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【结 构 式】 
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【药物名称】 【化学名称】N-(1,3-Benzodioxol-5-ylmethyl)-3(S)-[N2-(benzylsulfonyl)-L-arginyl-N2-methylglycinamido]-4-(cyclohexyl)-2-oxobutyramide 【CA登记号】 【 分 子 式 】C34H47N7O8S 【 分 子 量 】713.85979 |
【开发单位】Corvas (Originator) 【药理作用】Anticoagulants, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Coagulation Factor Xa Inhibitors |
合成路线1
Coupling of Boc-d-nitroarginine (I) with sarcosine methyl ester (II) in the presence of EDC and HOBt gave dipeptide (III). Subsequent deprotection of the Boc group of (III) afforded amine (IV), which was coupled with benzylsulfonyl chloride (V), yielding sulfonamide (VI). Then, saponification of the methyl ester of (VI) with LiOH furnished carboxylic acid (VII).
| 【1】 Semple, J.E.; et al.; Novel, potent, and selective factor Xa inhibitors featuring a hydrophobic P1-ketoamide moiety. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 193. |
| 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) | 39364 | Omega-nitro-Boc-D-arginine | 50913-12-7 | C11H21N5O6 | 详情 | 详情 |
| (II) | 10430 | methyl 2-(methylamino)acetate; methyl N-methylglycinate | 5473-12-1 | C4H9NO2 | 详情 | 详情 |
| (III) | 39347 | C15H28N6O7 | 详情 | 详情 | ||
| (IV) | 39348 | C10H20N6O5 | 详情 | 详情 | ||
| (V) | 25151 | phenylmethanesulfonyl chloride | 1939-99-7 | C7H7ClO2S | 详情 | 详情 |
| (VI) | 39349 | C17H26N6O7S | 详情 | 详情 | ||
| (VII) | 39350 | C16H24N6O7S | 详情 | 详情 |
合成路线2
In an alternative procedure, d-nitroarginine methyl ester (VIII) was condensed with sulfonyl chloride (V) giving sulfonamide (IX). The hydrolysis of the ester group of (IX) with LiOH produced carboxylic acid (X). Conversion of (X) to arginine lactam (XI) was effected by treatment with EDC and HOBt. Subsequent opening of the lactam ring of (XI) with sarcosine tert-butyl ester (XII) in the presence of AlMe3 gave rise to dipeptide (XIII). The tert-butyl ester of (XIII) was then cleaved by treatment with trifluoroacetic acid.
| 【1】 Semple, J.E.; et al.; Novel, potent, and selective factor Xa inhibitors featuring a hydrophobic P1-ketoamide moiety. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 193. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 25151 | phenylmethanesulfonyl chloride | 1939-99-7 | C7H7ClO2S | 详情 | 详情 |
| (VII) | 39350 | C16H24N6O7S | 详情 | 详情 | ||
| (VIII) | 39351 | D-Ornithine, N5-(imino(nitroamino)methyl)-, methyl ester; N5-(Imino(nitroamino)methyl)-D-ornithine methyl ester | 141968-19-6 | C7H15N5O4 | 详情 | 详情 |
| (IX) | 39352 | C14H21N5O6S | 详情 | 详情 | ||
| (X) | 39353 | C13H19N5O6S | 详情 | 详情 | ||
| (XI) | 39354 | C13H17N5O5S | 详情 | 详情 | ||
| (XII) | 39355 | tert-butyl 2-(methylamino)acetate | C7H15NO2 | 详情 | 详情 | |
| (XIII) | 39356 | C20H32N6O7S | 详情 | 详情 |
合成路线3
Cyclohexylalanine (XIV) was protected as the Boc derivative (XV) and then coupled with N,O-dimethylhydroxylamine to produce the Weinreb amide (XVI). Reduction of (XVI) with LiAlH4 at -78 C gave aldehyde (XVII) and subsequent addition of tert-butyl isonitrile furnished hydroxy amide (XVIII). After acid hydrolysis of (XVIII), amino acid (XIX) was protected as the N-Boc derivative (XX). This was coupled with benzodioxolylmethyl amine (XXI) yielding amide (XXII). Acid deprotection of the Boc group of (XXII) gave (XXIII), which was further coupled with dipeptide (VII) to generate tripeptide amide (XXIV). Following hydrogenolytic deprotection of the N-nitro group of (XXIV), Swern oxidation of the alcohol group gave rise to the title compound.
| 【1】 Semple, J.E.; et al.; Novel, potent, and selective factor Xa inhibitors featuring a hydrophobic P1-ketoamide moiety. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 193. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIII | 39362 | (3S)-3-amino-N-(1,3-benzodioxol-5-ylmethyl)-4-cyclohexyl-2-hydroxybutanamide | C18H26N2O4 | 详情 | 详情 | |
| (VII) | 39350 | C16H24N6O7S | 详情 | 详情 | ||
| (XIV) | 39357 | (2S)-2-amino-3-cyclohexylpropionic acid; L-Cyclohexylalanine | 27527-05-5 | C9H17NO2 | 详情 | 详情 |
| (XV) | 23050 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-cyclohexylpropionic acid | C14H25NO4 | 详情 | 详情 | |
| (XVI) | 39358 | tert-butyl (1S)-1-(cyclohexylmethyl)-2-[methoxy(methyl)amino]-2-oxoethylcarbamate | C16H30N2O4 | 详情 | 详情 | |
| (XVII) | 15853 | tert-butyl N-[(1S)-2-cyclohexyl-1-formylethyl]carbamate | C14H25NO3 | 详情 | 详情 | |
| (XVIII) | 39359 | tert-butyl (1S)-3-(tert-butylamino)-1-(cyclohexylmethyl)-2-hydroxy-3-oxopropylcarbamate | C19H36N2O4 | 详情 | 详情 | |
| (XIX) | 12329 | (2R,3S)-3-Amino-4-cyclohexyl-2-hydroxybutyric acid | C10H19NO3 | 详情 | 详情 | |
| (XX) | 39360 | (3S)-3-[(tert-butoxycarbonyl)amino]-4-cyclohexyl-2-hydroxybutyric acid | C15H27NO5 | 详情 | 详情 | |
| (XXI) | 33669 | 1,3-benzodioxol-5-ylmethylamine; 1,3-benzodioxol-5-ylmethanamine; 3,4-Methylendioxybenzylamine | 2620-50-0 | C8H9NO2 | 详情 | 详情 |
| (XXII) | 39361 | tert-butyl (1S)-3-[(1,3-benzodioxol-5-ylmethyl)amino]-1-(cyclohexylmethyl)-2-hydroxy-3-oxopropylcarbamate | C23H34N2O6 | 详情 | 详情 | |
| (XXIV) | 39363 | C34H48N8O10S | 详情 | 详情 |