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【结 构 式】 
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【分子编号】53263 【品名】n-Butyric acid vinyl ester; Vinyl n-butyrate; Vinyl butyrate 【CA登记号】123-20-6 |
【 分 子 式 】C6H10O2 【 分 子 量 】114.1442 【元素组成】C 63.14% H 8.83% O 28.03% |
合成路线1
该中间体在本合成路线中的序号：(IX)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 |
合成路线2
该中间体在本合成路线中的序号：(VIII)Synthesis of the alkenyl cuprate (XVII): Enzymatic acylation of the racemic acetylenic alcohol (VII) with vinyl butyrate (VIII) by means of Chirazyme L9 gives a mixture of the ester (R)-(IX) and the alcohol (S)-(X). Reaction of this mixture with Ms-Cl and TEA yields a mixture of ester (R)-(IX) and the mesylate (S)-(XI). Treatment of this mixture with butyric acid and TEA results in the acylation of mesylate (S)-(XI) with optical inversion, providing pure ester (R)-(IX). Enzymatic hydrolysis of (R)-(IX) with Chirazyme L2 affords the enantiomerically pure alcohol (R)-(XIII). Silylation of alcohol (XIII) with TBDMS-Cl and imidazole gives the silyl ether (XIV), which is iodinated with Cp2ZrCl2 and I2 to yield the iodovinyl derivative (XV). Finally, the reaction of compound (XV) with the lithium cuprate (XVI) prepared by lithiation of thiophene with BuLi followed by treatment with copper (I) cyanide affords the alkenyl cuprate (XVII). Condensation of the alkenyl cuprate (XVII) with the tricyclic ketone (VI) in toluene provides the bicyclic ketone (XVIII), which is submitted to a Baeyer-Villiger oxidation with peracetic acid to give a mixture of the regioisomeric lactones (XIX) and (XX). The minor and unwanted regioisomer (XIX) is selectively hydrolyzed by treatment with aqueous Na2CO3 and separated by crystallization. Reduction of lactone (XX) with DIBAL in toluene gives lactol (XXI), which is submitted to a Wittig condensation with (4-carboxybutyl)triphenylphosphonium bromide and t-BuOK in THF, followed by esterification with isopropyl iodide and DBU, yielding a mixture of the monosilylated compounds (XXIII) and (XXIV) due to migration of the silyl group on the cyclopentane ring. Finally, this mixture is deprotected with HCl in isopropanol.
| 【1】 Boulton, L.T.; Brick, D.; Fox, M.E.; et al.; Synthesis of the potent antiglaucoma agent, travoprost. Org Process Res Dev 2002, 6, 2, 138. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 53260 | (1R,3S,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}tricyclo[3.2.0.0~2,7~]heptan-6-one | n/a | C13H22O2Si | 详情 | 详情 |
| (VII) | 53262 | 1-[3-(trifluoromethyl)phenoxy]-3-butyn-2-ol | 88462-65-1 | C11H9F3O2 | 详情 | 详情 |
| (VIII) | 53263 | n-Butyric acid vinyl ester; Vinyl n-butyrate; Vinyl butyrate | 123-20-6 | C6H10O2 | 详情 | 详情 |
| (IX) | 53264 | (1R)-1-{[3-(trifluoromethyl)phenoxy]methyl}-2-propynyl butyrate | n/a | C15H15F3O3 | 详情 | 详情 |
| (X) | 53265 | (2S)-1-[3-(trifluoromethyl)phenoxy]-3-butyn-2-ol | n/a | C11H9F3O2 | 详情 | 详情 |
| (XI) | 53266 | (1S)-1-{[3-(trifluoromethyl)phenoxy]methyl}-2-propynyl methanesulfonate | n/a | C12H11F3O4S | 详情 | 详情 |
| (XII) | 53267 | Butanoic acid; Butyric acid; N-Butanic acid; N-Butanoic acid; n-Butyric acid; N-Ethylacetic acid; N-Propanecarboxylic acid; N-Propylformic acid | 107-92-6 | C4H8O2 | 详情 | 详情 |
| (XIII) | 53278 | (2R)-1-[3-(trifluoromethyl)phenoxy]-3-butyn-2-ol | n/a | C11H9F3O2 | 详情 | 详情 |
| (XIV) | 53268 | tert-butyl(dimethyl)[((1R)-1-{[3-(trifluoromethyl)phenoxy]methyl}-2-propynyl)oxy]silane; tert-butyl(dimethyl)silyl (1R)-1-{[3-(trifluoromethyl)phenoxy]methyl}-2-propynyl ether | n/a | C17H23F3O2Si | 详情 | 详情 |
| (XV) | 53269 | tert-butyl(dimethyl)silyl (1R,2E)-3-iodo-1-{[3-(trifluoromethyl)phenoxy]methyl}-2-propenyl ether; tert-butyl[((1R,2E)-3-iodo-1-{[3-(trifluoromethyl)phenoxy]methyl}-2-propenyl)oxy]dimethylsilane | n/a | C17H24F3IO2Si | 详情 | 详情 |
| (XVI) | 53270 | lithium cyano(2-thienyl)cuprate(1-) | n/a | C5H3CuLiNS | 详情 | 详情 |
| (XVII) | 53271 | n/a | C22H27CuF3Li2NO2SSi | 详情 | 详情 | |
| (XVIII) | 53272 | (5S)-5-{[tert-butyl(dimethyl)silyl]oxy}-7-{(E,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(trifluoromethyl)phenoxy]-1-butenyl}bicyclo[2.2.1]heptan-2-one | n/a | C30H47F3O4Si2 | 详情 | 详情 |
| (XIX) | 53273 | (6S)-6-{[tert-butyl(dimethyl)silyl]oxy}-8-{(E,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(trifluoromethyl)phenoxy]-1-butenyl}-3-oxabicyclo[3.2.1]octan-2-one | n/a | C30H47F3O5Si2 | 详情 | 详情 |
| (XX) | 53274 | (6S)-6-{[tert-butyl(dimethyl)silyl]oxy}-8-{(E,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(trifluoromethyl)phenoxy]-1-butenyl}-2-oxabicyclo[3.2.1]octan-3-one | n/a | C30H47F3O5Si2 | 详情 | 详情 |
| (XXI) | 53275 | (6S)-6-{[tert-butyl(dimethyl)silyl]oxy}-8-{(E,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(trifluoromethyl)phenoxy]-1-butenyl}-2-oxabicyclo[3.2.1]octan-3-ol | n/a | C30H49F3O5Si2 | 详情 | 详情 |
| (XXII) | 13616 | (4-Carboxybutyl)triphenylphosphonium bromide | 17814-85-6 | C23H24BrO2P | 详情 | 详情 |
| (XXIII) | 53276 | isopropyl (Z)-7-((1R,2R,3R,5S)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-{(E,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(trifluoromethyl)phenoxy]-1-butenyl}-3-hydroxycyclopentyl)-5-heptenoate | n/a | C38H63F3O6Si2 | 详情 | 详情 |
| (XXIV) | 53277 | isopropyl (Z)-7-((1R,2R,3R,5S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-{(E,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(trifluoromethyl)phenoxy]-1-butenyl}-5-hydroxycyclopentyl)-5-heptenoate | n/a | C38H63F3O6Si2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)The chiral intermediate (X) is prepared by two methods. Treatment of lactonitrile (I) with HCl/EtOH affords imidate (II), which is further reacted with ethanolic ammonia to produce amidine (III). Claisen condensation between ethyl acetate (IV) and ethyl formate (V) in the presence of NaH provides the sodium salt of ethyl 3-hydroxyacrylate (VI). Cyclization of (VI) with amidine (III) then furnishes the racemic pyrimidinone (VII). Kinetic resolution of (VII) is accomplished by acylation with vinyl butyrate (VIII) in the presence of lipase P30 to yield a mixture of unreacted (S)-alcohol (IX) and the desired (R)-butyrate ester (X), which can be separated by partition between CH2Cl2 and H2O.
| 【1】 Mylari, B.L.; Zembrowski, W.J.; Murry, J.A.; Chu-Moyer, M.Y. (Pfizer Products Inc.); Aminopyrimidines as sorbitol dehydrogenase inhibitors. EP 1185275; US 6414149; WO 0059510 . |
| 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) | 64060 | 2-hydroxypropanenitrile | C3H5NO | 详情 | 详情 | |
| (II) | 64061 | ethyl 2-hydroxypropanimidoate | C5H11NO2 | 详情 | 详情 | |
| (III) | 64062 | 2-hydroxypropanimidamide | C3H8N2O | 详情 | 详情 | |
| (IV) | 17491 | ethyl acetate | 141-78-6 | C4H8O2 | 详情 | 详情 |
| (V) | 16602 | ethyl formate | 109-94-4 | C3H6O2 | 详情 | 详情 |
| (VI) | 64063 | sodium (E)-3-ethoxy-3-oxo-1-propen-1-olate | C5H7NaO3 | 详情 | 详情 | |
| (VII) | 64064 | 2-(1-hydroxyethyl)-4(3H)-pyrimidinone | C6H8N2O2 | 详情 | 详情 | |
| (VIII) | 53263 | n-Butyric acid vinyl ester; Vinyl n-butyrate; Vinyl butyrate | 123-20-6 | C6H10O2 | 详情 | 详情 |
| (IX) | 64065 | 2-[(1S)-1-hydroxyethyl]-4(3H)-pyrimidinone | C6H8N2O2 | 详情 | 详情 | |
| (X) | 64066 | (1R)-1-(6-oxo-1,6-dihydro-2-pyrimidinyl)ethyl butyrate | C10H14N2O3 | 详情 | 详情 |