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【结 构 式】 
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【分子编号】59113 【品名】2-Chloro-5-(trifluoromethyl)pyridine; 5-Trifluoromethyl-2-chloropyridine 【CA登记号】52334-81-3 |
【 分 子 式 】C6H3ClF3N 【 分 子 量 】181.5444696 【元素组成】C 39.7% H 1.67% Cl 19.53% F 31.39% N 7.72% |
合成路线1
该中间体在本合成路线中的序号：(XXIII)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 |
合成路线2
该中间体在本合成路线中的序号：(I)Nucleophilic displacement of 2-chloro-5-(trifluoromethyl)pyridine (I) with ethanesulfonamide (II) in the presence of K2CO3 in hot DMSO afforded the N-pyridyl sulfonamide (III). Subsequent nitration of (III) with fuming nitric acid in HOAc gave the 3-nitro derivative (IV). Preparation of this intermediate was also reported by displacement of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (V) with the sodium salt of ethanesulfonamide (II). Subsequent reduction of the nitro group of (IV) to the corresponding 3-aminopyridine (VI) was carried out by means of catalytic hydrogenation, iron in HOAc, or sodium hydrosulfite as the reducing agents. Amine (VI) was coupled either with cyclohexanecarbonyl chloride (VII) or with cyclohexanecarboxylic acid (VIII) in the presence of EDC to produce the cyclohexanecarboxamide (IX). The acidic sulfonamide NH group of (IX) was finally converted to the sodium salt by treatment with NaOH.
| 【1】 Kimura, H.; et al.; Synthesis and antipancreatitis activities of novel N-(2-sulfonylamino-5-trifluoromethyl-3-pyridyl)carboxamide derivatives as phospholipase A2 inhibitors. Chem Pharm Bull 1995, 43, 10, 1696. |
| 【2】 Haga, T.; Sugi, H.; Shigehara, I.; Odawara, S.; Yotsuya, S.; Kimura, H.; Yamamoto, K. (Ishihara Sangyo Kaisha, Ltd.); Diaminotrifluoromethylpyridine derivs., process for their production and phospholipase A2 inhibitor containing them. EP 0465913; JP 1993170742; JP 1994247934; JP 1994263735; US 5229403; US 5260320; US 5348967; US 5492908 . |
| 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) | 59113 | 2-Chloro-5-(trifluoromethyl)pyridine; 5-Trifluoromethyl-2-chloropyridine | 52334-81-3 | C6H3ClF3N | 详情 | 详情 |
| (II) | 59114 | 1-ethanesulfonamide | C2H7NO2S | 详情 | 详情 | |
| (III) | 59115 | N-[5-(trifluoromethyl)-2-pyridinyl]-1-ethanesulfonamide | C8H9F3N2O2S | 详情 | 详情 | |
| (IV) | 59116 | N-[3-nitro-5-(trifluoromethyl)-2-pyridinyl]-1-ethanesulfonamide | C8H8F3N3O4S | 详情 | 详情 | |
| (V) | 59117 | 2-chloro-3-nitro-5-(trifluoromethyl)pyridine | C6H2ClF3N2O2 | 详情 | 详情 | |
| (VI) | 59118 | N-[3-amino-5-(trifluoromethyl)-2-pyridinyl]-1-ethanesulfonamide | C8H10F3N3O2S | 详情 | 详情 | |
| (VII) | 17220 | cyclohexanecarbonyl chloride; Cyclohexanecarboxylic acid chloride | 2719-27-9 | C7H11ClO | 详情 | 详情 |
| (VIII) | 44803 | cyclohexanecarboxylic acid | 98-89-5 | C7H12O2 | 详情 | 详情 |
| (IX) | 59119 | N-[2-[(ethylsulfonyl)amino]-5-(trifluoromethyl)-3-pyridinyl]cyclohexanecarboxamide | C15H20F3N3O3S | 详情 | 详情 |