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【结 构 式】 
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【药物名称】RPR-110754((-)-enantiomer), RPR-110750((+)-enantiomer), RPR-104632 【化学名称】2-(3-Bromobenzyl)-6,8-dichloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-3-carboxylic acid 1,1-dioxide 【CA登记号】154106-92-0 【 分 子 式 】C15H11BrCl2N2O4S 【 分 子 量 】466.13992 |
【开发单位】Aventis Pharma (Originator) 【药理作用】Cerebrovascular Diseases, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of, NMDA Antagonists |
合成路线1
This compound has been obtained by two related ways: 1) The sulfonation of 3,5-dichloroaniline (I) with chlorosulfonic acid gives 2-amino-4,6-dichlorobenzenesulfonyl chloride (II), which is condensed with 3-bromobenzylamine (III) by means of TEA yielding the corresponding sulfonamide (IV). The cyclization of (IV) with glyoxylic acid (A) in ethanol/sulfuric acid affords the esterified benzothiadiazine-3-carboxylate (V), which is finally hydrolyzed with aqueous NaOH. 2) The reaction of sulfonyl chloride (II) with liquid ammonia gives the corresponding sulfonamide (VI), which is cyclized with glyoxylic acid (A) as before yielding the benzothiadiazine (VII). Finally the alkylation of (VII) with 3-bromobenzyl bromide (VIII) by means of NaH affords the already reported benzothiadiazine-3-carboxylate (V). 3) The enantiomers of the title compound have been obtained in optically pure form by preparative liquid chromatography on a Pirkle-type chiral phase column.
| 【1】 Shot, J.H.; Biermacher, U.; Synthesis of potential diuretic agents. II. Dichloro-derivatives of 1,2,4-benzothiadiazine-1,1-dioxide. J Am Chem Soc 1960, 2, 1135-38. |
| 【2】 Mignani, S.; et al.; 2H-3,4-Dihydro-1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid derivatives, a novel family of glycine antagonists of the NMDA receptor channel complex. Drugs Fut 1995, 20, 11, 1133. |
| 【3】 Jimonet, P.; et al.; Synthesis and SAR of 2H-1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid derivatives as novel potent glycine antagonists of the NMDA receptor-channel complex. Bioorg Med Chem Lett 1994, 4, 23, 2735. |
| 【4】 Boireau, A.; Malgouris, C.; Burgevin, M.C.; et al.; Neuroprotective effects of RPR 104632, a novel antagonist at the glycine site of the NMDA receptor, in vitro. Eur J Pharmacol 1996, 300, 3, 237. |
| 【5】 Doble, A.; Boireau, A.; et al.; RPR 104632, a novel antagonist at the glycine site of the N-methyl-D-aspartate receptor-channel complex. Can J Physiol Pharmacol 1994, 72, Suppl. 1, 333. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 15618 | 2-Oxoacetic acid; Glyoxylic Acid | 298-12-4 | C2H2O3 | 详情 | 详情 |
| (I) | 26542 | 3,5-dichloroaniline | 626-43-7 | C6H5Cl2N | 详情 | 详情 |
| (II) | 41179 | 2-amino-4,6-dichlorobenzenesulfonyl chloride | C6H4Cl3NO2S | 详情 | 详情 | |
| (III) | 41180 | (3-bromophenyl)methanamine; 3-bromobenzylamine | C7H8BrN | 详情 | 详情 | |
| (IV) | 41181 | 2-amino-N-(3-bromobenzyl)-4,6-dichlorobenzenesulfonamide | C13H11BrCl2N2O2S | 详情 | 详情 | |
| (V) | 41182 | ethyl 2-(3-bromobenzyl)-6,8-dichloro-1,1-dioxo-1,2,3,4-tetrahydro-1lambda(6),2,4-benzothiadiazine-3-carboxylate | C17H15BrCl2N2O4S | 详情 | 详情 | |
| (VI) | 41183 | 2-amino-4,6-dichlorobenzenesulfonamide | C6H6Cl2N2O2S | 详情 | 详情 | |
| (VII) | 41184 | ethyl 6,8-dichloro-1,1-dioxo-1,2,3,4-tetrahydro-1lambda(6),2,4-benzothiadiazine-3-carboxylate | C10H10Cl2N2O4S | 详情 | 详情 | |
| (VIII) | 20466 | 1-bromo-3-(bromomethyl)benzene | 823-78-9 | C7H6Br2 | 详情 | 详情 |