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【结 构 式】 
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【药物名称】Cariporide mesilate, Hoe-642 【化学名称】[4-Isopropyl-3-(methylsulfonyl)benzoyl]guanidine methanesulfonate 【CA登记号】159138-81-5, 159138-80-4 (free base) 【 分 子 式 】C13H21N3O6S2 【 分 子 量 】379.45682 |
【开发单位】Aventis Pharma (Originator) 【药理作用】Acute Myocardial Infarction, Treatment of, CARDIOVASCULAR DRUGS, Coronary Bypass Surgery, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Na+/H+ Exchange type 1 (NHE-1) Inhibitors |
合成路线1
Cariporide has been obtained by two similar ways: 1) The oxidation of 4-isopropylbenzaldehyde (I) with sodium perborate in hot acetic acid gives 4-isopropylbenzoic acid (II), which is sulfonated with hot chlorosufonic acid yielding 3-(chlorosulfonyl)-4-isopropylbenzoic acid (III). The reduction of (III) with sodium sulfite in hot NaOH solution affords 4-isopropyl-3-sulfinobenzoic acid (IV), which is alkylated with methyl bromide and NaOH in DMF giving 4-isopropyl-3-(methylsulfonyl)benzoic acid (V). The reaction of (V) with SOCl2 in refluxing toluene yields 4-isopropyl-3-(methylsulfonyl)benzoyl chloride (VI), which is finally condensed with guanidine (VII) in DMF. 2) The iodination of 4-isopropylbenzoic acid (II) with iodine chloride or N-iodosuccinimide (NIS) gives 3-iodo-4-isopropylbenzoic acid (VIII), which is treated first with SOCl2 to afford the corresponding acyl chloride (IX), and then with methanol yielding 4-iodo-4-isopropylbenzoic methyl ester (X). The reaction of (X) with sodium methylsulfite (XI) gives 4-isopropyl-3-(methylsulfonyl)benzoic acid methyl ester (XII), which is finally treated with guanidine (VII) in refluxing THF.
| 【1】 Graul, A.; Prous, J.; Castañer, J.; Cariporide Mesylate. Drugs Fut 1997, 22, 11, 1197. |
| 【2】 Kleemann, H.-W.; Lang, H.-J.; Weichert, A.; Crause, P.; Scholz, W.; Albus, U.; Schwark, J.-R. (Aventis SA); Diacyl substd. guanidines, process for their preparation, their use as medicament or diagnostic reagent and medicament containing them. CA 2130703; DE 4328352; EP 0640587; JP 1995082234 . |
| 【3】 Lang, H.-J.; Weichert, A.; Kleemann, H.-W.; Englert, H.; Scholz, W.; Albus, U. (Aventis SA); Benzoylguanidines, process for their preparation and their use as antiarrhythmic agents. EP 0589336; JP 1994228082; US 5591754 . |
| 【4】 Kleemann, H.-W. (Aventis SA); Substd. benzoic acid esters, process for their preparation and their use for the synthesis of inhibitors of the cellular Na+/H+-exchange. DE 4428480 . |
| 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) | 23109 | 4-isopropylbenzaldehyde | 122-03-2 | C10H12O | 详情 | 详情 |
| (II) | 11698 | 4-Isopropylbenzoic acid | 536-66-3 | C10H12O2 | 详情 | 详情 |
| (III) | 16851 | 3-(chlorosulfonyl)-4-isopropylbenzoic acid | C10H11ClO4S | 详情 | 详情 | |
| (IV) | 16852 | 3-(dioxo-lambda(6)-sulfanyl)-4-isopropylbenzoic acid | C10H12O4S | 详情 | 详情 | |
| (V) | 16853 | 4-isopropyl-3-(methylsulfonyl)benzoic acid | C11H14O4S | 详情 | 详情 | |
| (VI) | 16854 | 4-isopropyl-3-(methylsulfonyl)benzoyl chloride | C11H13ClO3S | 详情 | 详情 | |
| (VII) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
| (VIII) | 16856 | 3-iodo-4-isopropylbenzoic acid | C10H11IO2 | 详情 | 详情 | |
| (IX) | 16857 | 3-iodo-4-isopropylbenzoyl chloride | C10H10ClIO | 详情 | 详情 | |
| (X) | 16858 | methyl 3-iodo-4-isopropylbenzoate | C11H13IO2 | 详情 | 详情 | |
| (XI) | 63963 | sodium methanesulfinate | CH3NaO2S | 详情 | 详情 | |
| (XII) | 16859 | methyl 4-isopropyl-3-(methylsulfonyl)benzoate | C12H16O4S | 详情 | 详情 |
合成路线2
Two new related ways for the synthesis of cariporide mesylate have been reported: 1) The reaction of 4-isopropylbenzoic acid (I) with chlorosulfonic acid gives 3-(chlorosulfonyl)-4-isopropylbenzoic acid (II), which is reduced wth sodium sulfite/NaOH to the sorresponding sulfinic acid (III). The methylation of (III) with methyl iodide/NaOH in dimethylacetamide affords 4-isopropyl-3-(methanesulfonyl)benzoic acid methyl ester (IV), which is finally condensed with gunidine (V). 2) The hydrolysis of benzoate (IV) with NaOH in methanol/water gives the corresponding free acid (VI), which is then condensed with guanidine (V) by means of dicyclohexylcarbodiimide (DCC) in THF. 3) Benzoic ester (IV) can also be obtained by alkylation of 4-bromo-3-(methanesulfonyl)benzoic acid methyl ester with isopropylmagnesium chloride by means of CuI, ZnCl2 and a PdCl2 catalyst in THF.
| 【1】 Lang, H.J.; Scholz, W.; Faber, S.; Weichert, A.; Jansen, H.W.; Synthesis of the highly selective Na+/H+ exchange inhibitors cariporide mesylate and (3-methanesulfonyl-4-piperidino-benzoyl)guanidine methanesulfonate. Arzneim-Forsch Drug Res 1997, 47, 11, 1204. |
| 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) | 11698 | 4-Isopropylbenzoic acid | 536-66-3 | C10H12O2 | 详情 | 详情 |
| (II) | 16851 | 3-(chlorosulfonyl)-4-isopropylbenzoic acid | C10H11ClO4S | 详情 | 详情 | |
| (III) | 16852 | 3-(dioxo-lambda(6)-sulfanyl)-4-isopropylbenzoic acid | C10H12O4S | 详情 | 详情 | |
| (IV) | 16859 | methyl 4-isopropyl-3-(methylsulfonyl)benzoate | C12H16O4S | 详情 | 详情 | |
| (V) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
| (VI) | 16853 | 4-isopropyl-3-(methylsulfonyl)benzoic acid | C11H14O4S | 详情 | 详情 | |
| (VII) | 17625 | methyl 4-bromo-3-(methylsulfonyl)benzoate | C9H9BrO4S | 详情 | 详情 | |
| (VIII) | 17626 | chloro(isobutyl)magnesium | 5674-02-2 | C4H9ClMg | 详情 | 详情 |