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【结 构 式】

【分子编号】55136

【品名】tert-butyl (2R,4R,5S)-1-benzyl-4-(hydroxymethyl)-5-vinyl-2-pyrrolidinecarboxylate

【CA登记号】

【 分 子 式 】C19H27NO3

【 分 子 量 】317.42832

【元素组成】C 71.89% H 8.57% N 4.41% O 15.12%
与该中间体有关的原料药合成路线共 3 条
合成路线1合成路线2合成路线3

合成路线1

该中间体在本合成路线中的序号：(IV)

The title compound was prepared by several synthetic routes: The condensation between N-benzylglycine t-butyl ester (I) and acrolein (II) furnished pyrrolidine (III) as a mixture of epimers at C-4. The mixture of aldehydes was further equilibrated to an 8:1 ratio by stirring the crude product with Et3N in EtOAc. Aldehyde reduction employing NaBH4 produced the corresponding mixture of alcohols, from which the desired isomer (IV) was isolated by column chromatography. After protection of the alcohol function as the acetate ester (V), dihydroxylation of the vinyl group of (V) with N-methylmorpholine N-oxide in the presence of OsO4 provided diol (VI). The N-benzyl group of (VI) was then removed by transfer hydrogenolysis with ammonium formate and Pd/C to give the secondary amine (VII), which was further converted to the N-Boc derivative (VIII). Selective silylation of the primary hydroxyl group of (VIII) employing triisopropylsilyl chloride and imidazole afforded the silyl ether (IX). The secondary hydroxyl group was then oxidized under Swern conditions to ketone (X). Reductive amination of (X) with ammonium acetate in the presence of NaBH3CN led to a mixture of epimeric amines (XI).

参考文献 中间体
合成目标
【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
(I) 55134 tert-butyl 2-(benzylamino)acetate C13H19NO2 详情 详情
(II) 17668 acrylaldehyde; Acrolein 107-02-8 C3H4O 详情 详情
(III) 55135 tert-butyl (2R,5S)-1-benzyl-4-formyl-5-vinyl-2-pyrrolidinecarboxylate C19H25NO3 详情 详情
(IV) 55136 tert-butyl (2R,4R,5S)-1-benzyl-4-(hydroxymethyl)-5-vinyl-2-pyrrolidinecarboxylate C19H27NO3 详情 详情
(V) 55137 tert-butyl (2R,4R,5S)-4-[(acetyloxy)methyl]-1-benzyl-5-vinyl-2-pyrrolidinecarboxylate C21H29NO4 详情 详情
(VI) 55138 tert-butyl (2R,4R,5R)-4-[(acetyloxy)methyl]-1-benzyl-5-(1,2-dihydroxyethyl)-2-pyrrolidinecarboxylate C21H31NO6 详情 详情
(VII) 55139 tert-butyl (2R,4R,5R)-4-[(acetyloxy)methyl]-5-(1,2-dihydroxyethyl)-2-pyrrolidinecarboxylate C14H25NO6 详情 详情
(VIII) 55140 di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-(1,2-dihydroxyethyl)-1,2-pyrrolidinedicarboxylate C19H33NO8 详情 详情
(IX) 55141 di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-{1-hydroxy-2-[(triisopropylsilyl)oxy]ethyl}-1,2-pyrrolidinedicarboxylate C28H53NO8Si 详情 详情
(X) 55142 di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-{2-[(triisopropylsilyl)oxy]acetyl}-1,2-pyrrolidinedicarboxylate C28H51NO8Si 详情 详情
(XI) 55143 di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-{1-amino-2-[(triisopropylsilyl)oxy]ethyl}-1,2-pyrrolidinedicarboxylate C28H54N2O7Si 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 condensation between N-benzylglycine t-butyl ester (I) and acrolein (II) furnished pyrrolidine (III) as a mixture of epimers at C-4. The mixture of aldehydes was further equilibrated to an 8:1 ratio by stirring the crude product with Et3N in EtOAc. Aldehyde (III) reduction employing NaBH4 produced the corresponding mixture of alcohols, from which the desired isomer (IV) was isolated by column chromatography. After protection of the alcohol function of (IV) as the acetate ester (V), dihydroxylation of the vinyl group of (V) with N-methylmorpholine N-oxide in the presence of OsO4 provided diol (VI). The N-benzyl group of (VI) was then removed by transfer hydrogenolysis with ammonium formate and Pd/C to give the secondary amine (VII), which was further converted to the N-Boc derivative (VIII). Selective silylation of the primary hydroxyl group of (VIII) employing triisopropylsilyl chloride and imidazole afforded the silyl ether (IX). The secondary hydroxyl group of (IX) was then oxidized under Swern conditions to ketone (X). Reductive amination of (X) with ammonium acetate in the presence of NaBH3CN led to a mixture of epimeric amines (XI).

参考文献 中间体
合成目标
【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
(I) 55134 tert-butyl 2-(benzylamino)acetate C13H19NO2 详情 详情
(II) 17668 acrylaldehyde; Acrolein 107-02-8 C3H4O 详情 详情
(III) 55135 tert-butyl (2R,5S)-1-benzyl-4-formyl-5-vinyl-2-pyrrolidinecarboxylate C19H25NO3 详情 详情
(IV) 55136 tert-butyl (2R,4R,5S)-1-benzyl-4-(hydroxymethyl)-5-vinyl-2-pyrrolidinecarboxylate C19H27NO3 详情 详情
(V) 55137 tert-butyl (2R,4R,5S)-4-[(acetyloxy)methyl]-1-benzyl-5-vinyl-2-pyrrolidinecarboxylate C21H29NO4 详情 详情
(VI) 55138 tert-butyl (2R,4R,5R)-4-[(acetyloxy)methyl]-1-benzyl-5-(1,2-dihydroxyethyl)-2-pyrrolidinecarboxylate C21H31NO6 详情 详情
(VII) 55139 tert-butyl (2R,4R,5R)-4-[(acetyloxy)methyl]-5-(1,2-dihydroxyethyl)-2-pyrrolidinecarboxylate C14H25NO6 详情 详情
(VIII) 55140 di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-(1,2-dihydroxyethyl)-1,2-pyrrolidinedicarboxylate C19H33NO8 详情 详情
(IX) 55141 di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-{1-hydroxy-2-[(triisopropylsilyl)oxy]ethyl}-1,2-pyrrolidinedicarboxylate C28H53NO8Si 详情 详情
(X) 55142 di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-{2-[(triisopropylsilyl)oxy]acetyl}-1,2-pyrrolidinedicarboxylate C28H51NO8Si 详情 详情
(XI) 55143 di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-{1-amino-2-[(triisopropylsilyl)oxy]ethyl}-1,2-pyrrolidinedicarboxylate C28H54N2O7Si 详情 详情

合成路线3

该中间体在本合成路线中的序号：(IV)

The condensation between N-benzylglycine t-butyl ester (I) and acrolein (II) furnished pyrrolidine (III) as a mixture of epimers at C-4. The mixture of aldehydes (III) was further equilibrated to an 8:1 ratio by stirring the crude product with Et3N in EtOAc. Aldehyde (III) reduction employing NaBH4 produced the corresponding mixture of alcohols, from which the desired isomer (IV) was isolated by column chromatography. After protection of the alcohol function of (IV) as the acetate ester (V), dihydroxylation of the vinyl group of (V) with N-methylmorpholine N-oxide in the presence of OsO4 provided diol (VI). The N-benzyl group of (VI) was then removed by transfer hydrogenolysis with ammonium formate and Pd/C to give the secondary amine (VII), which was further converted to the N-Boc derivative (VIII). Selective silylation of the primary hydroxyl group of (VIII) employing triisopropylsilyl chloride and imidazole afforded the silyl ether (IX). The secondary hydroxyl group of (IX) was then oxidized under Swern conditions to ketone (X). Reductive amination of (X) with ammonium acetate in the presence of NaBH3CN led to a mixture of epimeric amines (XI).

参考文献 中间体
合成目标
【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
(I) 55134 tert-butyl 2-(benzylamino)acetate C13H19NO2 详情 详情
(II) 17668 acrylaldehyde; Acrolein 107-02-8 C3H4O 详情 详情
(III) 55135 tert-butyl (2R,5S)-1-benzyl-4-formyl-5-vinyl-2-pyrrolidinecarboxylate C19H25NO3 详情 详情
(IV) 55136 tert-butyl (2R,4R,5S)-1-benzyl-4-(hydroxymethyl)-5-vinyl-2-pyrrolidinecarboxylate C19H27NO3 详情 详情
(V) 55137 tert-butyl (2R,4R,5S)-4-[(acetyloxy)methyl]-1-benzyl-5-vinyl-2-pyrrolidinecarboxylate C21H29NO4 详情 详情
(VI) 55138 tert-butyl (2R,4R,5R)-4-[(acetyloxy)methyl]-1-benzyl-5-(1,2-dihydroxyethyl)-2-pyrrolidinecarboxylate C21H31NO6 详情 详情
(VII) 55139 tert-butyl (2R,4R,5R)-4-[(acetyloxy)methyl]-5-(1,2-dihydroxyethyl)-2-pyrrolidinecarboxylate C14H25NO6 详情 详情
(VIII) 55140 di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-(1,2-dihydroxyethyl)-1,2-pyrrolidinedicarboxylate C19H33NO8 详情 详情
(IX) 55141 di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-{1-hydroxy-2-[(triisopropylsilyl)oxy]ethyl}-1,2-pyrrolidinedicarboxylate C28H53NO8Si 详情 详情
(X) 55142 di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-{2-[(triisopropylsilyl)oxy]acetyl}-1,2-pyrrolidinedicarboxylate C28H51NO8Si 详情 详情
(XI) 55143 di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-{1-amino-2-[(triisopropylsilyl)oxy]ethyl}-1,2-pyrrolidinedicarboxylate C28H54N2O7Si 详情 详情
Extended Information