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【结 构 式】 
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【分子编号】34823 【品名】2-(2-amino-5-pyrimidinyl)-N-(tert-butyl)benzenesulfonamide 【CA登记号】 |
【 分 子 式 】C14H18N4O2S 【 分 子 量 】306.38868 【元素组成】C 54.88% H 5.92% N 18.29% O 10.44% S 10.47% |
合成路线1
该中间体在本合成路线中的序号：(VII)The cyclization of 3-bromophenylhydrazine (I) with 2-(trichloroacetyl)-3-methoxycrotonic acid (II) in refluxing ethanol gives, after chromatographic separation, 1-(3-bromophenyl)-3-methylpyrazole-5-carboxylic acid ethyl ester (III), which by reaction with CuCN in refluxing N-methylpyrrolidone is converted into the 3-cyanophenyl analogue (IV). The hydrolysis of (IV) with LiOH in THF/water affords the corresponding carboxylic acid (V), which by reaction with oxalyl chloride in dichloromethane gives the acyl chloride (VI). The condensation of (VI) with 2-(2-aminopyrimidin-4-yl)-N-tert-butylbenzenesulfonamide (VII) by means of TEA in dichloromethane provides the corresponding amide (VIII), which is finally treated first with HCl in methanol, and then with ammonium carbonate in the same solvent.
| 【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 . |
| 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) | 37813 | (Z)-4-methoxy-2-(2,2,2-trichloroacetyl)-3-pentenoic acid | C8H9Cl3O4 | 详情 | 详情 | |
| (III) | 37814 | ethyl 1-(3-bromophenyl)-3-methyl-1H-pyrazole-5-carboxylate | C13H13BrN2O2 | 详情 | 详情 | |
| (IV) | 37815 | ethyl 1-(3-cyanophenyl)-3-methyl-1H-pyrazole-5-carboxylate | C14H13N3O2 | 详情 | 详情 | |
| (V) | 37816 | 1-(3-cyanophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid | C12H9N3O2 | 详情 | 详情 | |
| (VI) | 37817 | 1-(3-cyanophenyl)-3-methyl-1H-pyrazole-5-carbonyl chloride | C12H8ClN3O | 详情 | 详情 | |
| (VII) | 34823 | 2-(2-amino-5-pyrimidinyl)-N-(tert-butyl)benzenesulfonamide | C14H18N4O2S | 详情 | 详情 | |
| (VIII) | 37819 | N-(5-[2-[(tert-butylamino)sulfonyl]phenyl]-2-pyrimidinyl)-1-(3-cyanophenyl)-3-methyl-1H-pyrazole-5-carboxamide | C26H25N7O3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)3-Cyanobenzaldehyde (I) was converted to oxime (II) by reaction with hydroxylamine in pyridine. The intermediate nitrile oxide, generated from chlorination and further elimination of HCl, underwent a [2+3] cycloaddition with itaconic acid monomethyl ester (III) to produce the isoxazoline (IV). The carboxylate group of (IV) was then activated as the corresponding acid chloride (V) upon treatment with SOCl2. Boronic acid (VII) was prepared from N-tert-butyl benzenesulfonamide (VI) by lithiation with n-butyllithium, followed by reaction with triisopropyl borate and quenching with HCl. Subsequent Suzuki coupling of (VII) with 2-amino-5-bromopyrimidine (VIII) using Pd(PPh3)4 and Na2CO3 afforded the 2-amino-4-arylpyrimidine (IX). Condensation of amine (IX) with acid chloride (V) in the presence of Et3N gave amide (X). The N-tert-butyl group of (X) was then deprotected by means of trifluoroacetic acid to yield (XI) as the trifluoroacetate salt. The cyano group of (XI) was converted to imidate (XII) with HCl and MeOH. This was finally reacted with ammonium acetate in MeOH to furnish the title amidine.
| 【1】 Quan, M.L.; Liauw, A.Y.; Ellis, C.D.; et al.; Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 1. J Med Chem 1999, 42, 15, 2752. |
| 【2】 Quan, M.L.; Wityak, J.; Galemmo, R.A. Jr.; Stouten, P.F.W.; Pruitt, J.R. (DuPont Pharmaceuticals Co.); Isoxazoline, isothiazoline and pyrazoline factor Xa inhibitors. EP 0874629; US 5939418; WO 9723212 . |
| 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) | 13245 | 3-Formylbenzonitrile; 3-Cyanobenzaldehyde | 24964-64-5 | C8H5NO | 详情 | 详情 |
| (II) | 23357 | 3-[(hydroxyimino)methyl]benzonitrile | C8H6N2O | 详情 | 详情 | |
| (III) | 34820 | 2-(2-methoxy-2-oxoethyl)acrylic acid | 7338-27-4 | C6H8O4 | 详情 | 详情 |
| (IV) | 26630 | 3-(3-cyanophenyl)-5-(2-methoxy-2-oxoethyl)-4,5-dihydro-5-isoxazolecarboxylic acid | C14H12N2O5 | 详情 | 详情 | |
| (V) | 34821 | methyl 2-[5-(chlorocarbonyl)-3-(3-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate | C14H11ClN2O4 | 详情 | 详情 | |
| (VI) | 26626 | N-(tert-butyl)benzenesulfonamide | C10H15NO2S | 详情 | 详情 | |
| (VII) | 26627 | 2-[(tert-butylamino)sulfonyl]phenylboronic acid | C10H16BNO4S | 详情 | 详情 | |
| (VIII) | 34822 | 5-bromo-2-pyrimidinamine; 5-bromo-2-pyrimidinylamine | 7752-82-1 | C4H4BrN3 | 详情 | 详情 |
| (IX) | 34823 | 2-(2-amino-5-pyrimidinyl)-N-(tert-butyl)benzenesulfonamide | C14H18N4O2S | 详情 | 详情 | |
| (X) | 34824 | methyl 2-[5-[[(5-[2-[(tert-butylamino)sulfonyl]phenyl]-2-pyrimidinyl)amino]carbonyl]-3-(3-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate | C28H28N6O6S | 详情 | 详情 | |
| (XI) | 34825 | methyl 2-[5-[([5-[2-(aminosulfonyl)phenyl]-2-pyrimidinyl]amino)carbonyl]-3-(3-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate | C24H20N6O6S | 详情 | 详情 | |
| (XII) | 34826 | methyl 2-(5-[([5-[2-(aminosulfonyl)phenyl]-2-pyrimidinyl]amino)carbonyl]-3-[3-[imino(methoxy)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetate | C25H24N6O7S | 详情 | 详情 |