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【结 构 式】 
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【药物名称】Isosorbide 5-mononitrate, TY-368-OD(sustained release), BM-22145, AHR-4698, IS-5-MN, Dilavenil, Uniket, Monicor, Monoket, Imdur(extended release), Ismo 【化学名称】1,4:3,6-Dianhydro-D-glucitol 5-nitrate 【CA登记号】16051-77-7 【 分 子 式 】C6H9NO6 【 分 子 量 】191.14173 |
【开发单位】Roche (Originator), AstraZeneca (Not Determined), Key Pharmaceuticals (Not Determined), Pierre Fabre (Not Determined), Lacer (Licensee), Wyeth Pharmaceuticals (Licensee) 【药理作用】Angina pectoris, Treatment of, CARDIOVASCULAR DRUGS, Heart Failure Therapy, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Nitrates |
合成路线1
1. The nitration of isosorbide (I) with fuming HNO3 in acetic acid/acetic anhydride gives the dinitrate (II), which is selectively monoreduced by means of diisopropyltitanium tetrahydroborate (obtained by reaction of disopropyltitanium dichloride with benzyltriethylammonium borohydride) in dichloromethane to afford the isosorbide 5-nitrate. 2. The reduction of dinitrate (II) can also be performed with benzyl triethyl ammonium tetrathiomolibdate in DMF. 3. The reduction of dinitrate (II) can also be performed with H2 over PtO2/C in methanol. 4. The reduction of dinitrate (II) can also be performed with cobalt phthalocyanine and NaBH4 in methanol. 5. The reduction of dinitrate (II) can also be performed with Zn and HOAc in ethanol/water. 6. The reduction of dinitrate (II) can also be performed with H2 over Pd/C and NiCl2 in ethanol/water. 7. The reaction of isosorbide (I) with 4-nitrobenzoyl chloride (III) and pyridine in dichloromethane gives the isosorbide 2-O-(4-nitrobenzoate (IV), which is nitrated with HNO3 in acetic acid/acetic anhydride to yield the isosorbide 5-O-nitrate-2-O-(4-nitrobenzoate) (V). Finally, this compound is selectively hydrolyzed with KOH in methanol/dichloromethane.
| 【1】 Bhar, D.; Chandrasekaran, S.; A highly chemoselective reduction of isosorbide-2,5-dinitrate mediated by tetrathiomolybdate. Indian J Chem 1997, 36B, 9, 793. |
| 【2】 Ravikumar, K.S.; Chandrasekaran, S.; Highly chemoselective reduction of 2,5-dinitro-1,4:3,6-dianhydro-D-glucitol with titanium(III) tetrahydroborates: Efficient synthesis of isomerically pure 2- and 5-nitro-1,4:3,6-dianhydro-D-glucitols. Synthesis (Stuttgart) 1994, 10, 1032. |
| 【3】 Brown, C.; et al.; New preparative routes to isosorbide 5-mononitrate. J Chem Soc - Perkins Trans I 2000, 12, 1809. |
| 【4】 Camera, E.; Filipuzzi, F.; De Lucchi, O.; Modena, G. (Consiglio Nazionale delle Ricerche); Process for the preparation of isosorbide-5-mononitrate. EP 0201067; US 4713466 . |
| 【5】 Gallardo Carrera, A. (Fordonal SL); Process for the preparation of isosorbide-5-nitrate. ES 8402305 . |
| 【6】 Roberts, S.M.; Marston, R.W.; Quigley, P.F.; Brown, C.M.; Cross, S.J.; Synthesis of isosorbide mononitrate. EP 1248788; WO 0149692 . |
| 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) | 59337 | (1R,3aS,4S,6aS)octahydro-1,4-pentalenediol | C8H14O2 | 详情 | 详情 | |
| (II) | 59338 | (1R,3aS,4S,6aS)-1,4-bis(nitrooxy)octahydropentalene | C8H12N2O6 | 详情 | 详情 | |
| (III) | 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 |
| (IV) | 59340 | (1R,3aR,4R,6aR)-1,3a,6a-trimethyl-4-[2-(4-methylphenyl)-2-propenyl]octahydropentalene | C21H30 | 详情 | 详情 | |
| (V) | 59339 | (1S,3aS,4R,6aS)-4-(nitrooxy)octahydro-1-pentalenyl 4-nitrobenzoate | C15H16N2O7 | 详情 | 详情 |
合成路线2
8. The enantioselective monoacetylation of isosorbide (I) by means of vinyl acetate (VI) catalyzed by Pig liver esterase in dichloromethane gives isosorbide 2-O-acetate (VII), which is nitrated with HNO3 in acetic anhydride to yield isosorbide 2-O-acetate-5-O-nitrate (VIII). Finally, this compound is deacetylated by means of K2CO3 in methanol. 9. The enantioselective monoacylation of isosorbide (I) by means of vinyl butyrate (IX) catalyzed by Chiraclec-BL in THF or Carlsberg subtilisin in tert-butanol gives isosorbide 2-O-butyrate (X), which is nitrated with HNO3 in acetic anhydride to yield isosorbide 2-O-butyrate-5-O-nitrate (XI). Finally, this compound is deacylated by means of K2CO3 in methanol. 10. The acylation of isosorbide (I) with acetic anhydride and pyridine gives the diacetate (XII), which is enantioselectively monodeacetylated by means of lipase from Pseudomonas fluorescens in THF to yield isosorbide 2-O-acetate (VII). This compound is then nitrated to (VIII) and finally deacetylated as already described. 11. The acylation of isosorbide (I) with HOAc and Ac2O gives (after purification by crystallization) isosorbide 2-O-acetate (VII), which is nitrated to (VIII) and finally deacetylated as already described. 12. The acylation of isosorbide (I) with isobutyric acid (XIII) by means of sulfuric acid in refluxing chlorobenzene/toluene gives isosorbide 2-O-isobutyrate (XIV), which is nitrated with HNO3/H2SO4 to yield isosorbide 2-O-isobutyrate-5-O-nitrate (XV). Finally, this compound is deacylated by means of NaOH in toluene/water. 13. The nitration of isosorbide (I) by means of HNO3 in HOAc/Ac2O gives a 3.5/1 mixture of isosorbide-5-O-nitrate and isosorbide 2-O-nitrate that is separated by column chromatography over alumina. 14. The nitration of isosorbide (I) with HNO3 in benzene/HOAc/Ac2O, followed by a purification step yields the target isosorbide-5-O-nitrate.
| 【1】 Stoss, P.; Process for the preparation of isosorbide-5-nitrate. DE 3102947; EP 0057847; US 4371703 . |
| 【2】 Ito, T.; Ishibashi, K.; Ishiguro, S.; Shimada, F.; A method for the preparation of isosorbide-5-nitrate and sodium isosorbide-5-nitrate hydrate as a precursor thereof. EP 0143507; US 4584391 . |
| 【3】 Dvonch, W.; Alburn, H.E. (Wyeth); Mononitrate esters of 1,4:3,6-dianhydro-d-glucitol. DE 2221080; GB 1356374; US 3886186 . |
| 【4】 Lauer, K.; Kiegel, E. (Boehringer Ingelheim GmbH); Process for the preparation of 1,4:3,6-dianhydro-D-glucite 5-nitrate (isosorbide-5-nitrate). DE 3028873; EP 0045076; US 4431829 . |
| 【5】 Schonafinger, K. (Cassella AG); Process for the preparation of 5-isosorbide nitrate. DE 3117612; EP 0064194; US 4431830 . |
| 【6】 Roberts, S.M.; Marston, R.W.; Quigley, P.F.; Brown, C.M.; Synthesis of isosorbide cpds.. GB 2358859 . |
| 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) | 59337 | (1R,3aS,4S,6aS)octahydro-1,4-pentalenediol | C8H14O2 | 详情 | 详情 | |
| (VI) | 24543 | vinyl acetate | 108-05-4 | C4H6O2 | 详情 | 详情 |
| (VII) | 59341 | (1S,3aS,4R,6aS)-4-hydroxyoctahydro-1-pentalenyl acetate | C10H16O3 | 详情 | 详情 | |
| (VIII) | 59342 | (1S,3aS,4R,6aS)-4-(nitrooxy)octahydro-1-pentalenyl acetate | C10H15NO5 | 详情 | 详情 | |
| (IX) | 53263 | n-Butyric acid vinyl ester; Vinyl n-butyrate; Vinyl butyrate | 123-20-6 | C6H10O2 | 详情 | 详情 |
| (X) | 59343 | (1S,3aS,4R,6aS)-4-hydroxyoctahydro-1-pentalenyl butyrate | C12H20O3 | 详情 | 详情 | |
| (XI) | 59344 | (1S,3aS,4R,6aS)-4-(nitrooxy)octahydro-1-pentalenyl butyrate | C12H19NO5 | 详情 | 详情 | |
| (XII) | 59345 | (1R,3aS,4S,6aS)-4-(acetyloxy)octahydro-1-pentalenyl acetate | C12H18O4 | 详情 | 详情 | |
| (XIII) | 33399 | 2-methylpropionic acid | 79-31-2 | C4H8O2 | 详情 | 详情 |
| (XIV) | 59346 | (1S,3aS,4R,6aS)-4-hydroxyoctahydro-1-pentalenyl 2-methylpropanoate | C12H20O3 | 详情 | 详情 | |
| (XV) | 59347 | (1S,3aS,4R,6aS)-4-(nitrooxy)octahydro-1-pentalenyl 2-methylpropanoate | C12H19NO5 | 详情 | 详情 |