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    • 专利摘要:

    公开号:ES2827549T9
    申请号:ES18169756T
    申请日:2015-12-17
    公开日:2021-07-02
    发明作者:Haim Cyril Ben；Andras Horvath；Johan Erwin Edmond Weerts
    申请人:Aragon Pharmaceuticals Inc；
    IPC主号:
    专利说明:

    [0001] Process for the preparation of a diarylthiohydantoin compound
    [0002] Field of the invention
    [0003] The present disclosure is directed to the preparation of compound (X) and intermediates in their synthesis. More specifically, the present disclosure is directed to processes for the preparation of compound (X), disclosed in United States Patent No. 8,445,507, issued May 21, 2013.
    [0004] Background of the invention
    [0005] The compound (X) of the present invention is currently being investigated for the treatment of prostate cancer. The present invention describes a process and intermediate products for the preparation of said compound.
    [0006] WO 2008/119015 is directed towards a synthesis of a compound called A52, which is considered useful in the treatment of prostate cancer.
    [0007] CA 2908326 refers to imidazole diketone compound, method of preparation and use thereof. The compound is said to have good pharmacokinetic and / or pharmacodynamic performance.
    [0008] Summary of the invention
    [0009] The present invention is directed to a process according to the appended claims. The preparation of compound (X) is also disclosed.
    [0014] comprising, consisting of and / or consisting essentially of
    [0018] (i) reacting a compound of formula (X1-c), wherein P is a suitable amino protecting group, with compound (IV) under amide bond formation conditions; in the presence of an amide coupling reagent; and in the presence of a catalyst; in an organic solvent; at a temperature in the range of about 0 ° C to about 50 ° C; to give the corresponding compound of formula (XII-c); or,
    [0019] ho nh-p
    [0023] 5-isocyanate -3- (trifluoromethyl) picolinonitrile ( 2,2i -]) (ii) reaction of compound (IV) with phosgene or a phosgene analog; in the presence of an organic base; in an aprotic solvent; then treating a resulting isocyanate intermediate (IVa), optionally without isolation, with a compound of formula (Xl-c); in the presence of a non-nucleophilic base; at a temperature in the range of about -20 ° C to about 80 ° C; to give the corresponding compound of formula (Xll-c);
    [0026] reacting a compound of formula (XII-c) under suitable amino deprotection conditions; in an organic solvent; at a temperature higher than room temperature; to give the corresponding compound (XIII);
    [0031] reacting compound (XIII) with a compound of formula (2c-1) wherein X is chlorine, bromine or iodine and W is C 1-8 alkoxy or methylamino; in the presence of a source of Cu (0) or a copper salt; in the presence of an inorganic base; in an organic solvent; optionally in the presence of a ligand; optionally in the presence of a suitable reducing agent; at a temperature in the range from about room temperature to about 140 ° C; to give the corresponding compound of formula (2c-2) wherein W is C 1-8 alkoxy or methylamino;
    [0036] converting a compound of formula (2c-2) to compound (X), which is discussed in more detail below.
    [0037] In one embodiment, compound (XVII), where W is methylamino, is converted to compound (X), as shown in scheme (2e), by
    [0042] reacting compound (XVII) with a source of thiocarbonyl; in the presence of an activating agent; in an organic solvent; optionally in the presence of an organic base; at a temperature in the range of about -20 ° C to about 100 ° C; To give the corresponding compound (X).
    [0044] In another embodiment, a compound of formula (2c-2B), where W is C 1-8 alkoxy, is converted to a compound of formula (2e), as shown in scheme (2f), by
    [0047] reacting a compound of formula (2c-2B) with a source of thiocarbonyl; in the presence of an activating agent; in an organic solvent; at a temperature in the range of about -20 ° C to about 100 ° C; to give the corresponding compound of formula (2e); then
    [0051] treating a compound of formula (2e) with methylamine; in an organic solvent; at about room temperature; To give the corresponding compound (X).
    [0052] Detailed description of the invention
    [0053] The term "alkyl", whether used alone or as part of a substituent group, refers to straight and branched carbon chains having 1 to 8 carbon atoms. Therefore, the designated numbers of carbon atoms (eg, C 1-8 ) independently refer to the number of carbon atoms in an alkyl moiety or the alkyl portion of a larger alkyl-containing substituent. In substituent groups with multiple alkyl groups such as, (C 1-6 alkyl) 2 amino-, the C 1-6 alkyl groups of the dialkylamino may be the same or different. The term "alkoxy" refers to a group -O-alkyl, where the term "alkyl" is as defined above.
    [0054] The term "cycloalkyl" refers to a saturated or partially saturated monocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of such rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
    [0055] The term "aryl" refers to an aromatic, monocyclic, or bicyclic aromatic ring of 6 to 10 carbon members. Examples of aryl rings include phenyl and naphthalenyl.
    [0056] The term "halogen", "halide" or "halo" refers to fluorine, chlorine, bromine and iodine atoms.
    [0057] The term "carboxy" refers to the group C (= O) OH.
    [0058] The term "formyl" refers to the group -C (= O) H.
    [0059] The term "oxo" or "oxide" refers to the group (= O).
    [0060] The term "thiono" refers to the group (= S).
    [0061] The term "room temperature" or "room temperature", as used herein, refers to a temperature in the range of about 18 ° C to about 22 ° C.
    [0062] Whenever the term "alkyl" or "aryl" or any of its prefix roots appears in the name of a substituent (eg, arylalkyl, alkylamino), the name should be construed to include the limitations given above for "alkyl" and "aril". "Designated numbers of carbon atoms (eg, C 1 -DO 6 ) independently refer to the number of carbon atoms in an alkyl moiety, an aryl moiety, or in the alkyl portion of a substituent larger than the alkyl appears as its root prefix. For alkyl and alkoxy substituents, the designated number of carbon atoms includes all independent members included within a specified specified range. For example, c 1-6 alkyl would include methyl, ethyl, propyl, butyl, pentyl and hexyl individually, as well as their sub-combinations thereof (e.g., C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 2-6 , C 3-6 , C 4- 6 , C 5-6 , C 2-5 , etc.).
    [0063] In general, under the standard nomenclature rules used throughout this disclosure, the terminal part of the designated side chain is described first, followed by the adjacent functionality towards the connection point. So, for example, a "C". 1 -DO 6 "alkylcarbonyl substituent" refers to a group of formula:
    [0065] - S ¿- C 1 ------- C r C6 alkyl
    [0067] The abbreviations used in this specification, in particular the diagrams and examples, are as follows. following:
    [0068] Abbreviations
    [0070] ACN acetonitrile
    [0071] aq watery
    [0072] Boc ferc / o-butoxycarbonyl
    [0073] CDI 1,1'-carbonyldiimidazole
    [0074] DABCO 1,4-diazabicyclo [2.2.2] octane
    [0075] DBN 1,5-diazabicyclo (4.3.0) no 5-ene
    [0076] DBU 1,8-diazabicyclo [5.4.0] undec-7-ene
    [0077] DCM dichloromethane
    [0078] DIEA or DIPEA diisopropylethylamine
    [0079] DMA dimethylacetamide
    [0080] DMAPA dimethylaminopropylamine or N1, N1-dimethylpropane-1,3-diamine DMAP 4- (dimethylamino) pyridine
    [0081] DMF dimethylformamide
    [0082] DMSO dimethyl sulfoxide
    [0083] DMTMM 4- (4,6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium Dppf 1,1'-bis (diphenylphosphino) ferrocin chloride
    [0084] EDCI 1 -ethyl-3- (3-dimethylaminopropyl) carbodiimide
    [0085] EEDQ 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline
    [0086] h hour (s)
    [0087] Hydrochloric acid HCl
    [0088] HPLC high performance liquid chromatography
    [0089] iPrOAc isopropylacetate
    [0090] LiHMDS lithium hexamethyldisilazide
    [0091] Me methyl
    [0092] MeCN acetonitrile
    [0093] MEK methyl ethyl ketone
    [0094] MeOH Methyl Alcohol
    [0095] Mg milligram
    [0096] MTBD 9-methyl-2,3,4,6,7,8-hexahydropyrimido [1,2-a] pyrimidine NMP N-methyl-2-pyrrolidone
    [0097] PdCl 2 (dppf) CH 2 CI 2 1,1'-cis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex) PAG (o-toI) 3 trio-tolyl) phosphine
    [0098] rt room temperature
    [0099] T3P propylphosphonic anhydride
    [0100] TBD 1,5,7-triazabicyclo [4.4.0] dec-5-ene
    [0101] TCDI 1,1'-thiocarbonyl-di-imidazole
    [0102] THF tetrahydrofuran
    [0103] TMEDA W, W, W, W-tetramethylethylenediamine
    [0104] TMG tetramethylguanidine
    [0105] 2-MeTHF 2-methyl tetrahydrofuran
    [0106] General schemes
    [0107] The general scheme for the invention is illustrated in Scheme A, below.
    [0108] Scheme A
    [0112] In Scheme A, a compound of formula (XI-c) possesses the group P, a conventional amino protecting group such as a carbamate (-NHCO 2 R) where R is C 1-8 alkyl, phenyl, aryl (C 1-8 ) alkyl, or the like. A compound of formula (XI-c) can be reacted with compound (IV) under conditions of amide bond formation in the presence of an amide coupling reagent selected from 1,1-carbonyldiimidazole, T3P, EDCI, DMTMM, EEDQ , or the like; in the presence of a catalyst which can be (1) an amidine such as DBU or DBN, (2) a tertiary amine such as DABCO, triethylamine or DIPEA, (3) a guanidine such as TBD, TMG or MTBD, or (4) a base such such as NaH, KOtBu and LiHMDS, or the like; in an aprotic solvent, such as toluene, MeTHF, THF, iPrOAc, or DCM; or a protic solvent such as IPA or the like; at a temperature in the range of about 0 ° C to about 50 ° C; to give the corresponding compound of formula (XII-c). One skilled in the art will recognize that some reagents and bases may not be compatible with all solvents described herein, but compatibility of reagents and bases can be readily identified using knowledge already known or available in the scientific literature.
    [0113] In one embodiment, the amide coupling agent is 1,1-carbonyldiimidazole and the catalyst is DBU.
    [0114] Alternatively, compound (IV) may first be treated with phosgene or with a phosgene analog selected from triphosgene (bis (chloromethyl) carbonate), diphosgene (trichloromethyl chloroformate), or the like; in the presence of a tertiary amine base selected from triethylamine, ethyl diisopropylamine, or DABCO; in an aprotic solvent selected from DCM, toluene, THF or MeTHF; at a temperature in the range of about -20 ° C to about 50 ° C; to form 5-isocyanato-3- (trifluoromethyl) picolinonitrile (IVa) as an intermediate. Reaction of intermediate (IVa) with compound (XI-c); in the presence of a non-nucleophilic base which is (1) an amidine such as DBU or DBN, (2) a tertiary amine such as DABCO or triethylamine, or (3) a guanidine such as TBD, TMG or MTBD; at a temperature in the range of about -20 ° C to about 80 ° C; to give the corresponding compound of formula (XII-c).
    [0115] The amino group of a compound of formula (XII-c) can be deprotected using conventional methods such as under acidic conditions in an organic solvent such as isopropanol, toluene, MeTHF, THF, iPrOAc, DCM, IPA, water or the like; at a temperature higher than room temperature; To give the corresponding compound (XIII).
    [0116] Compound (XIII) can be reacted with a compound of formula (2c-1) wherein X is chlorine, bromine or iodine and W is C 1 -s alkoxy or methylamino; in the presence of (1) a source of Cu (0) such as copper powder or copper sponge, or (2) a copper salt selected from cuprous chloride, cuprous iodide, cuprous bromide, cuprous acetate or cupric bromide; in the presence of an inorganic base such as potassium acetate, potassium carbonate, cesium carbonate, CsF, sodium pivalate, or the like; in an organic solvent such as DMF, DMA, DMSO, acetonitrile, propionitrile, butyronitrile or an alcoholic solvent such as amyl alcohol; with or without the addition of a Cu (I) salt selected from cuprous chloride, cuprous iodide, cuprous bromide or cuprous acetate; and optionally in the presence of a ligand such as 2-acetylcyclohexanone, TMEDA or phenanthroline; and optionally in the presence of a reducing agent such as sodium ascorbate or sodium bisulfite; at a temperature in the range from about room temperature to about 140 ° C; to give the corresponding compound of formula (2c-2) wherein W is C 1 -s alkoxy or methylamino.
    [0117] In one embodiment, the copper salt is cuprous bromide and the ligand is TMEDA. In another embodiment, the source of Cu (0) is copper dust.
    [0118] In another embodiment, the source of Cu (0) is a copper sponge.
    [0119] In a further embodiment, the organic solvent is DMA.
    [0120] In a further embodiment, the organic solvent is DMSO.
    [0121] In another embodiment, the reaction of compound (XIII) with a compound of formula (2c-1) comprises, consists of, and / or consists essentially of, a copper salt such as cuprous bromide with the TMEDA ligand; in the presence of the inorganic potassium acetate base; in an organic solvent such as DMA; at a temperature range from about 80 ° C to about 140 ° C.
    [0122] In another embodiment, the reaction of compound (XIII) with a compound of formula (2c-1) comprises, consists of, and / or consists essentially of, a source of Cu (0) such as copper powder or copper sponge; in the presence of an inorganic base such as potassium acetate or sodium pivalate; in DMSO; at a temperature in the range of about 0 ° C to about 80 ° C.
    [0123] In another embodiment, the reaction of compound (XIII) with a compound of formula (2c-1) comprises, consists of, and / or consists essentially of, a source of Cu (0) such as copper powder or copper sponge; in the presence of an inorganic base such as potassium acetate; with the addition of a copper (I) salt selected from cuprous chloride, cuprous iodide, cuprous bromide or cuprous acetate; in an organic solvent such as DMSO; at a temperature in the range of about 0 ° C to about 80 ° C.
    [0124] The present disclosure further includes processes for the conversion of a compound of formula (2c-2) to compound (X), which is described in detail below.
    [0125] Compound (XVII), where W is methylamino, can be reacted with a thiocarbonyl source selected from 0,0'-di (pyndin-2-yl) carbonothioate, 1,1'-thiocarbonylbis (pyridin-2 ( 1H) -one), di (1) H-imidazol-1-yl) methanethione, thiophosgene, an aryl thiochloroformate (where aryl is phenyl, naphthyl, or tolyl), or bis (benzotriazole) thiocarbonyl; in the presence of an activating agent selected from DMAP, NaH or NaOH; in an organic solvent selected from DMA, DMF, toluene, DMSO, ACN, THF, DCM, EtOAc, acetone, MEK or dioxane; optionally in the presence of an organic base selected from triethylamine or DIPEA; at a temperature in the range of about -20 ° C to about 100 ° C; to produce the corresponding compound (X).
    [0126] In one embodiment, the thiocarbonyl source is 1,1'-thiocarbonylbis (pyridin-2 (1H) -one).
    [0127] In another embodiment, the activating agent is DMAP.
    [0128] In another embodiment, the organic solvent is DMA.
    [0129] In a further embodiment, the thiocarbonyl source is phenyl thionochloroformate; the activating agent is DMAP; the organic base is selected from triethylamine or DIPEA; the organic solvent is DMA; and at a temperature in the range of about -20 ° C to about 80 ° C.
    [0130] In another embodiment, phenyl thiionochloroformate can react with DMAP to form an isolable quaternary salt, compound (S1), shown below.
    [0134] The present disclosure further relates to a process comprising, consisting of, or essentially consisting of reacting compound (XVII) with compound S1; in the presence of an organic base selected from triethylamine or DIPEA; in the organic solvent DMA; at a temperature in the range of about -20 ° C to about 80 ° C; To give the corresponding compound (X).
    [0135] A compound of formula (2c-2B), wherein W is C 1 -s alkoxy, can be reacted with a thiocarbonyl source selected from 0,0'-di (pyridin-2-yl) carbonate, 1, 1 '- thiocarbonylbis (pyridin-2 ( 1H) -one), di (1) H-imidazol-1-yl) methanethione, thiophosgene, an aryl thiochloroformate (where aryl is phenyl, naphthyl, or tolyl), or thiocarbonyl bis (benzotriazole) ; in the presence of an activating agent selected from DMAP, NaH or NaOH; in an organic solvent selected from dimethylacetamide, DMF, toluene, DMSO, THF or dioxane; optionally in the presence of an organic base selected from triethylamine or DIPEA; at a temperature in the range of about -20 ° C to about 100 ° C; to give the yield of the corresponding compound (X).
    [0136] In one embodiment, W of a compound of formula (2c-2B) is methoxy, designated as compound (XV).
    [0137] The present disclosure further relates to a process that includes a reaction compound (2c-2B) with a compound S1; in the presence of an organic base selected from triethylamine or DIPEA; in the organic solvent DMA; at a temperature in the range of about -20 ° C to about 80 ° C; to produce the corresponding compound (X).
    [0138] The compound of formula (2e) can be treated with methylamine; in an organic solvent selected from THF, DMF, DMA, ethanol or an aqueous mixture thereof; at about room temperature; To give the corresponding compound (X).
    [0139] In one embodiment, the organic solvent is ethanol.
    [0140] In another embodiment, reaction conditions selected from F1 to F11, shown in Table 1, can be used for the conversion of Cpd (2c-2) to either compound (X) or a compound of formula (2e ), where W is methylamino or C 1 -s alkoxy, respectively.
    [0141] Table 1.
    [0143]
    [0146] In another embodiment, when the thiocarbonyl source is phenyl thiochloroformate, immediately after cyclization, DMAPA can be added.
    [0147] Specific examples
    [0148] The following examples are set forth to aid in an understanding of the invention, and are not intended and should not be construed as limiting in any way the invention set forth in the claims that follow. However, not all examples correspond to the invention. Only those that fall strictly within the claims are part of the invention.
    [0149] In the examples that follow, some synthesis products are listed as isolated as a residue. One skilled in the art will understand that the term "residue" does not limit the physical state in which the product was isolated and can include, for example, a solid, an oil, a foam, a gum, a syrup, and the like.
    [0150] Example 1
    [0153] Step A. Preparation of compound II
    [0157] A container was charged with 19 g of compound (I), 5 g of triethylamine hydrobromide, 49 g of xylenes and 67 g of DMF. A solution of 26 g of phosphorous oxybromide in 16 g of xylene was metered into the reaction mixture. The reaction mixture was heated to 100 ° C for 3 h. The mixture was then cooled to 70 ° C. To this mixture was added 75 g of a NaOH solution (10 M). After phase separation at room temperature, the organic layer was washed with 84 g of an aqueous NaOH solution (10 M), followed by 84 g of an aqueous NaCl solution (25%). The organic phase was carried on to the next stage without further purification. Isolation by crystallization from heptane was carried out for the characterization of compound (II). 1 H NMR (300 MHz, CDCl) 3 ) or 9.36, 8.75.
    [0159] Step B. Preparation of Compound III
    [0164] 8.7 g of sodium cyanide and 6.8 g of copper (I) iodide and 45 g of butyronitrile were added to the previous solution of compound (II) in xylenes. The mixture was heated at 120 ° C for 20 h. The reaction mixture was cooled, washed twice with an aqueous sodium carbonate solution (10%). The organic phase was carried to the next step. The isolation was carried out for the characterization of compound (III). 1H NMR (300 MHz, DMSO-O6) § 149.3, 145.4, 133.9, 131.9, 130.1, 119.5, 114.0.
    [0166] Step C. Preparation of compound IV.
    [0171] Preparation of modified catalyst suspension.
    [0173] In a 20 ml beaker, 0.156 g (0.129 ml, 50% w / w) of H3correos2 was added to a suspension of 1.00 g of 5% Pt / C of catalyst F101 R / W (from Evonik AG , contains approximately 60% water) and 4.0 ml deionized water. After 15 minutes while stirring with a magnetic stir bar, 58 mg of NH 4 VO 3 was added and the suspension was stirred again for 15 minutes.
    [0175] Hydrogenation
    [0177] A 100 ml autoclave was charged with a solution of 10.0 g of compound (III) (46.1 mmol) in 26.7 ml of xylenes and 13.3 ml of butyronitrile. To this solution, the modified catalyst suspension was added with the help of 2 ml of deionized water. The autoclave was closed and then inerted by pressurizing 3 times with nitrogen at 10 bar and 3 times with hydrogen at 10 bar. The reactor pressure was adjusted to 5.0 bar of hydrogen, stirring was started (hollow shaft turbine stirrer, 1200 rpm) and the mixture was heated to 70 ° C in 50 min. As soon as 70 ° C was reached, hydrogen uptake ceased. After stirring for another 40 minutes, heating was stopped and the autoclave was allowed to cool. The suspension was filtered through a glass fiber filter and washed in portions using 40 ml of xylenes at 20-23 ° C. Compound (IV) crystallized from solution after distillation of the butyronitrile solvent. 1 H NMR. (300 MHz, DMSO-ree) or 8.20 (d, J = 2.4Hz, 1H), 7.31 (d, J = 2.6Hz, 1H), 7.04 (s, NH).
    [0179] Step D. Preparation of compound (XII).
    [0184] Method A. To a mixture of 18 g (96.2 mmol) of compound (IV), 24.8 g (109.7 mmol) of compound (XI) in 54 mL of tetrahydrofuran (THF) were added 18.5 mL (106 mmol) of W, W -diisopropylethylamine (DIPEA) and 17 g (104 mmol) of carbonyldiimidazole (CDI) in portions at 20 ° C. The mixture was heated to 60 ° C and 15.4 g (101 mmol) of 1,8-diazabicyclo [ 5.4.0] undec-7-ene (DBU). After 2 h, the mixture was diluted with 108 ml of tetrahydrofuran (THF) and washed with an aqueous citric acid solution (50 g in 72 ml of water). Subsequently, the water was separated from the organic layer by azeotropic distillation. Compound (XII) in THF was used as such in the next step. A small sample was isolated for characterization purposes. 1H-NMR (300 MHz, CDCl) 3) or 10.4 (s, 1H), 8.74 (s, 2H), 5.18 (s, 1H), 2.79 (m, 2H), 2.22 (m, 2H), 2.12 (m , 2H), 1.49 (s, 9H); 13C NMR (CDCla, JMOD) or 172.7, 143.6, 138.2, 131.0, 123.5, 123.3, 114.4, 82.2, 59.9, 30.7, 28.3, 15.1.
    [0186] Method B. To a mixture of 40 g (214 mmol) of compound IV, 37.8 g (233 mmol) of carbonyldiimidazole (CDI, 109.7 mmol) in 120 ml of tetrahydrofuran (THF) was added a solution of 55 g (244 mmol) of compound (XI) in 240 ml of tetrahydrofuran (THF). The mixture was heated to 60 ° C and 33.7 ml (224 mmol) of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) was added. After 4 h, the mixture was washed with an aqueous citric acid solution (112 g in 160 ml of water). After phase separation at 50 ° C, the water was separated from the organic layer by azeotropic distillation. Compound (XII) in THF was used as such for the next step.
    [0188] Step E. Preparation of compound (XII) through 5-isocyanato-3- (trifluoromethyl) picolmomtril, (IVa)
    [0193] A reactor was charged with 0.2 g (1.1 mmol) of compound (IV), 6 ml of dry DCM and cooled to 0 ° C. Triphosgene (0.22 g, 0.67 eq) was added, followed by the dropwise addition of triethylamine (0.55 g, 5 eq). The mixture was stirred at 0 ° C and, after 2 h, compound (IV) was completely converted to compound (IVa) according to HPLC analysis. Compound (XI) (0.28 g, 1.2 eq) was added and the mixture was further stirred at 0 ° C. HPLC analysis after 1 hr showed a 42% conversion of compound (XII) in the mixture.
    [0195] Step F. Preparation of compound (XIII).
    [0198] A 6M solution of hydrochloric acid in isopropanol (2 eq.) Was added to the solution of compound (XII) in THF. The stirred reaction solution was heated at 70 ° C for 5 h. After completion of the reaction, the mixture is heated to reflux and changed with 2-propanol. The reaction was allowed to cool to 30 ° C and ammonium hydroxide solution (3 eq.) Was added. The mixture was stirred for 1 hr, then cooled to 5 ° C. A precipitate was collected by filtration. The filter cake was washed once with water and once with cold isopropanol. The filter cake was dried under partial vacuum at 50 ° C to form compound (XIII) in 80% yield. 1 H NMR (300 MHz, CDCl) 3) 10.2 (s, 1H), 8.84 (s, 2H), 2.81 (m, 2H), 2.13 (m, 2H), 2.07 (m, 2H); 13 C NMR (CDC b , JMOD) or 175.8, 143.4, 137.5, 122.9, 114.4, 59.3, 34.9, 14.3.
    [0200] Step G. Preparation of compound (XV)
    [0205] Method A. A solution of 2 g of compound (XIII) in 10 ml of DMA was added over 6 h to a reactor loaded with 1.2 eq of compound (XIV) -Cl (X = Cl), 2.5 eq of acetate of potassium, 1.0 eq of copper (I) chloride and 5 ml of DMA. The reaction mixture was stirred and heated to 130 ° C. After 17 h of additional stirring, HPLC analysis showed 40% compound (XV) in the reaction mixture.
    [0207] Method B. A reactor was charged with 1 g of compound (XIII), 1.18 g of compound (XIV) -I (X = I), 0.7 g of potassium acetate, 0.22 g of copper sponge (1 eq) and 7 ml of DMS o . The mixture was stirred at 25 ° C for 7 h. HPLC analysis showed 93% conversion of compound (XV). After the addition of EtOH, followed by water and concentrated ammonium hydroxide, compound (XV) was isolated by filtration in 90% yield. 1H NMR (300 MHz, CDCl) a) or 10.74 (m, 1H), 9.28 (m, 1H), 8.75 (m, 1H), 7.67 (t, J = 2 x 8.7 Hz, 1H), 7.55 (s, 1H), 7.20 (m, 2H), 6.33 (d, J = 8.5Hz, 1H), 6.18 (d, J = 13.8Hz, 1H), 3.75 (s, 3H) 2.76 (m, 2H), 2.24 (m , 2H), 1.98 (m, 2H)); 13C NMR (CDCla, JMOD) or 174.6, 164.4, 163.8, 161.1, 151.7, 151.6, 144.7, 139.0, 133.1, 128.8, 128.1, 123.8, 114.7, 109.10, 105.6, 60.6, 51.4, 30.1, 14.40.
    [0209] Step H. Preparation of compound (IX)
    [0214] Method A. A reactor was charged with 1 g of compound (XV), 1.1 g of 1,1'-thiocarbonylbis (pyridin-2 (1H) -one), 0.56 g of DMAP and 6.2 ml of DMA. The mixture was stirred and heated at 60 ° C for 20 h. At that time, 6 ml of EtOH was added, followed by 6 ml of water. The reaction was then cooled to 0 ° C. Compound (IX) was isolated by filtration with a yield of 70%. 1H NMR (300 MHz, DMSO) or 9.23 (s, J = 1.9Hz, 1H), 8.77 (s, J = 2.1Hz, 1H), 8.18 (t, J = 2x8.2Hz, 1H), 7.58 (dd, J = 10.9, 1.7 Hz, 1H), 7.48 (dd, J = 8.3, 1.7 Hz, 1H), 3.9 (s, 3H), 2.65 (m, 2H), 2.50 (m, 2H), 2.00 (m, 1H ), 1.61 (m, 1H); 13C NMR (DMSO, JMOD) or 179.6, 174.2, 163.3, 153.4 (ArH), 140.9, 135.5 (ArH), 132.9 (ArH), 128.9, 126.5 (ArH), 118.9 (ArH), 114.2, 67.7, 52.6 (CHa ), 31.2, 13.4.
    [0216] Method B. A reactor was charged with 0.5 g of compound (XV), 0.35 g (2.5 eq) of DMAP and 5 ml of DMA. The mixture was stirred and cooled to -20 ° C. To this mixture, phenyl thiochloroformate (0.5 g, 2.5 eq) was added, followed by 0.46 g (4 eq) of triethylamine. The mixture was allowed to warm to room temperature and stirred for 3 h. Analysis by HPLC showed a conversion of 97% in compound (IX).
    [0218] Step I. Preparation of Compound (X) through Compound (IX).
    [0221] A reactor was charged with 0.85 g of Compound (IX). A solution of methylamine in ethanol (8.5 ml) was added and the mixture was stirred at room temperature for 3 h. The reaction mixture was then poured into a mixture of 5.1 ml of acetic acid and 19 ml of water. Compound X) was isolated by filtration in 55% yield. 1H NMR (300 MHz, DMSO) or 9.22 (s, 1H), 8.79 (d, J = 1.9Hz, 1H), 8.52 (m, 1H), 7.83 (t, J = 8x2Hz, 1H), 7.48 (dd, J = 10.5, 1.8 Hz, 1H), 7.39 (dd, J = 8.2, 1.8 Hz, 1H), 2.8 (d, J = 4.5Hz, 3H), 2.65 (m, 2H), 2.50 (m, 2H), 2.00 (m, 1H), 1.61 (m, 1H).
    [0222] Example 2
    [0227] Step A. Preparation of compound (XVII)
    [0232] Method A. In a 1 l reactor, 7.8 g (38 mmol) of compound (XVI) -Br (X = Br) were charged, 69.7 g (2.5 eq., 79 mmol) of acetate of potassium, 12 g (0.3 eq., 9.5 mmol) of copper (I) bromide and 12.8 mL (0.3 eq., 9.5 mmol) of N, N, N N'-tetramethylethylenediamine and 27 ml of DMA. The mixture was stirred and heated to 120 ° C. A solution of 9.0 g of compound (XIII) in 12.7 ml of DMA was dosed over 2 h into the hot mixture. After 2 h of additional stirring, the mixture was cooled to 60 ° C. An addition of 27 ml of water was completed followed by 18 ml of acetonitrile. After seeding and aging for 1 h, 18 ml of water was slowly administered over 2 h. The mixture was cooled and then compound (XVII) was isolated by filtration in 84% yield. 1H NMR (300MHz, DMSO) or 10.7 (s, 1H), 9.3 (s, 1H), 8.74 (s, 1H), 7.73 (m, 1H), 7.47 (m , 1H), 7.19 (s, 1H) 6.30 (d, J = 8.3Hz, 1H), 6.10 (d, J = 13.9Hz, 1H), 2.70 (m, 3H), 2.70 (m), 2.17 ( m), 1.95 (m); 13C NMR (DMSO, JMOD) or 175.0, 163.7, 162.3, 159.1, 149.6, 149.4, 144.6 (ArH), 139.0, 131.5 (ArH), 129.4, 129.0, 123.6 (ArH), 122.4, 120.0, 114.7, 111.4, 111.2 , 109.2 (ArH), 99.5 (ArH), 60.6, 30.1, 26.2, 14.3.
    [0234] Method B. A reactor was charged with 500 mg of compound (XIII), 1.1 equivalents of compound (XVI) -Br (X = Br), 1 equivalent of copper powder, 2.0 equivalents of potassium acetate and 2 , 5 ml of DMSO. The mixture was stirred and heated at 60 ° C for 18 h, after which HPLC showed that 80% of compound XVII was formed.
    [0236] Step B. Preparation of compound (X) from compound (XVII).
    [0238] Method A. A reactor was charged with 48 g of Compound (XVII), 52.8 g of 1,1'-thiocarbonylbis (pyridin-2 (1H) -one), 13.5 g of 4-dimethylaminopyridine and 144 ml of DMA. The mixture was stirred and heated at 90 ° C for 2 h. The reaction was then cooled to 60 ° C. A volume of 37 ml of HCl (6M in isopropanol) was added, followed by 144 ml of isopropanol and 216 ml of water. Compound (X) was isolated by filtration in 80% yield.
    [0240] Method B.
    [0243] A portion of DMAP (b12 2.0 g) was dissolved in 20 ml of DCM and cooled to -30 ° C. Phenyl thionochloroformate (b11 4.3 g, 1.5 eq were added) and the mixture was stirred for 1 h. The mixture was filtered and the collected solid was dried at room temperature under reduced pressure to give 4.3 g of quaternary salt (S1) as a yellow crystalline product. 1 H NMR (400 MHz, CD 3 CN): 3.39 (6H, s), 7.04 (2H, d), 7.29 (2H, d), 7.44 (1H, t), 7.58 (2H, t), 9.04 (2H , d). Compound (x V iI) (0.5 g, 1.1 mmol) and triethylamine (0.93 g, 8.8 mmol) were dissolved in 5 ml of DMA at 21 ° C. Salt S1 (0.81 g, 2.75 mmol was added) and the solution was stirred at room temperature. Analysis of the solution by HPLC after 1 h showed a conversion of 38% to Compound (X).
    [0245] Method C. DMAP (4.41 g, 2.2 eq, 36.1 mmol) was dissolved in 107 ml of ethyl acetate and heated to 60 ° C. Compound (XVII) (7.15 g, 16.4 mmol) was added followed by distillation of 35 ml of ethyl acetate to remove water. At 50 ° C, 6.24 g (2.2 eq., 36.1 mmol) of phenyl thioflorate were added and the mixture was stirred for 1 hr before the addition of 9.16 mL (65.7 mmol) of triethylamine. The reaction was held at 50 ° C for 6 h, then cooled to 5 ° C. 13.7 ml (5 eq., 82.1 mmol) of 6M hydrochloric acid in 2-propanol was added. The mixture was then washed with 35.8 ml of water, followed by a brine wash. The resulting organic layer was evaporated and replaced with toluene and W-butanol. After seeding, the mixture was cooled and compound (X) was collected by filtration, washed and dried. Yield: 72%.
    [0247] Method D. DMAP (15.4 g, 2.2 eq) was dissolved in 250 ml of ethyl acetate. Compound (XVII) (25 g) was added followed by heating to 50 ° C. Phenyl thiochloroformate (2.2 eq.) Was added and the mixture was stirred for 1 hr before the addition of 32 ml (4.0 eq) of triethylamine. The reaction temperature was kept at 50 ° C for 6 h, then cooled to 20 ° C. N, N-dimethylpropane-1,3-diamine (DMAPA) (2 eq.) Was added and the mixture was stirred for 5 h. 6M hydrochloric acid in 2-propanol (125 ml) was added and stirred for 2 hours at 30 ° C. The organic layer was then washed with 125 ml of water. The resulting organic layer was concentrated and replaced with n-butanol. After seeding, the mixture was cooled and compound (X) was collected by filtration, washed and dried. Yield: 79%.
    权利要求:
    Claims (6)
    [1]
    1. A process for preparing compound (XII-c) from compound (IV)

    [2]
    2. The process of claim 1, wherein the suitable amino protecting group is a carbamate (-NHCO 2 R) wherein R is C 1-8 alkyl, phenyl, or aryl (C 1-8 ) alkyl.
    [3]
    The process of claim 1, wherein the amide bond formation conditions comprise reacting compound (IV) with compound (XII-c) in the presence of an amide coupling reagent selected from 1,1- carbonyldiimidazole, T3P, EDCI, DMTMM, or EEDQ in the presence of a catalyst.
    [4]
    The process of claim 3 wherein the catalyst is (1) an amidine such as DBU or DBN, (2) a tertiary amine such as DABCO, triethylamine, or DIPEA, (3) a guanidine such as TBD, TMG, or MTBD, or (4) a base such as NaH, KOtBu, and LiHMDS.
    [5]
    5. The process of claim 1, wherein compound (IV) is prepared by reacting compound (III)

    [6]
    6. The process of any of claims 1 to 5, wherein compound (III)

    is prepared by reacting a solution of compound (II)

    in xylenes with sodium cyanide in the presence of copper (I) iodide in butyronitrile at a temperature of about 120 ° C to obtain compound (III).
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