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【结 构 式】 
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【分子编号】31614 【品名】(3S)-5-chloro-3-([[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]amino]carbonyl)-5-hexenoic acid 【CA登记号】 |
【 分 子 式 】C21H36ClNO5 【 分 子 量 】417.97328 【元素组成】C 60.35% H 8.68% Cl 8.48% N 3.35% O 19.14% |
合成路线1
该中间体在本合成路线中的序号：(XII)Swern oxidation of protected (hydroxymethyl)pyrrolidine (I), followed by Wittig condensation of the resulting aldehyde (II) with methylene triphenylphosphorane provided vinylpyrrolidine (III). Hydroboration of (III) with 9-borabicyclo[3.3.1]nonane and subsequent oxidative treatment with sodium perborate gave alcohol (IV). Interconversion of the N-benzyl protecting group for an allyloxycarbonyl group was achieved by catalytic hydrogenation and then treatment of the deprotected amine (V) with allyloxycarbonyl chloride (VI). Alcohol (VII) was activated as the corresponding mesylate (VIII), which was condensed with imidazole (IX) in the presence of t-BuOK to afford the N-alkylated imidazole (X). Acid deprotection of the silyl ether of (X) yielded the corresponding secondary alcohol, which was further converted to mesylate (XI). Subsequent displacement in (XI) by potassium thioacetate furnished the thioacetate ester (XII).
| 【1】 Barrett, D.; Azami, H.; Matsuda, K.; et al.; Synthesis and antibacterial activity of novel 4-pyrrolidinylthio carbapenems. Part III: Novel 2-alkyl substituents containing cationic heteroaromatics linked via a C-N bond. Bioorg Med Chem 1999, 7, 8, 1665. |
| 【2】 Murata, M.; Tsutsumi, H.; Matsuda, K.; Hattori, K.; Nakajima, T. (Fujisawa Pharmaceutical Co., Ltd.); Substd. 3-pyrrolidinylthio-carbapenems as antimicrobial agents. EP 0636133; JP 1995505650; WO 9321186 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12893 | Ethanethioic S-acid | C2H4OS | 详情 | 详情 | ||
| 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 | |
| (I) | 32605 | ((2S,4S)-1-benzyl-4-[[tert-butyl(dimethyl)silyl]oxy]pyrrolidinyl)methanol | C18H31NO2Si | 详情 | 详情 | |
| (II) | 32606 | (2S,4S)-1-benzyl-4-[[tert-butyl(dimethyl)silyl]oxy]-2-pyrrolidinecarbaldehyde | C18H29NO2Si | 详情 | 详情 | |
| (III) | 32607 | (2S,4S)-1-benzyl-4-[[tert-butyl(dimethyl)silyl]oxy]-2-vinylpyrrolidine; (3S,5S)-1-benzyl-5-vinylpyrrolidinyl tert-butyl(dimethyl)silyl ether | C19H31NOSi | 详情 | 详情 | |
| (IV) | 32608 | 2-((2R,4S)-1-benzyl-4-[[tert-butyl(dimethyl)silyl]oxy]pyrrolidinyl)-1-ethanol | C19H33NO2Si | 详情 | 详情 | |
| (V) | 32609 | 2-((2R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]pyrrolidinyl)-1-ethanol | C12H27NO2Si | 详情 | 详情 | |
| (VII) | 32610 | allyl (2R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(2-hydroxyethyl)-1-pyrrolidinecarboxylate | C16H31NO4Si | 详情 | 详情 | |
| (VIII) | 32611 | allyl (2R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[2-[(methylsulfonyl)oxy]ethyl]-1-pyrrolidinecarboxylate | C17H33NO6SSi | 详情 | 详情 | |
| (IX) | 10255 | Imidazole; 1H-Imidazole | 288-32-4 | C3H4N2 | 详情 | 详情 |
| (X) | 32612 | allyl (2R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[2-(1H-imidazol-1-yl)ethyl]-1-pyrrolidinecarboxylate | C19H33N3O3Si | 详情 | 详情 | |
| (XI) | 32613 | allyl (2R,4S)-2-[2-(1H-imidazol-1-yl)ethyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C14H21N3O5S | 详情 | 详情 | |
| (XII) | 31614 | (3S)-5-chloro-3-([[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]amino]carbonyl)-5-hexenoic acid | C21H36ClNO5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)The condensation of dimethyl malonate (I) with 2-cloroallyl chloride (II) by means of sodium methoxide in hot methanol gives the alkylmalonate (III), which is treated with tert-butyl bromoacetate (IV), NaOH and benzyltriethylammonium chloride to yield the tricarboxylic ester (V). Partial decarboxylation of (V) with KOH in hot methanol/water affords the succinic acid derivative (VI), which is submitted to enzymatic hydrolysis with Alcalase 2.4L to provide the chiral monoester (VII). The condensation of monoacid (VII) with amine (VIII) by means of HOBT, DCC, and DIEA in THF gives the amide (IX), which is treated with TFA to eliminate the tert-butyl protecting group yielding the acid (X). The condensation of (X) with amine (XI) by means of NMM and pivaloyl chloride affords the amide (XII), which is treated with 2-methoxypropene (XIII) and TsOH in dichloromethane to protect the vicinal hydroxy groups giving the dioxolane (XIV). The bromination of the allyl double bond of (XIV) with NBS in tert-butyl methyl ether/water gives 3-bromo-2-oxopropyl derivative (XV).
| 【1】 Beaulieu, P.L.; et al.; Practical synthesis of BILA 2157 BS, a potent and orally active renin inhibitor: Use of an enzayme-catalyzed hydrolysis for the preparation of homochiral succinic acid derivatives. J Org Chem 1999, 64, 18, 6622. |
| 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) | 19373 | dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester | 108-59-8 | C5H8O4 | 详情 | 详情 |
| (II) | 31608 | 2,3-dichloro-1-propene | 78-88-6 | C3H4Cl2 | 详情 | 详情 |
| (III) | 31609 | dimethyl 2-(2-chloro-2-propenyl)malonate | C8H11ClO4 | 详情 | 详情 | |
| (IV) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (V) | 31610 | 1-(tert-butyl) 2,2-dimethyl 4-chloro-4-pentene-1,2,2-tricarboxylate | C14H21ClO6 | 详情 | 详情 | |
| (VI) | 31611 | 4-(tert-butyl) 1-methyl 2-(2-chloro-2-propenyl)succinate | C12H19ClO4 | 详情 | 详情 | |
| (VII) | 31612 | (2S)-2-[2-(tert-butoxy)-2-oxoethyl]-4-chloro-4-pentenoic acid | C11H17ClO4 | 详情 | 详情 | |
| (VIII) | 29543 | (2S,3R,4S)-2-amino-1-cyclohexyl-6-methyl-3,4-heptanediol | C14H29NO2 | 详情 | 详情 | |
| (IX) | 31613 | tert-butyl (3S)-5-chloro-3-([[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]amino]carbonyl)-5-hexenoate | C25H44ClNO5 | 详情 | 详情 | |
| (X) | 31614 | (3S)-5-chloro-3-([[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]amino]carbonyl)-5-hexenoic acid | C21H36ClNO5 | 详情 | 详情 | |
| (XI) | 29540 | 2-[(cyclohexylmethyl)amino]-N-methyl-N-[2-(2-pyridinyl)ethyl]acetamide | C17H27N3O | 详情 | 详情 | |
| (XII) | 31615 | (2S)-2-(2-chloro-2-propenyl)-N(4)-(cyclohexylmethyl)-N(1)-[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]-N(4)-(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)butanediamide | C38H61ClN4O5 | 详情 | 详情 | |
| (XIII) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (XIV) | 31616 | (2S)-2-(2-chloro-2-propenyl)-N(1)-[(1S)-2-cyclohexyl-1-[(4R,5S)-5-isobutyl-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]-N(4)-(cyclohexylmethyl)-N(4)-(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)butanediamide | C41H65ClN4O5 | 详情 | 详情 | |
| (XV) | 31617 | (2R)-2-(3-bromo-2-oxopropyl)-N(1)-[(1S)-2-cyclohexyl-1-[(4R,5S)-5-isobutyl-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]-N(4)-(cyclohexylmethyl)-N(4)-(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)butanediamide | C41H65BrN4O6 | 详情 | 详情 |