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【结 构 式】 
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【分子编号】14932 【品名】isobutyryl chloride; 2-methylpropanoyl chloride 【CA登记号】79-30-1 |
【 分 子 式 】C4H7ClO 【 分 子 量 】106.55168 【元素组成】C 45.09% H 6.62% Cl 33.27% O 15.02% |
合成路线1
该中间体在本合成路线中的序号：(D)The condensation of 2,3-dichloroanisole (I) with isobutyryl chloride (D) by means of AlCl3 in CH2Cl2 gives 2',3'-dichloro-4'-methoxyisobutyrophenone (VII), which is brominated with Br2 in acetic acid yielding 2-bromo-2',3'-dichloro-4'-methoxyisobutyrophenone (VIII). The dehydrobromination of (VIII) with LiBr in DMF affords (IX), which is cyclized with H2SO4 giving 6,7-dichloro-2-methyl-5-methoxy-1-indanone (X). The phenylation of (X) with diphenyliodonium chloride (E) and potassium tert-butoxide in tert-butanol gives 6,7-dichloro-2-methyl-2-phenyl-5-methoxy-1-indanone (XI), which is demethylated with pyridine hydrochloride at 190 C yielding 6,7-dichloro-2-methyl-2-phenyl-5-hydroxy-1-indanone (XII). Finally, (XII) is treated first with ethyl bromoacetate (G) and K2CO3 in DMF, and then with KOH in hot water-methanol. The phenol (XII) can also be treated with chloroacetonitrile (H) and K2CO3 in acetone to give 6,7-dichloro-2-methyl-2-phenyl-1-oxo-5-indanyloxyacetonitrile (XIII), which is finally hydrolyzed with H2SO4 in acetic acid. The phenol (XII) can also be condensed with diethyl bromomalonate (F) by means of NaH in dimethoxyethane giving diethyl 6,7-dichloro-2-methyl-2-phenyl-1-oxo-5-indanyloxymalonate (XIV), which is hydrolyzed with Na2CO3 in refluxing ethanol yielding 6,7-dichloro-2-methyl-2-phenyl-1-oxo-5-indanyloxymalonic acid (XV). Finally, this acid is decarboxylated by heating at 150 C.
| 【1】 Cragoe, E.J. Jr.; Woltersdorf, O.W. Jr. (Merck & Co., Inc.); Substituted indanones. DE 2448454; ES 430900; FR 2247218; GB 1474459 . |
| 【2】 Castaner, J.; Chatterjee, S.S.; MK 196. Drugs Fut 1977, 2, 3, 179. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (H) | 14443 | 2-chloroacetonitrile; chloroacetonitrile | 107-14-2 | C2H2ClN | 详情 | 详情 |
| (D) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |
| (G) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (F) | 35647 | diethyl 2-bromomalonate | 685-87-0 | C7H11BrO4 | 详情 | 详情 |
| (E) | 40097 | diphenyliodonium chloride | 1483-72-3 | C12H10ClI | 详情 | 详情 |
| (I) | 40081 | 1,2-dichloro-3-methoxybenzene; 2,3-dichlorophenyl methyl ether | 1984-59-4 | C7H6Cl2O | 详情 | 详情 |
| (VII) | 40088 | 1-(2,3-dichloro-4-methoxyphenyl)-2-methyl-1-propanone | C11H12Cl2O2 | 详情 | 详情 | |
| (VIII) | 40089 | 2-bromo-1-(2,3-dichloro-4-methoxyphenyl)-2-methyl-1-propanone | C11H11BrCl2O2 | 详情 | 详情 | |
| (IX) | 40090 | 1-(2,3-dichloro-4-methoxyphenyl)-2-methyl-2-propen-1-one | C11H10Cl2O2 | 详情 | 详情 | |
| (X) | 40091 | 6,7-dichloro-5-methoxy-2-methyl-1-indanone | C11H10Cl2O2 | 详情 | 详情 | |
| (XI) | 40092 | 6,7-dichloro-5-methoxy-2-methyl-2-phenyl-1-indanone | C17H14Cl2O2 | 详情 | 详情 | |
| (XII) | 40093 | 6,7-dichloro-5-hydroxy-2-methyl-2-phenyl-1-indanone | C16H12Cl2O2 | 详情 | 详情 | |
| (XIII) | 40094 | 2-[(6,7-dichloro-2-methyl-1-oxo-2-phenyl-2,3-dihydro-1H-inden-5-yl)oxy]acetonitrile | C18H13Cl2NO2 | 详情 | 详情 | |
| (XIV) | 40095 | diethyl 2-[(6,7-dichloro-2-methyl-1-oxo-2-phenyl-2,3-dihydro-1H-inden-5-yl)oxy]malonate | C23H22Cl2O6 | 详情 | 详情 | |
| (XV) | 40096 | 2-[(6,7-dichloro-2-methyl-1-oxo-2-phenyl-2,3-dihydro-1H-inden-5-yl)oxy]malonic acid | C19H14Cl2O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The synthesis of heptadeuterated flutamide has been reported: The reaction of deuterated isopropyl bromide (I) with Mg in THF gives the corresponding Grignard reagent (II), which is treated with CO2 yielding the deuterated isobutyric acid (III). The reaction of (III) with oxalyl chloride affords the expected acyl chloride (IV), which is finally condensed with 4-nitro-3-(trifluoromethyl)aniline (V).
| 【1】 Passarella, D.; et al.; Synthesis of flutamide-d7 and its main metabolite-d6. J Label Compd Radiopharm 1999, 42, 3, 275. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 32658 | 2-bromopropane | 75-26-3 | C3H7Br | 详情 | 详情 |
| (II) | 33398 | bromo(isopropyl)magnesium | 920-39-8 | C3H7BrMg | 详情 | 详情 |
| (III) | 33399 | 2-methylpropionic acid | 79-31-2 | C4H8O2 | 详情 | 详情 |
| (IV) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |
| (V) | 33400 | 4-nitro-3-(trifluoromethyl)phenylamine; 4-nitro-3-(trifluoromethyl)aniline; 3-Trifluoromethyl-4-nitroaniline | 393-11-3 | C7H5F3N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)By condensation of 4-nitro-3-trifluoromethylaniline (II) with isobutiryl (I) in pyridine.
| 【1】 Neri, R.O.; et al.; Substituierte Anilide. DE 2130450 . |
| 【2】 Neri, R.O.; et al.; Nouveaux anilides substitues therapeutiquement actifs et leurs procedes de fabrication. FR 2142803 . |
| 【3】 Thorpe, P.; Castaner, J.; Flutamide. Drugs Fut 1976, 1, 3, 108. |
合成路线4
该中间体在本合成路线中的序号：(A)By reaction of benzyl chloroformate (I) with epinine hydrobromide (II) in sodium tetraborate and 2N NaOH to give the compound (III), which is esterified with isobutanoyl chloride (A) in pyridine giving (IV), which is debenzylated with H2.
| 【1】 Casagrande, C.; Ferrari, G. (Simes SpA); Epinine esters and pharmaceutical compositions thereof. DE 2734678; ES 461399; FR 2360558; GB 1551661; JP 53021130; US 4218470 . |
| 【2】 Doherty, J.B.; Rupprecht, K.M.; Goulet, J.L.; Chen, M.-H.; Bao, J.; Liu, L.; Miao, S.; Hunt, J.A.; Hong, X.; Stelmach, J.E.; Ruzek, R.D.; Wisnoski, D.D.; Natarajan, S.R. (Merck & Co., Inc.); (Halo-benzo carbonyl)heterocyclic fused phenyl p38 kinase inhibiting agents. EP 1345603; WO 0258695 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |
| (I) | 24261 | 1-[2-(chlorooxy)-2-oxoethyl]benzene | C8H7ClO2 | 详情 | 详情 | |
| (II) | 32285 | 4-[2-(methylamino)ethyl]-1,2-benzenediol | C9H13NO2 | 详情 | 详情 | |
| (III) | 32286 | benzyl 3,4-dihydroxyphenethyl(methyl)carbamate | C17H19NO4 | 详情 | 详情 | |
| (IV) | 32287 | 4-[2-[[(benzyloxy)carbonyl](methyl)amino]ethyl]-2-(isobutyryloxy)phenyl 2-methylpropanoate | C25H31NO6 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：The reaction of (I) with acetonitrile in sulfuric acid provides the amide (II), which after hydrolysis in 12N HCl/methanol yields the 4-amino derivative (III). Acylation of (III) with isobutyryl chloride followed by reduction with borane-methylsulfide complex gives the racemate (V), MK-927 (2). The resolution of MK-927 is accomplished through the di-p-toluoyl-D-tartaric acid salt.
| 【1】 Baldwin, J.J.; Christy, M.E.; Ponticello, G.S.; Anyiglaucoma thieno-thiopyran and thieno-thiepin sulfonamide derivatives, compositions, and method of use thereof.. US 4677115 . |
| 【2】 Baldwin, J.J.; Ponticello, G.S.; Sugrue, M.F.; MK-417. Drugs Fut 1989, 14, 7, 636. |
| 【3】 Ponticello, G.S.; Freedman, M.B.; Habecker, C.N.; Lyle, P.A.; Schwam, H.; Varga, S.L.; Christy, M.E.; Randall, W.C.; Baldwin, J.J.; Thienothiopyran-2-sulfonamides: A novel class of water-soluble carbonic anhydrase inhibitors. J Med Chem 1987, 30, 591-7. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 | |
| (I) | 21040 | 4-hydroxy-1,1-dioxo-1,2,3,4-tetrahydro-2H-thieno[2,3-b]thiopyran-6-sulfonamide | C7H9NO5S3 | 详情 | 详情 | |
| (II) | 21041 | N-[6-(aminosulfonyl)-1,1-dioxo-1,2,3,4-tetrahydro-2H-thieno[2,3-b]thiopyran-4-yl]acetamide | C9H12N2O5S3 | 详情 | 详情 | |
| (III) | 21042 | 4-amino-1,1-dioxo-1,2,3,4-tetrahydro-2H-thieno[2,3-b]thiopyran-6-sulfonamide | C7H10N2O4S3 | 详情 | 详情 | |
| (IV) | 21043 | N-[6-(aminosulfonyl)-1,1-dioxo-1,2,3,4-tetrahydro-2H-thieno[2,3-b]thiopyran-4-yl]-2-methylpropanamide | C11H16N2O5S3 | 详情 | 详情 | |
| (V) | 21044 | 4-(isobutylamino)-1,1-dioxo-1,2,3,4-tetrahydro-2H-thieno[2,3-b]thiopyran-6-sulfonamide | C11H18N2O4S3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)The acylation of methylanthranilate (I) with isobutyryl chloride (II) gives 2-isobutyramidobenzoic acid methyl ester (III), which is reduced with LiAlH4 to 2-(isobutylamino)benzyl alcohol (IV). The methylation of (IV) with dimethyl sulfate yields 2-(N-isobutyl-N-methylamino)benzyl alcohol (V), which is treated with SOCl2 to afford the corresponding benzyl chloride (VI). The condensation of (VI) with benzimidazole-2-thiol (VII) by means of NaOH yields 2-[2-(N-isobutyl-N-methylamino)benzylsulfanyl)benzimidazole (VIII), which is finally oxidized with m-chloroperbenzoic acid (MCPBA) as usual.
| 【1】 Mealy, N.; Castaner, J.; Leminoprazole. Drugs Fut 1996, 21, 2, 155. |
| 【2】 Mazaki, M.; Yamakawa, T.; Nomura, Y. (Nippon Chemiphar Co., Ltd.); Method for the preparation of benzimidazole cpds. JP 1990078665 . |
| 【3】 Okabe, S.; Sato, M.; Yamakawa, T.; Nomura, T.; Hayashi, M. (Nippon Chemiphar Co., Ltd.); Cytoprotective agents for stomach and intestine. JP 1988230633 . |
| 【4】 Susumu, O.; Masaru, S.; Tomio, Y.; Yutaka, N.; Masatoshi, H. (Nippon Chemiphar Co., Ltd.); Benzimidazole derivs. and antiulcer agents contain. AU 8546409; BE 0903128; CH 665417; DE 3531487; ES 8703142; FR 2569691; GB 2163747; JP 1986060660; JP 1986221175; JP 1986221176; JP 1991223260; JP 1991223261; JP 1991223262; JP 1991227927 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 11161 | methyl 2-aminobenzoate; Methyl anthranilate | 134-20-3 | C8H9NO2 | 详情 | 详情 |
| (II) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |
| (III) | 14933 | methyl 2-(isobutyrylamino)benzoate | C12H15NO3 | 详情 | 详情 | |
| (IV) | 14934 | [2-(isobutylamino)phenyl]methanol | C11H17NO | 详情 | 详情 | |
| (V) | 14935 | [2-[isobutyl(methyl)amino]phenyl]methanol | C12H19NO | 详情 | 详情 | |
| (VI) | 14936 | 2-(chloromethyl)-N-isobutyl-N-methylaniline; N-[2-(chloromethyl)phenyl]-N-isobutyl-N-methylamine | C12H18ClN | 详情 | 详情 | |
| (VII) | 12821 | 2-Mercaptobenzinidiazole; 1H-Benzimidazol-2-ylhydrosulfide; 1H-Benzimidazole-2-thiol; 2-Benzimidazolethiol; o-Phenylenethiourea; 2-Benzimidazolinethione; 1,3-Dihydro-2H-benzimidazole-2-thione | 583-39-1 | C7H6N2S | 详情 | 详情 |
| (VIII) | 14938 | 2-[(1H-benzimidazol-2-ylsulfanyl)methyl]-N-isobutyl-N-methylaniline; N-[2-[(1H-benzimidazol-2-ylsulfanyl)methyl]phenyl]-N-isobutyl-N-methylamine | C19H23N3S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IV)1) The condensation of 2-(1,3-dixolan-2-yl)ethylamine (I) with ethyl 2-bromo-2-(4-fluorophenyl)acetate (II) by means of triethylamine in acetonitrile gives ethyl 2-[2-(1,3-dioxolan-2-yl)ethylamino]-2-(4-fluorophenyl)acetate (III), which is acylated with isobutyryl chloride (IV) and triethylamine in dichloromethane yielding the corresponding amide (V). Saponification of the ester (V) with NaOH in methanol/water affords the free acid (VI), which is cyclized with N,3-diphenylpropynamide (VII) [obtained in the reaction of 3-phenylpropynoic acid (VIII) with aniline (IX) by means of dicyclohexylcarbodiimide (DCC)] by heating at 90 C in acetic anhydride giving 1-[2-(1,3-dioxolan-2-yl)ethyl]-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenylpyrrole-3-carboxamide (X). The hydrolysis of the dioxolane group of (X) with HCl yields the corresponding aldehyde (XI), which is condensed with methyl acetoacetate (XII) by means of NaH in THF affording 7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N-phenylcarbamoyl)pyrrol-1-yl]-5-hydroxy-3-oxoheptanoic acid methyl ester (XIII). The reduction of the carbonyl group of (XIII) with tributylborane and NaBH4 in THF gives the (3R*,5R*)-dihydroxy ester (XIV), which is saponified with NaOH in water yielding the corresponding free acid (XV). The lactonization of (XV) by heating in refluxing toluene affords the (R*,R*)-lactone (XVI), which is submitted to optical resolution by reaction with (R)-1-phenylethylamine (XVII) followed by fractional crystallization thus obtaining the amide (XVII) as the pure (R,R,R)-enantiomer. The hydrolysis of the amide (XVIII) with NaOH, followed by heating in refluxing toluene gives the (R,R)-lactone (XIX), which is finally treated first with NaOH in methanol/water, and then with CaCl2 or calcium acetate.
| 【1】 Graul, A.; Castaner, J.; Atorvastatin Calcium. Drugs Fut 1997, 22, 9, 956. |
| 【2】 Roth, B.D.; Blankley, C.J.; Chucholowski, A.W.; Ferguson, E.; Hoefle, M.L.; Ortwine, D.F.; Newton, R.S.; Sekerke, C.S.; Sliskovic, D.R.; Stratton, C.D.; Wilson, M.W.; Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran-2-one inhibitors of HMG-CoA reductase. 2. Effects of introducing substituents at positions three and four of the pyrrole nucleus. J Med Chem 1991, 34, 1, 357-66. |
| 【3】 Roth, B.D. (Pfizer Inc.); Trans-6-[2-(3- or 4-carboxamido-substd. pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis. EP 0247633; US 4681893 . |
| 【4】 Roth, B.D. (Pfizer Inc.); (R-(R*R*)-2-(4-Fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl-3 -phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid, its lactone form and salts thereo. EP 0409281; JP 1991058967; US 5273995 . |
| 【5】 Mills, N.; Muhammad, N.A.; Weiss, J.; Nesbitt, R.U. (Pfizer Inc.); Stable oral CI-981 formulation and process for preparing same. EP 0680320; JP 1996505640; US 5686104; WO 9416693 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 15376 | 2-(1,3-dioxolan-2-yl)ethylamine; 2-(1,3-dioxolan-2-yl)-1-ethanamine | 5754-35-8 | C5H11NO2 | 详情 | 详情 |
| (II) | 15377 | ethyl 2-bromo-2-(4-fluorophenyl)acetate | 712-52-7 | C10H10BrFO2 | 详情 | 详情 |
| (III) | 15378 | ethyl 2-[[2-(1,3-dioxolan-2-yl)ethyl]amino]-2-(4-fluorophenyl)acetate | C15H20FNO4 | 详情 | 详情 | |
| (IV) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |
| (V) | 15380 | ethyl 2-[[2-(1,3-dioxolan-2-yl)ethyl](isobutyryl)amino]-2-(4-fluorophenyl)acetate | C19H26FNO5 | 详情 | 详情 | |
| (VI) | 15381 | 2-[[2-(1,3-dioxolan-2-yl)ethyl](isobutyryl)amino]-2-(4-fluorophenyl)acetic acid | C17H22FNO5 | 详情 | 详情 | |
| (VII) | 15382 | N,3-diphenyl-2-propynamide | C15H11NO | 详情 | 详情 | |
| (VIII) | 15383 | 3-phenyl-2-propynoic acid; Phenylpropiolic acid | 637-44-5 | C9H6O2 | 详情 | 详情 |
| (IX) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (X) | 15385 | 1-[2-(1,3-dioxolan-2-yl)ethyl]-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C31H31FN2O3 | 详情 | 详情 | |
| (XI) | 15386 | 5-(4-fluorophenyl)-2-isopropyl-1-(3-oxopropyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide | C29H27FN2O2 | 详情 | 详情 | |
| (XII) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (XIII) | 15388 | methyl 7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-5-hydroxy-3-oxoheptanoate | C34H35FN2O5 | 详情 | 详情 | |
| (XIV) | 15389 | methyl (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate | C34H37FN2O5 | 详情 | 详情 | |
| (XV) | 15390 | (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid | C33H35FN2O5 | 详情 | 详情 | |
| (XVI) | 15391 | 5-(4-fluorophenyl)-1-[2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl]-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C33H33FN2O4 | 详情 | 详情 | |
| (XVII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XVIII) | 15393 | 1-((3R,5R)-3,5-dihydroxy-7-oxo-7-[[(1R)-1-phenylethyl]amino]heptyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C41H44FN3O4 | 详情 | 详情 | |
| (XIX) | 15391 | 5-(4-fluorophenyl)-1-[2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl]-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C33H33FN2O4 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)Nolomirole is synthesized by acylation of (rac)-6-(methylamino)-5,6,7,8-tetrahydronaphthalene-1,2-diol, CHF-1024 (I) with isobutyryl chloride (II) in THF. Reductocondensation of 5,6-dimethoxy-2-tetralone (III) with methylamine (IV) by means of LiBH4 or NaBH4 gives N-(5,6-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylamine (V), which is treated with 48% HBr at 110 C.
| 【1】 Castaner, J.; Mealy, N.E.; Bayes, M.; Leeson, P.A.; Nolomirole Hydrochloride. Drugs Fut 2001, 26, 11, 1046. |
| 【2】 Chiesi, P.; Villani, V. (Chiesi Farmaceutici SpA); 1,2,3,4-Tetrahydronaphthaline derivs., process for their preparation and pharmaceutical compsns. containing them. DE 3320936; GB 2123410 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 49435 | 6-(methylamino)-5,6,7,8-tetrahydro-1,2-naphthalenediol | C11H15NO2 | 详情 | 详情 | |
| (II) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |
| (III) | 37386 | 5,6-dimethoxy-3,4-dihydro-2(1H)-naphthalenone | C12H14O3 | 详情 | 详情 | |
| (IV) | 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 详情 | 详情 |
| (V) | 37381 | N-(5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-N-methylamine; 5,6-dimethoxy-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine | C13H19NO2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(II)Activation of butyric acid derivative (I) with isobutyl chloroformate (II) by means of Et3N in THF, followed by coupling with ethylamine (III) in THF in the presence of Et3N, yields butyramide derivative (IV). Reduction of (IV) by means of (-)-B-chlorodiisopinocampheylborane (Ipc2BCl) in THF, followed by reaction with diethanolamine (A), affords hydroxy derivative (V), whose carbonyl group is removed by means of sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) in toluene/THF, followed by treatment with H2SO4 to provide compound (VI) . Separately, the synthesis of intermediate (XIV) is performed as follows: condensation of pentamethylene chlorohydrin (VII) with 3,4-dihydro-2H-pyran (VIII) by means of p-toluenesulfonic acid in Et2O furnishes 5-chloropentyl-2-tetrahydropyranyl ether (IX), which is then subjected to reaction with acetone (X) in THF by means of Mg in the presence of 1,2-dibromoethane (B) to provide tetrahydropyranyl ether (XI). Conversion of hydroxy derivative (XI) into the corresponding fluoro derivative (XII) is performed by reaction with diethylaminosulfur trifluoride (DAST) in CH2Cl2, and posterior reaction of (XII) with pyridinium p-toluenesulfonate in EtOH furnishes 6-fluoro-6-methyl-1-heptanol (XIII). Finally, intermediate (XIV) is obtained by reaction of (XIII) with NBS and PPh3 in benzene. Condensation of secondary amine (VI) with intermediate (XIV) by means of NaHCO3 in refluxing acetonitrile provides methanesulfonamide (XV), which is finally converted into the target product by formation of the hemifumarate salt by treatment with fumaric acid (XVI) in acetone.
| 【1】 Hester, J.B.; Progress toward the development of a safe and effective agent for treating reentrant cardiac arrhythmias: Synthesis and evaluation of ibutilide analogues with enhanced metabolic stability and diminished proarrhythmic potential. J Med Chem 2001, 44, 7, 1099. |
| 【2】 Hester, J.B. Jr.; Gibson, J.K. (Pharmacia Corp.); Antiarrhythmic (S)-enantiomers of methanesulfonamides. EP 0802900; JP 1999500418; WO 9621643 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (A) | 24273 | 2-[(2-hydroxyethyl)amino]-1-ethanol | 111-42-2 | C4H11NO2 | 详情 | 详情 |
| (I) | 14625 | 4-[4-[(methylsulfonyl)amino]phenyl]-4-oxobutyric acid | C11H13NO5S | 详情 | 详情 | |
| (II) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |
| (III) | 10928 | Ethanamine | 75-04-7 | C2H7N | 详情 | 详情 |
| (IV) | 48114 | N-ethyl-4-[4-[(methylsulfonyl)amino]phenyl]-4-oxobutanamide | C13H18N2O4S | 详情 | 详情 | |
| (V) | 48115 | (4S)-N-ethyl-4-hydroxy-4-[4-[(methylsulfonyl)amino]phenyl]butanamide | C13H20N2O4S | 详情 | 详情 | |
| (VI) | 48116 | N-[4-[(1S)-4-(ethylamino)-1-hydroxybutyl]phenyl]methanesulfonamide | C13H22N2O3S | 详情 | 详情 | |
| (VII) | 48117 | 5-chloro-1-pentanol | C5H11ClO | 详情 | 详情 | |
| (VIII) | 13684 | 3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran | 110-87-2 | C5H8O | 详情 | 详情 |
| (IX) | 48118 | 2-[(5-chloropentyl)oxy]tetrahydro-2H-pyran; 5-chloropentyl tetrahydro-2H-pyran-2-yl ether | C10H19ClO2 | 详情 | 详情 | |
| (X) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (XI) | 48119 | 2-methyl-6-(tetrahydro-2H-pyran-2-yloxy)-2-hexanol | C12H24O3 | 详情 | 详情 | |
| (XII) | 48120 | 5-fluoro-5-methylhexyl tetrahydro-2H-pyran-2-yl ether; 2-[(5-fluoro-5-methylhexyl)oxy]tetrahydro-2H-pyran | C12H23FO2 | 详情 | 详情 | |
| (XIII) | 48121 | 6-fluoro-6-methyl-1-heptanol | C8H17FO | 详情 | 详情 | |
| (XIV) | 48122 | 1-bromo-6-fluoro-6-methylheptane | C8H16BrF | 详情 | 详情 | |
| (XV) | 48123 | N-(4-[(1S)-4-[ethyl(6-fluoro-6-methylheptyl)amino]-1-hydroxybutyl]phenyl)methanesulfonamide | C21H37FN2O3S | 详情 | 详情 | |
| (XVI) | 23808 | Fumaric acid; (E)-2-butenedioic acid | 110-17-8 | C4H4O4 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(VII)Protection of 2-amino-4-methoxycarbonylphenyl triflate (I) with benzyl chloroformate provided carbamate (II). Stille coupling of aryl triflate (II) with 1-pentynyl (tributyl)stannane (III) furnished adduct (IV), which was further cyclized to the indole derivative (V) upon treatment with gold(III)sodium chloride. The N-benzyloxycarbonyl group of (V) was then removed by catalytic hydrogenolysis, yielding indole (VI). Friedel-Crafts acylation of (VI) with isobutyryl chloride (VII) produced the 3-isobutyryl indole (VIII). Subsequent alkylation of the indole N of (VIII) with 2-chlorobenzyl bromide (IX) in the presence of NaH gave the N-benzyl derivative (X). The methyl ester group of (X) was then hydrolyzed to the carboxylic acid (XI) under basic conditions. Finally, conversion of acid (XI) to the title amide was carried out via activation with EDC/HOBt, followed by quenching with ammonium hydroxide.
| 【1】 Oku, T.; Sawada, K.; Kuroda, A.; Ohne, K.; Nomoto, A.; Hosogai, N.; Nakajima, Y.; Nagashima, A.; Sogabe, K.; Tamura, K.; Kobayashi, M. (Fujisawa Pharmaceutical Co., Ltd.); Indole derivs. as cGMP-PDE inhibitors. EP 0820441; JP 1999503445; WO 9632379 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 53075 | methyl 3-amino-4-{[(trifluoromethyl)sulfonyl]oxy}benzoate | n/a | C9H8F3NO5S | 详情 | 详情 |
| (II) | 53076 | methyl 3-{[(benzyloxy)carbonyl]amino}-4-{[(trifluoromethyl)sulfonyl]oxy}benzoate | n/a | C17H14F3NO7S | 详情 | 详情 |
| (III) | 53077 | tributyl(1-pentynyl)stannane | n/a | C17H34Sn | 详情 | 详情 |
| (IV) | 53078 | methyl 3-{[(benzyloxy)carbonyl]amino}-4-(1-pentynyl)benzoate | n/a | C21H21NO4 | 详情 | 详情 |
| (V) | 53079 | 1-benzyl 6-methyl 2-propyl-1H-indole-1,6-dicarboxylate | n/a | C21H21NO4 | 详情 | 详情 |
| (VI) | 53080 | methyl 2-propyl-1H-indole-6-carboxylate | n/a | C13H15NO2 | 详情 | 详情 |
| (VII) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |
| (VIII) | 53081 | methyl 3-isobutyryl-2-propyl-1H-indole-6-carboxylate | n/a | C17H21NO3 | 详情 | 详情 |
| (IX) | 53082 | 1-(Bromomethyl)-2-chlorobenzene; 2-Chloro-alpha-bromotoluene; 2-Chlorobenzyl bromide; Alpha-Bromo-2-chlorotoluene; o-Chlorobenzyl bromide | 611-17-6 | C7H6BrCl | 详情 | 详情 |
| (X) | 53083 | methyl 1-(2-chlorobenzyl)-3-isobutyryl-2-propyl-1H-indole-6-carboxylate | n/a | C24H26ClNO3 | 详情 | 详情 |
| (XI) | 53084 | 1-(2-chlorobenzyl)-3-isobutyryl-2-propyl-1H-indole-6-carboxylic acid | n/a | C23H24ClNO3 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(II)The Friedel Crafts condensation of thioanisole (I) with isobutyryl chloride (II) by means of AlCl3 gives the propiophenone (III), which is alpha hydroxylated by means of Aliquant 336 and NaOH yielding the alpha hydroxy ketone (IV). The oxidation of the methylsulfanyl group of (IV) with magnesium monoperoxyphthalate (MMPP) affords the corresponding sulfone (V), which is finally cyclized with 2-(3,4-difluorophenoxy)acetic acid (VI) by means of 1-cyclohexyl-3-[2-(4-morpholinyl)ethyl]carbodiimide metho-p-toluenesulfonate (CMC), DMAP and DBU to furnish the target furanone.
| 【1】 Brideau, C.; Li, C.-S.; Chan, C.C.; Black, W.C.; et al.; A new structural variation on the methanesulfonylphenyl class of selective cyclooxygenase-2 inhibitors. Bioorg Med Chem Lett 1999, 9, 22, 3181. |
| 【2】 Belley, M.; Gauthier, J.Y.; Grimm, E.; Leblanc, Y.; Li, C.-S.; Therien, M.; Lau, C.-K.; Prasit, P.; Roy, P. (Merck Frosst Canada Inc.); (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors. EP 0863891; JP 1999500146; US 5981576; WO 9714691 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 19722 | 2-[(3aR,5S,7S,7aS)-7-hydroxy-7-(2-methoxyphenyl)octahydro-1H-isoindol-5-yl]acetonitrile | C17H22N2O2 | 详情 | 详情 | |
| (II) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |
| (III) | 36573 | 2-methyl-1-[4-(methylsulfanyl)phenyl]-1-propanone | C11H14OS | 详情 | 详情 | |
| (IV) | 36574 | 2-hydroxy-2-methyl-1-[4-(methylsulfanyl)phenyl]-1-propanone | C11H14O2S | 详情 | 详情 | |
| (V) | 36575 | 2-hydroxy-2-methyl-1-[4-(methylsulfonyl)phenyl]-1-propanone | C11H14O4S | 详情 | 详情 | |
| (VI) | 18826 | 2-(3,4-difluorophenoxy)acetic acid | C8H6F2O3 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(II)Friedel-Crafts acylation of thioanisole (I) with isobutyryl chloride (II) in the presence of AlCl3 gave ketone (III), which was hydroxylated with NaOH and a phase-transfer agent in CCl4-toluene to provide hydroxyketone (IV). Subsequent oxidation of the sulfide group employing Oxone(tm) gave rise to sulfone (V) (1). Further esterification of (V) with chloroacetyl chloride (VI) and pyridine yielded chloroacetate ester (VII), which was cyclized to the epoxy lactone (VIII) by treatment with DBU in acetonitrile. Finally, epoxide opening with the potassium salt of 5-bromo-2-hydroxypyridine (IX) produced the title (pyridyloxy)furanone.
| 【1】 Chan, C.C.; Lau, C.K.; Brideau, C.; et al.; Synthesis and biological evaluation of 3-heteroaryloxy-4-phenyl-2(5H)-furanones as selective COX-2 inhibitors. Bioorg Med Chem Lett 1999, 9, 22, 3187. |
| 【2】 Belley, M.; Gauthier, J.Y.; Grimm, E.; Leblanc, Y.; Li, C.-S.; Therien, M.; Lau, C.-K.; Prasit, P.; Roy, P. (Merck Frosst Canada Inc.); (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors. EP 0863891; JP 1999500146; US 5981576; WO 9714691 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 19272 | methyl phenyl sulfide; 1-(methylsulfanyl)benzene | 100-68-5 | C7H8S | 详情 | 详情 |
| (II) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |
| (III) | 36573 | 2-methyl-1-[4-(methylsulfanyl)phenyl]-1-propanone | C11H14OS | 详情 | 详情 | |
| (IV) | 36574 | 2-hydroxy-2-methyl-1-[4-(methylsulfanyl)phenyl]-1-propanone | C11H14O2S | 详情 | 详情 | |
| (V) | 36575 | 2-hydroxy-2-methyl-1-[4-(methylsulfonyl)phenyl]-1-propanone | C11H14O4S | 详情 | 详情 | |
| (VI) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (VII) | 36576 | 1,1-dimethyl-2-[4-(methylsulfonyl)phenyl]-2-oxoethyl 2-chloroacetate | C13H15ClO5S | 详情 | 详情 | |
| (VIII) | 36577 | 4,4-dimethyl-5-[4-(methylsulfonyl)phenyl]-3,6-dioxabicyclo[3.1.0]hexan-2-one | C13H14O5S | 详情 | 详情 | |
| (IX) | 36578 | potassium 5-bromo-2-pyridinolate | C5H3BrKNO | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(IX)The condensation of 2,4,6-trimethylaniline (I) with adipoin (II) in hot toluene, followed by reaction of the resulting intermediate (III) with malononitrile (IV), gave rise to the tetrahydroindole (V). Subsequent condensation of amino nitrile (V) with 2-methoxypropene (VI) produced the tetrahydropyrido[2,3-b]indole system (VII), which was dehydrogenated to (VIII) by means of Pd/C in boiling decalin. Acylation of (VIII) with isobutyryl chloride (IX) afforded amide (X), which was reduced to amine (XI) employing borane-dimethyl sulfide complex. Further acylation with chloroacetyl chloride (XII), and then reduction of the resulting chloroacetamide (XIII) with borane-dimethyl sulfide, provided the chloroethyl amine (XIV). This was finally treated with dimethylamine in hot N-methylpyrrolidinone in a steel bomb to furnish the desired dimethylamino compound.
| 【1】 Darrow, J.W.; Maynard, G.D.; Horvath, R.F. (Neurogen Corp.); Aminoalkyl substd. 9H-pyridino[2,3-b]indole and 9H-pyrimidino[4,5-b]indole derivs.. EP 1068207; US 6147085; WO 9951600 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 28804 | 2,4,6-trimethylaniline | 88-05-1 | C9H13N | 详情 | 详情 |
| (II) | 44979 | 2-hydroxycyclohexanone | 533-60-8 | C6H10O2 | 详情 | 详情 |
| (III) | 44980 | 2-(mesitylamino)-1-cyclohexen-1-ol | C15H21NO | 详情 | 详情 | |
| (IV) | 12061 | Malononitrile | 109-77-3 | C3H2N2 | 详情 | 详情 |
| (V) | 44981 | 2-amino-1-mesityl-4,5,6,7-tetrahydro-1H-indole-3-carbonitrile | C18H21N3 | 详情 | 详情 | |
| (VI) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (VII) | 44982 | 9-mesityl-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-ylamine; 9-mesityl-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-amine | C21H25N3 | 详情 | 详情 | |
| (VIII) | 44983 | 9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-ylamine; 9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-amine | C21H21N3 | 详情 | 详情 | |
| (IX) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |
| (X) | 44984 | N-(9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-yl)-2-methylpropanamide | C25H27N3O | 详情 | 详情 | |
| (XI) | 44985 | N-isobutyl-9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-amine; N-isobutyl-N-(9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-yl)amine | C25H29N3 | 详情 | 详情 | |
| (XII) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (XIII) | 44986 | 2-chloro-N-isobutyl-N-(9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-yl)acetamide | C27H30ClN3O | 详情 | 详情 | |
| (XIV) | 44987 | N-(2-chloroethyl)-N-isobutyl-9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-amine; N-(2-chloroethyl)-N-isobutyl-N-(9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-yl)amine | C27H32ClN3 | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(XXIV)An alternative procedure for the preparation of the carbapenem system was based on the desulfurative ring contraction of a 1-aza-3-thiabicyclo[4.2.0]octane. The required diethyl (mercaptomethyl)malonate (XXI) was prepared by condensation of diethyl malonate (XVIII) with paraformaldehyde to give methylene malonate (XIX). Conjugate addition of thioacetic acid to (XIX) afforded thioester (XX) and subsequent acid hydrolysis yielded the desired mercaptomethyl derivative (XXI). Coupling of (XXI) with azetidinonepropionic acid (XXII) via activation with CDI generated thioester (XXIII). Oxalic acid chloride isobutyryloxymethyl ester (XXV) was obtained from isobutyryl chloride (XXIV) by condensation with paraformaldehyde, followed by reaction of the resulting chloromethylbutyrate with monobenzyl oxalate tetrabutylammonium salt, hydrogenolysis of the benzyl group and chlorination with oxalyl chloride. Coupling of this acid chloride (XXV) with azetidinone (XXIII) gave imide (XXVI), which was reduced to the hydroxy derivative (XXVII) with Zn and AcOH. After chlorination of (XXVII) with SOCl2 and pyridine, cleavage of the methylenemalonate group, followed by cyclization in the presence of Et3N gave rise to the bicyclic system (XXIX).
| 【1】 Horikawa, H.; Iwasaki, T.; Kondo, K. (Tanabe Seiyaku Co., Ltd.); Process for preparing beta-lactam deriv. and synthetic intermediate thereof. EP 0559533 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIII) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (XIX) | 37725 | diethyl 2-methylenemalonate | C8H12O4 | 详情 | 详情 | |
| (XX) | 37726 | diethyl 2-[(acetylsulfanyl)methyl]malonate | C10H16O5S | 详情 | 详情 | |
| (XXI) | 37727 | diethyl 2-(sulfanylmethyl)malonate | C8H14O4S | 详情 | 详情 | |
| (XXII) | 30029 | (2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propionic acid | C14H27NO4Si | 详情 | 详情 | |
| (XXIII) | 37728 | diethyl 2-[([(2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propanoyl]sulfanyl)methyl]malonate | C22H39NO7SSi | 详情 | 详情 | |
| (XXIV) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |
| (XXV) | 37729 | [(2-chloro-2-oxoacetyl)oxy]methyl 2-methylpropanoate | C7H9ClO5 | 详情 | 详情 | |
| (XXVI) | 37730 | diethyl 2-[([(2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1-(2-[[(3-methylbutanoyl)oxy]methoxy]-2-oxoacetyl)-4-oxoazetidinyl]propanoyl]sulfanyl)methyl]malonate | C30H49NO12SSi | 详情 | 详情 | |
| (XXVII) | 37731 | diethyl 2-[([(2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1-(1-hydroxy-2-[[(3-methylbutanoyl)oxy]methoxy]-2-oxoethyl)-4-oxoazetidinyl]propanoyl]sulfanyl)methyl]malonate | C30H51NO12SSi | 详情 | 详情 | |
| (XXVIII) | 37732 | diethyl 2-[([(2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1-(1-chloro-2-[[(3-methylbutanoyl)oxy]methoxy]-2-oxoethyl)-4-oxoazetidinyl]propanoyl]sulfanyl)methyl]malonate | C30H50ClNO11SSi | 详情 | 详情 | |
| (XXIX) | 37733 | (isobutyryloxy)methyl (5R,6S,7S)-7-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-5-methyl-4,8-dioxo-3-thia-1-azabicyclo[4.2.0]octane-2-carboxylate | C21H35NO7SSi | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(VIII)Cyclohexanecarboxylic acid (I) is condensed with 1-bromo-2-ethylbutane (II) by means of lithium diisopropylamide (LDA) (NaH can also be added ) in THF or THF/cyclohexane to afford derivative (III). Treatment of carboxylic acid (III) with oxalyl chloride in CH2Cl2 (a small amount of DMF can be added) yields acid chloride (IV), which is then coupled with bis(2-aminophenyl) disulfide (V) in pyridine to provide disulfide derivative (VI). Reduction of the disulfide bond of (VI) with PPh3 in dioxane/H2O gives benzenethiol (VII), which is finally coupled with isobutyryl chloride (VIII) in pyridine/CHCl3 to furnish the target compound.
| 【2】 Maeda, K.; Okamoto, H.; Shinkai, H. (Japan Tobacco Inc.); CEPT activity inhibitors. EP 1020439; JP 1999049743; JP 1999222428; WO 9835937 . |
| 【1】 maeda, K.; Shinkai, H.; Yamasaki, T.; Okamoto, H.; Uchida, I.; Bis(2-(acylamino)phenyl) disulfides, 2-(acylamino)benzenethiols, and S-(2-(acylamino)phenyl) alkanethioates as novel inhibitors of cholesteryl ester transfer protein. J Med Chem 2000, 43, 19, 3566. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 44803 | cyclohexanecarboxylic acid | 98-89-5 | C7H12O2 | 详情 | 详情 |
| (II) | 44804 | 1-(1-ethylpropyl)-1lambda(3)-dibromane | C5H12Br2 | 详情 | 详情 | |
| (III) | 44805 | 1-(2-ethylbutyl)cyclohexanecarboxylic acid | C13H24O2 | 详情 | 详情 | |
| (IV) | 44806 | 1-(2-ethylbutyl)cyclohexanecarbonyl chloride | C13H23ClO | 详情 | 详情 | |
| (V) | 43460 | 2-[(2-aminophenyl)disulfanyl]aniline; 2-[(2-aminophenyl)disulfanyl]phenylamine | 1141-88-4 | C12H12N2S2 | 详情 | 详情 |
| (VI) | 44807 | 1-(2-ethylbutyl)-N-(2-[[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl]disulfanyl]phenyl)cyclohexanecarboxamide | C38H56N2O2S2 | 详情 | 详情 | |
| (VII) | 44808 | 1-(2-ethylbutyl)-N-(2-sulfanylphenyl)cyclohexanecarboxamide | C19H29NOS | 详情 | 详情 | |
| (VIII) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：(VI)The known aminoacid (I) is esterified to (II) employing methanolic H2SO4. Ester group reduction in (II) with LiAlH4 yields alcohol (III). The O-benzyl group of (III) is then removed by catalytic hydrogenation in the presence of Raney nickel, providing phenol (V). Alternatively, compound (III) is converted into diol (V) by O-benzyl group hydrogenolysis, followed by LiAlH4 reduction of the resultant ester (IV). Finally, selective monoesterification of diol (V) with isobutyryl chloride (VI) and triethylamine gives rise to the title compound.
| 【1】 Sorbera, L.A.; Castaner, J.; Leeson, P.A.; Fesoterodine. Drugs Fut 2003, 28, 7, 647. |
| 【2】 Meese, C. (Schwarz Pharma AG); Stable salts of novel derivs. of 3,3-diphenylpropylamines. DE 19955190; JP 2003514018; WO 0135957 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 60854 | 4-(benzyloxy)-3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]benzoic acid | C29H35NO3 | 详情 | 详情 | |
| (II) | 60855 | methyl 4-(benzyloxy)-3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]benzoate | C30H37NO3 | 详情 | 详情 | |
| (III) | 60856 | {4-(benzyloxy)-3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenyl}methanol | C29H37NO2 | 详情 | 详情 | |
| (IV) | 60857 | methyl 3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxybenzoate | C23H31NO3 | 详情 | 详情 | |
| (V) | 60858 | 2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenol | C22H31NO2 | 详情 | 详情 | |
| (VI) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |
合成路线17
该中间体在本合成路线中的序号：(XI)Acylation of cytidine (I) with benzoic anhydride in DMF provides N4-benzoylcytidine (II), which is regioselectively protected at the 3’- and 5’-hydroxyl groups with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane in pyridine, giving the cyclic siloxane derivative (III). Subsequent Swern oxidation of the 2’-alcohol group of compound (III) using DMSO, TFAA and Et3N followed by addition of methyllithium to the obtained ketone (IV) and desilylation with AcOH leads to the 2’-C-methylcytidine derivative (V). After reprotection of the primary and secondary hydroxyl groups of the cytidine (V) with benzoyl chloride in pyridine, the tertiary hydroxyl of compound (VI) is fluorinated using DAST in cold toluene to give the benzoyl-protected 2’-deoxy-2’-fluoro-2’-methylcytidine (VII) (1-3). In a different strategy, the nucleoside derivative (VII) is prepared by coupling of the methyl (VIIIa) (1-3) or acetyl (VIIIb) glycosides (4) or the glycosyl chloride (VIIIc) (5) with silylated N4-benzoylcytosine (IX) by means of either trimethylsilyl triflate or tin tetrachloride. The tribenzoylated precursor (VII) is then deprotected with methanolic NaOMe (1, 2) or ammonia (3, 4) to obtain PSI-6130 (X), which is finally esterified with isobutyryl chloride (XI) in the presence of DMAP and Et3N in THF/H2O (6). Scheme 1.
| 【1】 Clark, J. (Pharmasset Ltd.). Modified fluorinated nucleoside analogues. WO 2005003147. |
| 【2】 Clark, J.L., Hollecker, L., Mason, J.C. Design, synthesis, and antiviral activity of 2’-deoxy-2’-fluoro-2’-C-methylcytidine, a potent inhibitor of hepatitis C virus replication. J Med Chem 2005, 48(17): 5504-8. |
| 【3】 Clark, J. (Pharmasset, Inc.). Modified fluorinated nucleoside analogues. US 20080070861. |
| 【4】 Chun, B.-K., Wang, P. (Pharmasset, Inc.). Preparation of 2’-fluoro-2’-alkyl-substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives. WO 2006031725. |
| 【5】 Axt, S.D., Sarma, K., Vitale, J. et al. (Pharmasset, Inc.; F. Hoffmann La Roche AG). Preparation of nucleosides ribofuranosyl pyrimidines. WO 2008045419. |
| 【6】 Chun, B.-K., Clark, J., Sarma, K., Wang, P. (F. Hoffmann-La Roche AG; Pharmasset, Inc.). Antiviral nucleosides. WO 2007065829. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIIA) | 65911 | ((2S,3S,4S)-3-(benzoyloxy)-4-fluoro-5-methoxy-4-methyltetrahydrofuran-2-yl)methyl benzoate | C21H21FO6 | 详情 | 详情 | |
| (VIIIB) | 65912 | C22H21FO6 | 详情 | 详情 | ||
| (VIIIC) | 65913 | C20H17ClFO5 | 详情 | 详情 | ||
| (I) | 27920 | Cytidine; 4-amino-1-((2S,3S,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one;4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2(1H)-pyrimidinone | 65-46-3 | C9H13N3O5 | 详情 | 详情 |
| (II) | 61580 | N-Benzoylcytidine;N-[1-[3,4-Dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxopyrimidin-4-yl]benzamide;N-{1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2-oxo-1,2-dihydro-4-pyrimidinyl}benzamide | 13089-48-0 | C16H17N3O6 | 详情 | 详情 |
| (III) | 65906 | N-Benzoyl-3',5'-O-[1,1,3,3-tetrakis(1-methylethyl)-1,3-disiloxanediyl]cytidine; N-[1-[(6aR,8R,9R,9aS)-9-hydroxy-2,2,4,4-tetra(propan-2-yl)-6a,8,9,9a-tetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-2-oxopyrimidin-4-yl]benzamide | 69304-43-4 | C28H43N3O7Si2 | 详情 | 详情 |
| (IV) | 65907 | N-Benzoyl-2'-deoxy-2'-oxo-3',5'-O-[1,1,3,3-tetrakis(1-methylethyl)-1,3-disiloxanediyl]cytidine | 119411-03-9 | C28H41N3O7Si2 | 详情 | 详情 |
| (V) | 65908 | N-Benzoyl-2'-C-methyl-D-cytidine | C17H19N3O6 | 详情 | 详情 | |
| (VI) | 65909 | N-Benzoyl-3',5'-di-O-benzoyl-2'-C-methyl-D-cytidine | C31H27N3O8 | 详情 | 详情 | |
| (VII) | 65910 | (2'R)-N-Benzoyl-2'-deoxy-2'-fluoro-2'-methylcytidine 3',5'-dibenzoate | 817204-32-3 | C31H26FN3O7 | 详情 | 详情 |
| (IX) | 12715 | N-(2-Oxo-1,2-dihydro-4-pyrimidinyl)benzamide; N-Benzoylcytosine | 26661-13-2 | C11H9N3O2 | 详情 | 详情 |
| (X) | 65914 | 2'-Deoxy-2'-fluoro-2'-C-methylcytidine | 817204-33-4 | C10H14FN3O4 | 详情 | 详情 |
| (XI) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |