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【结 构 式】 
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【药物名称】DPC-423 【化学名称】1-[3-(Aminomethyl)phenyl]-N-[3-fluoro-2'-(methylsulfonyl)biphenyl-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide 【CA登记号】209957-47-1, 209957-48-2 (monotrifluoroacetate) 【 分 子 式 】C25H20F4N4O3S 【 分 子 量 】532.52075 |
【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
Condensation of 1,1,1-trifluoro-2,4-pentanedione (I) with 3-bromophenylhydrazine (II) produced an 88:12 mixture of regioisomeric pyrazoles (III) and (IV). Treatment of this mixture with copper cyanide in boiling NMP afforded the corresponding mixture of nitriles, from which the desired major isomer (V) was isolated by flash chromatography. Radical bromination of (V), followed by hydrolysis of the resulting bromomethylpyrazole (VI) with CaCO3 in aqueous dioxan, yielded alcohol (VII). Oxidation of (VII) to carboxylic acid (VIII) was then effected by treatment with sodium periodate in the presence of ruthenium trichloride. After conversion of (VIII) to the corresponding acid chloride (IX) with oxalyl chloride, coupling with 4-bromo-2-fluoroaniline (X) furnished amide (XI). Subsequent Suzuki coupling of (XI) with 2-(methylsulfanyl)phenylboronic acid (XII) gave rise to biphenyl derivative (XIII). The sulfide group of (XIII) was then oxidized to sulfone (XIV) using meta-chloroperbenzoic acid. Finally, catalytic hydrogenation of the cyano group of (XIV) over Pd/C yielded the title primary amine.
| 【1】 Orwat, M.J.; Cacciola, J.; Han, Q.; Fevig, J.M.; Pinto, D.J.P.; Rossi, K.A.; Pruitt, J.R.; Quan, M.L. (DuPont Pharmaceuticals Co.); Nitrogen containing heteroaromatics as factor Xa inhibitors. EP 0946508; WO 9828269 . |
| 【2】 Cacciola, J.; Han, Q.; Pinto, D.J.P.; Pruitt, J.R.; Rossi, K.A.; Fevig, J.M.; Orwat, M.M.; Quan, M.L. (DuPont Pharmaceuticals Co.); Nitrogen containing heteroaromatics as factor Xa inhibitors. US 6020357 . |
| 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) | 46384 | 1,1,1-trifluoro-2,4-pentanedione | C5H5F3O2 | 详情 | 详情 | |
| (II) | 37812 | 1-(3-bromophenyl)hydrazine | 27246-81-7 | C6H7BrN2 | 详情 | 详情 |
| (III) | 46385 | 1-(3-bromophenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole | C11H8BrF3N2 | 详情 | 详情 | |
| (IV) | 46386 | 1-(3-bromophenyl)-3-methyl-5-(trifluoromethyl)-1H-pyrazole | C11H8BrF3N2 | 详情 | 详情 | |
| (V) | 46387 | 3-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzonitrile | C12H8F3N3 | 详情 | 详情 | |
| (VI) | 46388 | 3-[5-(bromomethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzonitrile | C12H7BrF3N3 | 详情 | 详情 | |
| (VII) | 46389 | 3-[5-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzonitrile | C12H8F3N3O | 详情 | 详情 | |
| (VIII) | 46390 | 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid | C12H6F3N3O2 | 详情 | 详情 | |
| (IX) | 46391 | 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carbonyl chloride | C12H5ClF3N3O | 详情 | 详情 | |
| (X) | 14723 | 4-Bromo-2-fluorophenylamine; 4-Bromo-2-fluoroaniline | 367-24-8 | C6H5BrFN | 详情 | 详情 |
| (XI) | 46392 | N-(4-bromo-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide | C18H9BrF4N4O | 详情 | 详情 | |
| (XII) | 46393 | 2-(methylsulfanyl)phenylboronic acid | C7H9BO2S | 详情 | 详情 | |
| (XIII) | 46394 | 1-(3-cyanophenyl)-N-[3-fluoro-2'-(methylsulfanyl)[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide | C25H16F4N4OS | 详情 | 详情 | |
| (XIV) | 46395 | 1-(3-cyanophenyl)-N-[3-fluoro-2'-(methylsulfonyl)[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide | C25H16F4N4O3S | 详情 | 详情 |
合成路线2
The cyclization of 3-bromophenylhydrazine (I) with 1,1,1-trifluoropentane-2,4-dione (II) in refluxing acetic acid gives an inseparable regioisomeric mixture of pyrazoles (III) + (IV), which is treated with CuCN in refluxing NMP to yield the mixture of benzonitriles (V) + (VI). The reaction of this mixture with NBS in CCl4 affords the mixture of bromomethyl compounds (VII) + (VIII), which is treated with CaCO3 in dioxane/water to provide a mixture of hydroxymethyl compounds that is easily separated by chromatography. The desired hydroxymethyl pyrazole (IX) is oxidized with NaIO4 and RuCl3 to give the carboxylic acid (X), which is condensed with 3-fluoro-2'-(methylsulfonyl)biphenyl-4-amine (XI) by means of oxalyl chloride and DMAP in dichloromethane to yield the carboxamide (XII). Finally, the cyano group of (XII) is hydrogenated with H2 over Pd/C in methanol/HOAc.
| 【1】 Pinto, D.J.P.; Orwat, M.J.; Wang, S.; et al.; Discovery of 1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2'(methylsulfonyl)-[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a highly potent, selective, and orally biovailable inhibitor of blood coagulation factor Xa. J Med Chem 2001, 44, 4, 566. |
| 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) | 37812 | 1-(3-bromophenyl)hydrazine | 27246-81-7 | C6H7BrN2 | 详情 | 详情 |
| (II) | 46384 | 1,1,1-trifluoro-2,4-pentanedione | C5H5F3O2 | 详情 | 详情 | |
| (III) | 46386 | 1-(3-bromophenyl)-3-methyl-5-(trifluoromethyl)-1H-pyrazole | C11H8BrF3N2 | 详情 | 详情 | |
| (IV) | 46385 | 1-(3-bromophenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole | C11H8BrF3N2 | 详情 | 详情 | |
| (V) | 50961 | 3-[3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]benzonitrile | C12H8F3N3 | 详情 | 详情 | |
| (VI) | 46387 | 3-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzonitrile | C12H8F3N3 | 详情 | 详情 | |
| (VII) | 50962 | 3-[3-(bromomethyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]benzonitrile | C12H7BrF3N3 | 详情 | 详情 | |
| (VIII) | 46388 | 3-[5-(bromomethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzonitrile | C12H7BrF3N3 | 详情 | 详情 | |
| (IX) | 46389 | 3-[5-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzonitrile | C12H8F3N3O | 详情 | 详情 | |
| (X) | 46390 | 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid | C12H6F3N3O2 | 详情 | 详情 | |
| (XI) | 50963 | 3-fluoro-2'-(methylsulfonyl)[1,1'-biphenyl]-4-amine; 3-fluoro-2'-(methylsulfonyl)[1,1'-biphenyl]-4-ylamine | C13H12FNO2S | 详情 | 详情 | |
| (XII) | 46395 | 1-(3-cyanophenyl)-N-[3-fluoro-2'-(methylsulfonyl)[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide | C25H16F4N4O3S | 详情 | 详情 |