• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The present invention relates to a method of preparing 5-fluoronicotinic acid derivatives having the formula V-a, where R1 represents a hydrogen atom or a carboxyl- group protecting group and X represents a hydrogen or fluorine atom, by reacting an N-arylamidinoacetate with an α-fluoroacrylic acid derivative. The compounds of the invention can be used as starting materials in the synthesis of 1-(substituted aryl)-1,4-dihydro- 4-oxonaphthyridine derivatives having antibacterial activity against Gram-positive and Gram-negative bacteria. <IMAGE>
    公开号:NL9700011A
    申请号:NL9700011
    申请日:1997-11-06
    公开日:1998-02-02
    发明作者:
    申请人:Toyama Chemical Co Ltd；
    IPC主号:
    专利说明:

    Process for the preparation of nicotinic acid derivatives
    The present invention relates to a process for preparing 5-fluoro-nicotinic acid derivatives of the formula V-a of the formula sheet wherein R 1 represents a hydrogen atom or a carboxyl group protecting group and X represents a hydrogen or fluorine atom, or salts thereof. Such nicotinic acid derivatives can be converted into compounds of formula II which can then be converted into compounds of formula I which have an antibacterial activity. In formulas I and II, X and Rx have the meanings given above, while R2 is a hydroxyl group or a group obtainable by reaction of the hydroxyl group such as a halogen atom, an azido or nitro group, an optionally substituted alkylthio, alkoxy- , arylthio, alkane or arene sulfinyl, sulfonyl, sulfonyloxy, dialkyloxy or diaryloxyphosphyloloxy or 3-amino-1-pyrrolidinyl or 1-piperazinyl group.
    Program and Abstracts of the 24th ICAAC, pages 102 to 104, and Japanese Patent Application Laid-Open No. 228479/85 disclose that certain 1-aryl-substituted 1,4-dihydro-1-oxo-naphthyridine derivatives of Formula I and salts thereof exert a potent antibacterial action against both Gram-positive and Gram-negative bacteria and, when administered orally or parenterally, give high blood levels and excellent properties such as high safety.
    The present invention provides a process for the preparation of nicotinic acid derivatives, characterized in that a 5-fluoro-nicotinic acid derivative of the formula Va wherein R, represents a hydrogen atom or a carboxyl group protecting group and X represents a hydrogen or fluorine atom, is prepared by reaction of a compound of formula VI wherein Z represents a removable group and Rx and X have the above meaning, or a salt thereof, with a compound of formula VII wherein Z represents a removable group and the above meaning, or a salt thereof.
    In this specification, the carboxyl group protecting group for R includes those groups commonly used in this field, for example, the conventional carboxyl group protecting groups disclosed in Japanese Patent Application Laid-Open No. 80.665084, such as alkyl, benzyl, pivaloyloxymethyl, trimethylsilyl, etc.
    The removable group Z may be a halogen atom, a hydroxyl group or an optionally substituted acyl oxy, alkanesulfonyloxy, arene sulfonyloxy, dialkyloxyphosphinyloxy or diaryloxyphosphinyl group.
    The alkanesulfonyloxy group includes, for example, alkanesulfonyloxy groups of 1 to 5 carbon atoms, such as the methanesulfonyloxy or ethanesulfonyloxy group, etc., the arene sulfonyloxy group includes, for example, the benzenesulfonyloxy or naphthalenesulfonyloxy, oxyfoxyphoxy, oxydoxyphenoxy, such as a diethyl diethyl phosphoxy group, such as a diethyl , dipropoxyphosphinyloxy, dibutoxyphosphynyloxy, etc. and the diaryloxyphosphinyloxy group includes, for example, the diphenoxyphosphinyloxy group, etc.
    The aforementioned alkanesulfonyloxy, arene sulfonyloxy, dialkoxyphosphinyloxy and diaryloxyphosphinyloxy groups may have at least one substituent selected from the group consisting of halogen atoms such as fluorine, chlorine, bromine and iodine, etc., the nitro group, lower alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl etc., lower alkoxy groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butyoxy, tert- butoxy, etc., etc. are substituted.
    For example, the optionally substituted acyloxy group for Z includes the acetyloxy group and benzyloxy group.
    In any of the aforementioned compounds, salts include salts to the basic groups, such as to the amino group and corresponding groups, and to the acid groups, such as the carboxyl group, hydroxyl group and corresponding groups. For example, salts on the basic group include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and corresponding acids, salts with organic carboxylic acids such as oxalic acid, citric acid, trifluoroacetic acid and corresponding acids, salts with sulfonic acids such as methanesulfonic acid, p-toluene sulfonic acid naphthalene sulfonic acid and corresponding acids, etc. The salts on the acidic group include, for example, salts with alkali metals such as sodium, potassium and corresponding metals, salts with alkaline earth metals such as magnesium, calcium and corresponding metals, ammonium salts and salts with nitrogen-containing organic bases, such as procaine, dibenzylamine, N-benzyl-S-phenetylamine, 1-ephenamine, N, N-dibenzylethylenediamine, triethylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine.
    The compounds of formula Va or salts thereof can be prepared by reaction with a compound of formula VI or a salt thereof, prepared according to the method described in British Patent 1,409,987, with a compound of formula VII or a salt thereof, prepared on based on the method described in Bull. Soc. Chim. Fr., pp. 1,165-1,169 (1975), J. Chem. Soc. (C). pp. 2206-2207 (1967) and Program and Abstracts of the 105th meeting of the Japanese Pharmaceutical Society, p. 523 (1985).
    The solvent that can be used in this reaction can be any solvent that is inert in the reaction and includes, for example, water; alcohols such as methanol, ethanol, isopropyl alcohol, butyl alcohol, ethylene glycol, methyl Cellosolve, etc .; aromatic hydrocarbons such as benzene, toluene, etc., halogenated hydrocarbons, such as methylene chloride, chloroform, dichloroethane, etc., ethers, such as tetrahydrofuran, dioxane, anisole, diethylene glycol, dimethyl ether, dimethyl Cellosolve, etc. nitriles, such as acetonitrile, etc., ketones such as acetone, methyl ethyl ketone, etc., esters, such as methyl acetate, ethyl acetate, etc .; amides, such as N, N-dimethylformamide, N, N-dimethylacetamide, etc., sulfoxides, such as dimethylsulfoxide, etc. These solvents can be used in the form of a mixture of two or more.
    Condensing agents include, for example, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, etc.
    In this reaction, the amount of compound of formula VII or a salt thereof used is not critical, although it is at least equimolar to the compound of formula VI, preferably 1.0-3.0 per mole thereof. Usually this reaction is carried out at a temperature between 0 and 150 ° C, preferably between 15 and 100 ° C, for 5 min to 30 hours.
    The symbols used in the following example have the following meanings:
    Me: the methyl group, Et: the ethyl group, n-Pr: the n-propyl group, i-Pr: the isopropyl group and
    Ac: the acetyl group.
    Example (1) 50 g of ethyl-β-imino-phenoxypropionate hydrochloride and 27.8 g of 2,4-difluoroaniline were suspended in 300 ml of ethyl acetate and the resulting suspension was reacted for 2 hours under reflux. The deposited crystals were filtered and washed with two 200 mL portions of ethyl acetate to give 47 g (yield: 82.2%) of ethyl N- (2,4-difluorophenyl) amidinoacetate hydrochloride, mp 196-197 ° C obtained.
    IR (KBr) cm'1: uc = 0 1730 NMR (DMS0-d5) δ values: 1.26 (3H, t, J = 7 Hz), 4.07 (2H, s), 4.19 (2H, q, J = 7 Hz), 7.02-7.78 (3H, m), 9.11 (1H, bs), 10.26 (1H, bs), 12.28 (1H, bs) Similarly as described above, the following compounds were obtained: o Methyl-N- (2,4-difluorophenyl) amidinoacetate hydrochloride melting point: 192-193 ° C IR (KBr) cm -1: vCm0 1735 NMR (DMS0-d6) δ values: 3.74 (3H, s), 4.09 (2H, s), 6.91-7.73 (3H, m), 9.15 (1H, bs), 10.31 (1H, bs), 12.29 (1H, bs) o Methyl N- (4-fluorophenyl) amidinoacetate hydrochloride
    Melting point: 134-135 ° C IK (KBr) cm1: uc, 0 1730 NMR (DMSO-d6) δ values: 3.74 (3H, s), 4.05 (2H, s), 7.01-7.59 ( 4H, m), 8.96 (1H, bs), 10.06 (1H, bs), 12.26 (1H, bs) (2) In a mixture of 92 ml of water and 92 ml of methylene chloride, 23.0 g methyl N- (2,4-difluorophenyl) amidinoacetate hydrochloride and the pH of the solution was adjusted to 13 with a 2N aqueous sodium hydroxide solution. The organic layer was then separated, washed successively with 50 ml of water and 50 ml of a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. To this solution, 27.1 g of the sodium salt of ethyl-α-formyl-α-fluoroacetate was added at room temperature and the resulting mixture was refluxed for 4 hours, after which the solvent was distilled off under reduced pressure. 92 ml of water and 46 ml of ethyl acetate were added to the residue thus obtained, and the crystals which had been obtained were filtered off. The crystals thus obtained were suspended in 184 ml of water and the pH of this suspension was adjusted with 6 N hydrochloric acid to 1.0 and 46 ml of water and 46 ml of isopropyl alcohol were added to the crystalline material thus obtained, after which the crystals were filtered off, yielding 15.0 g (57.9% yield) of methyl 2 - (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinate, m.p. 222-223 ° C.
    Melting point: 222-223 ° C (recrystallized from ethyl acetate) IR (KBr) cm -1: uc. 0 1700 NMR (TFA-dJ δ values: 4.06 (3H, s), 6.71-7.65 (3H , m), 8.12 (1H, d, J = 11 Hz)
    In the same manner as described above, the following compounds were prepared: o Ethyl 2- (2,4-di-fluorophenylamino) -5-fluoro-6-hydroxynicotinate melting point: 177-178 ° C (recrystallized from ethyl acetate) NMR (TFA-dj ) δ values: 1.52 (3H, t, J = 7 Hz), 4.50 (2H, q, J = 7 Hz), 6.80-7.65 (3H, m), 8.15 (1H , d, J = 11 Hz) o Methyl-5-fluoro-2 - (4-fluorophenylamino) -6-hydroxy-nicotinate melting point: 227-228 ° C (recrystallized from ethyl acetate) IR (KBr) cm -1: uc * 0 1690 NMR (TFA-d ^ δ values: 4.05 (3H, s), 6.89-7.53 (4H, m), 8.11 (1H, d, J = 11 Hz) (3 ) In a mixture of 5 ml of water and 5 ml of methylene chloride, 500 mg of methyl N- (2,4-difluorophenyl) amino-dinoacetate hydrochloride was dissolved and the pH of the resulting solution was adjusted with a 2N solution of sodium hydroxide in water adjusted to 13.0 The organic layer was separated and washed successively with 3 ml of water and 3 ml of a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. in this solution, 820 mg of ethyl 3- (4-methylbenzenesulfonyloxy) -2-fluoroacrylate and then 120 mg of sodium methoxide (purity: 92.3%) and 5 ml of methanol were added at room temperature, and the resulting solution was stirred for 24 hours reacted at the same temperature. The solvent was then distilled off under reduced pressure and 10 ml of water and 2 ml of ethyl acetate were added to the resulting residue. The pH of the resulting solution was adjusted to 1.0 with 6 N hydrochloric acid and the crystals thus obtained were filtered and washed successively with 2 ml of water and 2 ml of isopropyl alcohol to give 370 mg (yield 65.7%) of methyl 2- (2 4-difluorophenylamino) -5-fluoro-6-hydroxynicotinate was obtained. The physical properties of this compound were identical to those of the compound obtained according to (2) above.
    (4) The same procedure as described in (3) above was repeated, except that one of the 3-substituted-2-fluoroacrylates listed in Table 2 was used instead of ethyl 3- (4-methylbenzenesulfonyloxy) -2-fluoroacrylate, yielding the results listed in Table 2.
    Table 2
    The physical properties of the compounds obtained in each case were identical to those of the compound obtained according to (2) above.
    权利要求:
    Claims (4)
    [1]
    A process for the preparation of a nicotinic acid derivative, characterized in that a 5-fluoro-nicotinic acid derivative of the formula Va in which a hydrogen atom or a carboxyl group is a protecting group and X represents a hydrogen or fluorine atom, or a salt thereof, prepared by reacting a compound of formula VI in which and X have the previously defined meanings, or a salt thereof, with a compound of formula VII in which Z represents a removable group and Rx has the aforementioned meaning, or a salt thereof.
    [2]
    Process according to claim 1, characterized in that Z represents a halogen atom, a hydroxyl group or an optionally substituted acyloxy, alkanesulfonyloxy, arene sulfonyloxy, dialkoxyphosphinyloxy or diaryloxyphosphinyl oxy group.
    [3]
    Process according to claim 2, characterized in that Z represents a hydroxyl group.
    [4]
    4. Process according to any one of claims 1-3, characterized in that the reaction is carried out at a room temperature between 0 and 150 ° C.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1998-02-02| A1B| A search report has been drawn up|
    1998-08-03| BC| A request for examination has been filed|
    2006-03-01| V4| Lapsed because of reaching the maximum lifetime of a patent|Effective date: 20060122 |
    优先权:
    申请号 | 申请日 | 专利标题
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    JP2839785|1985-02-18|
    JP60028397A|JPH0629246B2|1985-02-18|1985-02-18|2-acetic acid derivative and its salt|
    JP60043644A|JPH0665670B2|1985-03-07|1985-03-07|1,4-Dihydro-4-oxonaphthyridine derivatives and salts thereof|
    JP4364485|1985-03-07|
    JP6906185|1985-04-03|
    JP60069061A|JPH0665671B2|1985-04-03|1985-04-03|Novel process for producing 1-substituted aryl-1,4-dihydro-4-oxonaphthyridine derivative or salt thereof|
    JP60097065A|JPH0662619B2|1985-05-08|1985-05-08|Novel process for producing 1,4-dihydro-4-oxonaphthyridine derivative or salt thereof|
    JP9706585|1985-05-08|
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    JP60129323A|JPH0665672B2|1985-06-14|1985-06-14|Novel process for producing 1,4-dihydro-4-oxonaphthyridine derivative or salt thereof|
    NL8600138A|NL192986C|1985-01-23|1986-01-22|Process for preparing 1,4-dihydro-4-oxo-naphthyridine derivatives.|
    NL8600138|1986-01-22|
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