|
【结 构 式】 
|
【药物名称】SM-20302 【化学名称】3-[3-(4-Amidinobenzamido)propionamido]-2(S)-(4-ethylphenylsulfonamido)propionic acid 【CA登记号】169456-85-3, 169456-86-4 (monotrifluoroacetate) 【 分 子 式 】C22H27N5O6S 【 分 子 量 】489.55439 |
【开发单位】Sumitomo Pharmaceuticals (Originator) 【药理作用】Antiplatelet Therapy, Cerebrovascular Diseases, Treatment of, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Ischemic Stroke, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of, Integrin alphaIIbbeta3 (Fibrinogen gpIIb/IIIa) Antagonists |
合成路线1
The reaction of N-(benzyloxycarbonyl)-L-asparagine (I) with bis(trifluoroacetyl)iodobenzene (BTI) in DMF/water gives 3-amino-2(S)-(benzyloxycarbonylamino)propionic acid (II), wehich is protected at the amino group with tert-butoxycarbonyl anhydride yielding carbamate (III). The esterification of (III) with ethanol WSC and DMAP affords the expected ethyl ester (IV), which is selectively deprotected with methanesulfonic acid in acetonitrile providing 3-amino-2-(benzyloxycarbonylamino)propionic acid ethyl ester (V). The condensation of (V) with N-(tert-butoxycarbonyl)-beta-alanine (VI) by means of HOBT, WSC and triethylamine in DMF gives the protected propionamidopropionic ester (VII), which is selectively deprotected by hydrogenation with H2 over Pd/C in ethanol/ethyl acetate giving the 2-aminopropionic ester (VIII). The condensation of (VIII) with 4-ethylbenzenesulfonyl chloride (IX) by means of triethylamine in dichloromethane yields the sulfonamide (X), which is deprotected with methanesulfonic acid as before afording intermediate (XI) with a free amino group, which is condensed with 4-(tert-butoxycarbonylamino)benzoic acid (XII) by means of HOBT and WSC in DMF providing the fully protected target compound (XIII).
| 【1】 Ikeda, Y.; Ueki, Y.; Kishimoto, H.; Nishihara, T.; Kamikawa, Y. (Sumitomo Pharmaceuticals Co., Ltd.); 2,3-Diaminopropionic acid deriv.. US 5707994; US 6048854; WO 9511228 . |
| 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) | 14529 | (2S)-4-amino-2-[[(benzyloxy)carbonyl]amino]-4-oxobutyric acid | 2304-96-3 | C12H14N2O5 | 详情 | 详情 |
| (II) | 18008 | (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propionic acid; N(alpha)-Z-L-2,3-diaminopropionic acid | 35761-26-3 | C11H14N2O4 | 详情 | 详情 |
| (III) | 26613 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(tert-butoxycarbonyl)amino]propionic acid | C16H22N2O6 | 详情 | 详情 | |
| (IV) | 26614 | ethyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(tert-butoxycarbonyl)amino]propanoate | C18H26N2O6 | 详情 | 详情 | |
| (V) | 26615 | ethyl (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propanoate | C13H18N2O4 | 详情 | 详情 | |
| (VI) | 26616 | N-(tert-butoxycarbonyl)-beta-alanine | 3303-84-2 | C8H15NO4 | 详情 | 详情 |
| (VII) | 26617 | ethyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-([3-[(tert-butoxycarbonyl)amino]propanoyl]amino)propanoate | C21H31N3O7 | 详情 | 详情 | |
| (VIII) | 26618 | ethyl (2S)-2-amino-3-([3-[(tert-butoxycarbonyl)amino]propanoyl]amino)propanoate | C13H25N3O5 | 详情 | 详情 | |
| (IX) | 26619 | 4-ethylbenzenesulfonyl chloride | 16712-69-9 | C8H9ClO2S | 详情 | 详情 |
| (X) | 26620 | ethyl (2S)-3-([3-[(tert-butoxycarbonyl)amino]propanoyl]amino)-2-[[(4-ethylphenyl)sulfonyl]amino]propanoate | C21H33N3O7S | 详情 | 详情 | |
| (XI) | 26621 | ethyl (2S)-3-[(3-aminopropanoyl)amino]-2-[[(4-ethylphenyl)sulfonyl]amino]propanoate | C16H25N3O5S | 详情 | 详情 | |
| (XII) | 26622 | 4-[[(tert-butoxycarbonyl)amino](imino)methyl]benzoic acid | C13H16N2O4 | 详情 | 详情 | |
| (XIII) | 26623 | ethyl (2S)-3-[[3-([4-[[(tert-butoxycarbonyl)amino](imino)methyl]benzoyl]amino)propanoyl]amino]-2-[[(4-ethylphenyl)sulfonyl]amino]propanoate | C29H39N5O8S | 详情 | 详情 |
合成路线2
The deprotetion of (XIII) first with trifluoroacetic acid gives the ethyl ester (XIV), which is finally hydrolyzed with HCl in hot acetic acid.
| 【1】 Ikeda, Y.; Ueki, Y.; Kishimoto, H.; Nishihara, T.; Kamikawa, Y. (Sumitomo Pharmaceuticals Co., Ltd.); 2,3-Diaminopropionic acid deriv.. US 5707994; US 6048854; WO 9511228 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 26623 | ethyl (2S)-3-[[3-([4-[[(tert-butoxycarbonyl)amino](imino)methyl]benzoyl]amino)propanoyl]amino]-2-[[(4-ethylphenyl)sulfonyl]amino]propanoate | C29H39N5O8S | 详情 | 详情 | |
| (XIV) | 26624 | ethyl (2S)-3-[[3-([4-[amino(imino)methyl]benzoyl]amino)propanoyl]amino]-2-[[(4-ethylphenyl)sulfonyl]amino]propanoate | C24H31N5O6S | 详情 | 详情 |
合成路线3
The intermediate 4-(tert-butoxycarbonylamindino)benzoic acid (XII) has been obtained as follows: Comerciaally available 4-amidinobenzamide (XV) is hydrolyzed with aqueous HCl to give 4-amidinobenzoic acid (XVI), which is then treated with tert-butoxycarbonyl anhydride and N,O-bis(trimethylsilyl)acetamide in dichloromethane to afford the target intermediate (XII).
| 【1】 Ikeda, Y.; Ueki, Y.; Kishimoto, H.; Nishihara, T.; Kamikawa, Y. (Sumitomo Pharmaceuticals Co., Ltd.); 2,3-Diaminopropionic acid deriv.. US 5707994; US 6048854; WO 9511228 . |