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【结 构 式】 
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【药物名称】Mepindolol sulfate, SHE-222, Mepicor, Betagon, Corindolan 【化学名称】4-[2-Hydroxy-3-(isopropylamino)propoxy]-2-methylindole sulfate 【CA登记号】23694-81-7 (free base) 【 分 子 式 】C30H46N4O8S 【 分 子 量 】622.78712 |
【开发单位】Camillo Corvi (Originator), Schering AG (Originator) 【药理作用】Angina pectoris, Treatment of, CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, beta-Adrenoceptor Antagonists |
合成路线1
4-Benzyloxy-indole-2-carboxylic acid (I) is converted into the corresponding dimethylamide (III), via the corresponding acid chloride (II); the dimethylamide (III) is reduced with LiAlH4 to give 4-benzyloxy-2-dimethylaminomethyl-indole (IV), which is hydrogenated to 4-hydroxy-2-methyl-indole (V). The reaction of (V) with epichlorohydrin (A) in aqueous NaOH gives the crude epoxide which without isolation is treated with isopropylamine (B) in refluxing dioxane.
| 【1】 Seemann, F.; et al.; Synthetic indoles. 10. Chemistry of 4-hydroxy-indoles. Helv Chim Acta 1971, 54, 8, 2411-19. |
| 【2】 Troxler, F.; Hofmann, A.; Verfahren zur Herstellung neuer Indolderivate. AT 316542B; CH 502337 . |
| 【3】 Troxler, F.; Hofmann, A.; Verfahren zur Herstellung neuer Indolderivate. CH 543505 . |
| 【4】 Weetman, D.F.; Castaner, J.; Mepindolol. Drugs Fut 1978, 3, 5, 381. |
| 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) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (B) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (I) | 33536 | 4-(benzyloxy)-1H-indole-2-carboxylic acid | C16H13NO3 | 详情 | 详情 | |
| (II) | 33537 | 4-(benzyloxy)-1H-indole-2-carbonyl chloride | C16H12ClNO2 | 详情 | 详情 | |
| (III) | 33538 | 4-(benzyloxy)-N,N-dimethyl-1H-indole-2-carboxamide | C18H18N2O2 | 详情 | 详情 | |
| (IV) | 33539 | N-[[4-(benzyloxy)-1H-indol-2-yl]methyl]-N,N-dimethylamine; [4-(benzyloxy)-1H-indol-2-yl]-N,N-dimethylmethanamine | C18H20N2O | 详情 | 详情 | |
| (V) | 33540 | 4-Hydroxy-2-methylindole; 2-Methyl-1H-indol-4-ol | 35320-67-3 | C9H9NO | 详情 | 详情 |
合成路线2
4-Hydroxy-2-methyl-indole (IV) can be quaternized with MeI yielding the ammonium salt (VI), which by heating with aqueous NaCN in converted into 2-cyanomethyl-4-benzyloxyindole (VII). The hydrolysis of (VII) affords the corresponding acid (VIII), which is decarboxylated to 4-benzyloxy-2-methyl-indole (IX). Finally, this compound is hydrogenated to the previously obtained 4-hydroxy-2-methyl-indole (V).
| 【1】 Troxler, F.; Hofmann, A.; Verfahren zur Herstellung neuer Indolderivate. AT 316542B; CH 502337 . |
| 【2】 Weetman, D.F.; Castaner, J.; Mepindolol. Drugs Fut 1978, 3, 5, 381. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 33539 | N-[[4-(benzyloxy)-1H-indol-2-yl]methyl]-N,N-dimethylamine; [4-(benzyloxy)-1H-indol-2-yl]-N,N-dimethylmethanamine | C18H20N2O | 详情 | 详情 | |
| (V) | 33540 | 4-Hydroxy-2-methylindole; 2-Methyl-1H-indol-4-ol | 35320-67-3 | C9H9NO | 详情 | 详情 |
| (VI) | 33541 | [4-(benzyloxy)-1H-indol-2-yl]-N,N,N-trimethylmethanaminium iodide | C19H23IN2O | 详情 | 详情 | |
| (VII) | 33542 | 2-[4-(benzyloxy)-1H-indol-2-yl]acetonitrile | C17H14N2O | 详情 | 详情 | |
| (VIII) | 33543 | 2-[4-(benzyloxy)-1H-indol-2-yl]acetic acid | C17H15NO3 | 详情 | 详情 | |
| (IX) | 33544 | benzyl 2-methyl-1H-indol-4-yl ether; 4-(benzyloxy)-2-methyl-1H-indole | C16H15NO | 详情 | 详情 |
合成路线3
The reaction of 4-hydroxy-2-methyl-indole (V) with 1-(N-benzylisopropylamino)-3-chloro-2-propanol (D) by means of NaOH in refluxing aqueous dioxane yields the corresponding benzylamine (X), which is debenzylated by catalytic hydrogenation. The reaction of 4-hydroxy-2-methyl-indole (V) with epichlorohydrin (A) and benzylamine (B) gives 4-(3-benzylamino-2-hydroxypropoxy)-2-methyl-indole (XI), which is debenzylated by hydrogenolysis to 4-(3-amino-2-hydroxypropoxy)-2-methyl-indole (XII). The condensation of (XII) with refluxing acetone (C) affords the corresponding N-isopropylidene derivative (XIII), which is finally hydrogenated with H2 over Pd/C in methanol.
| 【1】 Seemann, F.; et al.; Synthetic indoles. 10. Chemistry of 4-hydroxy-indoles. Helv Chim Acta 1971, 54, 8, 2411-19. |
| 【2】 Troxler, F.; Verfahren zur Herstellung neuer Indolderivate. CH 472404; ES 337457 . |
| 【3】 Troxler, F.; Verfahren zur Herstellung neuer Indolderivate. CH 469002; ES 337458 . |
| 【4】 Troxler, F.; Verfahren zur Herstellung von neuem 4-(2-Hydroxy-3-isopropylaminopropoxy)-2-methylindol und seiner Saureadditionssalze Indolderivate. AT 317199 . |
| 【5】 Weetman, D.F.; Castaner, J.; Mepindolol. Drugs Fut 1978, 3, 5, 381. |
| 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) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (B) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (D) | 33549 | 1-[benzyl(isopropyl)amino]-3-chloro-2-propanol | C13H20ClNO | 详情 | 详情 | |
| (V) | 33540 | 4-Hydroxy-2-methylindole; 2-Methyl-1H-indol-4-ol | 35320-67-3 | C9H9NO | 详情 | 详情 |
| (X) | 33548 | 1-[benzyl(isopropyl)amino]-3-[(2-methyl-1H-indol-4-yl)oxy]-2-propanol | C22H28N2O2 | 详情 | 详情 | |
| (XI) | 33545 | 1-(benzylamino)-3-[(2-methyl-1H-indol-4-yl)oxy]-2-propanol | C19H22N2O2 | 详情 | 详情 | |
| (XII) | 33546 | 1-amino-3-[(2-methyl-1H-indol-4-yl)oxy]-2-propanol | C12H16N2O2 | 详情 | 详情 | |
| (XIII) | 33547 | 1-[(1-methylethylidene)amino]-3-[(2-methyl-1H-indol-4-yl)oxy]-2-propanol | C15H20N2O2 | 详情 | 详情 | |
| (C) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |