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【结 构 式】 
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【分子编号】14341 【品名】L-Alaninol; (2S)-2-Amino-1-propanol; L-(+)-Alaninol 【CA登记号】2749-11-3 |
【 分 子 式 】C3H9NO 【 分 子 量 】75.1106 【元素组成】C 47.97% H 12.08% N 18.65% O 21.3% |
合成路线1
该中间体在本合成路线中的序号：Reaction of ethyl 2,3,4,5-tetrafluorobenzoate (I) with the anion of di-tert-butyl malonate followed by in situ decarboxylation with CF3CO2H affords ethyl 4-carboxymethyl-2,3,5-trifluorobenzoate (II), which is esterfied with diphenyldiazomethane to give ethyl 4-(diphenylmethoxycarbonylmethyl)-2,3,5-trifluorobenzoate (III). Compound (III) is treated with p-formaldehyde in the presence of sodium methoxide to give ethyl 4-[1-(diphenylmethoxycarbonyl)-2-hydroxyethyl]-2,3,5-trifluorobenzoate (IV), which is dehydrated with mesyl chloride and triethylamine to give ethyl 4-[1-(diphenylmethoxycarbonyl)vinyl]-2,3,5-trifluorobenzoate (V). Cyclopropanation of (V) with trimethylsulfoxonium iodide affords ethyl 4-(1-carboxycyclopropyl)-2,3,5-trifluorobenzoate (VII). Treatment of (VII) with ethyl chlorocarbonate and sodium azide followed by reaction with benzyl alcohol affords ethyl 4-[1-(benzyloxycarbonylamino)cyclopropyl]-2,3,5-trifluorobenzoate (VIII), which is hydrolyzed to 4-[1-(benzyloxycarbonylamino)cyclopropyl]-2,3,5-trifluorobenzoic acid (IX) on treatment with NaOH. Reaction of (IX) with magnesium ethoxycarbonylacetate and 1,1'-carbonyldiimidazole yields ethyl 4-[1-(benzyloxycarbonylamino)cyclopropyl]-2,3,5-trifluorobenzoylacetate (X) , which is then sequentially reacted with N,N-dimethylformamide dimethylacetal and (S)-2-amino-1-propanol to give (S)-ethyl 2-[4-[1-(benzyloxycarbonylamino)cyclopropyl]-2,3,5-trifluorobenzoyl]-3-(2-hydroxy-1-methylethylamino)acrylate (XI). Cyclization of (XI) with sodium hydride or with K2CO3 (2) affords (S)-ethyl 10-[1-(benzyloxycarbonylamino)cyclopropyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate (XII), which is hydrolyzed on treatment with sodium hydroxide to give (S)-10-[1-(benzyloxycarbonylamino)cyclopropyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (XIII). Deprotection of (XIII) by hydrogenation over Pd in acetic acid, followed by treatment with hydrochloric acid, affords the monohydrochloride of T-3761 (XIV), which is finally converted to free T-3761 with potassium hydroxide.
| 【1】 Narita, H.; Todo, Y.; Nitta, J.; Takagi, H.; Iino, F.; Miyajima, M.; Fukuoka, Y.; Saikawa, I. (Toyama Chemical Co., Ltd.); Pyridonecarboxylic acid derivs. and their salts, process for their preparation as well as antibacterial agent containing them. CH 680793; DE 3913245; JP 1993043464; US 4990508 . |
| 【2】 Takakura, I.; Yamakawa, T.; Kitayama, I.; Fujishima, T. (Toyama Chemical Co., Ltd.); Dissolution method for quinolonecarboxylic acids or their salts. JP 1990264724 . |
| 【3】 Prous, J.; Mealy, N.; Castaner, J.; T-3761. Drugs Fut 1993, 18, 8, 717. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 14341 | L-Alaninol; (2S)-2-Amino-1-propanol; L-(+)-Alaninol | 2749-11-3 | C3H9NO | 详情 | 详情 | |
| (I) | 14314 | ethyl 2,3,4,5-tetrafluorobenzoate | C9H6F4O2 | 详情 | 详情 | |
| (II) | 14315 | 2-[4-(ethoxycarbonyl)-2,3,6-trifluorophenyl]acetic acid | C11H9F3O4 | 详情 | 详情 | |
| (III) | 14316 | ethyl 4-[2-(benzhydryloxy)-2-oxoethyl]-2,3,5-trifluorobenzoate | C24H19F3O4 | 详情 | 详情 | |
| (IV) | 14317 | ethyl 4-[2-(benzhydryloxy)-1-(hydroxymethyl)-2-oxoethyl]-2,3,5-trifluorobenzoate | C25H21F3O5 | 详情 | 详情 | |
| (V) | 14318 | ethyl 4-[1-[(benzhydryloxy)carbonyl]vinyl]-2,3,5-trifluorobenzoate | C25H19F3O4 | 详情 | 详情 | |
| (VI) | 14319 | ethyl 4-[1-[(benzhydryloxy)carbonyl]cyclopropyl]-2,3,5-trifluorobenzoate | C26H21F3O4 | 详情 | 详情 | |
| (VII) | 14320 | 1-[4-(ethoxycarbonyl)-2,3,6-trifluorophenyl]cyclopropanecarboxylic acid | C13H11F3O4 | 详情 | 详情 | |
| (VIII) | 14321 | ethyl 4-(1-[[(benzyloxy)carbonyl]amino]cyclopropyl)-2,3,5-trifluorobenzoate | C20H18F3NO4 | 详情 | 详情 | |
| (IX) | 14322 | 4-(1-[[(benzyloxy)carbonyl]amino]cyclopropyl)-2,3,5-trifluorobenzoic acid | C18H14F3NO4 | 详情 | 详情 | |
| (X) | 14323 | ethyl 3-[4-(1-[[(benzyloxy)carbonyl]amino]cyclopropyl)-2,3,5-trifluorophenyl]-3-oxopropanoate | C22H20F3NO5 | 详情 | 详情 | |
| (XI) | 14324 | ethyl (Z)-2-[4-(1-[[(benzyloxy)carbonyl]amino]cyclopropyl)-2,3,5-trifluorobenzoyl]-3-[[(1S)-2-hydroxy-1-methylethyl]amino]-2-propenoate | C26H27F3N2O6 | 详情 | 详情 | |
| (XII) | 14325 | ethyl (3S)-10-(1-[[(benzyloxy)carbonyl]amino]cyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate | C26H25FN2O6 | 详情 | 详情 | |
| (XIII) | 14326 | (3S)-10-(1-[[(benzyloxy)carbonyl]amino]cyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid | C24H21FN2O6 | 详情 | 详情 | |
| (XIV) | 14327 | (3S)-10-(1-aminocyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid | C16H15FN2O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)A new synthesis of T-3761 has been described: The esterification of 2,3,4,5-tetrafluorobenzoic acid (I) with ethyl bromide and K2CO3 in DMSO gives the corresponding ethyl ester (II), which is condensed with tert-butyl cyanoacetate (III) by means of K2CO3, yielding 4-(cyanomethyl)-2,3,5-trifluorobenzoic acid ethyl ester (V) through the intermediate (IV). The cyclopropanation of (V) with 1,2-dibromoethane and benzyltriethylammonium chloride and NaOH in water/dichloromethane affords 4-(1-cyanocyclopropyl)-2,3,5-trifluorobenzoic acid, which by treatment with H2O2 and NaOH is converted to 4-(1-carbamoylcyclopropyl)-2,3,5-trifluorobenzoic acid (VII). Degradation of amide (VII) with Cl2 and NaOH gives the corresponding 4-aminocyclopropyl derivative (VIII), which is acetylated with acetic anhydride to the acetamide (IX). The reaction of (IX) with SOCl2 yields the acid chloride (X), which is condensed with malonic acid monoethyl ester potassium salt (XI) by means of triethylamine to afford 2-[4-(1-acetamidocyclopropyl)-2,3,5-trifluorobenzoyl]acetic acid ethyl ester (XII). The consecutive reaction of (XII) first with dimethylformamide dimethylacetal (XIII) in acetic acid and then with 2(S)-aminopropanol (XIV) gives the benzoylacrylic intermediate (XV), which, without isolation, is treated with K2CO3 in DMSO at 100 C to afford the ethyl ester of the acetylated T-3761 (XVI). Finally, this compound is deprotected by successive treatment first with ethanolic NaOH and then with hot 6N HCl.
| 【1】 Iino, F.; Momonoi, K.; Hayashi, K.; Todo, Y.; Kuroda, H.; Takagi, H.; Narita, H.; Takata, M.; Practical synthesis of T-3761, (S)-10-(1-aminocyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid. Chem Pharm Bull 1994, 42, 12, 2629. |
| 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) | 14328 | 2,3,4,5-tetrafluorobenzoic acid | 1201-31-6 | C7H2F4O2 | 详情 | 详情 |
| (II) | 14313 | diethyl (2S)-2-[(4-[2-[(6R)-2-(acetamido)-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl]ethyl]benzoyl)amino]pentanedioate | C27H35N5O7 | 详情 | 详情 | |
| (III) | 14330 | tert-Butyl cyanoacetate; tert-butyl 2-cyanoacetate | 1116-98-9 | C7H11NO2 | 详情 | 详情 |
| (IV) | 14331 | ethyl 4-[2-(tert-butoxy)-1-cyano-2-oxoethyl]-2,3,5-trifluorobenzoate | C16H16F3NO4 | 详情 | 详情 | |
| (V) | 14332 | ethyl 4-(cyanomethyl)-2,3,5-trifluorobenzoate | C11H8F3NO2 | 详情 | 详情 | |
| (VI) | 14333 | ethyl 4-(1-cyanocyclopropyl)-2,3,5-trifluorobenzoate | C13H10F3NO2 | 详情 | 详情 | |
| (VII) | 14334 | 4-[1-(aminocarbonyl)cyclopropyl]-2,3,5-trifluorobenzoic acid | C11H8F3NO3 | 详情 | 详情 | |
| (VIII) | 14335 | 4-(1-aminocyclopropyl)-2,3,5-trifluorobenzoic acid | C10H8F3NO2 | 详情 | 详情 | |
| (IX) | 14336 | 4-[1-(acetamido)cyclopropyl]-2,3,5-trifluorobenzoic acid | C12H10F3NO3 | 详情 | 详情 | |
| (X) | 14337 | 4-[1-(acetamido)cyclopropyl]-2,3,5-trifluorobenzoyl chloride | C12H9ClF3NO2 | 详情 | 详情 | |
| (XI) | 14338 | potassium 3-ethoxy-3-oxopropanoate | 6148-64-7 | C5H7KO4 | 详情 | 详情 |
| (XII) | 14339 | ethyl 3-[4-[1-(acetamido)cyclopropyl]-2,3,5-trifluorophenyl]-3-oxopropanoate | C16H16F3NO4 | 详情 | 详情 | |
| (XIII) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (XIV) | 14341 | L-Alaninol; (2S)-2-Amino-1-propanol; L-(+)-Alaninol | 2749-11-3 | C3H9NO | 详情 | 详情 |
| (XV) | 14342 | ethyl (E)-2-[4-[1-(acetamido)cyclopropyl]-2,3,5-trifluorobenzoyl]-3-[[(1S)-2-hydroxy-1-methylethyl]amino]-2-propenoate | C20H23F3N2O5 | 详情 | 详情 | |
| (XVI) | 14343 | ethyl (3S)-10-[1-(acetamido)cyclopropyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate | C20H21FN2O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Condensation of L-alaninol (I) with benzaldehyde produced imine (II), which was further reduced to the N-benzyl amine (III) by means of NaBH4. Subsequent acylation of N-benzyl alaninol (III) with chloroacetyl chloride (IV) provided the chloroacetamide (V). This was subjected to intramolecular cyclization in the presence of NaH to afford morpholinone (VI). Lactam (VI) reduction employing LiAlH4 furnished the substituted morpholine (VII). The N-benzyl group of (VII) was then removed by hydrogenation in the presence of Pd/C, yielding (S)-3-methylmorpholine (VIII).
| 【1】 Powers, J.P. (Tularik Inc.); Arylsulfonic acid salts of pyrimidine-based antiviral agents. US 6410726; WO 0151485 . |
| 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) | 14341 | L-Alaninol; (2S)-2-Amino-1-propanol; L-(+)-Alaninol | 2749-11-3 | C3H9NO | 详情 | 详情 |
| (II) | 55056 | (2S)-2-{[(E)-phenylmethylidene]amino}-1-propanol | C10H13NO | 详情 | 详情 | |
| (III) | 55057 | (2S)-2-(benzylamino)-1-propanol | C10H15NO | 详情 | 详情 | |
| (IV) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (V) | 55058 | N-benzyl-2-chloro-N-[(1S)-2-hydroxy-1-methylethyl]acetamide | C12H16ClNO2 | 详情 | 详情 | |
| (VI) | 55059 | (5S)-4-benzyl-5-methyl-3-morpholinone | C12H15NO2 | 详情 | 详情 | |
| (VII) | 55060 | (3S)-4-benzyl-3-methylmorpholine | C12H17NO | 详情 | 详情 | |
| (VIII) | 55061 | (3S)-3-methylmorpholine | C5H11NO | 详情 | 详情 |