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【结 构 式】 
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【分子编号】33399 【品名】2-methylpropionic acid 【CA登记号】79-31-2 |
【 分 子 式 】C4H8O2 【 分 子 量 】88.10632 【元素组成】C 54.53% H 9.15% O 36.32% |
合成路线1
该中间体在本合成路线中的序号：(III)The synthesis of heptadeuterated flutamide has been reported: The reaction of deuterated isopropyl bromide (I) with Mg in THF gives the corresponding Grignard reagent (II), which is treated with CO2 yielding the deuterated isobutyric acid (III). The reaction of (III) with oxalyl chloride affords the expected acyl chloride (IV), which is finally condensed with 4-nitro-3-(trifluoromethyl)aniline (V).
| 【1】 Passarella, D.; et al.; Synthesis of flutamide-d7 and its main metabolite-d6. J Label Compd Radiopharm 1999, 42, 3, 275. |
| 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) | 32658 | 2-bromopropane | 75-26-3 | C3H7Br | 详情 | 详情 |
| (II) | 33398 | bromo(isopropyl)magnesium | 920-39-8 | C3H7BrMg | 详情 | 详情 |
| (III) | 33399 | 2-methylpropionic acid | 79-31-2 | C4H8O2 | 详情 | 详情 |
| (IV) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |
| (V) | 33400 | 4-nitro-3-(trifluoromethyl)phenylamine; 4-nitro-3-(trifluoromethyl)aniline; 3-Trifluoromethyl-4-nitroaniline | 393-11-3 | C7H5F3N2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)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3
该中间体在本合成路线中的序号：(VII)Coupling of N-Boc-D-serine (I) with L-glutamic acid 1-methylamide 5-benzyl ester (II) by means of EDC and HOBt affords the dipeptide derivative (III). Subsequent glycosylation of the serine hydroxyl group of (III) with the perbenzylfucose donor (IV) in the presence of SnCl2 and AgOTf gives the alpha-glycoside (V). The N-Boc protecting group of (V) is removed under acidic conditions to furnish amine (VI), which is acylated by 2-tetradecylhexadecanoic acid (VII), yielding amide (VIII). The O-benzyl protecting groups of (VIII) are then removed by hydrogenolysis in the presence of Pearlman's catalyst, and the resultant carboxylic acid is finally converted to the corresponding arginine salt.
| 【1】 Hiramatsu, Y.; Moriyama, H.; Koyoi, T.; Tsukida, T.; Inoue, Y.; Kondo, H.; Studies on selectin blockers. 6. Discovery of homologous fucose sugar unit necessary for E-selectin binding. J Med Chem 1998, 41, 13, 2302. |
| 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) | 20126 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropionic acid | C8H15NO5 | 详情 | 详情 | |
| (II) | 18551 | benzyl (4S)-4-amino-5-(methylamino)-5-oxopentanoate | C13H18N2O3 | 详情 | 详情 | |
| (III) | 60186 | phenylmethyl 4-{[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3-hydroxypropanoyl]amino}-5-(methylamino)-5-oxopentanoate | C21H31N3O7 | 详情 | 详情 | |
| (IV) | 60187 | 1-{5-fluoro-3,4-bis[(phenylmethyl)oxy]tetrahydro-2-furanyl}ethyl phenylmethyl ether; 2-fluoro-3,4-bis[(phenylmethyl)oxy]-5-{1-[(phenylmethyl)oxy]ethyl}tetrahydrofuran | C27H29FO4 | 详情 | 详情 | |
| (V) | 60188 | phenylmethyl 4-{[3-[(3,4-bis[(phenylmethyl)oxy]-5-{1-[(phenylmethyl)oxy]ethyl}tetrahydro-2-furanyl)oxy]-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)propanoyl]amino}-5-(methylamino)-5-oxopentanoate | C48H59N3O11 | 详情 | 详情 | |
| (VI) | 60189 | phenylmethyl 4-({2-amino-3-[(3,4-bis[(phenylmethyl)oxy]-5-{1-[(phenylmethyl)oxy]ethyl}tetrahydro-2-furanyl)oxy]propanoyl}amino)-5-(methylamino)-5-oxopentanoate | C43H51N3O9 | 详情 | 详情 | |
| (VII) | 33399 | 2-methylpropionic acid | 79-31-2 | C4H8O2 | 详情 | 详情 |
| (VIII) | 60190 | phenylmethyl 4-({3-[(3,4-bis[(phenylmethyl)oxy]-5-{1-[(phenylmethyl)oxy]ethyl}tetrahydro-2-furanyl)oxy]-2-[(2-tetradecylhexadecanoyl)amino]propanoyl}amino)-5-(methylamino)-5-oxopentanoate | C73H109N3O10 | 详情 | 详情 |