di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-{1-amino-2-[(triisopropylsilyl)oxy]ethyl}-1,2-pyrrolidinedicarboxylate -Drug Synthesis Database

【结构式】

【分子编号】55143

【品名】di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-{1-amino-2-[(triisopropylsilyl)oxy]ethyl}-1,2-pyrrolidinedicarboxylate

【CA登记号】

【分子式】C₂₈H₅₄N₂O₇Si

【分子量】558.83154

【元素组成】C 60.18% H 9.74% N 5.01% O 20.04% Si 5.03%

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：(XI)

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：(XI)

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	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

该中间体在本合成路线中的序号：(XI)

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4

该中间体在本合成路线中的序号：(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	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5

该中间体在本合成路线中的序号：(XI)

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

合成路线6

该中间体在本合成路线中的序号：(XI)

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	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

Extended Information