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Step 2 To a suspension OF 6-TRIFLUOROMETHYLPYRIDINE-2-CARBOXYLIC acid (2.53 g, 13.2 mmol) in THF (50 mL) cooled to-5 C was added triethylamine (1.84 mL, 13.2 mmol) followed by addition of ethyl CHLOROFORMATE (1.26 mL, 13.2 mmol) and the reaction mixture was stirred for 30 min at 0 C. Lithium borohydride (718 mg, 33 mmol) was added in portions, maintaining the temperature BELOW-5 C. After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 1 h. Temperature was lowered to-5 C and methanol (10 mL) was added followed by addition of aqueous sodium hydroxide (10 mL, 10 %). After the addition of ethyl acetate (50 mL) and water (40 mL), dilute hydrochloric acid was added to obtain pH = 5.0. After washing aqueous layer thoroughly with ethyl acetate the combined organic extracts were dried over MGS04 and concentrated. Purification by flash column (30% EtOAc-Hexane) gave (6-trifluoromethylpyridin-2-yl) methanol (760 mg) as an oil.
Example 79: 2-r2-(Azetidin-3-yloxy)-4-chloro-phenoxynnethyl1-6-trifluoroiotainethyl- pyridine.; Step A: Preparation of (6-Trifluoronnethyl-pyridin-2-yl)-nnethanol.; To a solution of 6-trifluoromethyl-pyhdine-2-carboxylic acid (500 mg, 3 mmol) in dry THF at 0 0C, was added triethylamine (0.36 ml_, 2.6 mmol) followed by ethyl chloroformate (0.25 ml_, 2.6 mmol). After 30 min, LiBH4 (2 M in THF, 3.3 ml_, 6.5 mmol) was added. After an additional 30 min, the ice bath was removed. After 1 h, the reaction was cooled to 0 0C and quenched with MeOH followed by 1 N NaOH and EtOAc. The pH of the solution was adjusted to pH=5 with 1 N HCI and the mixture extracted with EtOAc (2X). The combined organic fractions were dried to provide the title compound that was used without further purification. 1H NMR (CDCI3): 7.89 (dd, J = 7.8, 7.8 Hz, 1 H), 7.61 (d, J = 7.7 Hz, 1 H), 7.51 (d, J = 7.9 Hz, 1 H), 4.85 (s, 2H).
Step 2; To a suspension of 6-trifluoromethylpyridine-2-carboxylic acid (2.53 g, 13.2 mmol) in THF (50 niL) cooled to -5 0C was added triethylamine (1.84 mL, 13.2 mmol) followed by addition of ethyl chloroformate (1.26 mL, 13.2 mmol) and the reaction mixture was stirred for 30 min at 0 0C. Lithium borohydride (718 mg, 33 mmol) was added in portions, maintaining the temperature below -5 0C. After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 1 h. Temperature was lowered to -5 0C and methanol (10 mL) was added followed by addition of aqueous sodium hydroxide (10 mL, 10 %). After the addition of ethyl acetate (50 mL) and water (40 mL), dilute hydrochloric acid was added to obtain pH = 5.0. After washing aqueous layer thoroughly with ethyl acetate the combined organic extracts were dried over MgSO4 and concentrated. Purification by flash column (30% EtOAc-Hexane) gave (6-trifluoromethylpyridin-2-yl)methanol (760 mg) as an oil.
Step 3 (6-Trifluoromethylpyridin-2-yl) methanol (760 mg, 4.3 mmol) was dissolved in CH2C12 and THIONYL chloride was added slowly at room temperature. The reaction mixture was stirred at room temperature for 4 h. Solvent was removed under the reduced pressure, the pH was adjusted to 5, and the product was extracted with EtOAc. Purification by flash column (5% EtOAc-Hexane) gave 2-chloromethyl-6-trifluoromethylpyridine (200 mg) as a white solid.
With thionyl chloride; In dichloromethane; at 20℃; for 4h;
Step 3; (6-Trifluoromethylpyridin-2-yl)methanol (760 mg, 4.3 mmol) was dissolved in CH2Cl2 and thionyl chloride was added slowly at room temperature. The reaction mixture was stirred at room temperature for 4 h. Solvent was removed under the reduced pressure, the pH was adjusted to 5, and the product was extracted with EtOAc. Purification by flash column ( 5% EtOAc-Hexane) gave 2-chloromethyl-6-trifluoromethylpyridine (200 mg) as a white solid.
With di-tert-butyl-diazodicarboxylate; In dichloromethane; at 20℃; for 24h;
Examples 29-32A 0.125 M stock solution of tert-butyl (3RS)-3-(4-hydroxyphenyl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate in dichloromethane (1.0 mL, 0.125 mmol) was added to each vial containing the appropriate alcohol (0.150 mmol). A 0.1 M PS-PPh3 suspension in dichloromethane (2 mL) and a 0.2 M DBAD solution in dichloromethane (1 mL) were added to each vial. The vials were capped and shaken at RT for 24 hours. The reaction mixtures were filtered and concentrated. The resultant residues were treated with 25% trifluoroacetic acid/dichloromethane (1.5 ml_) and shaken for 2 hours at RT. The reactions were concentrated and the resultant residues were treated with a 0.0625 M solution of phenyl (3,4-dimethylisoxazol-5-yl)carbamate in acetonitrile (2 ml_) followed by triethylamine (0.250 ml_). After shaking overnight at room temperature, the vials were concentrated. The residues were dissolved in DMSO (1.5 ml_) and purified by reverse phase HPLC (acetonitrile/water/0.01 % trifluoroacetic acid/0.04% formic acid) to give racemic Examples 29-32. The purified compounds were analyzed by LCMS (Phenomenex Gemini C18 4.6 X 50 mm 5mum; 0.04% Formic Acid, 0.01 % TFA / MeCN).
(4) Production of (6-Trifluoromethylpyridin-2-yl) Methanol A solution containing 2.00 g of 2-bromo-6-trifluoromethylpyridine dissolved in 50 ml of toluene was cooled to -78C followed by dropping in 4.0 ml of n-butyllithium (2.77 mol/L) and stirring for 10 minutes at -78C. 0.96 g of N,N-dimethylformamide were dropped therein followed by further stirring for 10 minutes at -78C following completion of the reaction. 0.67 g of sodium borohydride and 5 ml of methanol were added to the resulting reaction mixture followed by heating to room temperature and stirring for 1 hour at room temperature. Following completion of the reaction, aqueous ammonium chloride solution was added to the reaction liquid followed by extraction with ethyl acetate. The ethyl acetate layer was dried by addition of anhydrous magnesium sulfate followed by filtering and distilling off the solvent from the filtrate under reduced pressure to obtain 1.70 g of a crude product in the form of (6-trifluoromethylpyridin-2-yl) methanol. [1H-NMR Data of (6-Trifluoromethylpyridin-2-yl) Methanol] 1H-NMR (CDCl3/TMS, delta ppm): 7.88(dd,1H), 7.60(d,1H), 7.50(d,1H), 4.85(s,2H), 3.36(bs,1H)
With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 20℃; for 1h;
3.78 g of carbon tetrabromide and 2.78 g of triphenylphosphine were added to a solution containing 1.70 g of the (6-trifluoromethylpyridin-2-yl) methanol obtained in (4) dissolved in 30 ml of methylene chloride followed by stirring for 1 hour at room temperature. 30 ml of acetonitrile, 1.52 g of N-(t-butoxycarbonyl) hydroxylamine and 1.74 g of 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) were added to this reaction solution followed by stirring for 3 hours at room temperature. Following completion of the reaction, aqueous ammonium chloride solution was added to the reaction mixture followed by extraction with ethyl acetate. The ethyl acetate layer was dried by addition of anhydrous magnesium sulfate followed by filtration and distilling off the solvent from the filtrate under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent; n-hexane:ethyl acetate = 3:1 (volume ratio)) to obtain 1.54 g of the target compound of t-butyl N-[(6-trifluoromethylpyridin-2-yl)methyloxy] carbamate (yield: 59%). [1H-NMR Data of t-Butyl N-[(6-trifluoromethylpyridin-2-yl)methyloxy] Carbamate 1H-NMR (CDCl3/TMS, delta ppm): 7.90(dd,1H), 7.73(d,1H), 7.62(d,1H), 7.44(bs,1H), 1.48(s,9H)
a) 2-Chloro-4-((6-(trifluoromethyl)pyridin-2-yl)methoxy)pyridine <strong>[131747-53-0]6-(Trifluoromethyl)-2-pyridinemethanol</strong> (2.20 g, 12.8 mmol) was reacted according to Example 113 (step c) to provide the title compound (3.30 g, 89%) as a white foam: ESI MS m/z 289 [M+H]+.
2-chloro-4-(pyrimidin-5-yl)-5,6,7,8-tetrahydroquinoline[ No CAS ]
[ 131747-53-0 ]
4-(pyrimidin-5-yl)-2-[6-(trifluoromethyl)pyridin-2-yl]methoxy}-5,6,7,8-tetrahydroquinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37 mg
With 4,5-bis-(di-tert-butyl-phosphanyl)-9,9-dimethyl-9H-xanthene; tris(dibenzylideneacetone)dipalladium(0) chloroform complex; caesium carbonate; In toluene; at 100℃;Inert atmosphere;
Example 154 4-(Pyrimidin-5-yl)-2-[6-(trifluoromethyl)pyridin-2 -yl]methoxy}-5,6,7,8-tetrahydroquinoline hydrochloride To 2-chloro-4-(pyrimidin-5-yl)-5,6,7,8-tetrahydroquino line (30 mg), <strong>[131747-53-0][6-(trifluoromethyl)pyridin-2-yl]methanol</strong> (28 mg), Pd2(dba)3·CHCl3 (8.3 mg), t-Bu-X-Phos (8.3 mg) and cesium carbonate (80 mg) was added toluene (1.6 mL), and the mixture was degassed, then stirred under Ar atmosphere at 100C overnight. After the reaction mixture was allowed to return to room temperature, diluted with ethyl acetate, filtered through Celite, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (37 mg) as a pink solid. [MS (ESI) m/z 388.2 (M+H)+]
[6-(trifluoromethyl)pyridin-2-yl]methyl methanesulfonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With triethylamine; In dichloromethane; at 0℃;Inert atmosphere;
TEA (1.4 g, 1.9 mL, 14 mmol) was added dropwise to 0 C(6-trifluoromethyl-pyridin-2-yl) -methanol(1.61 g,9.09 mmol) in DCM (20 mL) was added MsCl (1.2 g, 11 mmol) under nitrogen,The reaction was then continued at 0 C. The reaction mixture was concentrated under reduced pressure, then saturated aqueous sodium bicarbonate (40 mL)Dichloromethane (50 mL x 3)The organic phase was dried over anhydrous Na2SO4 and the concentrated crude product was isolated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 7 /3) to give 2.2 g of a yellow solid, yield: 95%.
With triethylamine; In dichloromethane; at 0 - 20℃; for 22h;
Methanesulfonyl chloride (0.15 mL, 1.96 mmol) was added to a 0 C cooled solution of <strong>[131747-53-0][6-(trifluoromethyl)pyridin-2-yl]methanol</strong> (0.32, 1.78 mmol) and Et3N (0.30 mL, 2.13 mmol) in CH2Cl2 (15 mL). The reaction mixture was stirred at room temperature for 22 h and concentrated to dryness, rendering the title compound as a white sticky solid, which was used in the next step without further purification. HPLC-MS (Method H): Ret, 9.06 min; ESI+-MS m/z: 256 (M+1).
With methanol; sodium tetrahydroborate; at 0 - 20℃; for 2.5h;
NaBH4 (67 mg, 1.78 mmol) was added to a 0 C cooled solution of 6- (trifluoromethyl)picolinaldehyde (260 mg, 1.48 mmol) in MeOH (15 mL); the reaction was allowed to reach room temperature and stirred for 2.5 h. The mixture was poured into water (20 mL) and was extracted with CH2Cl2 (2x30 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated to give the title compound as a yellow oil, 0.28 g, more than 100% weight. This oil was used in the next step without further purification. HPLC-MS (Method H): Ret, 7.71 min; ESI+-MS m/z: 178 (M+1).
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