Statistics shows that 2-Methyl-4-(trifluoromethyl)-1H-imidazole is playing an increasingly important role. we look forward to future research findings about 33468-67-6.
Reference of 33468-67-6, These common heterocyclic compound, 33468-67-6, name is 2-Methyl-4-(trifluoromethyl)-1H-imidazole, its traditional synthetic route has been very mature, but the traditional synthetic route has various shortcomings, such as complicated route, low yield, poor purity, etc, below Introduce a new synthetic route.
Example 42 Synthesis of (S)-l-(l-(4-chlorophenyl)-5-isopropyl-lH-pyrazol-4-yl)-3-(2-methyl-4- (trifluoromethyl)-lH-imidazol-l-yl)pyrrolidin-2-one and ( ?)-l-(l-(4-chlorophenyl)-5- isopropyl-lH-pyrazol-4-yl)-3-(2-methyl-4-(trifluoromethyl)-lH-imidazol-l- yl)pyrrolidin-2-one step e [0203] a) To a solution of a-bromo-y-valerolactone (19.8 g, 120 mmol) and 2-methyl-4- (trifluoromethyl)- lH-imidazole (4.50 g, 30 mmol) in acetonitrile (60 mL) was added K3PO4 (19.1 g, 90 mmol). The slurry was heated to 80 C for 2 days, then cooled to room temperature, diluted with EtOAc (200 mL), filtered through Celite, and concentrated. The residue was purified by flash chromatography (S1O2, 0 – 3.5% methanol/CH2Cl2) to give the product as a pasty colorless solid. [0204] b) A mixture of the lactone intermediate (700 mg, 5.1 mmol) from step a and (5)- phenylglycinol (1.09 g, 4.64 mmol) was heated at 80 C for 18 h, cooled to room temperature, and purified by flash chromatography (Si02, 0.5-2% methanol/EtOAc) to give two diastereomeric products as colorless foams. The first eluting isomer (310 mg) was obtained in 99: 1 diastereomeric ratio (XH NMR) and the second eluting isomer (200 mg) in 1 1 : 1 diastereomeric ratio (XH NMR). Each diastereomer was carried through steps c and d independently. [0205] c) To a mixture of the product from step b (186 mg, 0.5 mmol) in dioxane (2 mL) was added 6 M H2S04 (1.25 mL, 7.5 mmol). The resulting slurry was heated at 80 C for 1 h, cooled to room temperature, and purified by reverse phase HPLC (CI 8 column, acetonitrile-H20 with 0.1% TFA as eluent). The resulting lactone FontWeight=”Bold” FontSize=”10″ TFA salt was neutralized to provide a colorless solid (53 mg, 0.23 mmol) that was used without further purification. [0206] d) A mixture of the lactone product from step c and l-(4-chlorophenyl)-5- isopropyl- lH-pyrazol-4-amine (50 mg, 0.21 mmol) in 1 ,2-dichloroethane (1 mL) was treated with AlMe3 (2 M solution in toluene, 210 mu, 0.42 mmol) at room temperature for 30 min. The reaction was quenched with saturated NH4C1 (5 mL) and extracted with EtOAc (3 x 3 mL). The organic layer was dried on MgS04, filtered, concentrated, and purified by flash chromatography (Si02, 0 – 100% EtOAc/CH2Cl2) to give the desired product (50 mg, 0.1 mmol, 50% yield). [0207] e) The product from step d (50 mg, 0.1 mmol) in dichloromethane (0.5 mL) was treated with Et3N (40 mu, 0.29 mmol) and methanesulfonyl chloride (20 mu, 0.23 mmol) for 30 min at room temperature. The mixture was then diluted with 1,2-dichloroethane (1 mL) and washed with water (1 mL). The organic layer was dried on Na2S04 and filtered. To the filtrate was added triethylamine (100 mu^, 0.7 mmol) and the mixture was stirred at 65 C for 90 min, concentrated, and purified by reverse phase HPLC (CI 8 column, acetonitrile-H20 with 0.1% TFA as eluent). The resulting TFA salt was neutralized to provide the titled compound (19 mg, 0.041 mmol) as a white solid. XH NMR (400 MHz, CDC13) delta 7.55 (s, 1 H), 7.48 (d, J= 8.6, 2 H), 7.36 (d, J= 8.6, 2 H), 7.22 (d, J= 0.8 Hz, 1 H), 5.07 (dd, J= 10.5, 8.9 Hz, 1 H), 3.91-3.77 (m, 2 H), 3.05 (hept, J= 7.0 Hz, 1 H), 2.90-2.82 (m, 1 H), 2.52 (s, 3 H), 2.42-2.31 (m, 1 H), 1.24 (d, J= 3.2 Hz, 3 H), 1.23 (d, J= 3.2 Hz, 3 H); MS: (ES) m/z calculated for C2iH22ClF3N50 [M + H]+ 452.1, found 451.9. The titled compounds were analyzed by chiral normal phase chromatography (Regis Cell cat 784104, 25 cm x 4.6 mm, 5 micron; eluent: 0.1% diethylamine/IPA, 0.6 ml/min). The (5)-enantiomer generated from the first-eluting diasteromer from step b had a retention time of 6.8 min (isolated in 8: 1 er). The (R)-enantiomer generated from the second-eluting diasteromer from step b had a retention time of 7.3 min (isolated in 78: 1 er).
Statistics shows that 2-Methyl-4-(trifluoromethyl)-1H-imidazole is playing an increasingly important role. we look forward to future research findings about 33468-67-6.
Reference:
Patent; CHEMOCENTRYX, INC.; CHEN, Xi; FAN, Pingchen; LI, Yandong; POWERS, Jay P.; MALATHONG, Viengkham; PUNNA, Sreenivas; TANAKA, Hiroko; ZHANG, Penglie; WO2014/89495; (2014); A1;,
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