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【结 构 式】

【分子编号】55150

【品名】di(tert-butyl) (2R,4S,5R)-5-[(1R,2R)-1-(acetylamino)-2-hydroxypentyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate

【CA登记号】

【 分 子 式 】C24H42N2O6

【 分 子 量 】454.60736

【元素组成】C 63.41% H 9.31% N 6.16% O 21.12%
与该中间体有关的原料药合成路线共 6 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6

合成路线1

该中间体在本合成路线中的序号：(XVIII)

The mixture of amines (XI) was converted to the respective acetamides, and the desired isomer (XII) was then isolated by column chromatography. Hydrolysis of the acetate ester function of (XII) provided alcohol (XIII), which was oxidized to aldehyde (XIV) under Swern conditions. Wittig reaction of aldehyde (XIV) with ethyl triphenylphosphonium bromide and potassium tert-butoxide led to the (Z)-olefin (XV). After removal of the O-silyl protecting group of (XV) by means of tetrabutylammonium fluoride, the resultant alcohol (XVI) was oxidized to aldehyde (XVII) employing the Dess-Martin periodinane reagent. Addition of propylmagnesium bromide to aldehyde (XVII) furnished the alcohol adduct (XVIII).

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
(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
(XII) 55144 di(tert-butyl) (2R,4R,5R)-5-{(1R)-1-(acetylamino)-2-[(triisopropylsilyl)oxy]ethyl}-4-[(acetyloxy)methyl]-1,2-pyrrolidinedicarboxylate C30H56N2O8Si 详情 详情
(XIII) 55145 di(tert-butyl) (2R,4R,5R)-5-{(1R)-1-(acetylamino)-2-[(triisopropylsilyl)oxy]ethyl}-4-(hydroxymethyl)-1,2-pyrrolidinedicarboxylate C28H54N2O7Si 详情 详情
(XIV) 55146 di(tert-butyl) (2R,4R,5R)-5-{(1R)-1-(acetylamino)-2-[(triisopropylsilyl)oxy]ethyl}-4-formyl-1,2-pyrrolidinedicarboxylate C28H52N2O7Si 详情 详情
(XV) 55147 di(tert-butyl) (2R,4S,5R)-5-{(1R)-1-(acetylamino)-2-[(triisopropylsilyl)oxy]ethyl}-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate C30H56N2O6Si 详情 详情
(XVI) 55148 di(tert-butyl) (2R,4S,5R)-5-[(1R)-1-(acetylamino)-2-hydroxyethyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate C21H36N2O6 详情 详情
(XVII) 55149 di(tert-butyl) (2R,4S,5R)-5-[(1R)-1-(acetylamino)-2-oxoethyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate C21H34N2O6 详情 详情
(XVIII) 55150 di(tert-butyl) (2R,4S,5R)-5-[(1R,2R)-1-(acetylamino)-2-hydroxypentyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate C24H42N2O6 详情 详情

合成路线2

该中间体在本合成路线中的序号：(XVIII)

Oxidation of alcohol (XVIII) employing the Dess-Martin periodinane reagent furnished ketone (XIX). Subsequent addition of methylmagnesium bromide to ketone (XIX) gave rise to a mixture of diastereoisomeric carbinols from which alcohol (XX) was isolated as the major isomer. The methyl ether (XXI) was prepared by alkylation of the sodium alkoxide of (XX) with iodomethane in THF. Trifluoroacetic acid-promoted cleavage of the tert-butyl ester and N-Boc protecting groups provided the title compound in the racemic form (+/-)-(XXII). The ethyl ester prepared by esterification of (+/-)-(XXII) with EtOH and SOCl2 was then resolved using chiral HPLC. The desired enantiomer (XXIII) was finally hydrolyzed with LiOH to the title levo carboxylic acid.

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
(XVIII) 55150 di(tert-butyl) (2R,4S,5R)-5-[(1R,2R)-1-(acetylamino)-2-hydroxypentyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate C24H42N2O6 详情 详情
(XIX) 55151 di(tert-butyl) (2R,4S,5R)-5-[(1R)-1-(acetylamino)-2-oxopentyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate C24H40N2O6 详情 详情
(XX) 55152 di(tert-butyl) (2R,4S,5R)-5-[(1R,2S)-1-(acetylamino)-2-hydroxy-2-methylpentyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate C25H44N2O6 详情 详情
(XXI) 55153 di(tert-butyl) (2R,4S,5R)-5-[(1R,2S)-1-(acetylamino)-2-methoxy-2-methylpentyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate C26H46N2O6 详情 详情
(XXII) 55154 (2R,4S,5R)-5-[(1R,2S)-1-(acetylamino)-2-methoxy-2-methylpentyl]-4-[(Z)-1-propenyl]-2-pyrrolidinecarboxylic acid C17H30N2O4 详情 详情
(XXIII) 55166 ethyl (2R,4S,5R)-5-[(1R,2S)-1-(acetylamino)-2-methoxy-2-methylpentyl]-4-[(Z)-1-propenyl]-2-pyrrolidinecarboxylate C19H34N2O4 详情 详情

合成路线3

该中间体在本合成路线中的序号：(XVIII)

The mixture of amines (XI) was converted to the respective acetamides, and the desired isomer (XII) was then isolated by column chromatography. Hydrolysis of the acetate ester function of (XII) provided alcohol (XIII), which was oxidized to aldehyde (XIV) under Swern conditions. Wittig reaction of aldehyde (XIV) with ethyl triphenylphosphonium bromide and potassium tert-butoxide led to the (Z)-olefin (XV). After removal of the O-silyl protecting group of (XV) by means of tetrabutylammonium fluoride, the resultant alcohol (XVI) was oxidized to aldehyde (XVII) employing the Dess-Martin periodinane reagent. Addition of propylmagnesium bromide to aldehyde (XVII) furnished the alcohol adduct (XVIII).

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
(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
(XII) 55144 di(tert-butyl) (2R,4R,5R)-5-{(1R)-1-(acetylamino)-2-[(triisopropylsilyl)oxy]ethyl}-4-[(acetyloxy)methyl]-1,2-pyrrolidinedicarboxylate C30H56N2O8Si 详情 详情
(XIII) 55145 di(tert-butyl) (2R,4R,5R)-5-{(1R)-1-(acetylamino)-2-[(triisopropylsilyl)oxy]ethyl}-4-(hydroxymethyl)-1,2-pyrrolidinedicarboxylate C28H54N2O7Si 详情 详情
(XIV) 55146 di(tert-butyl) (2R,4R,5R)-5-{(1R)-1-(acetylamino)-2-[(triisopropylsilyl)oxy]ethyl}-4-formyl-1,2-pyrrolidinedicarboxylate C28H52N2O7Si 详情 详情
(XV) 55147 di(tert-butyl) (2R,4S,5R)-5-{(1R)-1-(acetylamino)-2-[(triisopropylsilyl)oxy]ethyl}-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate C30H56N2O6Si 详情 详情
(XVI) 55148 di(tert-butyl) (2R,4S,5R)-5-[(1R)-1-(acetylamino)-2-hydroxyethyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate C21H36N2O6 详情 详情
(XVII) 55149 di(tert-butyl) (2R,4S,5R)-5-[(1R)-1-(acetylamino)-2-oxoethyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate C21H34N2O6 详情 详情
(XVIII) 55150 di(tert-butyl) (2R,4S,5R)-5-[(1R,2R)-1-(acetylamino)-2-hydroxypentyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate C24H42N2O6 详情 详情

合成路线4

该中间体在本合成路线中的序号：(XVIII)

Oxidation of alcohol (XVIII) employing the Dess-Martin periodinane reagent furnished ketone (XIX). Subsequent addition of MeMgBr to ketone (XIX) gave rise to a mixture of diastereoisomeric carbinols from which alcohol (XX) was isolated as the major isomer. The methyl ether (XXI) was prepared by alkylation of the sodium alkoxide of (XX) with iodomethane in THF. Trifluoroacetic acid-promoted cleavage of the tert-butyl ester and N-Boc protecting groups of (XXI) provided the carboxylic acid (XXII). The title ester enantiomer was then obtained by esterification of racemic (XXII) with EtOH and SOCl2, followed by resolution using chiral HPLC.

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
(XVIII) 55150 di(tert-butyl) (2R,4S,5R)-5-[(1R,2R)-1-(acetylamino)-2-hydroxypentyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate C24H42N2O6 详情 详情
(XIX) 55151 di(tert-butyl) (2R,4S,5R)-5-[(1R)-1-(acetylamino)-2-oxopentyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate C24H40N2O6 详情 详情
(XX) 55152 di(tert-butyl) (2R,4S,5R)-5-[(1R,2S)-1-(acetylamino)-2-hydroxy-2-methylpentyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate C25H44N2O6 详情 详情
(XXI) 55153 di(tert-butyl) (2R,4S,5R)-5-[(1R,2S)-1-(acetylamino)-2-methoxy-2-methylpentyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate C26H46N2O6 详情 详情
(XXII) 55154 (2R,4S,5R)-5-[(1R,2S)-1-(acetylamino)-2-methoxy-2-methylpentyl]-4-[(Z)-1-propenyl]-2-pyrrolidinecarboxylic acid C17H30N2O4 详情 详情

合成路线5

该中间体在本合成路线中的序号：(XVIII)

The mixture of amines (XI) was converted to the respective acetamides and the desired isomer (XII) was then isolated by column chromatography. Hydrolysis of the acetate ester function of (XII) provided alcohol (XIII), which was oxidized to aldehyde (XIV) under Swern conditions. Wittig reaction of aldehyde (XIV) with ethyl triphenylphosphonium bromide and potassium tert-butoxide led to the (Z)-olefin (XV). After removal of the O-silyl protecting group of (XV) by means of tetrabutylammonium fluoride, the resultant alcohol (XVI) was oxidized to aldehyde (XVII) employing the Dess-Martin periodinane reagent. Addition of propylmagnesium bromide to aldehyde (XVII) furnished the alcohol adduct (XVIII).

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
(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
(XII) 55144 di(tert-butyl) (2R,4R,5R)-5-{(1R)-1-(acetylamino)-2-[(triisopropylsilyl)oxy]ethyl}-4-[(acetyloxy)methyl]-1,2-pyrrolidinedicarboxylate C30H56N2O8Si 详情 详情
(XIII) 55145 di(tert-butyl) (2R,4R,5R)-5-{(1R)-1-(acetylamino)-2-[(triisopropylsilyl)oxy]ethyl}-4-(hydroxymethyl)-1,2-pyrrolidinedicarboxylate C28H54N2O7Si 详情 详情
(XIV) 55146 di(tert-butyl) (2R,4R,5R)-5-{(1R)-1-(acetylamino)-2-[(triisopropylsilyl)oxy]ethyl}-4-formyl-1,2-pyrrolidinedicarboxylate C28H52N2O7Si 详情 详情
(XV) 55147 di(tert-butyl) (2R,4S,5R)-5-{(1R)-1-(acetylamino)-2-[(triisopropylsilyl)oxy]ethyl}-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate C30H56N2O6Si 详情 详情
(XVI) 55148 di(tert-butyl) (2R,4S,5R)-5-[(1R)-1-(acetylamino)-2-hydroxyethyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate C21H36N2O6 详情 详情
(XVII) 55149 di(tert-butyl) (2R,4S,5R)-5-[(1R)-1-(acetylamino)-2-oxoethyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate C21H34N2O6 详情 详情
(XVIII) 55150 di(tert-butyl) (2R,4S,5R)-5-[(1R,2R)-1-(acetylamino)-2-hydroxypentyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate C24H42N2O6 详情 详情

合成路线6

该中间体在本合成路线中的序号：(XVIII)

Oxidation of alcohol (XVIII) employing the Dess-Martin periodinane reagent furnished ketone (XIX). Subsequent addition of methylmagnesium bromide to ketone (XIX) gave rise to a mixture of diastereoisomeric carbinols from which alcohol (XX) was isolated as the major isomer. The methyl ether (XXI) was prepared by alkylation of the sodium alkoxide of (XX) with iodomethane in THF. Trifluoroacetic acid-promoted cleavage of the tert-butyl ester and N-Boc protecting groups of (XXI) provided the carboxylic acid (XXII). The title isopropyl ester was then obtained by esterification of acid (XXII) with 2-propanol and SOCl2.

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
(XVIII) 55150 di(tert-butyl) (2R,4S,5R)-5-[(1R,2R)-1-(acetylamino)-2-hydroxypentyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate C24H42N2O6 详情 详情
(XIX) 55151 di(tert-butyl) (2R,4S,5R)-5-[(1R)-1-(acetylamino)-2-oxopentyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate C24H40N2O6 详情 详情
(XX) 55152 di(tert-butyl) (2R,4S,5R)-5-[(1R,2S)-1-(acetylamino)-2-hydroxy-2-methylpentyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate C25H44N2O6 详情 详情
(XXI) 55153 di(tert-butyl) (2R,4S,5R)-5-[(1R,2S)-1-(acetylamino)-2-methoxy-2-methylpentyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate C26H46N2O6 详情 详情
(XXII) 55154 (2R,4S,5R)-5-[(1R,2S)-1-(acetylamino)-2-methoxy-2-methylpentyl]-4-[(Z)-1-propenyl]-2-pyrrolidinecarboxylic acid C17H30N2O4 详情 详情
Extended Information