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【结 构 式】 
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【分子编号】22787 【品名】(2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylic acid 【CA登记号】 |
【 分 子 式 】C18H24N2O5 【 分 子 量 】348.39904 【元素组成】C 62.05% H 6.94% N 8.04% O 22.96% |
合成路线1
该中间体在本合成路线中的序号：(XVIII)An alternative synthesis has been reported employing pure (2R,3S)-aminoalcohol (XVII). Treatment of isobutyl iodide (X) with sodium nitrite in the presence of urea in DMF afforded 2-methyl-1-nitropropane (XI). Further condensation of fluoral hydrate (XII) with this nitrocompound using K2CO3 provided a diastereomeric mixture of nitroalcohols (XIII). Fractional crystallization from pentane yielded the racemic threo-nitroalcohol (XIV), which was converted to the alredy reported racemic threo-aminoalcohol (VII) by catalytic hydrogenation. This compound (VII) was treated with triphosgene and NaOH to produce oxazolidone (XV). After conversion of (XV) to the corresponding lithium salt with BuLi at -70 C, its condensation with (-)-menthyl chloroformate gave a diastereomeric mixture of carbamates, from which the desired isomer (XVI) was isolated by fractional crystallization from ether/hexane. The chiral auxiliary and the oxazolidone ring were then cleaved by hydrolysis with KOH yielding the (2R,3S)-aminoalcohol (XVII)(1). The coupling of (XVII) with the amino protected dipeptide (XVIII) (obtained by treatment of peptide (I) with trifluoroacetic acid) afforded dipeptide amide (XIX), The N-(benzyloxycarbonyl) protecting group of (XIX) was subsequently removed by catalytic hydrogenation, and the resulting amino compound was condensed with anisoyl chloride (III) to furnish the anisoyl dipeptide (XX). Finally, oxidation of the alcohol group of (XX) using the modified Pfitner-Moffat procedure produced some epimerization of the resulting ketone, the oxidation with KMnO4 in the presence of NaOH yielded the target S,S,S-peptide.
| 【1】 Bohnert, C.M.; Bernstein, P.R.; Veale, C.A.; et al.; Orally active trifluoromethyl ketone inhibitors of. J Med Chem 1997, 40, 20, 3173. |
| 【2】 Pegg, S.J.; Sependa, G.J.; Davies, E.P.; Veale, C.A. (AstraZeneca plc); Diastereomeric pure trifluoromethyl ketone peptide. EP 0743953; JP 1997508902; US 5739157; US 6037363; WO 9521855 . |
| 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) | 22770 | tert-butyl (2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylate | C22H32N2O5 | 详情 | 详情 | |
| (III) | 22671 | 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride | 100-07-2 | C8H7ClO2 | 详情 | 详情 |
| (VII) | 22776 | (2R,3S)-3-amino-1,1,1-trifluoro-4-methyl-2-pentanol | C6H12F3NO | 详情 | 详情 | |
| (X) | 18168 | 1-iodo-2-methylpropane | 513-38-2 | C4H9I | 详情 | 详情 |
| (XI) | 11782 | 2-Methyl-1-nitropropane | C4H9NO2 | 详情 | 详情 | |
| (XII) | 22781 | 2,2,2-trifluoro-1,1-ethanediol | 421-53-4 | C2H3F3O2 | 详情 | 详情 |
| (XIII) | 11783 | 1,1,1-Trifluoro-4-methyl-3-nitro-2-pentanol | C6H10F3NO3 | 详情 | 详情 | |
| (XIV) | 22783 | (2R,3S)-1,1,1-trifluoro-4-methyl-3-nitro-2-pentanol | C6H10F3NO3 | 详情 | 详情 | |
| (XV) | 22784 | (4S,5R)-4-isopropyl-5-(trifluoromethyl)-1,3-oxazolidin-2-one | C7H10F3NO2 | 详情 | 详情 | |
| (XVI) | 22785 | (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (4S,5R)-4-isopropyl-2-oxo-5-(trifluoromethyl)-1,3-oxazolidine-3-carboxylate | C18H28F3NO4 | 详情 | 详情 | |
| (XVII) | 22776 | (2R,3S)-3-amino-1,1,1-trifluoro-4-methyl-2-pentanol | C6H12F3NO | 详情 | 详情 | |
| (XVIII) | 22787 | (2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylic acid | C18H24N2O5 | 详情 | 详情 | |
| (XIX) | 22788 | benzyl (1S)-2-methyl-1-[[(2S)-2-([[(1S,2R)-3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl]amino]carbonyl)pyrrolidinyl]carbonyl]propylcarbamate | C24H34F3N3O5 | 详情 | 详情 | |
| (XX) | 22789 | (2S)-1-[(2S)-2-[(4-methoxybenzoyl)amino]-3-methylbutanoyl]-N-[(1S,2R)-3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl]-2-pyrrolidinecarboxamide | C24H34F3N3O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)The reaction of N-(benzyloxycarbonyl)-L-valine (I) with paraformaldehyde and Ts-OH gives the oxazolidinone (II), which is treated with trimethyl trifluoromethylsilane and CsF in THF to yield the trifluoromethyloxazolidine (III). The cleavage of the oxazolidine ring of (III) by means of ZnCl2 and NaBH4 in t-butyl methyl ether affords the protected aminoalcohol (IV), which is deprotected by means of H2 over Pd(OH)2 in ethyl acetate to provide the free aminoalcohol (V). The condensation of (V) with N-(benzyloxycarbonyl)-L-valyl-L-proline (VI) by means of EDC in dichloromethane gives the protected tripeptide analogue (VII), which is deprotected with H2 over Pd(OH)2 in ethanol to yield the tripeptide analogue (VIII). The condensation of (VIII) with the imidazolidinoneacetic acid derivative (IX) by means of EDC, as before, affords the acylated tripeptide (X), which is oxidized with DMP in dichloromethane to provide the acylated-L-valyl-L-prolyl-L-valyl-trifluoromethane (XI). Finally, this compound is deprotected with TFA in dichloromethane to give the target peptide analogue. The imidazolidinoneacetic acid derivative (IX) intermediate is obtained as follows: the reaction of 2-imidazolidinone (XII) with tert-butyl 2-bromoacetate (XIII) by means of lithium tert-butoxide in DMF gives the bis tert-butyl acetate (XIV), which is selectively monohydrolyzed by means of KOH in hot ethanol/water to afford the target imidazolidinoneacetic acid derivative (IX).
| 【1】 Sato, F.; Inoue, Y.; Honda, S.; Komiya, M.; Takemura, T.; Omodani, T.; Shiratake, R. (Dainippon Pharmaceutical Co., Ltd.); Heterocyclic cpds., intermediates thereof and elastase inhibitors. EP 1157998; JP 2000256396; WO 0052032 . |
| 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) | 18092 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid | C13H17NO4 | 详情 | 详情 | |
| (II) | 55779 | benzyl (4S)-4-isopropyl-5-oxo-1,3-oxazolidine-3-carboxylate | C14H17NO4 | 详情 | 详情 | |
| (III) | 55780 | benzyl (4S,5R)-5-hydroxy-4-isopropyl-5-(trifluoromethyl)-1,3-oxazolidine-3-carboxylate | C15H18F3NO4 | 详情 | 详情 | |
| (IV) | 55781 | benzyl (1S,2S)-3,3,3-trifluoro-2-hydroxy-1-isopropylpropylcarbamate | C14H18F3NO3 | 详情 | 详情 | |
| (V) | 55782 | (2S,3S)-3-amino-1,1,1-trifluoro-4-methyl-2-pentanol | C6H12F3NO | 详情 | 详情 | |
| (VI) | 22787 | (2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylic acid | C18H24N2O5 | 详情 | 详情 | |
| (VII) | 55783 | benzyl (1S)-2-methyl-1-{[(2S)-2-({[(1S,2S)-3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl]amino}carbonyl)pyrrolidinyl]carbonyl}propylcarbamate | C24H34F3N3O5 | 详情 | 详情 | |
| (VIII) | 55784 | (2S)-1-[(2S)-2-amino-3-methylbutanoyl]-N-[(1S,2S)-3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl]-2-pyrrolidinecarboxamide | C16H28F3N3O3 | 详情 | 详情 | |
| (IX) | 55785 | 2-{3-[2-(tert-butoxy)-2-oxoethyl]-2-oxo-1-imidazolidinyl}acetic acid | C11H18N2O5 | 详情 | 详情 | |
| (X) | 55786 | tert-butyl 2-(3-{2-[((1S)-2-methyl-1-{[(2S)-2-({[(1S,2S)-3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl]amino}carbonyl)pyrrolidinyl]carbonyl}propyl)amino]-2-oxoethyl}-2-oxo-1-imidazolidinyl)acetate | C27H44F3N5O7 | 详情 | 详情 | |
| (XI) | 55787 | tert-butyl 2-(3-{2-[((1S)-2-methyl-1-{[(2S)-2-({[(1S)-3,3,3-trifluoro-1-isopropyl-2-oxopropyl]amino}carbonyl)pyrrolidinyl]carbonyl}propyl)amino]-2-oxoethyl}-2-oxo-1-imidazolidinyl)acetate | C27H42F3N5O7 | 详情 | 详情 | |
| (XII) | 36228 | 2-imidazolidinone | 120-93-4 | C3H6N2O | 详情 | 详情 |
| (XIII) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (XIV) | 55788 | tert-butyl 2-{3-[2-(tert-butoxy)-2-oxoethyl]-2-oxo-1-imidazolidinyl}acetate | C15H26N2O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)N-Cbz-L-Valinal cyanohydrin (I) is converted into imidate (II) and then condensed with 2-aminophenol (III) to afford benzoxazole (IV). Removal of the N-Cbz group of (IV) with H2 and Pd/C provides amine (V), which is then coupled to N-Cbz-valyl proline (VI), yielding the dipeptide amide (VII). After hydrogenolysis of the N-Cbz protecting group of (VII), the free amine (VIII) is coupled to the acid fragment (IX) by means of EDC/pyridine to furnish (X).
| 【1】 Sato, F.; Inoue, Y.; Omodani, T.; Imano, K.; Okazaki, H.; Takemura, T.; Komiya, M.; Design and synthesis of peptide-based carboxylic acid-containing transition-state inhibitors of human neutrophil elastase. Bioorg Med Chem Lett 2002, 12, 4, 551. |
| 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) | 62768 | benzyl (1S)-1-[cyano(hydroxy)methyl]-2-methylpropylcarbamate | C14H18N2O3 | 详情 | 详情 | |
| (II) | 62769 | ethyl (3S)-3-{[(benzyloxy)carbonyl]amino}-2-hydroxy-4-methylpentanimidoate | C16H24N2O4 | 详情 | 详情 | |
| (III) | 18663 | o-aminophenol; 2-aminophenol | 95-55-6 | C6H7NO | 详情 | 详情 |
| (IV) | 62770 | benzyl (1S)-1-[1,3-benzoxazol-2-yl(hydroxy)methyl]-2-methylpropylcarbamate | C20H22N2O4 | 详情 | 详情 | |
| (V) | 62771 | (2S)-2-amino-1-(1,3-benzoxazol-2-yl)-3-methyl-1-butanol | C12H16N2O2 | 详情 | 详情 | |
| (VI) | 22787 | (2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylic acid | C18H24N2O5 | 详情 | 详情 | |
| (VII) | 62772 | benzyl (1S)-1-({(2S)-2-[({(1S)-1-[1,3-benzoxazol-2-yl(hydroxy)methyl]-2-methylpropyl}amino)carbonyl]pyrrolidinyl}carbonyl)-2-methylpropylcarbamate | C30H38N4O6 | 详情 | 详情 | |
| (VIII) | 55792 | (2S)-1-[(2S)-2-amino-3-methylbutanoyl]-N-{(1S)-1-[(S)-1,3-benzoxazol-2-yl(hydroxy)methyl]-2-methylpropyl}-2-pyrrolidinecarboxamide | C22H32N4O4 | 详情 | 详情 | |
| (IX) | 62773 | 2-({4-[2-(tert-butoxy)-2-oxoethoxy]benzoyl}amino)acetic acid | C15H19NO6 | 详情 | 详情 | |
| (X) | 62774 | tert-butyl 2-(4-{[(2-{[(1S)-1-({(2S)-2-[({(1S)-1-[1,3-benzoxazol-2-yl(hydroxy)methyl]-2-methylpropyl}amino)carbonyl]pyrrolidinyl}carbonyl)-2-methylpropyl]amino}-2-oxoethyl)amino]carbonyl}phenoxy)acetate | C37H49N5O9 | 详情 | 详情 |