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【结 构 式】 
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【分子编号】48731 【品名】benzyl (5S)-2-oxo-5-[(trityloxy)methyl]-1-pyrrolidinecarboxylate 【CA登记号】 |
【 分 子 式 】C32H29NO4 【 分 子 量 】491.5866 【元素组成】C 78.19% H 5.95% N 2.85% O 13.02% |
合成路线1
该中间体在本合成路线中的序号：(III)The condensation of 5(S)-(trityloxymethyl)-2-pyrrolidinone (I) with benzyl chloroformate (II) and BuLi in THF gives the carbamate (III), which is alkylated with tert-butyl 2-chloroacetate (IV) and LHMDS in THF to yield 2-[1-(benzyloxycarbonyl)-2-oxo-5(S)-(trityloxymethyl)pyrrolidin-2(S)-yl]acetic acid tert-butyl ester (V). The hydrogenation of (V) with H2 over Pd/C in hot tert-butanol affords 2-[5(S)-(hydroxymethyl)-2-oxopyrrolidin-2(S)-yl]acetic acid tert-butyl ester (VI), which is treated with MsCl and TEA in dichloromethane to provide the methanesulfonate (VII). The condensation of (VII) with 4'-hydroxybiphenyl-4-carbonitrile (VIII) by means of potassium tert-butoxide in DMF gives the adduct (IX), which by treatment with HCl in methanol and with ammonia in the same solvent yields 2-[5(S)-(4'-amidinobiphenyl-4-yloxymethyl)-2-oxopyrrolidin-3(S)-yl]acetic acid methyl ester (X). Finally, this compound is hydrolyzed with NaOH in methanol to afford the target acetic acid derivative.
| 【1】 Himmelsbach, F.; Austel, V.; Pieper, H.; Eisert, W.; Müller, T.; Weisenberger, J.; Linz, G.; Krüger, G. (Dr. Karl Thomae GmbH); Cyclic imino derivs., process for their preparation and drugs containing them. DE 4035961; EP 0483667; JP 1992264068; US 5591769 . |
| 【2】 Himmelsbach, F.; Austel, V.; Pieper, H.; Linz, G.; Wisenberger, J.; Muller, T. (Dr. Karl Thomae GmbH); Cyclic imino derivs., medicaments containing these cpds. and processes for the production thereof. DE 4213919; EP 0567966; JP 1994073001 . |
| 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) | 48730 | (S)-(+)-5-(Trityloxymethyl)-2-pyrrolidinone | C24H23NO2 | 详情 | 详情 | |
| (II) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (III) | 48731 | benzyl (5S)-2-oxo-5-[(trityloxy)methyl]-1-pyrrolidinecarboxylate | C32H29NO4 | 详情 | 详情 | |
| (IV) | 40664 | tert-butyl 2-chloroacetate | 107-59-5 | C6H11ClO2 | 详情 | 详情 |
| (V) | 48732 | benzyl (3S,5S)-3-[2-(tert-butoxy)-2-oxoethyl]-2-oxo-5-[(trityloxy)methyl]-1-pyrrolidinecarboxylate | C38H39NO6 | 详情 | 详情 | |
| (VI) | 48733 | tert-butyl 2-[(3S,5S)-5-(hydroxymethyl)-2-oxopyrrolidinyl]acetate | C11H19NO4 | 详情 | 详情 | |
| (VII) | 48734 | tert-butyl 2-((3S,5S)-5-[[(methylsulfonyl)oxy]methyl]-2-oxopyrrolidinyl)acetate | C12H21NO6S | 详情 | 详情 | |
| (VIII) | 48735 | 4-Cyano-4'-hydroxybiphenyl; 4-Hydroxy-4'-cyanodiphenyl; 4'-Cyano-4-biphenylol; 4'-Hydroxy-4-biphenylcarbonitrile | 19812-93-2 | C13H9NO | 详情 | 详情 |
| (IX) | 48736 | tert-butyl 2-((3S,5S)-5-[[(4'-cyano[1,1'-biphenyl]-4-yl)oxy]methyl]-2-oxopyrrolidinyl)acetate | C24H26N2O4 | 详情 | 详情 | |
| (X) | 48737 | methyl 2-[(3S,5S)-5-[([4'-[amino(imino)methyl][1,1'-biphenyl]-4-yl]oxy)methyl]-2-oxopyrrolidinyl]acetate | C21H23N3O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)The condensation of 5(S)-(trityloxymethyl)-2-pyrrolidinone (I) with benzyl chloroformate (II) and BuLi in THF gives the carbamate (III), which is alkylated with tert-butyl 2-chloroacetate (IV) and LHMDS in THF to yield 2-[1-(benzyloxycarbonyl)-2-oxo-5(S)-(trityloxymethyl)pyrrolidin-2(S)-yl]acetic acid tert-butyl ester (V). The hydrogenation of (V) with H2 over Pd/C in hot tert-butanol affords 2-[5(S)-(hydroxymethyl)-2-oxopyrrolidin-2(S)-yl]acetic acid tert-butyl ester (VI), which is treated with MsCl and TEA in dichloromethane to provide the methanesulfonate (VII). The condensation of (VII) with 4'-hydroxybiphenyl-4-carbonitrile (VIII) by means of potassium tert-butoxide in DMF gives the adduct (IX), which by treatment with HCl in methanol, and with ammonia in the same solvent yields 2-[5(S)-(4'-amidinobiphenyl-4-yloxymethyl)-2-oxopyrrolidin-3(S)-yl]acetic acid methyl ester (X). Finally, this compound is condensed with methyl chloroformate (XI) by means of NaOH in dichloromethane to afford the target compound.
| 【1】 Himmelsbach, F.; Austel, V.; Pieper, H.; Eisert, W.; Müller, T.; Weisenberger, J.; Linz, G.; Krüger, G. (Dr. Karl Thomae GmbH); Cyclic imino derivs., process for their preparation and drugs containing them. DE 4035961; EP 0483667; JP 1992264068; US 5591769 . |
| 【2】 Himmelsbach, F.; Austel, V.; Pieper, H.; Linz, G.; Wisenberger, J.; Muller, T. (Dr. Karl Thomae GmbH); Cyclic imino derivs., medicaments containing these cpds. and processes for the production thereof. DE 4213919; EP 0567966; JP 1994073001 . |
| 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) | 48730 | (S)-(+)-5-(Trityloxymethyl)-2-pyrrolidinone | C24H23NO2 | 详情 | 详情 | |
| (II) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (III) | 48731 | benzyl (5S)-2-oxo-5-[(trityloxy)methyl]-1-pyrrolidinecarboxylate | C32H29NO4 | 详情 | 详情 | |
| (IV) | 40664 | tert-butyl 2-chloroacetate | 107-59-5 | C6H11ClO2 | 详情 | 详情 |
| (V) | 48732 | benzyl (3S,5S)-3-[2-(tert-butoxy)-2-oxoethyl]-2-oxo-5-[(trityloxy)methyl]-1-pyrrolidinecarboxylate | C38H39NO6 | 详情 | 详情 | |
| (VI) | 48733 | tert-butyl 2-[(3S,5S)-5-(hydroxymethyl)-2-oxopyrrolidinyl]acetate | C11H19NO4 | 详情 | 详情 | |
| (VII) | 48734 | tert-butyl 2-((3S,5S)-5-[[(methylsulfonyl)oxy]methyl]-2-oxopyrrolidinyl)acetate | C12H21NO6S | 详情 | 详情 | |
| (VIII) | 48735 | 4-Cyano-4'-hydroxybiphenyl; 4-Hydroxy-4'-cyanodiphenyl; 4'-Cyano-4-biphenylol; 4'-Hydroxy-4-biphenylcarbonitrile | 19812-93-2 | C13H9NO | 详情 | 详情 |
| (IX) | 48736 | tert-butyl 2-((3S,5S)-5-[[(4'-cyano[1,1'-biphenyl]-4-yl)oxy]methyl]-2-oxopyrrolidinyl)acetate | C24H26N2O4 | 详情 | 详情 | |
| (X) | 48737 | methyl 2-[(3S,5S)-5-[([4'-[amino(imino)methyl][1,1'-biphenyl]-4-yl]oxy)methyl]-2-oxopyrrolidinyl]acetate | C21H23N3O4 | 详情 | 详情 | |
| (XI) | 10257 | methyl 2-chloroacetate; methyl chloroacetate | 96-34-4 | C3H5ClO2 | 详情 | 详情 |