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【结 构 式】 
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【药物名称】ST-368 【化学名称】(-)-3-(3-Amino-4-chlorophenyl)-5-(methylsulfonamidomethyl)-N-[5-(2-sulfamoylphenyl)pyridin-2-yl]-4,5-dihydroisoxazole-5-carboxamide 【CA登记号】 【 分 子 式 】C23H23ClN6O6S2 【 分 子 量 】579.05736 |
【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
Conversion of the bromo derivative (I) into the corresponding azido compound (II) is performed by treatment with NaN3 in DMSO. Separately, aldehyde (III) is treated with hydroxylamine to provide oxime (IV), which is then condensed with derivative (II) by means of bleach in CH2Cl2 to furnish isoxazoline derivative (V). Hydrolysis of the methyl ester of (V) by means of LiOH in THF affords carboxylic acid (VI), which is treated with SOCl2 and then condensed with amine (VII) by means of Et3N to give carboxamide (VIII). Reduction of the azido moiety of (VIII) by means of P(OEt)3 in THF yields amine (IX), which is then derivatized by reaction with mesyl chloride (MeSO2Cl) to provide mesylate (X). Finally, the desired compound is obtained by treatment of (X) with TFA for tert-butyl group removal, followed by reduction of the nitro moiety with SnCl2.
| 【1】 Wong, P.C.; Ellis, C.D.; Rossi, K.A.; Wexler, R.R.; Wright, M.R.; Quan, M.L.; Lam, P.Y.; He, M.Y.; Knabb, R.M.; Liauw, A.Y.; Nonbenzamidine isoxazolin derivatives as factor Xa inhibitors. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 52. |
| 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) | 32407 | methyl 2-(bromomethyl)acrylate | C5H7BrO2 | 详情 | 详情 | |
| (II) | 50083 | methyl 2-(azidomethyl)acrylate | C5H7N3O2 | 详情 | 详情 | |
| (III) | 50084 | 3-Nitro-4-chlorobenzaldehyde; 4-Chloro-3-nitrobenzaldehyde | 16588-34-4 | C7H4ClNO3 | 详情 | 详情 |
| (IV) | 50085 | N-(4-chloro-3-nitrobenzyl)hydroxylamine; 1-chloro-4-[(hydroxyamino)methyl]-2-nitrobenzene | C7H7ClN2O3 | 详情 | 详情 | |
| (V) | 50086 | methyl 5-(azidomethyl)-3-(4-chloro-3-nitrophenyl)-4,5-dihydro-5-isoxazolecarboxylate | C12H10ClN5O5 | 详情 | 详情 | |
| (VI) | 50087 | 5-(azidomethyl)-3-(4-chloro-3-nitrophenyl)-4,5-dihydro-5-isoxazolecarboxylic acid | C11H8ClN5O5 | 详情 | 详情 | |
| (VII) | 32412 | 2-(6-amino-3-pyridinyl)-N-(tert-butyl)benzenesulfonamide | C15H19N3O2S | 详情 | 详情 | |
| (VIII) | 50088 | 5-(azidomethyl)-N-(5-[2-[(tert-butylamino)sulfonyl]phenyl]-2-pyridinyl)-3-(4-chloro-3-nitrophenyl)-4,5-dihydro-5-isoxazolecarboxamide | C26H25ClN8O6S | 详情 | 详情 | |
| (IX) | 50089 | 5-(aminomethyl)-N-(5-[2-[(tert-butylamino)sulfonyl]phenyl]-2-pyridinyl)-3-(4-chloro-3-nitrophenyl)-4,5-dihydro-5-isoxazolecarboxamide | C26H27ClN6O6S | 详情 | 详情 | |
| (X) | 50090 | N-(5-[2-[(tert-butylamino)sulfonyl]phenyl]-2-pyridinyl)-3-(4-chloro-3-nitrophenyl)-5-[[(methylsulfonyl)amino]methyl]-4,5-dihydro-5-isoxazolecarboxamide | C27H29ClN6O8S2 | 详情 | 详情 |