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【结 构 式】 
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【分子编号】50438 【品名】1-ethyl-2-[2-[(2S)pyrrolidinyl]ethyl]-1H-indole-6-carbonitrile 【CA登记号】 |
【 分 子 式 】C17H21N3 【 分 子 量 】267.37396 【元素组成】C 76.37% H 7.92% N 15.72% |
合成路线1
该中间体在本合成路线中的序号：(XV)Fischer esterification of L-proline (IX) with MeOH and HCl gave (X). Treatment of (X) with di-tert-butyl dicarbonate provided N-Boc-proline methyl ester (XI). The ester function of (XI) was then reduced to aldehyde (XII) by employing DIBAL in toluene at -78 C. Wittig condensation between aldehyde (XII) and phosphonium bromide (VIII) in the presence of DBU yielded the (indolylvinyl)pyrrolidine (XIII), which was further hydrogenated to (XIV) in the presence of Pd/C. The N-Boc group of (XIV) was then cleaved by treatment with trifluoroacetic acid to furnish (XV).
| 【1】 Koo, B.A.; Min, J.K.; Hong, W.S.; Ryu, E.J.; Nam, W.H.; Kim, J.M. (C & C Research Laboratories); Aromatic amidine derivs. useful as selective thrombin inhibitors. EP 0918768; JP 2000504030; US 6201006; WO 9745424 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 50434 | [(6-cyano-1-ethyl-1H-indol-2-yl)methyl](triphenyl)phosphonium bromide | C30H26BrN2P | 详情 | 详情 | |
| (IX) | 16731 | L-proline | 147-85-3 | C5H9NO2 | 详情 | 详情 |
| (X) | 29552 | methyl (2S)-2-pyrrolidinecarboxylate | 2133-40-6 | C6H11NO2 | 详情 | 详情 |
| (XI) | 50435 | 1-(tert-butyl) 2-methyl (2S)-1,2-pyrrolidinedicarboxylate | C11H19NO4 | 详情 | 详情 | |
| (XII) | 16724 | tert-Butyl (2S)-2-formyltetrahydro-1H-pyrrole-1-carboxylate; tert-Butoxycarbonyl-L-prolinal | 69610-41-9 | C10H17NO3 | 详情 | 详情 |
| (XIII) | 50436 | tert-butyl (2S)-2-[(E)-2-(6-cyano-1-ethyl-1H-indol-2-yl)ethenyl]-1-pyrrolidinecarboxylate | C22H27N3O2 | 详情 | 详情 | |
| (XIV) | 50437 | tert-butyl (2S)-2-[2-(6-cyano-1-ethyl-1H-indol-2-yl)ethyl]-1-pyrrolidinecarboxylate | C22H29N3O2 | 详情 | 详情 | |
| (XV) | 50438 | 1-ethyl-2-[2-[(2S)pyrrolidinyl]ethyl]-1H-indole-6-carbonitrile | C17H21N3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XV)Pyrrolidine (XV) was coupled with N-Boc-D-proline (XVI) using EDC to provide amide (XVII). After acid cleavage of the Boc protecting group of (XVII), the resultant amine (XVIII) was further coupled with N-Boc-L-aspartic acid alpha-benzyl ester (XIX) to yield peptide (XX). Pinner reaction of nitrile (XX) with EtOH and HCl, with concomitant transesterification and Boc group cleavage, furnished imidate (XXI). Subsequent treatment of the imidate (XXI) with methanolic ammonia produced the corresponding amidine ester (XXII) along with some amide analogue (XXIII). Finally, basic hydrolysis of this mixture yielded the desired amidino acid.
| 【1】 Koo, B.A.; Min, J.K.; Hong, W.S.; Ryu, E.J.; Nam, W.H.; Kim, J.M. (C & C Research Laboratories); Aromatic amidine derivs. useful as selective thrombin inhibitors. EP 0918768; JP 2000504030; US 6201006; WO 9745424 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XV) | 50438 | 1-ethyl-2-[2-[(2S)pyrrolidinyl]ethyl]-1H-indole-6-carbonitrile | C17H21N3 | 详情 | 详情 | |
| (XVI) | 19061 | (2R)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid; (2R)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-D-proline | C10H17NO4 | 详情 | 详情 | |
| (XVII) | 50439 | tert-butyl (2R)-2-([(2S)-2-[2-(6-cyano-1-ethyl-1H-indol-2-yl)ethyl]pyrrolidinyl]carbonyl)-1-pyrrolidinecarboxylate | C27H36N4O3 | 详情 | 详情 | |
| (XVIII) | 50440 | 1-ethyl-2-(2-[(2S)-1-[(2R)pyrrolidinylcarbonyl]pyrrolidinyl]ethyl)-1H-indole-6-carbonitrile | C22H28N4O | 详情 | 详情 | |
| (XIX) | 50441 | (3S)-4-(benzyloxy)-3-[(tert-butoxycarbonyl)amino]-4-oxobutyric acid | C16H21NO6 | 详情 | 详情 | |
| (XX) | 50442 | benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-[(2R)-2-([(2S)-2-[2-(6-cyano-1-ethyl-1H-indol-2-yl)ethyl]pyrrolidinyl]carbonyl)pyrrolidinyl]-4-oxobutanoate | C38H47N5O6 | 详情 | 详情 | |
| (XXI) | 50445 | ethyl (2S)-2-amino-4-((2R)-2-[[(2S)-2-(2-[6-[ethoxy(imino)methyl]-1-ethyl-1H-indol-2-yl]ethyl)pyrrolidinyl]carbonyl]pyrrolidinyl)-4-oxobutanoate | C30H43N5O5 | 详情 | 详情 | |
| (XXII) | 50443 | ethyl (2S)-2-amino-4-((2R)-2-[[(2S)-2-(2-[6-[amino(imino)methyl]-1-ethyl-1H-indol-2-yl]ethyl)pyrrolidinyl]carbonyl]pyrrolidinyl)-4-oxobutanoate | C28H40N6O4 | 详情 | 详情 | |
| (XXIII) | 50444 | (2S)-2-amino-4-((2R)-2-[[(2S)-2-(2-[6-[amino(imino)methyl]-1-ethyl-1H-indol-2-yl]ethyl)pyrrolidinyl]carbonyl]pyrrolidinyl)-4-oxobutanamide | C26H37N7O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)The reaction of perhydroazepinone (I) with ethyl 2-bromoacetate (II) by means of LiHMDS in THF, followed by hydrolysis with KOH in methanol/water, gives the perhydroazepinylacetic acid (III), which is condensed with the pyrrolidine derivative (IV) by means of HOBt, WSCl and DIEA in dichloromethane to yield the adduct (V). The cleavage of the carbamate group of (V) with TFA in dichloromethane affords the 3-aminoperhydroazepinone (VI), which is condensed with ethyl 4-bromobutyrate (VII) by means of DIEA in acetonitrile to provide the 4-aminobutyrate derivative (VIII). The reaction of the cyano group of (VIII) with HCl in ethanol, followed by amonolysis with NH3 in the same solvent, gives the carboxamidine derivative (IX), which is hydrolyzed with KOH in ethanol/water to yield the target butyric acid derivative.
| 【1】 Park, C.-H.; Koo, B.-A.; Nam, W.-H. (C & C Research Laboratories); Substd. aromatic amidine deriv. and medicinal compsn. comprising the same. WO 0055156 . |
| 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) | 54736 | 2,2-dimethyl-N-[(3R)-2-oxoazepanyl]propanamide | C11H20N2O2 | 详情 | 详情 | |
| (II) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (III) | 54737 | 2-{(3R)-3-[(2,2-dimethylpropanoyl)amino]-2-oxoazepanyl}acetic acid | C13H22N2O4 | 详情 | 详情 | |
| (IV) | 50438 | 1-ethyl-2-[2-[(2S)pyrrolidinyl]ethyl]-1H-indole-6-carbonitrile | C17H21N3 | 详情 | 详情 | |
| (V) | 54738 | N-[(3R)-1-(2-{(2R)-2-[2-(6-cyano-1-ethyl-1H-indol-2-yl)ethyl]pyrrolidinyl}-2-oxoethyl)-2-oxoazepanyl]-2,2-dimethylpropanamide | C30H41N5O3 | 详情 | 详情 | |
| (VI) | 54739 | 2-[2-((2R)-1-{2-[(3R)-3-amino-2-oxoazepanyl]acetyl}pyrrolidinyl)ethyl]-1-ethyl-1H-indole-6-carbonitrile | C25H33N5O2 | 详情 | 详情 | |
| (VII) | 11263 | ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate | 2969-81-5 | C6H11BrO2 | 详情 | 详情 |
| (VIII) | 54740 | ethyl 4-{[(3R)-1-(2-{(2R)-2-[2-(6-cyano-1-ethyl-1H-indol-2-yl)ethyl]pyrrolidinyl}-2-oxoethyl)-2-oxoazepanyl]amino}butanoate | C31H43N5O4 | 详情 | 详情 | |
| (IX) | 54741 | ethyl 4-[((3R)-1-{2-[(2R)-2-(2-{6-[amino(imino)methyl]-1-ethyl-1H-indol-2-yl}ethyl)pyrrolidinyl]-2-oxoethyl}-2-oxoazepanyl)amino]butanoate | C31H46N6O4 | 详情 | 详情 |