added. After 2 hours, the suspension was filtered and the solid washed with dichloromethane. The filtrate was concentrated and the residue azeotroped with toluene. The residue was dissolved in ethanol and sodium borohydride (2.5 g) was added. The suspension was stirred overnight at room temperature. 1N citric acid was added and the mixture was diluted with ether. The resulting two layers were separated, the aqueous layer was extracted with ether, and the combined organic layers were dried (MgSO ₄ ) and concentrated. The residue was purified by flash chromatography (1: 1 hexanes / EtOAc) to give an oil (4.2 g, 73%). MS, m / z (relative intensity): 276 [M + H, 100%].
[756] (S) -l-phenyl-ethyl) -pyrrolidin-2-one 90 &lt; RTI ID = 0.0 &
[757] NaH (368 mg, 60% in oil) was added to the alcohol 89 (2 g, 7.66 mmol) in DMSO (60 mL) at room temperature. After 30 min, methyl iodide (1.08 g, 7.66 mmol) was added and the solution was stirred at room temperature overnight, and the reaction was diluted with water (500 mL). The solution was extracted with ether and the combined organic extracts were dried (MgSO ₄ ) and concentrated. The residue was purified by flash chromatography (90% to 50% hexane / acetone) to give product 90 (1.1 g, 52%) as an oil. MS m / z 290 (M + H, 100%).
[758] (S) -4- (4-methoxy-2-methyl-butyl) -pyrrolidin-
[759] The lactam 91 was obtained as an oil using a method analogous to the synthesis of 4- (2-methyl-pentyl) -pyrrolidin-2-one 77. MS m / z 186 (M + H, 100%).
[760] (S) -3-Aminomethyl-7-methoxy-5-methyl-heptanoic acid (Example 6)
[761] A method similar to the synthesis of Example 3 was carried out. Recrystallization of the resulting product amino acid isolated from ion exchange chromatography from methanol / ethyl acetate gave Example 6 as a white solid. MS m / z 204 (M + H, 100%). Calcd for _{C l0 H 21 N 1 O 3} C, 59.09; H, 10.41; N, 6.89. Found: C, 58.71; H, 10.21; N, 6.67.
[762] Example 7: Synthesis of (S) -3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid
[763]
[764] Methyl-2 - [(S) -5-oxo-l- ((S) -l- phenyl- ethyl) -pyrrolidin- 3- ylmethyl] -malonic acid dimethyl ester 92
[765] NaH (291 mg of a 60% dispersion in oil) was added to dimethyl methyl malonate (1.06 g, 7.29 mmol) in DMSO (7 mL) at room temperature. After the bubbling ceased, lactam 85 (2 g, 7.29 mol) in DMSO (5 mL) was added. After 1 hour, water was added and the aqueous solution was extracted with ether. Collecting the organic extracts were dried (MgSO ₄₎ and concentrated. The residue was purified by flash chromatography (1: 1 hexanes / acetone) to give the product as an oil (1.7 g, 81%). MS m / z 348 (M + H, 100%).
[766] Methyl-3 - [(S) -5-oxo-l- ((S) -l- phenyl- ethyl) -pyrrolidin-3- yl] -propionic acid methyl ester 93
[767] Ester 92 (483 mg, 1.4 mmol), NaCl (104 mg, 1.8 mmol), water (105 L) and DMSO (5 mL) were heated to reflux for 2 hours. The solution was cooled to room temperature, water was added and the aqueous solution was extracted with ether. Collecting the organic extracts were dried (MgSO ₄₎ and concentrated. The residue was purified by flash chromatography (80% to 66% hexane / acetone) to give the product as an oil (160 mg, 40%). MS m / z 290 (M + H, 100%).
[768] (S) -l-phenyl-ethyl) -pyrrolidin-2-one 37 &lt; RTI ID = 0.0 &
[769] Was added _{NaBH 4 (3.7 g, 0.10 mol} ) in ethanol ester 93 (4.82 g, 0.017 mol) in (100 ml), and the mixture was heated under reflux for 2.5 hours. The solution was cooled to 0 &lt; 0 &gt; C and 1M citric acid was carefully added and water was added. The solution was concentrated to half volume and extracted with ether. Collecting the organic extracts were dried (MgS0 ₄₎ and concentrated. The residue was purified by flash chromatography (1: 1 hexane / acetone) to give the product as an oil (2.6 g, 59%). MS m / z 262 (M + H, 100%).
[770] (S) -l-phenyl-ethyl) -pyrrolidin-2-one 94 &lt; RTI ID = 0.0 &
[771] The alcohol 37 in CH ₂ Cl ₂ (10 mL) at -78 was added to ℃ DAST (1 g, 6.2 mmol) in _{CH 2 Cl 2 (20 mL)} . After standing at -78 ° C for 1 hour, the solution was warmed to room temperature. After 7 hours, the solution was carefully quenched with saturated aqueous sodium bicarbonate solution and the two layers were separated. The organic layer was dried (MgS0 ₄₎ and concentrated. The residue was purified by flash chromatography (90% to 66% hexane / acetone) to give the product as an oil (600 mg, 37%). MS m / z 264 (M + H, 100%).
[772] (S) -4- (3-Fluoro-2-methyl-propyl) -pyrrolidin-
[773] The lactam was obtained as an oil (242 mg, 68%) using a method analogous to the preparation of 4- (2-methyl-pentyl) -pyrrolidin- MS m / z 159 (M, 100%).
[774] (S) -3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid (Example 7)
[775] A method similar to the synthesis of Example 3 was carried out. The resulting amino acid isolated from ion exchange chromatography was recrystallized from methanol / ethyl acetate to give Example 7 as a white solid. MS m / z 177 (M, 100%). Calcd for C ₈ H ₁₆ F ₁ N ₁ O ₂ : 0.02 H ₂ O: C, 54.11; H, 9.10; N, 7.89. Found: C, 53.75; H, 9.24; N, 7.72.
[776] Example 8: Synthesis of (S) -3-aminomethyl-6-methoxy-5-methyl-hexanoic acid
[777]
[778] (S) -l-phenyl-ethyl) -pyrrolidin-2-one 96 &lt; RTI ID = 0.0 &
[779] The title compound was prepared using an analogous procedure to the synthesis of (S) -4- (4-methoxy-2-methyl-butyl) To give ether 96 (90 mg, 37%). MS m / z 276 (M + H, 100%).
[780] (S) -4- (3-Methoxy-2-methyl-propyl) -pyrrolidin-
[781] Compound 97 was obtained as an oil (760 mg, 93%) using a method analogous to the synthesis of 4- (2-methyl-pentyl) -pyrrolidin- MS m / z 171 (M + H, 100%).
[782] (S) -3-Aminomethyl-6-methoxy-5-methyl-hexanoic acid (Example 8)
[783] A method similar to the synthesis of Example 3 was carried out. Recrystallization of the resulting product amino acid isolated from ion exchange chromatography from methanol / ethyl acetate gave Example 8 as a white solid. MS m / z 190 (M + H, 100%). Calcd for C ₉ H ₁₉ N ₁ O ₃ : C, 57.12; H, 10.12; N, 7.40. Found: C, 57.04; H, 10.37; N, 7.30. (: 5 ratio of C5 isomers by ¹ H NMR) of the second batch precipitated from the mother liquor. MS m / z 190 (M + H, 100%).
[784] Example 9: Synthesis of (3S, 5R) -3-aminomethyl-5-methyl-octanoic acid hydrochloride
[785]
[786] (R) -2,6-dimethyl-non-2-ene 98
[787] Followed by LiCl (4.3 g) (S) of the CuCl ₂ (6.8 g) at 0 ℃ THF (800 mL) - it was added to the nelril bromide (50 g, 0.228 mol) in a sheet. After 30 min, magnesium chloride (152 mL of a 3M solution in THF, Aldrich) was added and the solution was warmed to room temperature. After 10 hours, the solution was cooled to 0 &lt; 0 &gt; C and a saturated aqueous ammonium chloride solution was carefully added. The resulting two layers were separated and the aqueous layer was extracted with ether. The combined organic layers were dried (MgSO ₄ ) and concentrated to give an oil (32.6 g; 93%). It was used without further purification. ¹³ C NMR (100 MHz; CDCl ₃ ) 131.13, 125.28, 39.50, 37.35, 32.35, 25.92, 25.77, 20.31, 19.74, 17.81, 14.60.
[788] (R) -4-methyl-heptanoic acid 99
[789] A solution of CrO ₃ (39 g, 0.39 mol) in H ₂ SO ₄ (33 mL) / H ₂ O (146 mL) was added to the alkene 98 (20 g, 0.13 mol) in acetone (433 mL) . After 6 hours, CrO ₃ (26 g, 0.26 mol) in H ₂ SO ₄ (22 mL) / H ₂ O (100 mL) was further added. After 12 h, the solution was diluted with brine and the solution was extracted with ether. The combined organic layers were dried (MgSO ₄ ) and concentrated. Flash chromatography (gradient of 6: 1 to 2: 1 hexanes / EtOAc gradient) gave the product 99 as an oil (12.1 g; 65%). MS, m / z (relative intensity): 143 [MH, 100%].
[790] ( 4R, 5S) -4-Methyl-3 - ((R) -4-methyl-heptanoyl) -5-phenyl-oxazolidin-
[791] Trimethylacetyl chloride (20 g, 0.17 mol) was added to the acid 99 (19 g, 0.132 mol) and triethylamine (49.9 g, 0.494 mol) in THF (500 mL) at 0 ° C. After 1 hour, LiCl (7.1 g, 0.17 mol) was added followed by oxazolidinone (30 g, 0.17 mol). The mixture was allowed to warm to room temperature and after 16 h the filtrate was removed by filtration and the solution was concentrated under reduced pressure. Flash chromatography (7: 1 hexanes / EtOAc) gave the product 100 as an oil (31.5 g; 79%). _{[α] D = 5.5 (CHCl} c1 of _3). MS, m / z (relative intensity): 304 [M + H, 100%].
[792] (3S, 5R) -5-Methyl-3 - ((4R, 5S) -4-methyl-2-oxo-5-phenyl- oxazolidine-3-carbonyl) -octanoic acid tert- butyl ester 101
[793] NaHMDS (48 mL of 1M solution in THF) was added to oxazolidinone 100 (12.1 g, 0.04 mol) in THF (200 ml) at -50 <0> C. After 30 minutes, t-butyl bromoacetate (15.6 g, 0.08 mol) was added. The solution was stirred at -50 &lt; 0 &gt; C for 4 hours, then warmed to room temperature. After 16 h, saturated aqueous ammonium chloride solution was added and the two layers were separated. The organic layer was collected and the aqueous layer extracted with ether, dried (MgS0 ₄₎ and concentrated. Flash chromatography (9: 1 hexanes / EtOAc) gave the product 101 as a white solid (12 g; 72%). [α] _D = 30.2 (c1 in CHCl _3). ¹³ C NMR (100 MHz; CDCl ₃ ) 176.47, 171.24, 152.72, 133.63, 128.87, 125.86, 80.85, 78.88, 55.34, 39.98, 38.77, 38.15, 37.58, 30.60, 28.23, 20.38, 20.13, 14.50, 14.28.
[794] (S) -2 - ((R) -2-methyl-pentyl) -succinic acid 4-tert-butyl ester 102
[795] A premix solution of LiOH (51.2 mL of a 0.8 M solution) and H ₂ O ₂ (14.6 mL of a 30% solution) was added to a solution of the ester 101 (10.8 g, 0.025 mmol) in H ₂ O (73 mL) and THF mol). After 4 hours, LiOH (0.8 M solution) was added to 12.8 ml and H ₂ 0 ₂ (30% solution) was added to 3.65 ml. After 30 min, sodium bisulfite (7 g), sodium sulfite (13 g) and water (60 mL) were added followed by hexane (100 mL) and ether (100 mL). The two layers were separated and the aqueous layer was extracted with ether. The combined organic layers were concentrated to an oil which was dissolved in heptane (300 ml). The resulting solid was filtered off and the filtrate was dried (MgSO ₄ ) and concentrated to give an oil (6 g, 93%) which was used without further purification. MS, m / z (relative intensity): 257 [M + H, 100%].
[796] (3S, 5R) -3-hydroxymethyl-5-methyl-octanoic acid tert-butyl ester 103
[797] BH ₃ .Me ₂ (36 mL of a 2M solution in THF, Aldrich) was added at 0 ° C to the acid 102 (3.68 g, 0.014 mol) in THF (100 mL) and the solution was allowed to warm to room temperature. After 15 hours, ice was carefully added to the solution (to control foaming) and brine was added. The solution was extracted with ether and the combined organic layers were dried (MgSO ₄ ) and concentrated under reduced pressure. Flash chromatography (4: 1 hexanes / EtOAc) gave alcohol 103 (2.0 g, 59%) as an oil. ¹³ C NMR (100 MHz; CDCl ₃ ) 173.56, 80.85, 65.91, 39.74, 39.20, 38.90, 35.65, 29.99, 28.31, 20.18, 19.99, 14.56.
[798] (3S, 5R) -5-methyl-3- (toluene-4-sulfonyloxymethyl) -octanoic acid tert-butyl ester 104
[799] Was added to alcohol 103 (1.98 g, 8.1 mmol) in CH ₂ Cl ₂ (40 mL) at room temperature, triethylamine (2.4 g, 0.024 mol), DMAP (20 mg) and tosyl chloride . After 14 hours, 1N HCl was added and the two layers were separated. The aqueous layer was extracted with ether and the combined organic layers were dried (MgSO ₄ ) and concentrated. Flash chromatography (95% hexanes / EtOAc) was performed to give tosylate 104 (2.94 g, 91%) as an oil. ¹³ C NMR (100 MHz; CDCl ₃ ) 171.60, 144.92, 133.07, 130.02, 128.12, 80.80, 72.15, 39.73, 38.09, 37.89, 32.67, 29.71, 28.22, 21.83, 20.10, 19.54, 14.49.
[800] (3S, 5R) -3-azidomethyl-5-methyl-octanoic acid tert-butyl ester 105
[801] Tosylate 104 (2.92 g, 7.3 mmol) and sodium azide (1.43 g, 0.02 mol) were warmed to-50 C in DMSO (30 mL). After 2 hours, the solution was cooled to room temperature and diluted with water. The solution was extracted with ether and the combined organic layers were dried (MgSO ₄ ) and concentrated to give an oil (1.54 g, 79%). Further purification with flash chromatography (95% hexanes / EtOAc) gave an oil. [α] _D = -8.3 (c1 in CHCl _3). ¹³ C NMR (100 MHz; CDCl ₃ ) 172.01, 80.73, 54.89, 39.73, 39.46, 39.00, 33.40, 29.85, 28.30, 20.15, 18.82, 14.52.
[802] (S) -4 - ((R) -2-methyl-pentyl) -pyrrolidin-
[803] The azide 105 was treated with 5% Pd / C and 200 mg of 5% Pd / C was further added while shaking under a hydrogen atmosphere for 20 hours. After 6 h, the filtrate was concentrated to an oil, which was identified by ¹ H NMR as a mixture of primary amine 106 and lactam 107 (1.75 g), which was used without further purification.
[804] (3S, 5R) -3-Aminomethyl-5-methyl-octanoic acid hydrochloride (Example 9)
[805] A mixture of amine 106 and lactam 107 (1.74 g) was treated with 3N HCl (40 mL) and the solution was heated to 50 &lt; 0 &gt; C for 4 hours and then cooled to room temperature. After 12 h, the solution was concentrated and the residue was recrystallized from ethyl acetate to give amino acid (605 mg) as a white solid. MS, m / z (relative intensity): 188 [M + H, 100%]. C ₁₀ H ₂₁ N ₁ O ₂ : Calculated for H ₁ Cl ₁ : C, 53.68; H, 9.91; N, 6.26. Found: C, 53.83; H, 10.12; N, 6.07.
[806] Example 10: Synthesis of (3S, 5R) -3-aminomethyl-5-methyl-heptanoic acid
[807]
[808] Methanesulfonic acid (S) -3,7-dimethyl-oct-6-enyl ester 108
[809] _{(- -) - CH 2 Cl} 2 (200 mL) methanesulfonyl chloride S in (26 mL, 0.329 mol) from _{0 ℃ CH 2 Cl 2 (800} mL) in a nelrol (42.8 g, 0.274 mol) sheet and Was added to triethylamine (91 mL, 0.657 mol). After 2 h, the solution was washed with 1N HCl at 0 &lt; 0 &gt; C followed by brine. Dry the organic layer (MgSO ₄₎ and concentrated to give an oil (60.5 g, 94%) which was used without further purification. ^{1 H NMR (400 MHz; CDCl} 3) 5.05 (1H, m), 4.2 (2H, m), 2. 95 (3H, s), 1.98 (2H, m), 1.75 (1H, m), 1.6 (3H , 1.55 (4H, m), 1.35 (2H, m), 1.2 (1H, m), 0.91 (3H, d, J = 6.5 Hz).
[810] (R) -2,6-dimethyl-oct-2-ene 109
[811] Lithium aluminum hydride (3.8 g, 0.128 mol) was added to the alkene 108 (60 g, 0.256 mol) in THF (1 L) at 0 ° C. After 7 hours, 3.8 g of lithium aluminum hydride was further added, and the solution was warmed to room temperature. After 18 hours, 3.8 g of lithium aluminum hydride was further added. After 21 hours, the reaction was carefully quenched with 1N citric acid and the solution was further diluted with brine. The resulting two layers were separated and the organic layer was dried (MgSO ₄ ) and concentrated to give an oil to be used without further purification. MS, m / z (relative intensity): 139 [MH, 100%].
[812] (R) -4-methyl-hexanoic acid 110
[813] (9.3 g, 56%) as a oil using a similar method to the synthesis of (R) -4-methyl-heptanoic acid 99. MS, m / z (relative intensity): 129 [M-H, 100%].
[814] (4R, 5S) -4-methyl-3 - ((R) -4-methyl-hexanoyl) -5-phenyl- oxazolidin-
[815] (R) -4-methyl-heptanoyl) -5-phenyl-oxazolidin-2-one 100 as an oil using an analogous procedure to the synthesis of (4R, 5S) -4-methyl- (35.7 g, 95%). MS, m / z (relative intensity): 290 [M + H, 100%].
[816] (3S, 5R) -5-methyl-3- [1 - ((4R, 5S) -4-methyl- - butyl ester 112
[817] Preparation of (3S, 5R) -5-methyl-3 - ((4R, 5S) -4-methyl-2-oxo-5-phenyl- oxazolidine- To give Compound 112 as an oil (7.48 g; 31%).
[818] (S) -2 - ((R) -2-methyl-butyl) -succinic acid 4-tert-butyl ester 113
[819] A premix solution of LiOH (37 mL of a 0.8 M solution) and H ₂ O ₂ (10.57 mL of a 30% solution) was added to a solution of the ester 112 (7.26 g, 0.018 mmol) in H ₂ O (53 mL) and THF (176 mL) mol), and the solution was warmed to room temperature. After 2 hours, sodium bisulfite (7 g), sodium sulfite (13 g) and water (60 mL) were added, the two layers were separated and the aqueous layer was extracted with ether. The combined organic layers were concentrated to an oil which was dissolved in heptane (200 mL). The resulting solid was filtered off and the filtrate was dried (MgSO ₄ ) and concentrated to give an oil (4.4 g) which was used without further purification.
[820] (3S, 5R) -3-Hydroxymethyl-5-methyl-heptanoic acid tert-butyl ester 114
[821] Alcohol 114 (2.68 g, 69%) was obtained as an oil using a method analogous to the preparation of (3S, 5R) -3-hydroxymethyl-5-methyl-octanoic acid tert-butyl ester 103. MS, m / z (relative intensity): 216 [89%], 174 [M- (CH 3) 3 C, 100%].
[822] (3S, 5R) -5-Methyl-3- (toluene-4-sulfonyloxymethyl) -heptanoic acid tert-butyl ester 115
[823] (2.53 g, 0.011 mmol) in CH ₂ Cl ₂ (140 mL) at 0 ° C was added pyridine (2.6 g, 0.033 mol), DMAP (100 mg) and tosyl chloride (3.15 g, 0.016 mol) The solution was allowed to warm to room temperature over 3.5 hours, and then DMAP and TsCl (3.15 g) were further added. After 14 hours, 1N HCl was added and the two layers were separated. Then, the organic layer was washed with brine, dried (MgSO ₄₎ and concentrated. Flash chromatography (95% to 86% hexanes / EtOAc) was performed to give tosylate 115 (1.53 g, 36%) as an oil. ¹³ C NMR (100 MHz; CDCl ₃ ) 130.03, 128.12, 72.18, 37.89, 37.71, 32.67, 31.49, 29.88, 28.22, 21.83, 19.07, 11.37.
[824] (3S, 5R) -3-azidomethyl-5-methyl-heptanoic acid tert-butyl ester 116
[825] (0.956 g, 97%) was obtained using a method analogous to the preparation of (3S, 5R) -3-azidomethyl-5-methyl-octanoic acid tert-butyl ester 105. MS, m / z (relative intensity): 228 [MN ₂ , 80%].
[826] (3S, 5R) -3-Aminomethyl-5-methyl-heptanoic acid tert-butyl ester 117 &lt; RTI ID = 0.0 &
[827] The azide 116 (689 mg) was treated with 20% Pd / C (90 mg) in THF (20 mL) and shaken under a hydrogen atmosphere for 36 h. The catalyst was removed by filtration and the resulting oil used without further purification.
[828] (3S, 5R) -3-Aminomethyl-5-methyl-heptanoic acid (Example 10)
[829] The mixture of amine 117 and lactam 118 was treated with 6N HCl and the solution was heated to 50 &lt; 0 &gt; C for 17 h, then cooled to room temperature and concentrated. Purification of the resulting oil by ion exchange chromatography using 5% ammonium hydroxide gave a creamy solid which was recrystallized from methanol / ethyl acetate to give (3S, 5R) -3-aminomethyl-5- Methyl-heptanoic acid, Example 10 was obtained. MS, m / z (relative intensity): 174 [M + H, 100%]. Calcd for _{C 19 H 19 N 1 O 2} C, 62.39; H, 11.05; N, 8.08. Found: C, 62.23; H, 11.33; N, 7.89.
[830] Example 11: Synthesis of (3S, 5S) -3-aminomethyl-5-methyl-octanoic acid
[831]
[832] (S) -2,6-dimethyl-non-2-ene 119
[833] CuCl ₂ (5.36 g, 39.7 mmol) and LiCl (3.36, 80.0 mmol) were stirred together in dry THF (40 mL) for 15 min. The resulting solution was added to 3.0 M of methylmagnesium chloride in THF (168 mL) at 0 &lt; 0 &gt; C under a nitrogen atmosphere and stirred at this temperature for 15 minutes. (R) - (-) - citronellyl bromide (55.16 g, 251.8 mmol) in THF (100 mL) was slowly added to the reaction suspension and stirred at 0 ° C for 2.5 hours. The mixture was warmed to room temperature and stirred for an additional 1 hour. The mixture was cooled to 0 &lt; 0 &gt; C and quenched with saturated ammonium chloride solution. The suspension was then extracted with ether, washed with water and dried over magnesium sulfate. This solution was concentrated under reduced pressure to give (S) -2,6-dimethyl-non-2-ene (36.3 g; 94%) as an oil. MS, m / z (relative intensity): 153 [M-1H, 100%], 194 [M-1H + CH 3 CN, 45%].
[834] (S) -4-methyl-heptanoic acid 120
[835] The Jones reagent (2.7 M, 600 mL) was added dropwise over 1.5 hours to (S) -2,6-dimethyl-non-2-ene 119 (39.0 g, 253.2 mmol) in acetone (1 L) Lt; / RTI &gt; The reaction mixture was poured into saturated Na ₂ SO ₄ solution and extracted with ether. The mixture was washed with brine and concentrated in vacuo. The oily residue was dissolved in methanol (70 mL) and 1 M NaOH (700 mL) and stirred for 30 min. Washing the aqueous with CH ₂ Cl ₂ and acidified with 10% HCl and extracted with CH ₂ Cl _2. This solution was dried over magnesium sulfate and concentrated to dryness to give (S) -4-methyl-heptanoic acid (24.22 g; 66%) as an oil. MS, m / z (relative intensity): 143 [M-1H, 100%].
[836] (4R, 5S) -4-methyl-3 - ((S) -4-methyl-heptanoyl) -5-phenyl-oxazolidin-
[837] (4R, 5S) -4-methyl-3 - ((R) -4-methyl-heptanoyl) -5-phenyl-oxazolidin- 5S) -4-methyl-3 - ((S) -4-methyl-heptanoyl) -5-phenyl-oxazolidin-2-one 121 (6.2 g; 80.0%). MS, m / z (relative intensity): 304 [M + 1H, 90%], 355 [M + lH + CH 3 CN, 60%].
[838] (3S, 5S) -5-Methyl-3 - ((4R, 5S) -4-methyl-2-oxo-5-phenyl- oxazolidine-3-carbonyl) -octanoic acid tert- butyl ester 122
[839] 1.6 M n-BuLi in hexanes (18.0 mL, 30.1 mmol) was added dropwise to a solution of diisopropylamine (4.6 mL, 32.6 mmol) in anhydrous THF (50 mL) at -5 ° C under nitrogen, 0.0 &gt; 0 C. &lt; / RTI &gt; The mixture was stirred at -5 &lt; 0 &gt; C for 20 minutes and then cooled to -78 &lt; 0 &gt; C. 121 (7.6 g, 25.1 mmol) in anhydrous THF (12 mL) was added to the LDA solution and stirred at -78 <0> C for 30 min. t-Butyl bromoacetate (4.8 mL, 32.6 mmol) was added to the reaction and stirring was continued at -78 <0> C for 2 h. The reaction was warmed to room temperature and stirred for an additional 18 hours. The reaction was quenched with saturated NaH ₂ PO ₄ solution, extracted with ethyl acetate and dried over magnesium sulfate. This solution was concentrated to give a solid residue which was dissolved in hot hexane. The hexane solution was cooled to room temperature and then further cooled in an ice bath. The resulting precipitate was collected and air dried to give 122 (4.3 g; 41%) as a fuzzy white solid. MS, m / z (relative _{intensity): 362 [MC (CH 3} ) 3 + 1H, 100%], 418 [M + 1H, 20%].
[840] (S) -2 - ((S) -2-methyl-pentyl) -succinic acid 4-tert-butyl ester and (3S, 5S) -3-hydroxymethyl-5-methyl-octanoic acid tert-butyl ester 123
[841] A premixed solution of 30% H ₂ O ₂ (12.2 mL) and LiOH (0.8 M, 42.7 mL) was added to the ester 122 in a mixture of THF (203.0 mL) and water (61.0 mL) at 0 ° C. The resulting solution was stirred at 0 &lt; 0 &gt; C for 4 hours. Sodium bisulfite (7 g), sodium sulfite (13 g) and water (60 mL) were added to the reaction. A 1: 1 mixture of ether / hexane (200 mL) was then added and the organic layer was separated. The aqueous layer was extracted with ether and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in heptane and stirred for 5 minutes. The resulting precipitate was filtered and the filtrate was concentrated to dryness to give an oil.
[842] (3S, 5S) -3-Hydroxymethyl-5-methyl-octanoic acid tert-butyl ester 123
[843] (4.0 g; 76.0%) as an oil using a similar method to the preparation of (3S, 5R) -3-hydroxymethyl-5-methyl-octanoic acid tert-butyl ester 103. MS, m / z (relative _{intensity): 230 [MC (CH 3} ) 3 + 1H + CH 3 CN, 100%], 189 [MC (CH 3) 3 + 1H, 70%].
[844] (3S, 5S) -5-Methyl-3- (toluene-4-sulfonyloxymethyl) -octanoic acid tert-butyl ester 124
[845] 6.9 g of 124 was obtained using a method analogous to the preparation of (3S, 5R) -5-methyl-3- (toluene-4-sulfonyloxymethyl) -octanoic acid tert-butyl ester 104. MS, m / z (relative _{intensity): 343 [MC (CH 3} ) 3 + 1H, 70%], 384 [MC (CH 3) 3 + 1H + CH 3 CN, 100%].
[846] (3S, 5S) -3-azidomethyl-5-methyl-heptanoic acid tert-butyl ester 125
[847] (2.9 g; 66%) as an oil using a similar method to the preparation of (3S, 5R) -3-azidomethyl-5-methyl-octanoic acid tert-butyl ester 105. MS, m / z (relative _{intensity): 212 [MC (CH 3} ) 3 -1H, 45%].
[848] (3S, 5S) -3-Aminomethyl-5-methyl-octanoic acid tert-butyl ester 126
[849] A mixture of 125 (2.8 g, 10.4 mmol) and 10% Pd / C (1.0 g) in methanol (50.0 mL) was hydrogenated at 41 psi for 96 h. The solution was filtered to give 1.7 g of crude 126 which was used in the next step without further purification. MS, m / z (relative intensity): 244 [M + 1H, 100%], 285 [M + 1H + CH 3 CN, 25%].
[850] (3S, 5S) -3-Aminomethyl-5-methyl-octanoic acid (Example 11)
[851] Example 10 Example 11 (380 mg; 29.0%) was obtained using a method analogous to the preparation of (3S, 5R) -3-aminomethyl-5-methyl-heptanoic acid. _{^{1 H NMR (CD 3 0D)}} δ2.90 (dd, J = 3.9, 8.8 Hz, 1H), 2.80 (dd, J = 7.6, 5.1 Hz, 1H), 2.40 (dd, J = 3.2, 12.51 Hz, 1H ), 2.20 (dd, J = 8.8, 6.8 Hz, IH), 2.05 (m, IH), 1.55 (m, IH), 1.30 (m, ; MS, m / z (relative intensity): 187 [M + 1H, 100%], 211 [M + 1H + CH 3 CN, 30%].
[852] Example 12: Synthesis of (3S, 5S) -3-aminomethyl-5-methyl-heptanoic acid
[853]
[854] (S) -2,6-dimethyl-oct-2-ene 127
[855] (R) - (-) - citronellyl bromide (49.1 g, 224.2 mmol) was added dropwise to a 1.0 M solution of LAH in THF (336 mL, 336 mmol) at 0 C over 45 min. 0.0 &gt; 0 C &lt; / RTI &gt; for further 4 hours. The reaction was slowly quenched with saturated ammonium chloride solution and then ether (100 mL) was added. The resulting white slurry was filtered and the filtrate was dried over magnesium sulfate. This solution was concentrated under reduced pressure to give 127 (26.2 g; 83%) as an oil. MS, m / z (relative intensity): 180 [M-1H + CH 3 CN, 100%], 139 [M-1H, 90%].
[856] (S) -4-methyl-hexanoic acid 128
[857] 15.9 g of 128 as an oil was obtained using a method analogous to that used to prepare compound 120. MS, m / z (relative intensity): 129 [M-1H, 100%], 170 [M-1H + CH 3 CN, 70%].
[858] (4R, 5S) -4-Methyl-3 - ((S) -4-methyl-hexanoyl) -5- phenyl-oxazolidin-
[859] The title compound was prepared using an analogous procedure to that used to prepare (4R, 5S) -4-methyl-3 - ((S) -4-methyl-heptanoyl) -5-phenyl-oxazolidin- (4R, 5S) -4-methyl-3 - ((S) -4-methyl-hexanoyl) -5-phenyl-oxazolidin-2-one 129 was obtained as 35.0 g. This was used in the next step without further purification. MS, m / z (relative intensity): 290 [M + 1H, 100%], 331 [M + 1H + CH 3 CN, 20%].
[860] (3S, 5S) -5-methyl-3 - ((4R, 5S) -4-methyl-2-oxo-5-phenyl- oxazolidine-
[861] (3S, 5S) -5-methyl-3 - ((4R, 5S) -4-methyl-2-oxo-5-phenyl- oxazolidine- (46.0 g, 25.4%) as a white solid. &Lt; RTI ID = 0.0 &gt; MS, m / z (relative _{intensity): 348 [MC (CH 3} ) 3 + 1H, 100%], 443 [M-1H + CH 3 CN, 100%], 402 [M-1H, 55%], 404 [M + 1H, &lt; / RTI &gt; 45%].
[862] (3S, 5S) -3-Hydroxymethyl-5-methyl-heptanoic acid tert-butyl ester 131
[863] (1.2 g, 52.1%) as an oil using a method analogous to that used to prepare (3S, 5S) -3-hydroxymethyl-5-methyl-octanoic acid tert-butyl ester 123. MS, m / z (relative _{intensity): 175 [MC (CH 3} ) 3 + 1H, 100%], 173 [MC (CH 3) 3 -1H, 100%], 216 [MC (CH 3) 3 + 1H _{+ CH 3 CN, 95%]} .
[864] (3S, 5S) -5-methyl-3- (toluene-4-sulfonyloxymethyl) -heptanoic acid tert-butyl ester 132
[865] 2.1 g of 132 as an oil were obtained using a method analogous to the preparation of (3S, 5R) -5-methyl-3- (toluene-4- sulfonyloxymethyl) -octanoic acid tert-butyl ester 104. The product was used in the next step without further purification. MS, m / z (relative _{intensity): 329 [MC (CH 3} ) 3 + 1H, 85%], 370 [MC (CH 3) 3 + 1H + CH 3 CN, 65%].
[866] (3S, 5S) -3-azidomethyl-5-methyl-heptanoic acid tert-butyl ester 133
[867] (0.76 g, 54.0%) as an oil using a method analogous to the preparation of (3S, 5R) -3-azidomethyl-5-methyl-octanoic acid tert-butyl ester 105. MS, m / z (relative _{intensity): 198 [MC (CH 3} ) 3 -1H, 100%]
[868] (3S, 5S) -3-Aminomethyl-5-methyl-heptanoic acid tert-butyl ester 134
[869] 0.62 g of 134 as an oil was obtained using a method analogous to that used for (3S, 5S) -3-Aminomethyl-5-methyl-octanoic acid tert-butyl ester 126. The product was used in the next step without further purification. MS, m / z (relative intensity): 230 [M + 1H, 100%], 271 [M + 1H + CH 3 CN, 45%].
[870] (3S, 5S) -3-Aminomethyl-5-methyl-heptanoic acid (Example 12)
[871] (3S, 5S) -3-Aminomethyl-5-methyl-heptanoic acid (0.3 g, 65.1%) was obtained as a white solid using a method analogous to that used in Example 11. _{^{1 H NMR (CD 3 OD)}} δ2.80-3.00 (m, 2H), 2.40 (m, 1H), 2.20 (dd, J = 8.2, 7.1 Hz, 1H), 2.05 (m, 1H), 1.30-1.50 (m, 3 H), 1.00 - 1.20 (m, 2 H), 0.9 (m, 6 H); MS, m / z (relative intensity): 187 [M + 1H, 100%], 211 [M + 1H + CH 3 CN, 30%]. MS, m / z (relative intensity): 174 [M + 1H, 100%], 172 [M-1H, 100%], 215 [M + 1H + CH 3 CN, 20%].
[872] Example 13: Synthesis of (3S, 5R) -3-aminomethyl-5-methyl-nonanoic acid hydrochloride
[873]
[874] (R) -4-methyl-octanoic acid 136
[875] Lithium chloride (0.39 g, 9.12 mmol) and copper (I) chloride (0.61 g, 4.56 mmol) were pooled in 45 mL THF at ambient temperature and stirred for 15 min, then cooled to 0 & (1 M solution in THF, 45 mL, 45 mmol). (S) -carnonylbromide (5.0 g, 22.8 mmol) was added dropwise and the solution was slowly warmed to ambient temperature with stirring over night. The reaction was quenched by careful addition of saturated NH ₄ Cl (aq), and stirred for 30 minutes with Et ₂ 0 and saturated NH ₄ Cl (aqueous). The layers were separated and the organic layer was dried (MgSO ₄ ) and concentrated. The crude product was used without further purification.
[876] Jones reagent (2.7 M in H ₂ SO ₄ (aqueous solution), 108 mmol) was added to a solution of alkene 135 (3.8 g, 22.8 mmol) in 50 mL acetone at 0 ° C and the solution was stirred at ambient temperature &Lt; / RTI &gt; The mixture was partitioned between Et ₂ O and water, the layers separated and the organic layer was washed with brine, dried (MgSO ₄ ) and concentrated. The residue was purified by flash chromatography (8: 1 hexanes: EtOAc) to give 2.14 g (59%) of the acid 136 as a colorless oil. LRMS: m / z 156.9 (M &lt; + &gt;); ¹ H NMR (CDCl ₃ ): 2.33 (m, 2H), 1.66 (m, 1H), 1.43 (m, 2H), 1.23 ). The Jones reagent was prepared as a 2.7 M solution by collecting 26.7 g CrO ₃ , 23 mL H ₂ SO ₄ and diluting to 100 mL with water.
[877] (4R, 5S) -4-Methyl-3 - ((R) -4-methyl- octanoyl) -5-phenyl- oxazolidin-
[878] Three drops of DMF followed by oxalyl chloride (1.42 mL, 16.2 mmol) was added to the acid 136 (2.14 g, 13.5 mmol) in 25 mL of CH ₂ Cl ₂ at 0 ° C to generate vigorous gas. The solution was heated directly to ambient temperature, stirred for 30 minutes and concentrated. Meanwhile, n-butyllithium (1.6 M solution in hexane, 9.3 mL, 14.9 mmol) was added dropwise to a solution of oxazolidinone (2.64 g, 14.9 mmol) in 40 mL of THF at -78 <0> C. The mixture was stirred for 10 minutes while the acid chloride in 10 mL THF was added dropwise to the mixture. It warmed directly to ambient temperature and then the reaction was at -78 ℃ stirred for 30 min and quenched with saturated NH ₄ Cl. The mixture was partitioned between Et ₂ O and saturated NH ₄ Cl (aqueous solution), the layers were separated and the organic layer was dried (MgSO ₄ ) and concentrated to give 3.2 g of oxazolidinone 137 as a colorless oil. LRMS: m / z 318.2 (M &lt; + &gt;); _{^{1 H NMR (CDCl 3):}} δ7.34 (m, 5H), 5.64 (d, J = 7.3 Hz, 1H), 4.73 (quint, J = 6.8 Hz, 1H), 2.96 (m, 1H), 2.86 ( (m, 1H), 1.66 (m, 1H), 1.66 (m, 2H). The crude product was used without purification.
[879] (3S, 5R) -5-methyl-3 - ((4R, 5S) -4-methyl-2-oxo-5-phenyl- oxazolidine-
[880] (1.6 M solution in hexane, 7.6 mL, 12.1 mmol) was added at -78 <0> C to a solution of diisopropylamine (1.8 mL, 12.6 mmol) in 30 mL THF and a solution of oxazolidinone 137 (3.2 g, 10.1 mmol) was added dropwise to the mixture while stirring the mixture for 10 minutes. The solution was stirred for 30 minutes, t-butyl bromoacetate (1.8 mL, 12.1 mmol) was added dropwise at -50 ° C and the mixture was slowly warmed to 10 ° C over 3 hours. The mixture was partitioned between Et ₂ O and saturated NH ₄ Cl (aqueous solution), the layers were separated, and the organic layer was dried (MgSO ₄ ) and concentrated. The residue was purified by flash chromatography (16: 1 to 8: 1 hexanes: EtOAc) to give 2.65 g (61%) of ester 138 as a colorless crystalline solid. Melting point = 84-86 占 폚. ^{_{[α] D 23 +17.1 (c}} = 1.00, CHCl 3); _{^{1 H NMR (CDCl 3):}} δ7.34 (m, 5H), 5.62 (d, J = 7.3 Hz, 1H), 4.73 (quint, J = 6.8 Hz, 1H), 4.29 (m, 1H), 2.67 ( 1H), 1.38 (s, 9H), 1.28 (m, 7H), 1.08 (d, J = 9.8,16.4 Hz, 1H), 2.40 (dd, J = 5.1, 16.4 Hz, m, 1 H), 0.88 (m, 9 H); ¹³ C NMR (CDCl ₃ ) δ 176.45, 171.22, 152.71, 133.64, 128.86, 125.86, 80.83, 78.87, 55.33, 40.02, 38.21, 37.59, 36.31, 30.86, 29.29, 28.22, 23.14, 20.41, 14.36, 14.26. Calcd for C ₂₅ H ₃₇ NO ₅ : C, 69.58; H, 8.64; N, 3.25. Found: C, 69.37; H, 8.68; N, 3.05.
[881] (S) -2 - ((R) -2-methyl-hexyl) -succinic acid 4-tert-butyl ester 139
[882] (0 ° C) of LiOH monohydrate (1.0 g, 23.8 mmol) and hydrogen peroxide (30 wt% aqueous solution, 5.0 mL) in 10 mL of H ₂ was added at 0 ° C. to a solution of ester 138 , 6.14 mmol). The mixture was thoroughly stirred for 90 minutes, then warmed to ambient temperature and stirred for 90 minutes. 0 ℃ in the reaction by the addition of 100 mL 10% NaHS0 ₃ (aqueous) and extracted with then quenched, Et ₂ 0. The layers were separated and the organic layer was washed with brine, dried over magnesium sulfate and concentrated. The crude 139 was used without purification.
[883] (3S, 5R) -3-hydroxymethyl-5-methyl-nonanoic acid tert-butyl ester 140
[884] A solution of borane-dimethyl sulfide (2.0 M solution in THF, 4.6 mL, 9.2 mmol) was added at 0 &lt; 0 &gt; C to a solution of crude 139 (6.14 mmol) in 30 mL THF and the mixture was slowly warmed to ambient temperature overnight. The acid was further added to BH ₃ -DMS (about 5 mL) until it is fully consumed. The reaction was then quenched by addition of MeOH, and partitioned into a NaHC0 ₃ saturated with Et ₂ 0 (water). The layers were separated and the organic layer was washed with brine, dried over magnesium sulfate and concentrated to give alcohol 140. LRMS: m / z 226.1; _{^{1 H NMR (CDCl 3):}} δ3.63 (dd, J = 11.0, 4.2 Hz, 1H), 3.42 (dd, J = 11.0, 6.8 Hz, 1H), 2.30 (dd, J = 14.9, 7.6 Hz, 1H ), 2.20 (dd, J = 14.9,5.6 Hz, 1H), 2.03 (m, 2H), 1.42 (s, 9H), 1.24 (m, 6H), 1.02 . The crude product was used without purification.
[885] (3S, 5R) -5-methyl-3- (toluene-4-sulfonyloxymethyl) -nonanoic acid tert-butyl ester 141
[886] To DMAP (0.1 g), p-toluenesulfonyl chloride (1.37 g, 7.2 mmol) was added at 0 ° C to alcohol 140 (6.14 mmol) in 30 mL CH ₂ Cl ₂ followed by triethylamine (1.8 mL, 13 mmol) Lt; / RTI &gt; After the addition, the mixture was immediately warmed to ambient temperature and stirred overnight, and the reaction was not complete. The mixture was partitioned between Et ₂ O and 1 N HCl (aqueous solution), the layers separated and the organic layer was washed with saturated NaHCO ₃ (aqueous solution), dried over magnesium sulfate and concentrated to afford tosylate 141. This product was used without further purification.
[887] (3S, 5R) -3-azidomethyl-5-methyl-nonanoic acid tert-butyl ester 142
[888] (3S, 5R) -3-azidomethyl-5-methyl-octanoic acid tert-butyl ester 105 was used to afford azide 142 as a colorless oil. LRMS: m / z 200.1; _{^{1 H NMR (CDCl 3):}} δ3.31 (dd, J = 12.2, 4.2 Hz, 1H), 3.19 (dd, J = 12.2, 5.9 Hz, 1H), 2.22 (m, 1H), 2.10 (m, 1H ), 1.39 (s, 9H), 1.21 (m, 8H), 1.00 (m, 2H), 0.81 (m, 6H).
[889] (3S, 5R) -3-Aminomethyl-5-methyl-nonanoic acid hydrochloride (Example 13)
[890] The azide 142 (1.0 g) was hydrogenated at 45 psi H ₂ in the presence of 20% Pd / C, EtOH for 15 h to give the crude amino ester 143 which was used without concentration for purification. 6 mL 6N HCl (aqueous solution) was added to the amino ester 143 and the mixture was heated to reflux for 90 minutes, cooled and concentrated. Recrystallization from EtOAc: hexane gave 0.38 g (45% from azide) of (3S, 5R) -3-aminomethyl-5-methyl-nonanoic acid hydrochloride as a colorless crystalline solid (HCl salt) A second harvest of mg (10% from azide) was also obtained. Melting point = 146-156 &lt; 0 &gt; C. LRMS: m / z 200.1 (M &lt; + &gt;); _{^{1 H NMR (CDCl 3):}} δ2.87 (dd, J = 13.2, 5.4 Hz, 1H), 2.79 (dd, J = 13.2, 7.3 Hz, 1H), 2.29 (d, J = 6.8 Hz, 2H), 1H), 2.08 (m, 1H), 1.31 (m, 1H), 1.09 (m, 7H), 0.92 (m, Calcd for C ₁₁ H ₂₄ NO ₂ Cl: C, 55.57; H, 10.17; N, 5.89. Found: C, 55.69; H, 10.10; N, 5.86.
[891] Example 14: Synthesis of (3S, 5S) -3-aminomethyl-5-methyl-nonanoic acid
[892]
[893] (S) -Acid 145 was prepared from (R) -citralenyl bromide according to the method for the preparation of (R) -4-methyl-octanoic acid 136 described above. The yield was similar and the ¹ H NMR spectrum was identical to that of the (R) -acetic acid enantiomer. LRMS: m / z 158.9 (M + 1).
[894] Oxazolidinone 146 was prepared according to the procedure for the preparation of (4R, 5S) -4-methyl-3 - ((R) -4-methyl-octanoyl) -5- 145. LRMS: m / z 290.1 (M-27); _{^{1 H NMR (CDCl 3):}} δ7.38 (m, 3H), 7.28 (m, 2H), 5.64 (d, J = 7.1 Hz, 1H), 4.74 (quint, J = 6.8 Hz, 1H), 2.92 ( m, 2H), 1.71 (m, 1H), 1.42 (m, 7H), 1.18 (m, 1H), 0.88 (m, 9H).
[895] Butyl ester 147 was prepared from oxazolidinone 146 according to the method for preparation of compound 138 described above. LRMS: m / z 348.1 (M-83).
[896] Butyl ester 147 was prepared according to the process for the preparation of (3S, 5R) -3-hydroxymethyl-5-methyl-nonanoic acid tert-butyl ester 140 described above. _{^{1 H NMR (CDCl 3):}} δ3.60 (dd, J = 11.0, 4.6 Hz, 1H), 3.45 (dd, J = 11.0, 6.8 Hz, 1H), 2.24 (m, 2H), 2.04 (m, 2H ), 1.42 (s, 9H), 1.17-1.38 (m, 7H), 1.11 (m, 1H), 0.84 (m, 6H).
[897] (3S, 5S) -3-Aminomethyl-5-methyl-nonanoic acid (Example 14)
[898] (3S, 5S) -3-Aminomethyl-5-methyl-nonanoic acid was obtained from compound 149 according to the process for the preparation of (3S, 5R) -3-aminomethyl-5-methyl-nonanoic acid hydrochloride described above. Thus, by purifying the crude HCl salt obtained by ion exchange chromatography on Dowex 50WX8 50-100 mesh (H- form of resin) using a 10% NH ₄ OH eluting agent to give the free base. The waxy solid was washed twice with Et ₂ O and dried to yield an amorphous white solid. Melting point 144-146 [deg.] C. LRMS: m / z 172.0 (M-28); _{^{1 H NMR (CDCl 3):}} δ2.76 (d, J = 5.9 Hz, 2H), 2.14 (m, 1H), 1.96 (m, 2H), 1.25 (m, 1H), 1.12 (m, 6H), 0.96 (m, 2H), 0.66 (m, 6H).
[899] Example 15: Synthesis of (3S, 5R) -3-aminomethyl-5-methyl-decanoic acid
[900]
[901] (R) -2,6-dimethylundec-2-ene 153
[902] Compound 153 was obtained as a colorless oil (20.16 g, 98%) using a method analogous to the preparation of (S) -2,6-dimethyl-non-2- ene 119. ^{1 H NMR (400 MHz, CDCl} 3) δ5.10-5.06 (m, 1H), 2.10-1.89 (m, 2H), 1.66 (s, 3H), 1.58 (s, 3H), 1.34-1.23 (m, 4H), 1.15-1.06 (m, 2H), 0.88-0.81 (m, 11H).
[903] (R) -4-methylnonanoic acid 154
[904] (R) -2,6-dimethylundec-2-ene 153 (10.03 g, 55.03 mmol) was dissolved in acetone (270 mL) and cooled to 0 ° C. The Jones reagent (CrO ₃ / H ₂ SO ₄ ) (2.7 M, 120 mL) was added dropwise and the reaction was allowed to warm to room temperature over 18 h. The reaction was poured into water / Na ₂ SO ₄ (200 mL) and the aqueous layer was extracted with ethyl acetate (4 x 100 mL). The combined organics were dried over magnesium sulfate, filtered and rotary evaporated to give an oil. The crude oil was dissolved in CH ₂ Cl ₂ (400 mL) and cooled to -78 ° C. To remove (6E) (3S) -3,7-dimethylocta-1,6-diene, which is a minor impurity, ozone was bubbled into the reaction until blue. Dimethyl sulfide (5 mL) was added and the reaction was stirred at room temperature for 2 hours. The solvent was removed and the crude material was purified by chromatography on silica eluting with 20% EtOAc / hexane to give an oil. The oil was dissolved in ether (100 mL) and extracted with 10% NaOH (2 x 25 mL). The aqueous layer was collected and extracted with ether (50 mL). The aqueous layer was cooled to 0 &lt; 0 &gt; C and acidified with HCl. The acidic layer was extracted with EtOAc (3 x 100 mL) and the combined extracts were dried over magnesium sulfate, filtered and rotary evaporated to give 154 as an oil (6.86 g, 54%). ¹ H NMR (400 MHz, CDCl ₃ ) 2.40-2.25 (m, 4H), 1.70-1.62 (m, 2H), 1.47-1. 11 (m, 8H), 0.87-0.84 (m, 6H); [α] _D = -11.4 (c1 in CHCl _3).
[905] (4R, 5S) -4-Methyl-3 - ((R) -4-methyl-nonanoyl) -5- phenyl-oxazolidin-
[906] Compound 154 (6.504 g, 37.76 mmol) was dissolved in THF (95 mL) and cooled to 0 &lt; 0 &gt; C. Triethylamine (19.74 mL, 141.6 mmol) was added dropwise, and then trimethylacetyl chloride (6.98 mL, 56.64 mmol) was added dropwise. The thick white suspension was stirred at 0 &lt; 0 &gt; C for 90 minutes. 3-oxazolidin-2-one (6.824 g, 38.51 mmol) and THF (70 mL) were added to a solution of LiCl (1.86 g, 41.54 mmol) The reaction was allowed to warm to room temperature overnight. The solvent was evaporated. The solid was dissolved in EtOAc, filtered off and washed thoroughly with EtOAc. The filtrate was washed with water (2 x 50 mL) and brine, and the organics were dried over magnesium sulfate, filtered and rotary evaporated. The crude material was purified by chromatography on silica eluting with 10% EtOAc / hexanes to give 155 as an oil (10.974 g, 88%). ^{1 H NMR (400 MHz, CDCl} 3) δ7.44-7.35 (m, 3H), 7. 31-7.26 (m, 2H), 5.66 (d, J = 7.33 Hz, 1H), 4.76 (quint, J = 1H), 1.46-1. 36 (m, 1H), 1.46-1. 36 (m, , 1.27-1.16 (m, 2H), 0.92-0.87 (m, 8H); [α] _D = +34.1 (c1 in CHCl _3).
[907] (3S, 5R) -5-methyl-3 - ((4R, 5S) -4-methyl-2-oxo-5-phenyl- oxazolidine- 3- carbonyl) -decanoic acid tert- butyl ester 156
[908] Preparation of (3S, 5S) -5-methyl-3 - ((4R, 5S) -4-methyl-2-oxo-5-phenyl- oxazolidine- 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -deca as an oil using an analogous procedure to (3S, 5R) Butyl ester 156 (0.668 g, 90%). ^{1 H NMR (400 MHz, CDCl} 3) δ7.41-7.28 (m, 5H), 5.63 (d, J = 7.33 Hz, 1H), 4.74 (quin, J = 6.84 Hz, 1H), 4.33-4.26 (m J = 6.6 Hz, 1H), 1.50-1.32 (m, 1H), 2.68 (dd, J = 16.4, 9.77 Hz, 10H), 1.28-1.21 (m, 1H), 1.15-1.08 (m, 1H), 0.90-0.86 (m, 9H); MS (APCI) m / z 348 (M @ ^{+ =} 97, 100%); [α] _D = +18.8 (c1 in CHCl _3).
[909] (S) -2 - ((R) -2-methyl-heptyl) -succinic acid 4-tert-butyl ester 157
[910] Compound 156 (5.608 b, 12.59 mmol) was dissolved in THF / H ₂ O (60 mL / 14 mL) and cooled to 0 ° C. Of LiOH (1N, 18.89 mL) and H ₂ 0 ₂ and then combined (35%, 4.45 mL, 50.4 mmol) was added dropwise to the reaction temperature while maintaining less than 5 ℃. The reaction was stirred at 0 ℃ for 4 hours, quenched with _{Na 2 S0 3 (6.3 g)} , it was added dropwise NaHS0 ₃ (3.4 g) in 50 mL H ₂ 0. The reaction was stirred for 15 minutes and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 100 mL), the combined extracts were dried over magnesium sulfate, filtered and rotary evaporated to give an oil. The crude material was dissolved in EtOAc (10 mL) and added dropwise to heptane (250 mL). The suspension was stirred for 20 minutes, and the solid was filtered and washed with heptane. The filtrate was washed with _{60 ℃ H 2 0 (100 mL} ) , dried over magnesium sulfate, filtered and rotary evaporated to give 157 (3.52 g) as an oil. This material was used directly in the next step.
[911] (3S, 5R) -3-Hydroxymethyl-5-methyl-decanoic acid tert-butyl ester 158
[912] Compound 157 (3.52 g, 12.3 mmol) was dissolved in anhydrous THF (123 mL) and cooled to 0 &lt; 0 &gt; C. After dropwise addition of borane dimethylsulfide complex (10 M, 3.69 mL), the reaction was warmed to room temperature and stirred for 1 hour. The reaction was cooled to 0 C and MeOH (20 mL) was added dropwise to quench the reaction. The reaction was stirred for 18 hours and the solvent was removed by rotary evaporation. The crude material was purified by chromatography on silica eluting with 20% EtOAc / hexanes to give 158 (2.28 g, 68%) as an oil. ¹ H NMR (400 MHz, CDCl ₃ ) 3.65-3.59 (m, 1H), 3.43 (dd, J = (d, J = 15.1, 5.62 Hz, 1H), 2.06-2.02 (m, 1H), 1.43 (s, 9H), 1.40-1.25 (m, 4H), 1.07-1.13 (m, 1 H), 0.86 - 0.84 (m, 6 H); MS (APCI) m / z 216 (M @ ⁺ 56, 100%).
[913] (3S, 5R) -5-Methyl-3- (toluene-4-sulfonyloxymethyl) -decanoic acid tert-butyl ester 159
[914] Compound 158 (2.27 g, 8.33 mmol) was dissolved in CH ₂ Cl ₂ (30 mL) and cooled to 0 ° C. Tosyl chloride (1.91 g, 10.0 mmol) and catalyst DMAP were added followed by the dropwise addition of triethylamine (2.55 mL, 18.33 mmol). The reaction was then stirred at 0 &lt; 0 &gt; C for 18 hours. The solvent was removed by rotary evaporation (under reduced pressure) and the crude material was washed with EtOAc and filtered. The solid was washed with EtOAc and the filtrate was washed with 0.5N HCl (20 mL) and brine (30 mL), dried over magnesium sulfate, filtered and then rotary evaporated. The oil was purified by chromatography on silica eluting with a gradient of 5% to 10% concentration EtOAc / hexanes to give 159 (3.399 g, 96%) as an oil. ^{1 H NMR (400 MHz, CDCl} 3) δ7.75 (d, J = 8.30 Hz, 2H), 7.31 (d, J = 8.30 Hz, 2H), 3.99 (dd, J = 9.65, 3.54 Hz, 1H), 1H), 2.10 (dd, J = 8.4 Hz, 1H), 3.89 (dd, J = 9.52, 5.37 Hz, 14.9, 6.35 Hz, 1H), 1.38 (s, 9H), 1.31-1.17 (m, 3H), 1.08-0.81 (m, 2H), 0.79-0.76 (m, 6H); [α] _D = -10.1 (c1 in CHCl _3).
[915] (3S, 5R) -3-azidomethyl-5-methyl-decanoic acid tert-butyl ester 160
[916] Compound 159 (3.01 g, 7.05 mmol), sodium azide (1.26 g, 19.40 mmol) and DMSO (12 mL) were combined and heated to 60 <0> C for 3 h. EtOAc (100 mL) was added to the reaction and filtered. The solid was washed with EtOAc (20 mL) and the filtrate was evaporated. The crude material was purified by chromatography on silica eluting with 5% EtOAc / hexanes to give 160 (1.86 g, 89%) as an oil.
[917] (3S, 5R) -3-Aminomethyl-5-methyl-decanoic acid tert-butyl ester 161
[918] Compound 160 (1.86 g, 6.25 mmol) in THF (50 mL) was shaken for 8 h on 5% Pd / C under a hydrogen pressure of 3 purging hydrogen. The catalyst was removed by filtration and the filtrate was evaporated. The crude material was purified by chromatography on silica eluting with methanol to give 161 (1.21 g, 71%) as an oil. ¹ H NMR (400 MHz, CDCl ₃ ) 2.70 (dd, J = 12.9, 4.40 Hz, 1H), 2.54 (dd, J = 1H), 1.43 (s, 12H), 1.39-1.25 (m, 4H), 1.14-1.07 (m, 1H), 1.03-0.97 (m, 1H), 0.86-0.82 (m, 6H).
[919] (3S, 5R) -3-Aminomethyl-5-methyl-decanoic acid (Example 15)
[920] Compound 161 (1.20 g, 4.44 mmol) was heated to 50 &lt; 0 &gt; C in 3 N HCl (30 mL) for 4 h. The solvent was evaporated and the oil was washed with toluene and evaporated. Following the crude material in water and passed through an ion exchange column, eluting with 0.5N NH ₄ 0H (Dowex 50WX8-100, strongly acidic). (3S, 5R) -3-Aminomethyl-5-methyl-decanoic acid (0.725 g, 75%) which was isolated as a white solid. Melting point = 174-175 DEG C; ^{1 H NMR (400 MHz, CDCl} 3) δ2.83 (dd, J = 12.69, 4.88 Hz, 1H), 2.70 (dd, J = 13.1, 7.45 Hz, 1H), 2.08 (d, J = 6.59 Hz, 2H ), 1.98 (m, 1H), 1.28-1.20 (m, 1H), 1.19-1.09 (m, 2H), 0.99-0.91 (m, 2H), 0.66 (m, 6H); MS (APCI) m / z 215 (M ^&lt; ^{+ &gt;} , 10%), 174 (M ⁺ -41,100%); [ ] _D = -5.7 (c 1.025 in water).
[921] Example 16: Synthesis of (3S, 5S) -3-aminomethyl-5-methyl-decanoic acid
[922]
[923] (S) -2,6-dimethyl-undec-2-ene 162
[924] n propyl magnesium chloride / ether solution (2.0 M, 228 mL) was cooled to -20 ℃ under a N ₂ atmosphere. Combined LiCl (3.87 g, 91.25 mmol) , CuC1 2 (6.13 g, 45.63 mmol) , and distillation of THF (456 mL) was stirred for 30 minutes. A Li ₂ CuCl ₄ solution was added via cannula to the Grignard reagent and the resulting solution was stirred at -20 ° C for 30 minutes. R - (-) - citronellyl bromide (50 g, 228.1 mmol) was dissolved in THF (60 mL) and added dropwise to the Grignard solution. The reaction was stirred at 0 &lt; 0 &gt; C for 1 hour. The reaction was cooled to-40 C and NH ₄ Cl (sat., 200 mL) was added dropwise to quench the reaction. The layers were separated and the aqueous layer was extracted with ether (3 x 100 mL). The combined organics were dried over magnesium sulfate, filtered and then rotary evaporated to give an oil. The crude material was purified by chromatography on silica eluting with hexanes to give 162 (9.15 g, 22%) as a colorless oil. ^{1 H NMR (400 MHz, CDCl} 3) δ5.10-5.06 (m, 1H), 2.10-1.89 (m, 2H), 1.66 (s, 3H), 1.58 (s, 3H), 1.34-1.23 (m, 4H), 1.15-1.06 (m, 2H), 0.88-0.81 (m, 11H).
[925] (S) -4-methylnonanoic acid 163
[926] Compound 162 (7.97 g, 43.7 mmol) was dissolved in acetone (214 mL) and cooled to 0 &lt; 0 &gt; C. It was added dropwise Jones reagent _{(CrO 3 / H 2 SO 4} ) (2.7 M, 95 mL) , followed by heating the reaction to room temperature over 18 hours. The reaction was poured into water / Na ₂ SO ₄ (200 mL) and the aqueous layer was extracted with ethyl acetate (4 x 100 mL). The combined organics were dried over magnesium sulfate, filtered and then rotary evaporated to give an oil. The crude oil was purified by chromatography on silica eluting with hexane to give 163 (5.56 g, 74%) as an oil. ¹ H NMR (400 MHz, CDCl ₃ ) 2.40-2.25 (m, 4H), 1.70-1.62 (m, 2H), 1.47-1.11 (m, 8H), 0.87-0.84 (m, 6H); MS APCI m / z 170.9 (M-1,100%).
[927] (4R, 5S) -4-Methyl-3 - ((S) -4-methyl-nonanoyl) -5-phenyl-oxazolidin-
[928] (10.70 g 100%) as an oil using a method analogous to that used to prepare compound 155, except that (S) -4-methylnonanoic acid 163 (5.56 g, 32.27 mmol) was used as the reactant. . ^{1 H NMR (400 MHz, CDCl} 3) δ7.42-7.34 (m, 3H), 7.28 (d, J = 6.59 Hz, 2H), 5.64 (d, J = 7.33 Hz, 1H), 4.74 (quin, J 1H), 1.94-1.23 (m, 7H), 0.90-0.84 (m, 8H) ).
[929] (3S, 5S) -5-Methyl-3 - ((4R, 5S) -4-methyl-2-oxo-5-phenyl- oxazolidine-3-carbonyl) -decanoic acid tert-
[930] 165 (4.25 g, 61%) was obtained as a solid using a method analogous to that used to prepare compound 156. MS (APCI) m / z 446 (M ⁺ +1, 10%), 390 (M ⁺ -55, 100%, -tBu).
[931] (S) -2 - ((S) -2-methyl-heptyl) -succinic acid 4-tert-butyl ester 166
[932] 166 (5.81 g) was obtained as an oil using a procedure analogous to that used for the preparation of 157, except that the ester 165 (8.42 g, 18.89 mmol) was used as the reactant. This material was used directly in the next step. MS (APCI) m / z 285 (M-1, 100%).
[933] (3S, 5S) -3-Hydroxymethyl-5-methyl-decanoic acid tert-butyl ester 167
[934] (S) -2 - ((S) -2-methyl-heptyl) -succinic acid 4-tert-butyl ester 166 (5.78 g, 20.18 mmol) 167 &lt; / RTI &gt; (4.18 g, 76%) as an oil. ^{1 H NMR (400 MHz, CDCl} 3) δ3.64-3.58 (m, 1H), 3.84-3.42 (m, 1H), 2.28-2.20 (m, 1H), 2.09-2.02 (m, 1H), 1.43 ( s, 9H), 1.26-1.18 (m, 8H), 1.11-1.04 (m, 2H), 0.87-0.83 (m, 6H); MS (APCI) m / z 217 (M ^&lt; ^{+ &gt;} -55, 50%, -tBu).
[935] (3S, 5S) -5-methyl-3- (toluene-4-sulfonyloxymethyl) -decanoic acid tert-butyl ester 168
[936] The title compound was prepared by a similar method to that used for preparing compound 159 except that (3S, 5S) -3-hydroxymethyl-5-methyl-decanoic acid tert-butyl ester 167 (4.164 g, 15.29 mmol) To give 168 (4.17 g, 64%) as an oil. ^{1 H NMR (400 MHz, CDCl} 3) δ7.75 (d, J = 8.30 Hz, 2H), 7.31 (d, J = 8.30 Hz, 2H), 3.97 (dd, J = 9.52, 4.15 Hz, 1H), 2H), 1.37 (s, 9H), 1.27-1.01 (m, 11H), 0.85 (m, 2H), 3.90 (dd, J = 9.52,5.13 Hz, t, J = 7.08 Hz, 3H), 0.76 (d, J = 6.35 Hz, 3H).
[937] (3S, 5S) -3-azidomethyl-5-methyl-decanoic acid tert-butyl ester 169
[938] Compound 160 was prepared except that (4S, 5S) -5-methyl-3- (toluene-4-sulfonyloxymethyl) -decanoic acid tert-butyl ester 168 (4.155 g, 9.74 mmol) 169 (2.77 g, 96%) was obtained as an oil using a method similar to the method used. MS (APCI) m / z 270 (M ⁺ -27, 30%, - N ₂ ), 214 (M ⁺ -87, 100%, -tBu, -N ₂ ).
[939] (3S, 5S) -3-Aminomethyl-5-methyl-decanoic acid tert-butyl ester 170
[940] A similar procedure to that used for preparing compound 161 was performed except that the reaction was carried out using 169 (2.50 g, 8.405 mmol) of (3S, 5S) -3-azidomethyl-5-methyl-decanoic acid tert- To give 170 (1.648 g, 72%) as an oil. MS (APCI) m / z 272 (M ^& lt ^; + ^& gt ^; + 1,100%).
[941] (3S, 5S) -3-Aminomethyl-5-methyl-decanoic acid (Example 16)
[942] A similar procedure to that used for Example 15 was followed except that tert-butyl (3S, 5S) -3- (aminomethyl) -5-methyldecanoate 170 (1.6 g, 6.00 mmol) Example 16 was obtained as a white solid (72%). MS (APCI) m / z 272 (M ^&lt; + & gt ^; +1, 100%). Melting point = 174-175 DEG C; ^{1 H NMR (400 MHz, CD} 3 0D) δ2.91 (dd, J = 12.9, 3.91 Hz, 1H), 2.83 (dd, J = 12.7, 7.57 Hz, 1H), 2.43 (dd, J = 15.6, 3.17 1H), 1.53 (m, 1H), 1.38-1.27 (m, 7H), 1.78-1.03 (m, 1H), 2.19 (dd, J = 15.6,8.8Hz, 1H), 2.08-2.04 2H), 0.90-0.86 (m, 6H), 0.66 (m, 6H); MS (APCI) m / z 216 (M + + 1,100%), 214 (M -1, 100%); [ ] _D = +21.4 (c1 in MeOH).
[943] Example 17: Synthesis of (3R, 4R) -3-aminomethyl-4,5-dimethyl-hexanoic acid
[944]
[945] (S) -2-Benzyl-3-methyl-butan-1-ol 172
[946] (JACS 1997; 119: 6510. Amide 171).
[947] 171 from (S) -2-benzyl-3-methylbutyl ester 173 in a large amount
[948] To a solution of diisopropylamine (108.9 g, 150.9 mL, 1.076 mol, 4.20 eq) in THF (600 mL) was added n-butyllithium (10 M in hexane, Respectively. The resulting solution was stirred for 10 minutes, warmed to 0 &lt; 0 &gt; C, and held at this temperature for 10 minutes. The borane-ammonia complex (31.65 g, 1.025 mmol, and 4.0 eq.) Was added in portions and the suspension was stirred at 0 &lt; 0 &gt; C for 15 min and at 23 &lt; 0 &gt; C for 15 min. A solution of amide 171 (86 g, 256.41 mmol, 1 eq) in THF via cannula was added to the cooled hydride over 3 minutes. The solution was stirred at 23 &lt; 0 &gt; C overnight and then cooled to 0 &lt; 0 &gt; C. 3N HCl (700 mL) was slowly added to quench the excess hydride. The reaction mixture was diluted with more aqueous HCl (3N, 200 mL) and brine then extracted with ether (4 x 15 mL). The ether solution was concentrated to a small volume, and 200 mL 2N NaOH was added, followed by stirring at 23 DEG C for 2.5 hours. More ether was added and the layers were separated. The aqueous layer was saturated with salt and extracted with ether (3 x 200 mL). The combined organics were washed with brine and dried over sodium sulfate. The residue was purified by flash chromatography (mineral oil ether-25% ether-TEA) to give alcohol 172 (50 g). _{NMR (CDCl 3) δ7.35-7.16 (m} , 5H, C 6 H 5), 3.55 ( approximate _{t, 2H, -CH 2 0H)} , 2.71 (dd, 1H, ArCH 2 CH-), 2.52 (dd, _{1H, ArCH 2 CH), 1.87} (m, 1H, CHCH (Me)), 1.67 (m, 1H, CH (Me) 2), 0.98 (d, 3H, CH 3) and 0.96 (d, 3H, CH ₃ ).
[949] For characterization, 3.3 g of sample was stored and the remainder was immediately acetylated at room temperature overnight (50 mL of triethylamine, 4.6 g of DMAP, 32 mL of acetic anhydride). After finishing, the residue was purified by chromatography on silica gel eluting with mineral oil ether followed by 10% ether in mineral oil ether to give 62 g of 173. _{NMR (CDCl 3) δ7.30-7.14 (m} , 5H, C 6 H 5), 3.98 (m, 2H, -CH 2 OAc), 2.71 (dd, 1H, ArCH 2 CH-), 2.51 (dd, 1H _{, ArCH 2 CH), 1.99 (} s, 3H, CH 3 C = O), 1.82 (m, 1H, CHCH (Me) and _{CH (Me) 2), 0.97} (d, 3H, CH 3) and 0.95 (d , 3H, CH _3).
[950] (S) -acetoxymethyl-4-methyl-pentanoic acid 174 and (S) -4-isopropyl-dihydrofuran-
[951] The acetate 173 (15 g, 68.18 mmol) was dissolved in CH ₃ CN (150 mL), carbon tetrachloride (150 mL) and HPLC grade water (300 mL) and stirred. And sodium oxoate (262.50 g, 1220 mmol) followed by ruthenium chloride (650 mg, 3.136 mmol). After stirring overnight, the mixture was diluted with ether and water and filtered through a pad of celite. The organic layer was separated and the aqueous layer was further extracted with ether. After drying over magnesium sulphate, the solvent was evaporated. Potassium carbonate (42 g) was added to the residue and refluxed in methanol (250 mL) overnight and then cooled to room temperature. After evaporation, water was added to dissolve the solid, and the pH was adjusted to 2 by the addition of concentrated hydrochloric acid. Chloroform was added and extracted overnight. The organic layer was separated, and the aqueous layer was further extracted with chloroform. The combined organic extracts were dried and evaporated, and the product was purified on a silica gel column and the compound was eluted with 20% ether in methylene chloride. Fractions were monitored by TLC and points were detected with I ₂ / KI solution. The fractions were pooled to give 4.6 g of lactone 175. NMR (CDCl ₃₎ δ4. _{38 (dd, 1H, CH a} H b O), 3.93 ( approximate _{t, 1H, CH a H b} O), 2.54 (dd, 1H, CH C H d C = O), 2.23 (m, 2H, CHCH ( Me) and _{CH C H d C = O)} , 1.60 (m, 1H, CH (Me) 2), 0.92 (d, 3H, CH 3) and _{0.85 (d, 3H, CH 3} ).
[952] (3R, 4R) -3-Benzyl-4-isopropyl-dihydro- furan-2-one 176
[953] Lithium bis (trimethylsilyl) amide (1.0 M solution in THF, 92 mL, 92 mmol) was added at -78 <0> C under argon to a solution of (S) Was added to a solution of lactone 175 (11.68 g, 91.25 mmol) for 3-5 minutes. The mixture was stirred for 1 hour and a solution of benzyl iodide (21.87 g, 100.37 mmol) in anhydrous THF was added rapidly. Stirring was continued for 1.5 h, brine solution was added followed by ethyl acetate and quenched at -78 &lt; 0 &gt; C. The organic layer was separated, and the aqueous layer was further extracted with ether. Purified by chromatography on silica gel eluting with 5% methylene chloride in mineral oil ether and finally by chromatography on silica gel eluting with 10% ether in mineral oil ether to give the desired compound (11.6 g, 58%) Respectively. _{NMR (CDCl 3) δ7.19 (m} , 5H, C 6 H 5), 4.02 ( approximate _{t, 1H, CH a H b} O), 3.87 (dd, 1H, CH a H b O), 2.98 (d, _{2H, ArCH 2), 2.57 (} q, 1H, BnCHC = O), 2.05 (m, 1H, CHCH (Me) 2), 1.55 (m, 1H, CH (Me) 2), 0.81 (d, 3H, CH ₃₎ and _{0.72 (d, 3H, CH 3} ).
[954] (2R, 3R) -2-Benzyl-3-bromomethyl-4-methyl-pentanoic acid ethyl ester 177
[955] Lactone 176 (6.5 g, 29.8 mmol) was dissolved in anhydrous ethanol (80 mL) and cooled in an ice bath. Anhydrous HBr was bubbled through the solution for 1 hour and stirred overnight at room temperature while maintaining the reaction under a dry atmosphere. This solution was poured into an ice-cold mixture of mineral oil ether and brine. The organic layer was separated and the aqueous layer was further extracted with mineral oil ether. The collected organic solution was repeatedly washed with cold water and dried. The solvent was removed in vacuo to give 7.0 g of crude compound. _{NMR (CDCl 3) δ7.27 (m} , 5H, C 6 H 5), 4.02 (m, 2H, CH 3 CH 2 0), 3.70 (dd, 1H, CH a H b Br), 3.55 (dd, 1H _{, CH a H b Br),} 2.97 (m, 2H, ArCH 2), 2.83 (q, 1H, BnCHC = O), 2.11 (m, 1H, CHCH (Me) 2), 1.97 (m, 1H, CH ( _{Me) 2), 1.10 (t} , 3H, CH 3 CH 2 0), 0.96 (d, 3H, CH 3) and _{0.93 (d, 3H, CH 3} ).
[956] (2R, 3R) -2-Benzyl-3,4-dimethyl-pentanoic acid ethyl ester 178
[957] The bromo ester 177 (7.25 g, about 80% purity) in ethanol (100 mL) containing triethylamine (3.2 mL) was hydrogenated overnight in the presence of 20% Pd / C (1.0 g). The solution was filtered through a pad of celite and the cake was washed with ethanol. Here solids and evaporation of the solvent, dissolve the residue in ether (Et ₃ N. HCl) is separated. The solid was filtered off. The filtrate was concentrated and this process was repeated to remove all hydrochloride. The product was purified by chromatography on a silica gel column eluting with mineral oil ether to give 3.35 g of the target des brominated compound. _{NMR (CDCl 3) δ7.21 (m} , 5H, C 6 H 5), 3.95 (m, 2H, CH 3 CH 2 0), 2.85 (m, 2H, ArCH 2), 2.64 (q, 1H, BnCHC = O), 1.85 (m, 1H , CHCH (Me) 2), 1.62 (m, 1H, CH (Me) 2), 1.05 (t, 3H, CH 3 CH 2 0), 0.95 (d, 3H, CH 3 ) 0.84 (d, 3H, CH 3) and _{0.82 (d, 3H, CH 3} ). The _{MS 290 (M + CH 3 CN} ), 249 (M + 1), and passed lactone from the previous step by further elution with other 203. ether (2.25 g) was obtained.
[958] Acetic acid (2R, 3R) -2-Benzyl-3,4-dimethyl-pentyl-ester 179
[959] The ethyl ester 178 (3.20 g, 12.85 mmol) was dissolved in absolute ether and cooled in an inert atmosphere in an inert atmosphere. Lithium aluminum hydride (500 mg, 13.15 mmol) was added and the suspension was stirred overnight at room temperature. This reaction was carefully added with ethyl acetate while stirring in an ice bath to destroy excess LAH. Saturated sodium sulfate was carefully added to solidify the alumina separated into white precipitate at room temperature. The reaction mixture was diluted with methylene chloride and anhydrous sodium sulfate was added to the dried mixture. After filtration, the solution was concentrated to give 3.0 g of an oil.
[960] This material (3.0 g) was dissolved in dichloromethane (30 mL) and triethylamine (2.5 mL), DMAP (200 mg) and acetic anhydride (1.5 mL) were added. The solution was stirred at room temperature for 3 hours and diluted with ether. The ether solution was washed with waster, 1N HCl, saturated sodium bicarbonate and brine and dried. The solution was concentrated in vacuo to give 3.16 g of the acetoxy compound 179. _{NMR (CDCl 3) δ7.19 (m} , 5H, C 6 H 5), 4.03 (m, 2H, CH 3 CH 2 0), 2.69 (m, 2H, ArCH 2), 2.09 (m, 1H, BnCHCH 2 0), 2.02 (s, 3H , CH 3 C = O), 1.68 (m, 1H, CH 3 CHCH (Me) 2), 1.23 (m, 1H, CH (Me) 2), 0.87 (d, 3H, CH ₃ ), 0.84 (d, 3H, CH ₃ ) and 0.81 (d, 3H, CH ₃ ).
[961] (R) -4 - ((R) -l, 2-Dimethyl-propyl) -dihydro-furan-
[962] And an aromatic compound in the oxo-acid sodium (86.24 g, 403.32 mmol, 20 eq) followed by _{RuCl 3 (414 mg, 10 mol} %) with HPLC grade acetonitrile (60 mL), carbon tetrachloride (60 mL) and water (120 mL) to 179 &lt; / RTI &gt; (5.0 g, 20.16 mmol). The mixture was stirred thoroughly overnight at room temperature and diluted with methylene chloride (400 mL). The mixture was filtered through a pad of celite to remove the solid precipitate. The organic layer was separated, and the aqueous layer was further extracted with methylene chloride. The combined organic layers were concentrated and the residue was dissolved in ether and added to a Florisil column. The compound was eluted with 3% methanol in ether and evaporated to give a paste which was dissolved in methanol (100 mL). Potassium carbonate (8.0 g) was added and the mixture was refluxed for 6 hours. The solvent was evaporated and the solid residue was dissolved in water. The pH was adjusted to 2 by carefully adding concentrated hydrochloric acid while cooling in an ice-water bath and stirring. Chloroform (200 mL) was added to the solution and stirred overnight at room temperature. The organic layer was separated, and the aqueous layer was further extracted with chloroform. After drying, the solvent was evaporated to obtain 5.0 g of lactone 180. NMR (CDCl ₃₎ δ4.36 (approximate _{t, 1H, CH a H b} O), 3.85 ( approximate _{t, 1H, CH a H b} O), 2.46 (m, 2H, CH C H d C = O), _{2.13 (m, 2H, CHCH 2} C = O), 1.60 (m, 1H, CH (Me) 2), 1.35 (m, 1H, CH 3 CHCH (Me) 2), 0.86 (d, 3H, CH 3) and _{0.72 (t, 3H, CH 3} ).
[963] (3R, 4R) -3-Bromomethyl-4,5-dimethyl-hexanoic acid ethyl ester 181
[964] Lactone 180 (5.0 g) was dissolved in anhydrous ethanol (25 mL) and filled with argon. Anhydrous HBr gas was bubbled through the mixture for 45 minutes while cooling in an ice bath and placed at room temperature overnight. The mixture was poured into ice-salt water and hexane. The organic layer was separated, and the aqueous layer was further extracted with hexane. The combined organic extracts were dried and evaporated. Flash chromatography on silica gel column eluting with 10% ether in mineral oil ether gave 3.54 g of the bromo ester 181. _{NMR (CDCl 3) δ4.14 (q} , 2H, CH 3 H 2 0), 3.60 (dd, 1H, CH a H b Br), 3.41 (dd, 1H, CH C H b Br), 2.54 (dd, _{1H, CH a H b C =} O), 2.44 (dd, 1H, CH a H b C = O), 2.22 (m, 1H, O = CCH 2 CHCH 2 Br), 1.67 (m, 1H, CHCH 3 CH _{(Me) 2, 1.37 (m} , 1H, CH (Me) 2), 1.26 (t, 3H, CH 3 CH 2 0), 0.94 (d, 3H, CHCH 3 CH (Me) 2), 0.81 (d, _{3H, ((CH 3) 2} ) CHCH 3 CH) and 0.79 (d, 3H, (( CH 3) 2) CHCH 3 CH).
[965] (3R, 4R) -3-Amidinomethyl-4,5-dimethyl-hexanoic acid ethyl ester 182 and (3R, 4R)
[966] The bromo ester 181 (3.54 g, 13.34 mmol) and sodium azide (1.04 g, 16.13 mmol) in anhydrous DMF (8.0 mL) was stirred overnight at room temperature. Water (16 mL) and hexane were added, the organic layer was separated, and the aqueous layer was further extracted with hexane. Dried and evaporated to give 3.0 g of the azido ester. _{NMR (CDCl 3) δ4.14 (q} , 2H, CH 3 H 2 0), 3.48 (dd, 1H, CH a H b N 3), 3.21 (dd, 1H, CH C H b N 3), 2.34 ( _{m, 2H, CH a H b} C = O), 2.20 (m, 1H, O = CCH 2 CHCH 2 N 3), 1.60 (m, 1H, CHCH 3 CH (Me) was hydrogenated for ₂ compound (HPL, The crude was dissolved in 6N HCl and refluxed overnight. The solvent was evaporated in vacuo and the residue azeotroped with toluene. The crude was loaded onto ion exchange column chromatography (Dowex 50Wb x 8-100) after washing with HPLC grade water to zero neutral elution was eluted the compound in 0.5N NH ₄ 0H solution. to give the 720 mg of the product was crystallized from _{methanol. NMR (CD 3 0D) δ3.04} (dd, 1 H _{, CH a H b NH 2)} , 2.82 (dd, 1H, CHCH b NH 2), 2.52 (dd, 1H, CH a H b C = O), 2.40 (dd, 1H, CH a H b C = O) , 2.07 (m, 1H, O = CCH 2 CHCH 2 NH 2), 1.67 (m, 1H, CHCH 3 CH (Me) 2), 1.35 (m, 1H, CH (Me) 2), 0.97 (d, 3H , CHCH ₃ CH (Me) ₂ ), 0.88 (d, 3H, ((CH ₃ ) ₂ CHCH ₃ CH) and 0.83 (CH ₃ ) ₂ ) CHCH ₃ CH ₂ ) [ ] _D -5.3 (c, MeOH, 1.9 mg / mL) Calcd for C ₉ H ₁₉ NO ₂ : C 62.39, H 11.05, N 8.08. , H 11.35 and N 7.88 MS results, ions appear at 215 (M + CH ₃ CN), 197 (M + Na ⁺ ) and 174 (M + H ⁺ ). Reversed phase HPLC (Hypersil BDS C ₁₈ 5 micron and mobile phase 50/50 CH ₃ CN- obtain a purity of 99.93% at a retention time of 8.21 minutes from the derivatives analyzed by water containing 0.1% TFA).
[967] Examples 18-20: Synthesis of 3-aminomethyl-4-isopropyl-heptanoic acid
[968]
[969] 2-Cyano-4-methyl-2-pentenoic acid methyl ester 61
[970] A solution of isobutyraldehyde (30.0 g, 416 mmol), methyl-cyano-acetate (20.6 g, 208 mmol), ammonium hydroxide (3.2 g, 41.6 mmol) and acetic acid (5.0 g, 83.2 mmol) in 500 mL of toluene Was heated to reflux under a Dean-Stark trap for 12 hours. The mixture was cooled to room temperature and extracted with saturated NaHSO ₃ (3 x 100 mL), saturated NaHCO ₃ (3 x 100 mL) and brine 100 mL. The organic layer was dried over sodium sulfate and the solvent was evaporated. The remaining oil was distilled under high vacuum (0.5 mm Hg, BP = 115-120 ° C) to give 28.8 g of 2-cyano-4-methyl-2-pentenoic acid methyl ester 61 as an oil (90% yield).
[971] 2-Cyano-3-isopropyl-hexanoic acid methyl ester 183
[972] A 2.0M solution of propylmagnesium chloride in Et ₂ O (9.8 mL, 19.6 mmol) was added to a solution of 2-cyano-4-methyl-2-pentanoic acid in 50 mL of THF cooled to -40 ° C in an IPA / 3.0 g, 19.6 mmol). This solution and the reaction was quenched by stirring and the addition of saturated KH ₂ PO ₄ 50 mL for 4 h. The THF was evaporated and the remaining oil was purified by chromatography on silica gel eluting with 50% CH ₂ Cl ₂ / hexane under medium pressure. 1.9 g (50% yield) of 2-cyano-3-isopropyl-hexanoic acid methyl ester as an oil were obtained.
[973] 2-Cyano-2- (1-isopropyl-butyl) -succinic acid 4-tert-butyl ester 1-methyl ester 184
[974] A solution of 2-cyano-3-isopropyl-hexanoic acid methyl ester (1.9 g, 9.6 mmol) in 10 mL of THF was added NaH (washed with hexane, 0.23 g, 9.6 mmol) in 20 mL of THF cooled in an ice- ) Slurry. The solution was stirred for 10 min and t-butyl bromoacetate (2.1 g, 10.6 mmol) was added. The solution was allowed to warm to room temperature. After 12 hours, the reaction was quenched by the addition of saturated KH ₂ PO ₄ 50 mL, THF was evaporated. The organic product was extracted with Et ₂ O (3 x 50 mL) and the combined organic layers were dried over MgSO ₄ . The solvent was evaporated and the remaining oil was purified with 25% hexane / CH ₂ Cl ₂ on silica gel chromatography eluting with a medium under pressure. 1.3 g (yield 42%) of 2-cyano-2- (1-isopropyl-butyl) -succinic acid 4-tert-butyl ester 1-methyl ester as an oil were obtained.
[975] 3-Cyano-4-isopropyl-heptanoic acid t-butyl ester 185
[976] Butyl ester 1-methyl ester (1.3 g, 4.2 mmol), NaCl (0.25 g, 4.2 mmol) and H ₂ 0 (0.15 g, 8.3 mmol) was heated to 130 &lt; 0 &gt; C for 12 h. The mixture was cooled to room temperature and diluted with 100 mL of brine. The organic product was extracted with _{Et 2 O (3 x 50 mL} ). The organic layer was collected and washed with 50 mL of H ₂ O and 50 mL of brine. Drying over sodium sulfate and evaporation of the solvent gave 0.8 g (75% yield) of 3-cyano-4-isopropylheptanoic acid t-butyl ester as an oil.
[977] 4- (l-isopropyl-butyl) -2-pyrrolidone 186
[978] 3-Cyano-4-isopropyl-heptanoic acid t-butyl ester (0.8 g, 3.2 mmol) was reduced to 50 psi H ₂ in MeOH containing TEA and Ra 2 Ni. When the theoretical amount of H ₂ had dissolved, the catalyst was removed by filtration and the solvent was evaporated to give 0.6 g (100% yield) of 4- (1-isopropyl-butyl) -2-pyrrolidone as an oil .
[979] 3-Aminomethyl-4-isopropyl-heptanoic acid (Example 18)
[980] 4- (l-Isopropyl-butyl) -2-pyrrolidone (0.6 g, 2.3 mmol) was heated to reflux in 50 mL of 6.0 M HCl for 12 h. The solution was cooled to room temperature and filtered through celite. The filtrate was evaporated and the remaining solid was recrystallized from MeOH / EtOAc. 0.035 g (6% yield) of 3-aminomethyl-4-isopropyl-heptanoic acid as hydrochloride was obtained. Melting point 160-170 占 폚. _{^{1 H NMR (CD 3 0D)}} δ0.9 (m, 9H), 1.30 (m, 5H), 1.78 (m, 1H), 2.30 (m, 2H), 2.45 (m, 1H), 2.95 (m, 2H ). _{MS (APCI, CH 3 CN,} H 2 0) 201 (M +, 100%).
[981] 3-Aminomethyl-4-isopropyl-octanoic acid (Example 19)
[982] 0.13 g (15%) of 3-aminomethyl-4-isopropyl-octanoic acid was prepared according to the method of Example 18. Melting point = 160-170 占 폚. _{^{1 H NMR (CD 3 0D)}} δ0.9 (m, 9H), 1.30 (m, 7H), 1.78 (m, 1H), 2.30 (m, 1H), 2.45 (m, 2H), 2.95 (m, 2H ). _{MS (APCI, CH 3 CN,} H 2 0) 198 (M-17,100%), 216 (M +, 50%).
[983] 3-Aminomethyl-4-isopropyl-hexanoic acid (Example 20)
[984] 0.11 g (42%) of 3-aminomethyl-4-isopropyl-hexanoic acid was prepared according to the method of Example 18. Melting point = 170-180 占 폚. _{^{1 H NMR (CD 3 0D)}} δ0.9 (m, 9H), 1.18 (m, 1H), 1.39 (m, 3H), 1.78 (m, 1H), 2.30 (m, 1H), 2.45 (m, 1H ), 2.95 (m, 2H). _{MS (APCI, CH 3 CN,} H 2 0) 188 (M +, 100%).
[985] Example 21
[986]
[987] (i) MeO ₂ CCH = PPh ₃ , THF, 40 ° C; (ii) MeNO _2, DBU; (iii) Raney Nickel, H _2, MeOH; (iv) Pd-C, MeOH , H 2; (v) 6N HCl
[988] Synthesis of unsaturated ester 188
[989] (S) - (-) - Citronellal 187 (2.0 mL, 11.03 mmol) was added to anhydrous tetrahydrofuran (30 mL) containing methyltriphenylphosphoranylidene acetate (3.69 g, 11.03 mmol) Lt; / RTI &gt; After 8 hours, the mixture was cooled to room temperature and stirred overnight. The solvent was removed in vacuo and the residue was stirred with n-pentane (50 mL). After 1 hour the solid was filtered off and the solvent removed in vacuo to give an oil which was purified by flash chromatography (silica, ethyl acetate: heptane 1: 9) to give 2.05 g (88% ) Of 188 was obtained. ¹ H NMR (400 MHz) (CDCl ₃ ) 0.90 (3H, d, J = 6 Hz); 1.12-1.40 (2H, m); 1.60 (3 H, s); 1.62 (1 H, m); 1.68 (3H, s); 2.01 (3 H, m); 2.21 (1 H, m); 3.73 (3 H, s); 5.08 (1 H, m); 5.82 (1H, doublet, J = 16 Hz); 6.94 (1 H, m). MS (CI ⁺ ) (m / z): 211 (MH ⁺ , 75%), 179 (78%), 151 (100%). IR (thin film) (cm ^-1 ) : 1271, 1436, 1728, 2917.
[990] Synthesis of nitro ester 189
[991] Ester 188 (2.02 g, 9.6 mmol) was dissolved in nitromethane (25 mL) containing 1,8-diazacyclo [5,4,0] undec-7-ene (1.44 mL, 9.6 mmol) Lt; / RTI &gt; After 23 hours, the mixture was diluted with diethyl ether (150 mL), washed with water (50 mL) and then with 2 N HCl (50 mL). The organic layer was collected, dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica, ethyl acetate: heptane 3: 7) to give 2.26 g (87%) of 189 as a clear oil. This compound and all subsequent compounds were confirmed to be an equimolar mixture of two diastereoisomers. ¹ H NMR (400 MHz) (CDCl ₃ ) 0.90 (2 x 3H, each d, J = 6 Hz); 1.09-1.58 (1 H, m); 1.602 (6 H, s); 1.685 (6 H, s); 1.94 (4 H, m); 2.42 (4 H, m); 2.66 (2 H, m); 3.70 (6H, s); 4.42 (4 H, m); 5.07 (2 H, m). MS (CI ⁺ ) (m / z): 272 (MH ⁺ , 90%), 240 (100%), 151 (100%). IR (laminate ^{film) (cm -l) ν: 1554} , 1739, 2918.
[992] Synthesis of lactam 191
[993] The nitro ester 189 (2.09 g, 7.7 mmol) was dissolved in methanol (75 mL) and shaken on Raney nickel (catalyst, prewashed with methanol followed by methanol) at 39 [deg.] C under hydrogen gas atmosphere (39 psi). After 17 h, the mixture was filtered through celite. The solvent was removed in vacuo to give an oil. ¹ H NMR showed that there was a partial reduction of the double bond, so it was continued to be used without further purification. A sample of this partially reduced product (440 mg, 2.1 mmol) was dissolved in methanol (40 mL) and shaken on 5% Pd-C under hydrogen gas atmosphere. After 18 hours, the catalyst was removed by filtration through Celite to give 442 mg (99% from partially reduced material) as a clear oil which was not further purified. This compound and all subsequent compounds were confirmed to be an equimolar mixture of two diastereoisomers. ¹ H NMR (400 MHz) (CDCl ₃ ) : 0.88 (18H, m); 1.04-1.58 (20 H, m); 1.96 (2H, m); 2.40 (2 H, m); 2.58 (2 H, m); 2.98 (2 H, m); 3.45 (2H, m), 5.82 (2H, broad). MS (CI ⁺ ) (m / z): 212 (MH ^&lt; ⁺ & gt ^; , 100%).
[994] Synthesis of Example 21
[995] Lactam 191 (428 mg, 2.0 mmol) was heated to reflux in 6N HCl (20 mL). After 5 h, the mixture was cooled to room temperature and washed with dichloromethane (2 x 10 mL). The aqueous layer was collected and the solvent was removed in vacuo. The residue was dissolved in water (10 mL) and lyophilized to give 382 mg (71%) of Example 34 as a white solid. This compound was confirmed to be an equimolar mixture of two diastereoisomers. ^{1 H NMR (400 MHz) (} d 6 -DMSO) δ0.82 (18H, m); 0.95-1.55 (20 H, m); 2.05-2.45 (6 H, m); 2.75 (4 H, m); 7.98 (6 H, br s).
[996] MS (CI ⁺ ) (m / z): 230 ([MH-HCl] ⁺ , 90%), 212 (100%).
[997] Calcd for _{C 13 H 28 NO 2 Cl:} : Microanalysis C 58.74; H 10.62; N 5.27. Found: C 58.46; H 10.50; N 5.33.
[998] One of ordinary skill in the art will be able to obtain the opposite C5-stereochemical compound of Example 21 using (R) - (+) - citronellal.

权利要求:
Claims (25)
[1" claim-type="Currently amended] Claims 1. Compounds of the general formula &lt; RTI ID = 0.0 &gt; I &lt; / RTI &gt;
(I)

In this formula,
R &lt; ¹ &gt; is hydrogen, straight or branched chain alkyl of 1 to 6 carbon atoms, or phenyl;
R ² is selected from the group consisting of straight or branched chain alkyl having 1 to 8 carbon atoms, straight or branched alkenyl having 2 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, alkoxy having 1 to 6 carbon atoms, alkyl Cycloalkyl, alkylalkoxy, alkyl OH, alkylphenyl, alkylphenoxy, phenyl or substituted phenyl;
R ¹ is methyl if R ² is a 1 to 6 carbon atoms straight or branched chain alkyl or phenyl.
[2" claim-type="Currently amended] 2. The compound of claim 1 wherein R &lt; ¹ &gt; is hydrogen and R &lt; ² &gt; is alkyl.
[3" claim-type="Currently amended] 2. The compound of claim 1 wherein R &lt; ¹ &gt; is methyl and R &lt; ² &gt; is alkyl.
[4" claim-type="Currently amended] 2. The compound according to claim 1, wherein R &lt; ¹ &gt; is methyl and R &lt; ² &gt; is methyl or ethyl.
[5" claim-type="Currently amended] The method according to claim 1,
3-Aminomethyl-5-methyl-heptanoic acid;
3-Aminomethyl-5-methyl-octanoic acid;
3-Aminomethyl-5-methyl-nonanoic acid;
3-Aminomethyl-5-methyl-decanoic acid;
3-Aminomethyl-5-methyl-undecanoic acid;
3-Aminomethyl-5-methyl-dodecanoic acid;
3-Aminomethyl-5-methyl-tridecanoic acid;
3-Aminomethyl-5-cyclopropyl-hexanoic acid;
3-Aminomethyl-5-cyclobutyl-hexanoic acid;
3-Aminomethyl-5-cyclopentyl-hexanoic acid;
3-Aminomethyl-5-cyclohexyl-hexanoic acid;
3-Aminomethyl-5-trifluoromethyl-hexanoic acid;
3-Aminomethyl-5-phenyl-hexanoic acid;
3-Aminomethyl-5- (2-chlorophenyl) -hexanoic acid;
3-Aminomethyl-5- (3-chlorophenyl) -hexanoic acid;
3-Aminomethyl-5- (4-chlorophenyl) -hexanoic acid;
3-Aminomethyl-5- (2-methoxyphenyl) -hexanoic acid;
3-Aminomethyl-5- (3-methoxyphenyl) -hexanoic acid;
3-Aminomethyl-5- (4-methoxyphenyl) -hexanoic acid; And
3-Aminomethyl-5- (phenylmethyl) -hexanoic acid
&Lt; / RTI &gt;
[6" claim-type="Currently amended] The method according to claim 1,
(3R, 4S) 3-Aminomethyl-4,5-dimethyl-hexanoic acid;
3-Aminomethyl-4,5-dimethyl-hexanoic acid;
(3R, 4S) 3-Aminomethyl-4,5-dimethyl-hexanoic acid MP;
(3S, 4S) 3-Aminomethyl-4,5-dimethyl-hexanoic acid;
(3R, 4R) 3-Aminomethyl-4,5-dimethyl-hexanoic acid MP;
3-Aminomethyl-4-isopropyl-hexanoic acid;
3-Aminomethyl-4-isopropyl-heptanoic acid;
3-Aminomethyl-4-isopropyl-octanoic acid;
3-Aminomethyl-4-isopropyl-nonanoic acid;
3-Aminomethyl-4-isopropyl-decanoic acid; And
3-Aminomethyl-4-phenyl-5-methyl-hexanoic acid
&Lt; / RTI &gt;
[7" claim-type="Currently amended] 3. The compound of claim 1 selected from (3S, 5R) -3-aminomethyl-5-methyl-heptanoic acid.
[8" claim-type="Currently amended] 4. The compound of claim 1 selected from (3S, 5R) -3-aminomethyl-5-methyl-octanoic acid.
[9" claim-type="Currently amended] 3. The compound of claim 1 selected from (3S, 5R) -3-aminomethyl-5-methyl-nonanoic acid.
[10" claim-type="Currently amended] 3. The compound of claim 1 selected from (3S, 5R) -3-aminomethyl-5-methyl-decanoic acid.
[11" claim-type="Currently amended] 3. The compound of claim 1 selected from (3S, 5R) -3-aminomethyl-5-methyl-undecanoic acid.
[12" claim-type="Currently amended] 3. The compound of claim 1 selected from (3S, 5R) -3-aminomethyl-5-methyl-dodecanoic acid.
[13" claim-type="Currently amended] The method according to claim 1,
(3S, 5R) -3-Aminomethyl-5,9-dimethyl-decanoic acid;
(3S, 5R) -3-Aminomethyl-5-methyl-heptanoic acid;
(3S, 5R) -3-Aminomethyl-5,7-dimethyl-octanoic acid;
(3S, 5R) -3-Aminomethyl-5,10-dimethyl-undecanoic acid;
(3S, 5R) -3-Aminomethyl-5,8-dimethyl-nonanoic acid;
(3S, 5R) -3-Aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;
(3S, 5R) -3-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;
(3S, 5R) -3-Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;
(3S, 5R) -3-Aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;
(3S, 5R) -3-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;
(3S, 5R) -3-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;
(3S, 5R) -3-Aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;
(3S, 5R) -3-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;
(3S, SR) -3-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;
(3S, 5R) -3-Aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;
(3S, 5R) -3-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;
(3S, 5R) -3-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;
(3S, 5S) -3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-7-fluoro-5-methyl-heptanoic acid;
(3S, 5R) -3-Aminomethyl-8-fluoro-5-methyl-octanoic acid;
(3S, 5R) -3-Aminomethyl-9-fluoro-5-methyl-nonanoic acid;
(3S, 5S) -3-Aminomethyl-7,7,7-trifluoro-5-methyl-heptanoic acid; And
(3S, 5S) -3-Aminomethyl-8,8,8-trifluoro-5-methyl-octanoic acid
&Lt; / RTI &gt;
[14" claim-type="Currently amended] The method according to claim 1,
(3S, 5S) -3-Aminomethyl-5-methoxy-hexanoic acid;
(3S, 5S) -3-Aminomethyl-8-hydroxy-5-methyl-octanoic acid;
(3S, 5S) -3-Aminomethyl-5-ethoxy-hexanoic acid;
(3S, 5S) -3-Aminomethyl-5-propoxy-hexanoic acid;
(3S, 5S) -3-Aminomethyl-5-isopropoxy-hexanoic acid;
(3S, 5S) -3-Aminomethyl-5-tert-butoxy-hexanoic acid;
(3S, 5S) -3-Aminomethyl-5-fluoromethoxy-hexanoic acid;
(3S, 5S) -3-Aminomethyl-5- (2-fluoro-ethoxy) -hexanoic acid;
(3S, 5S) -3-Aminomethyl-5- (3,3,3-trifluoro-propoxy) -hexanoic acid;
(3S, 5S) -3-Aminomethyl-5-phenoxy-hexanoic acid;
(3S, 5S) -3-Aminomethyl-5- (4-chloro-phenoxy) -hexanoic acid;
(3S, 5S) -3-Aminomethyl-5- (3-chloro-phenoxy) -hexanoic acid;
(3S, 5S) -3-Aminomethyl-5- (2-chloro-phenoxy) -hexanoic acid;
(3S, 5S) -3-Aminomethyl-5- (4-fluoro-phenoxy) -hexanoic acid;
(3S, 5S) -3-Aminomethyl-5- (3-fluoro-phenoxy) -hexanoic acid;
(3S, 5S) -3-Aminomethyl-5- (2-fluoro-phenoxy) -hexanoic acid;
(3S, 5S) -3-Aminomethyl-5- (4-methoxy-phenoxy) -hexanoic acid;
(3S, 5S) -3-Aminomethyl-5- (3-methoxy-phenoxy) -hexanoic acid;
(3S, 5S) -3-Aminomethyl-5- (2-methoxy-phenoxy) -hexanoic acid;
(3S, 5S) -3-Aminomethyl-5- (4-nitro-phenoxy) -hexanoic acid;
(3S, 5S) -3-Aminomethyl-5- (3-nitro-phenoxy) -hexanoic acid;
(3S, 5S) -3-Aminomethyl-5- (2-nitro-phenoxy) -hexanoic acid;
(3S, 5S) -3-Aminomethyl-6-hydroxy-5-methyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-6-methoxy-5-methyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-6-ethoxy-5-methyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-5-methyl-6-propoxy-hexanoic acid;
(3S, 5S) -3-Aminomethyl-6-isopropoxy-5-methyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-6-tert-butoxy-5-methyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-6-fluoromethoxy-5-methyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-6- (2-fluoro-ethoxy) -5-methyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-5-methyl-6- (3,3,3-trifluoro-propoxy) -hexanoic acid;
(3S, 5S) -3-Aminomethyl-5-methyl-6-phenoxy-hexanoic acid;
(3S, 5S) -3-Aminomethyl-6- (4-chloro-phenoxy) -5-methyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-6- (3-chloro-phenoxy) -5-methyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-6- (2-chloro-phenoxy) -5-methyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-6- (4-fluoro-phenoxy) -5-methyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-6- (3-fluoro-phenoxy) -5-methyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-6- (2-fluoro-phenoxy) -5-methyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-6- (4-methoxy-phenoxy) -5-methyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-6- (3-methoxy-phenoxy) -5-methyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-6- (2-methoxy-phenoxy) -5-methyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-5-methyl 6- (4-trifluoromethyl-phenoxy) -hexanoic acid;
(3S, 5S) -3-Aminomethyl-5-methyl 6- (3-trifluoromethyl-phenoxy) -hexanoic acid;
(3S, 5S) -3-Aminomethyl-5-methyl 6- (2-trifluoromethyl-phenoxy) -hexanoic acid;
(3S, 5S) -3-Aminomethyl-5-methyl 6- (4-nitro-phenoxy) -hexanoic acid;
(3S, 5S) -3-Aminomethyl-5-methyl 6- (3-nitro-phenoxy) -hexanoic acid;
(3S, 5S) -3-Aminomethyl-5-methyl 6- (2-nitro-phenoxy) -hexanoic acid;
(3S, 5S) -3-Aminomethyl-6-benzyloxy-5-methyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-7-hydroxy-5-methyl-heptanoic acid;
(3S, 5S) -3-Aminomethyl-7-methoxy-5-methyl-heptanoic acid;
(3S, 5S) -3-Aminomethyl-7-ethoxy-5-methyl-heptanoic acid;
(3S, 5S) -3-Aminomethyl-5-methyl-7-propoxy-heptanoic acid;
(3S, 5S) -3-Aminomethyl-7-isopropoxy-5-methyl-heptanoic acid;
(3S, 5S) -3-Aminomethyl-7-tert-butoxy-5-methyl-heptanoic acid;
(3S, 5S) -3-Aminomethyl-7-fluoromethoxy-5-methyl-heptanoic acid;
(3S, 5S) -3-Aminomethyl-7- (2-fluoro-ethoxy) -5-methyl-heptanoic acid;
(3S, 5S) -3-Aminomethyl-5-methyl-7- (3,3,3-trifluoro-propoxy) -heptanoic acid;
(3S, 5S) -3-Aminomethyl-7-benzyloxy-5-methyl-heptanoic acid;
(3S, 5S) -3-Aminomethyl-5-methyl-7-phenoxy-heptanoic acid;
(3S, 5S) -3-Aminomethyl-7- (4-chloro-phenoxy) -5-methyl-heptanoic acid;
(3S, 5S) -3-Aminomethyl-7- (3-chloro-phenoxy) -5-methyl-heptanoic acid;
(3S, 5S) -3-Aminomethyl-7- (2-chloro-phenoxy) -5-methyl-heptanoic acid;
(3S, 5S) -3-Aminomethyl-7- (4-fluoro-phenoxy) -5-methyl-heptanoic acid;
(3S, 5S) -3-Aminomethyl-7- (3-fluoro-phenoxy) -5-methyl-heptanoic acid;
(3S, 5S) -3-Aminomethyl-7- (2-fluoro-phenoxy) -5-methyl-heptanoic acid;
(3S, 5S) -3-Aminomethyl-7- (4-methoxy-phenoxy) -5-methyl-heptanoic acid;
(3S, 5S) -3-Aminomethyl-7- (3-methoxy-phenoxy) -5-methyl-heptanoic acid;
(3S, 5S) -3-Aminomethyl-7- (2-methoxy-phenoxy) -5-methyl-heptanoic acid;
(3S, 5S) -3-Aminomethyl-5-methyl-7- (4-trifluoromethyl-phenoxy) -heptanoic acid;
(3S, 5S) -3-Aminomethyl-5-methyl-7- (3-trifluoromethyl-phenoxy) -heptanoic acid;
(3S, 5S) -3-Aminomethyl-5-methyl-7- (2-trifluoromethyl-phenoxy) heptanoic acid;
(3S, 5S) -3-Aminomethyl-5-methyl-7- (4-nitro-phenoxy) -heptanoic acid;
(3S, 5S) -3-Aminomethyl-5-methyl-7- (3-nitro-phenoxy) -heptanoic acid;
(3S, 5S) -3-Aminomethyl-5-methyl-7- (2-nitro-phenoxy) -heptanoic acid;
(3S, 5S) -3-Aminomethyl-5-methyl-6-phenyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-6- (4-chloro-phenyl) -5-methyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-6- (3-chloro-phenyl) -5-methyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-6- (2-chloro-phenyl) -5-methyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-6- (4-methoxy-phenyl) -5-methyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-6- (3-methoxy-phenyl) -5-methyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-6- (2-methoxy-phenyl) -5-methyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-6- (4-fluoro-phenyl) -5-methyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-6- (3-fluoro-phenyl) -5-methyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-6- (2-fluoro-phenyl) -5-methyl-hexanoic acid;
(3S, 5R) -3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid;
(3S, 5R) -3-Aminomethyl-7- (4-chloro-phenyl) -5-methyl-heptanoic acid;
(3S, 5R) -3-Aminomethyl-7- (3-chloro-phenyl) -5-methyl-heptanoic acid;
(3S, 5R) -3-Aminomethyl-7- (2-chloro-phenyl) -5-methyl-heptanoic acid;
(3S, 5R) -3-Aminomethyl-7- (4-methoxy-phenyl) -5-methyl-heptanoic acid;
(3S, 5R) -3-Aminomethyl-7- (3-methoxy-phenyl) -5-methyl-heptanoic acid;
(3S, 5R) -3-Aminomethyl-7- (2-methoxy-phenyl) -5-methyl-heptanoic acid;
(3S, 5R) -3-Aminomethyl-7- (4-fluoro-phenyl) -5-methyl-heptanoic acid;
(3S, 5R) -3-Aminomethyl-7- (3-fluoro-phenyl) -5-methyl-heptanoic acid;
(3S, 5R) -3-Aminomethyl-7- (2-fluoro-phenyl) -5-methyl-heptanoic acid;
(3S, 5S) -3-Aminomethyl-5-methyl-hept-6-enoic acid;
(3S, 5R) -3-Aminomethyl-5-methyl-oct-7-enoic acid;
(3S, 5R) -3-Aminomethyl-5-methyl-non-8-enoic acid;
(E) - (3S, 5S) -3-Aminomethyl-5-methyl-oct-6-enoic acid;
(Z) - (3S, 5S) -3-Aminomethyl-5-methyl-oct-6-enoic acid;
(Z) - (3S, 5S) -3-Aminomethyl-5-methyl-non-6-enoic acid;
(E) - (3S, 5S) -3-Aminomethyl-5-methyl-non-6-enoic acid;
(E) - (3S, 5R) -3-Aminomethyl-5-methyl-non-7-enoic acid;
(Z) - (3S, 5R) -3-Aminomethyl-5-methyl-non-7-enoic acid;
(Z) - (3S, 5R) -3-Aminomethyl-5-methyl-de-7-enoic acid;
(E) - (3S, 5R) -3-Aminomethyl-5-methyl-undec-7-enoic acid;
(3S, 5S) -3-Aminomethyl-5,6,6-trimethyl-heptanoic acid;
(3S, 5S) -3-Aminomethyl-5, 6-dimethyl-heptanoic acid;
(3S, 5S) -3-Aminomethyl-5-cyclopropyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-5-cyclobutyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-5-cyclopentyl-hexanoic acid;
(3S, 5S) -3-Aminomethyl-5-cyclohexyl-hexanoic acid
(3S, 5R) -3-Aminomethyl-5-methyl-8-phenyl-octanoic acid;
(3S, 5S) -3-Aminomethyl-5-methyl-6-phenyl-hexanoic acid;
(3S, 5R) -3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid;
(3R, 4R, 5R) -3-Aminomethyl-4,5-dimethyl-heptanoic acid; And
(3R, 4R, 5R) -3-Aminomethyl-4,5-dimethyl-octanoic acid
&Lt; / RTI &gt;
[15" claim-type="Currently amended] A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
[16" claim-type="Currently amended] A method of treating epilepsy comprising administering a therapeutically effective amount of a compound according to claim 1 to a mammal in need thereof.
[17" claim-type="Currently amended] 15. A method for treating ataxia, hypotonia, and cranial disease, comprising administering a therapeutically effective amount of a compound according to claim 1 to a mammal in need of treatment for a disorder of the pituitary, hypokinesia and cranial disease.
[18" claim-type="Currently amended] A method of treating a neurodegenerative disease comprising administering to a mammal in need thereof a therapeutically effective amount of a compound according to claim 1.
[19" claim-type="Currently amended] A method of treating depression comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to claim 1.
[20" claim-type="Currently amended] A method of treating anxiety, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound according to claim 1.
[21" claim-type="Currently amended] A method of treating panic disorder comprising administering a therapeutically effective amount of a compound according to claim 1 to a mammal in need of treatment for panic disorder.
[22" claim-type="Currently amended] A method of treatment of pain comprising administering a therapeutically effective amount of a compound of claim 1 to a mammal in need thereof.
[23" claim-type="Currently amended] A method of treating a neuropathologic disorder comprising administering a therapeutically effective amount of a compound according to claim 1 to a mammal in need of such treatment for a neuropathological disorder.
[24" claim-type="Currently amended] A method of treating a sleep disorder, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to claim 1.
[25" claim-type="Currently amended] A method of treating an IBS and / or gastric lesion comprising administering a therapeutically effective amount of a compound according to claim 1 to a mammal in need of treatment for irritable bowel syndrome (IBS) and / or gastric injuries.

类似技术:

---

公开号 | 公开日 | 专利标题

---

US10259776B2|2019-04-16|Branched 3-phenylpropionic acid derivatives and their use

---

US10478412B2|2019-11-19|GABA conjugates and methods of use thereof

---

RU2553263C2|2015-06-10|Substituted 3-phenylpropionic acids and using them

---

DE60318456T2|2008-12-24|Analogue of omega-3 pufa derived lipid mediators and method of use

---

US5223516A|1993-06-29|3,3,3-trifluoro-2-mercaptomethyl-N-tetrazolyl substituted propanamides and method of using same

---

KR101314277B1|2013-10-02|Diaminoalkane aspartic protease inhibitors

---

US6117906A|2000-09-12|GABA and L-glutamic acid analogs for antiseizure treatment

---

CN1210268C|2005-07-13| alkyl substituted-.gamma.-aminobutyric acid derivatives |, their preparation and their use in the treatment of neurolog disorders

---

CN1131855C|2003-12-24|1-substituted-1-aminomethyl-cycloalkane derivatives |, their preparation and their use in the treatment of neurological disorders

---

EP2406215B1|2014-04-16|Oxo-heterocyclically substituted alkyl carboxylic acids and use thereof

---

JP4673833B2|2011-04-20|Macrocyclic β-secretase inhibitor for the treatment of Alzheimer&#39;s disease

---

JP4494212B2|2010-06-30|Phenylcarboxamide beta-secretase inhibitor for the treatment of Alzheimer&#39;s disease

---

KR100599004B1|2006-07-12|Novel derivatives of 3,3-diphenyl propylamines

---

CN1059436C|2000-12-13|Benzoazepine-Benzooxaazepine-Benzothiaazepine-N-acetate derivant

---

CN1210253C|2005-07-13|Asymmetric synthesis |-|-3-|-5-methylhexanoic

---

US7923575B2|2011-04-12|Asymmetric synthesis of |-|-3-|-5-methylhexanoic acid

---

Barrow et al.1995|Total synthesis of cryptophycins. Revision of the structures of cryptophycins A and C

---

TWI225855B|2005-01-01|Bicyclic amino acids as pharmaceutical agents

---

JP5373405B2|2013-12-18|Selective androgen receptor modulator

---

CA2134674C|2004-12-21|Gaba and l-glutamic acid analogs for antiseizure treatment

---

AU734173B2|2001-06-07|Novel substituted cyclic amino acids as pharmaceutical agents

---

EP1673078B1|2008-05-28|Benzylether and benzylamino beta-secretase inhibitors for the treatment of alzheimer&#39;s disease

---

KR101127390B1|2012-03-23|Compounds for the treatment of metabolic disorders

---

US20030078300A1|2003-04-24|Fused bicyclic or tricyclic amino acids

---

US7749985B2|2010-07-06|Acyloxyalkyl carbamate prodrugs, methods of synthesis and use

同族专利:

---

公开号 | 公开日

---

RS20090257A|2010-03-02|

---

AU776723B2|2004-09-16|

---

NZ515668A|2004-02-27|

---

JP2003502308A|2003-01-21|

---

CA2374755A1|2000-12-21|

---

GEP20074142B|2007-07-10|

---

PL352431A1|2003-08-25|

---

SK287247B6|2010-04-07|

---

BR0011727A|2002-03-05|

---

ZA200109711B|2003-03-20|

---

CU23101A3|2005-12-20|

---

NO327746B1|2009-09-14|

---

CN1310872C|2007-04-18|

---

AU5311900A|2001-01-02|

---

CA2689997A1|2000-12-21|

---

NO20015949D0|2001-12-05|

---

NO20091094L|2001-12-05|

---

SK287399B6|2010-08-09|

---

RS50352B|2009-11-10|

---

PT1192125E|2009-03-05|

---

NO20015949L|2001-12-05|

---

CO5200791A1|2002-09-27|

---

CN1196671C|2005-04-13|

---

JP3904452B2|2007-04-11|

---

CR6529A|2003-11-25|

---

DK1192125T3|2009-02-16|

---

HK1046401A1|2005-12-02|

---

HU0201601A3|2002-11-28|

---

EP1192125B1|2008-12-31|

---

CN1660779A|2005-08-31|

---

EA004398B1|2004-04-29|

---

PE20010285A1|2001-03-22|

---

BG65561B1|2008-12-30|

---

IL146969A|2008-03-20|

---

ES2317839T3|2009-05-01|

---

YU87001A|2004-07-15|

---

BG106292A|2002-05-31|

---

HK1076626A1|2007-11-09|

---

CZ20014285A3|2002-07-17|

---

HK1046401B|2005-12-02|

---

SI1192125T1|2009-04-30|

---

SK17642001A3|2002-10-08|

---

HU0201601A2|2002-10-28|

---

OA11962A|2006-04-17|

---

CY1108827T1|2014-04-09|

---

MA26804A1|2004-12-20|

---

DE60041256D1|2009-02-12|

---

TR200103587T2|2002-04-22|

---

WO2000076958A3|2001-04-12|

---

IS6181A|2001-11-28|

---

AU776723C|2005-06-02|

---

MEP44808A|2011-02-10|

---

CZ300834B6|2009-08-19|

---

MXPA01012319A|2002-07-22|

---

AT419231T|2009-01-15|

---

IL146969D0|2002-08-14|

---

CA2374755C|2010-03-30|

---

AP200202388A0|2002-03-31|

---

HRP20020025A2|2003-12-31|

---

UA72519C2|2005-03-15|

---

DZ3253A1|2000-12-21|

---

EA200101134A1|2002-06-27|

---

EP1192125B9|2009-09-16|

---

CN1355784A|2002-06-26|

---

EE200100672A|2003-02-17|

---

EP1192125A2|2002-04-03|

---

AP1397A|2005-04-19|

---

CZ301608B6|2010-04-28|

---

KR100694735B1|2007-03-14|

---

AR033335A1|2003-12-17|

---

WO2000076958A2|2000-12-21|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

法律状态:
1999-06-10|Priority to US13848599P

---

1999-06-10|Priority to US60/138,485

---

2000-05-31|Application filed by 로즈 암스트롱, 크리스틴 에이. 트러트웨인, 워너-램버트 캄파니

---

2002-02-01|Publication of KR20020009631A

---

2007-03-14|Application granted

---

2007-03-14|Publication of KR100694735B1

优先权:

---

申请号 | 申请日 | 专利标题

---

US13848599P| true| 1999-06-10|1999-06-10|

---

US60/138,485|1999-06-10|