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【结 构 式】 
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【药物名称】 【化学名称】1-(4-Methoxyphenyl)-3-methyl-N-(2'-sulfamoylbiphenyl-4-yl)-1H-pyrazole-5-carboxamide 【CA登记号】218629-72-2 【 分 子 式 】C24H22N4O4S 【 分 子 量 】462.53134 |
【开发单位】Bristol-Myers Squibb (Originator) 【药理作用】Anticoagulants, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Coagulation Factor Xa Inhibitors |
合成路线1
The intermediate biphenylamine (IV) was prepared by Suzuki coupling of N-Boc-4-bromoaniline (I) with 2-(N-tert-butylaminosulfonyl)phenylboronic acid (II), followed by deprotection of the Boc group.
| 【1】 Galemmo, R.A. Jr.; Fevig, J.; Lam, P.Y.; et al.; New functional groups for interaction with the S1 pocket of factor Xa: The discovery of 1-(4-methoxyphenyl)pyrazole inhibitors. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 290. |
| 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) | 26633 | tert-butyl 4-bromophenylcarbamate | C11H14BrNO2 | 详情 | 详情 | |
| (II) | 26627 | 2-[(tert-butylamino)sulfonyl]phenylboronic acid | C10H16BNO4S | 详情 | 详情 | |
| (III) | 44128 | 4-[(tert-butoxycarbonyl)amino]-2'-[(tert-butylamino)sulfonyl]-1,1'-biphenyl; tert-butyl 2'-[(tert-butylamino)sulfonyl][1,1'-biphenyl]-4-ylcarbamate | C21H28N2O4S | 详情 | 详情 | |
| (IV) | 23363 | 4'-amino-N-(tert-butyl)[1,1'-biphenyl]-2-sulfonamide | C16H20N2O2S | 详情 | 详情 |
合成路线2
Ethyl 2,4-dioxopentanoate (V) was converted into the O-methyloxime (VI) and subsequently cyclized with 4-methoxyphenylhydrazine (VII) to furnish pyrazole (VIII) (1,2). Optionally, ester (VIII) was hydrolyzed and then converted to acid chloride (IX) by treatment with oxalyl chloride (1). Biphenylamine (IV) was coupled with ester (VIII) in the presence of trimethylaluminium (2) or, alternatively, with acid chloride (IX) (1) to give amide (X). The N-tert-butyl group of (X) was finally removed by refluxing in trifluoroacetic acid.
| 【1】 Galemmo, R.A. Jr.; Fevig, J.; Lam, P.Y.; et al.; New functional groups for interaction with the S1 pocket of factor Xa: The discovery of 1-(4-methoxyphenyl)pyrazole inhibitors. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 290. |
| 【2】 Dominguez, C.; Fevig, J.M.; Galemmo, R.A. Jr.; Pinto, D.J.P.; Pruitt, J.R.; lma, P.; Quan, M.L.; Han, Q. (DuPont Pharmaceuticals Co.); Inhibitors of factor Xa with a neutral P1 specificity group. US 5998424; WO 9857937 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 23363 | 4'-amino-N-(tert-butyl)[1,1'-biphenyl]-2-sulfonamide | C16H20N2O2S | 详情 | 详情 | |
| (V) | 42500 | ethyl 2,4-dioxopentanoate | 615-79-2 | C7H10O4 | 详情 | 详情 |
| (VI) | 44129 | ethyl 2-(methoxyimino)-4-oxopentanoate | C8H13NO4 | 详情 | 详情 | |
| (VII) | 12688 | 4-Hydrazinophenyl methyl ether; 1-(4-Methoxyphenyl)hydrazine | 3471-32-7 | C7H10N2O | 详情 | 详情 |
| (VIII) | 44130 | ethyl 1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-5-carboxylate | C14H16N2O3 | 详情 | 详情 | |
| (IX) | 44131 | 1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-5-carbonyl chloride | C12H11ClN2O2 | 详情 | 详情 | |
| (X) | 44132 | N-[2'-[(tert-butylamino)sulfonyl][1,1'-biphenyl]-4-yl]-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-5-carboxamide | C28H30N4O4S | 详情 | 详情 |