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【结 构 式】 
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【分子编号】55180 【品名】tert-butyl (2R,3S,5R)-2-[(1R,2S)-1-(acetylamino)-2-methoxy-2-methylpentyl]-5-cyano-3-[(Z)-1-propenyl]-1-pyrrolidinecarboxylate 【CA登记号】 |
【 分 子 式 】C22H37N3O4 【 分 子 量 】407.5536 【元素组成】C 64.84% H 9.15% N 10.31% O 15.7% |
合成路线1
该中间体在本合成路线中的序号：(XXXVII)Acidic hydrolysis of the acetonide (XXXI) gave rise to diol (XXXII), which was subjected to oxidative cleavage in the presence of NaIO4, yielding aldehyde (XXXIII). Addition of propylmagnesium chloride to aldehyde (XXXIII) furnished alcohol (XXXIV). After oxidation of (XXXIV) to the corresponding ketone (XXXV), addition of methylmagnesium bromide provided carbinol (XXXVI). The methyl ether (XXXVII) was prepared by alkylation of the sodium alkoxide of (XXXVI) with iodomethane. Finally, hydrolysis of the cyano group of (XXXVII) with concomitant Boc group cleavage under acidic conditions led to the title compound.
| 【1】 Inhibitors of neuraminidases. WO 0128996 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXI) | 55174 | tert-butyl (2R,3S,5R)-2-{(R)-(acetylamino)[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-5-cyano-3-[(Z)-1-propenyl]-1-pyrrolidinecarboxylate | C21H33N3O5 | 详情 | 详情 | |
| (XXXII) | 55175 | tert-butyl (2R,3S,5R)-2-[(1R,2S)-1-(acetylamino)-2,3-dihydroxypropyl]-5-cyano-3-[(Z)-1-propenyl]-1-pyrrolidinecarboxylate | C18H29N3O5 | 详情 | 详情 | |
| (XXXIII) | 55176 | tert-butyl (2R,3S,5R)-2-[(1R)-1-(acetylamino)-2-oxoethyl]-5-cyano-3-[(Z)-1-propenyl]-1-pyrrolidinecarboxylate | C17H25N3O4 | 详情 | 详情 | |
| (XXXIV) | 55177 | tert-butyl (2R,3S,5R)-2-[(1R)-1-(acetylamino)-2-hydroxypentyl]-5-cyano-3-[(Z)-1-propenyl]-1-pyrrolidinecarboxylate | C20H33N3O4 | 详情 | 详情 | |
| (XXXV) | 55178 | tert-butyl (2R,3S,5R)-2-[(1R)-1-(acetylamino)-2-oxopentyl]-5-cyano-3-[(Z)-1-propenyl]-1-pyrrolidinecarboxylate | C20H31N3O4 | 详情 | 详情 | |
| (XXXVI) | 55179 | tert-butyl (2R,3S,5R)-2-[(1R,2S)-1-(acetylamino)-2-hydroxy-2-methylpentyl]-5-cyano-3-[(Z)-1-propenyl]-1-pyrrolidinecarboxylate | C21H35N3O4 | 详情 | 详情 | |
| (XXXVII) | 55180 | tert-butyl (2R,3S,5R)-2-[(1R,2S)-1-(acetylamino)-2-methoxy-2-methylpentyl]-5-cyano-3-[(Z)-1-propenyl]-1-pyrrolidinecarboxylate | C22H37N3O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXXVII)Acidic cleavage of the chiral sulfinimide group of (LII) provided amine (LIII), which was acylated with Ac2O, yielding acetamide (XXXVII). Finally, hydrolysis and deprotection of (XXXVII) as in Scheme 30409701e gave rise to the title compound.
| 【1】 Inhibitors of neuraminidases. WO 0128996 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXVII) | 55180 | tert-butyl (2R,3S,5R)-2-[(1R,2S)-1-(acetylamino)-2-methoxy-2-methylpentyl]-5-cyano-3-[(Z)-1-propenyl]-1-pyrrolidinecarboxylate | C22H37N3O4 | 详情 | 详情 | |
| (LII) | 55195 | tert-butyl (2R,3S,5R)-5-cyano-2-((1R,2S)-2-methoxy-2-methyl-1-{[(4-methylphenyl)sulfinyl]amino}pentyl)-3-[(Z)-1-propenyl]-1-pyrrolidinecarboxylate | C27H41N3O4S | 详情 | 详情 | |
| (LIII) | 55196 | tert-butyl (2R,3S,5R)-2-[(1R,2S)-1-amino-2-methoxy-2-methylpentyl]-5-cyano-3-[(Z)-1-propenyl]-1-pyrrolidinecarboxylate | C20H35N3O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXXVII)In a related procedure, aldehyde (XLVI) was condensed with triphenylmethanesulfenamide (LIV), producing the S-trityl sulfenimine (LV). Aldol-type condensation of (LV) with the silyloxy pyrrole (XLIX) gave rise to a diastereoisomeric mixture of adducts from which the desired isomer (LVI) was isolated as the major compound. Diastereoselectivity was increased using triflic acid as the condensation catalyst. Conjugate addition to (LVI) of propenylmagnesium bromide in the presence of CuBr yielded (LVII). Conversion of pyrrolidinone (LVII) to the cyano pyrrolidine (LVIII) was accomplished by the same sequence as above. Then, acidic cleavage of the tritylsulfanyl group of (LVIII), followed by N-acetylation, furnished the intermediate (XXXVII), which was finally processed as in the preceding methods.
| 【1】 Barnes, D.M.; et al.; Synthesis of an influenza neuraminidase inhibitor intermediate via a highly diastereoselective coupling reaction. Org Lett 2002, 4, 9, 1427. |
| 【2】 Inhibitors of neuraminidases. WO 0128996 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXVII) | 55180 | tert-butyl (2R,3S,5R)-2-[(1R,2S)-1-(acetylamino)-2-methoxy-2-methylpentyl]-5-cyano-3-[(Z)-1-propenyl]-1-pyrrolidinecarboxylate | C22H37N3O4 | 详情 | 详情 | |
| (XLVI) | 55189 | (2S)-2-methoxy-2-methylpentanal | C7H14O2 | 详情 | 详情 | |
| (XLIX) | 55192 | tert-butyl 2-{[tert-butyl(dimethyl)silyl]oxy}-1H-pyrrole-1-carboxylate | C15H27NO3Si | 详情 | 详情 | |
| (LIV) | 55197 | Triphenylmethanesulfenamide | C19H17NS | 详情 | 详情 | |
| (LV) | 55198 | N-[(E,2S)-2-methoxy-2-methylpentylidene](triphenyl)methanesulfenamide | C26H29NOS | 详情 | 详情 | |
| (LVI) | 55199 | tert-butyl (2R)-2-{(1R,2S)-2-methoxy-2-methyl-1-[(tritylsulfanyl)amino]pentyl}-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate | C35H42N2O4S | 详情 | 详情 | |
| (LVII) | 55200 | tert-butyl (2R,3S)-2-{(1R,2S)-2-methoxy-2-methyl-1-[(tritylsulfanyl)amino]pentyl}-5-oxo-3-[(Z)-1-propenyl]-1-pyrrolidinecarboxylate | C38H48N2O4S | 详情 | 详情 | |
| (LVIII) | 55201 | tert-butyl (2R,3S,5R)-5-cyano-2-{(1R,2S)-2-methoxy-2-methyl-1-[(tritylsulfanyl)amino]pentyl}-3-[(Z)-1-propenyl]-1-pyrrolidinecarboxylate | C39H49N3O3S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXXVII)Addition of the lithium anion of tert-butyl propiolate (LXIX) to nitrone (LXVIII) in the presence of BF3·Et2O gave adduct (LXX). Reduction of the hydroxylamine (LXX), with concomitant cyclization by treatment with Zn and HOAc, produced pyrrolidone (LXXI). The propenyl group of (LXXII) was introduced by conjugate addition of the corresponding organocuprate reagent to the unsaturated lactam (LXXI). Acidic Boc group cleavage in (LXXII), followed by acetylation of the resultant amine, afforded acetamide (LXXIII). Oxidative cleavage of the p-methoxybenzyl group of (LXXIII) using ammonium cerium nitrate gave pyrrolidone (LXXIV), which was further protected as the N-Boc derivative (LXXV). Introduction of the cyano group in (LXXV) as in the above methods led to the common precursor (XXXVII).
| 【1】 Hanessian, S.; et al.; Total synthesis of A-315675: A potent inhibitor of influenza neuraminidase. J Am Chem Soc 2002, 124, 17, 4716. |
| 【2】 Inhibitors of neuraminidases. WO 0128996 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXVII) | 55180 | tert-butyl (2R,3S,5R)-2-[(1R,2S)-1-(acetylamino)-2-methoxy-2-methylpentyl]-5-cyano-3-[(Z)-1-propenyl]-1-pyrrolidinecarboxylate | C22H37N3O4 | 详情 | 详情 | |
| (LXVIII) | 55210 | {(Z,2R,3S)-2-[(tert-butoxycarbonyl)amino]-3-methoxy-3-methylhexylidene}(4-methoxybenzyl)ammoniumolate | C21H34N2O5 | 详情 | 详情 | |
| (LXIX) | 28925 | tert-butyl propiolate | 13831-03-3 | C7H10O2 | 详情 | 详情 |
| (LXX) | 55211 | tert-butyl (5R,6S)-5-[(tert-butoxycarbonyl)amino]-4-[hydroxy(4-methoxybenzyl)amino]-6-methoxy-6-methyl-2-nonynoate | C28H44N2O7 | 详情 | 详情 | |
| (LXXI) | 55212 | tert-butyl (1R,2S)-2-methoxy-1-[(2R)-1-(4-methoxybenzyl)-5-oxo-2,5-dihydro-1H-pyrrol-2-yl]-2-methylpentylcarbamate | C24H36N2O5 | 详情 | 详情 | |
| (LXXII) | 55213 | tert-butyl (1R,2S)-2-methoxy-1-{(2R,3S)-1-(4-methoxybenzyl)-5-oxo-3-[(Z)-1-propenyl]pyrrolidinyl}-2-methylpentylcarbamate | C27H42N2O5 | 详情 | 详情 | |
| (LXXIII) | 55214 | N-((1R,2S)-2-methoxy-1-{(2R,3S)-1-(4-methoxybenzyl)-5-oxo-3-[(Z)-1-propenyl]pyrrolidinyl}-2-methylpentyl)acetamide | C24H36N2O4 | 详情 | 详情 | |
| (LXXIV) | 55215 | N-((1R,2S)-2-methoxy-2-methyl-1-{(2R,3S)-5-oxo-3-[(Z)-1-propenyl]pyrrolidinyl}pentyl)acetamide | C16H28N2O3 | 详情 | 详情 | |
| (LXXV) | 55216 | tert-butyl (2R,3S)-2-[(1R,2S)-1-(acetylamino)-2-methoxy-2-methylpentyl]-5-oxo-3-[(Z)-1-propenyl]-1-pyrrolidinecarboxylate | C21H36N2O5 | 详情 | 详情 |