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【结 构 式】 
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【药物名称】A-322278 【化学名称】5(R)-[1(R)-Acetamido-2(S)-methoxy-2-methylpentyl]-4(S)-[1(Z)-propenyl] pyrrolidine-2(R)-carboxylic acid isopropyl ester 【CA登记号】 【 分 子 式 】C20H36N2O4 【 分 子 量 】368.52092 |
【开发单位】Abbott (Originator) 【药理作用】ANTIINFECTIVE THERAPY, Anti-Influenza Virus Drugs, Antiviral Drugs, Chemical Delivery Systems, DRUG DELIVERY, Drug Delivery Systems, Neuraminidase (Sialidase) Inhibitors |
合成路线1
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).
| 【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
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).
| 【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3
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.
| 【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 |