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【结 构 式】 
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【分子编号】65607 【品名】2-Hydroxy-5-trifluoromethylpyridine; 5-(Trifluoromethyl)pyridin-2-ol 【CA登记号】33252-63-0 |
【 分 子 式 】C6H4F3NO 【 分 子 量 】163.0991096 【元素组成】C 44.19% H 2.47% F 34.95% N 8.59% O 9.81% |
合成路线1
该中间体在本合成路线中的序号：(XXVII)Two procedures have been reported for the synthesis of the intermediate 2-methyl-2-[5-(trifluoromethyl)pyridin-2-yloxy]propionic acid (I). 2-Chloro-5-(trifluoromethyl)pyridine (XXIII) is coupled with lithium lactate (XXIV) employing NaH in hot DMF to produce the 2-(pyridyloxy)propionic acid (XXV). After esterification of acid (XXV) with trimethylsilyldiazomethane in MeOH/CH2Cl2, the resulting methyl ester is alkylated with iodomethane and sodium hexamethyldisilazide to furnish the (pyridyloxy)isobutyrate (XXVI). Subsequent hydrolysis of methyl ester (XXVI) with NaOH in H2O/MeOH/THF provides the target carboxylic acid intermediate (I) (1). Alternatively, the condensation of 2-hydroxy-5-(trifluoromethyl)pyridine (XXVII) with ethyl 2-bromoisobutyrate (XXVIII) in the presence of cesium carbonate provides the 2-(pyridyloxy)isobutyrate ester (XXIX), which is hydrolyzed to the corresponding carboxylic acid (I) by means of NaOH in acetonitrile/water (2, 3). Scheme 3.
| 【1】 Hagmann, W.K., Lin, L.S., Shah, S.K. et al. (Merck & Co., Inc.). Substituted amides. CA 2478183, EP 1496838, JP 2005519958, JP 2006257090, US 2004058820, US 6972295, WO 03077847. |
| 【2】 Hagmann, W.K., Lin, L.S., Shah, S.K. et al. (Merck & Co., Inc.). Substituted amides active at the cannabinoid-1 receptor. WO 2004048317. |
| 【3】 Lin, L.S., Lanza, T.J. Jr., Jewell, J.P. et al. Discovery of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-[[5-(trifluoromethyl)pyridin-2-yl]oxy]propanamide (MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity. J Med Chem 2006, 49(26): 7584-7. |
| 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) | 65585 | 2-Methyl-2-[[5-(Trifluoromethyl)-2-Pyridinyl]Oxy]Propanoic Acid | 605680-62-4 | C10H10F3NO3 | 详情 | 详情 |
| (XXIII) | 59113 | 2-Chloro-5-(trifluoromethyl)pyridine; 5-Trifluoromethyl-2-chloropyridine | 52334-81-3 | C6H3ClF3N | 详情 | 详情 |
| (XXIV) | 65604 | Lithium Lactate | 16891-53-5 | C3H5LiO3 | 详情 | 详情 |
| (XXV) | 65605 | C9H8F3NO3 | 详情 | 详情 | ||
| (XXVI) | 65606 | C11H12F3NO3 | 详情 | 详情 | ||
| (XXVII) | 65607 | 2-Hydroxy-5-trifluoromethylpyridine; 5-(Trifluoromethyl)pyridin-2-ol | 33252-63-0 | C6H4F3NO | 详情 | 详情 |
| (XXVIII) | 39799 | ethyl 2-bromo-2-methylpropanoate | 600-00-0 | C6H11BrO2 | 详情 | 详情 |
| (XXIX) | 65608 | 2-Methyl-2-[[5-(Trifluoromethyl)-2-Pyridinyl]Oxy]-Propanoic Acid Ethyl Ester | 913849-17-9 | C12H14F3NO3 | 详情 | 详情 |