2,2,2-trifluoro-1-phenylethanamine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: L-Tartaric acid (36 g, 240.0 mmol) was added to a solution of 2,2,2-trifluoro-1-phenylethanamine (40 g, 228.57 mmol) in isopropanol (400 mL). The solution was heated to reflux for 30 min. The mixture was cooled and the solid was collected by filtration. The material was diluted with Na2CO3/H2O and the aqueous mixture was extracted with methylene chloride (3×100 mL). The combined organic extracts were dried over K2CO3 and concentrated under reduced pressure to afford (1R)-2,2,2-trifluoro-1-phenylethanamine (12.5 g, 31% yield) as a white solid. The solution was heated to reflux for 30 min The mixture was cooled the solid was collected by filtration The material was diluted with Na2CO3/H2O the aqueous mixture was extracted with methylene chloride (3×100 mL) The combined organic extracts were dried over K2CO3 concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: L-Tartaric acid (36 g, 240.0 mmol) was added to a solution of 2,2,2-trifluoro-1-phenylethanamine (40 g, 228.57 mmol) in isopropanol (400 mL). The solution was heated to reflux for 30 min. The mixture was cooled and the solid was collected by filtration. The material was diluted with Na2CO3/H2O and the aqueous mixture was extracted with methylene chloride (3×100 mL). The combined organic extracts were dried over K2CO3 and concentrated under reduced pressure to afford (1R)-2,2,2-trifluoro-1-phenylethanamine (12.5 g, 31% yield) as a white solid. The solution was heated to reflux for 30 min The mixture was cooled the solid was collected by filtration The material was diluted with Na2CO3/H2O the aqueous mixture was extracted with methylene chloride (3×100 mL) The combined organic extracts were dried over K2CO3 concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-({2-[(tert-butoxycarbonyl)amino]-2-methyl-3-phenylpropoxy}methyl)-5-[(methylsulfonyl)(propyl)amino]benzoic acid (intermediate XI, 10.0 mg, 0.019 mmol) and (2,2,2-trifluoro-1-phenylethyl)amine (7.6 mg, 0.056 mmol) in DMF (500 μL) were added BOP reagent (10.0 mg, 0.022 mmol), ethyl(diisopropyl)amine (5.0 μL, 0.028 mmol). After sitting at rt for 4 hr, the reaction was purified by preparative HPLC (5->95% CH3CN/H2O, 0.1% added TFA, C18 PRO YMC 20×150 mm) to afford tert-butyl {1-benzyl-1-methyl-2-[(3-[(methylsulfonyl)(propyl)amino]-5-{[(2,2,2-trifluoro-1-phenylethyl)amino]carbonyl}benzyl)oxy]ethyl}carbamate which was taken up in HCl(g) saturated EtOAc (1 mL). After 15 hr, it was purified by preparative HPLC (5->95% CH3CN/H2O, 0.1% added TFA, C18 PRO YMC 20×150 mm) to provide 3-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-5-[(methylsulfonyl)(propyl)amino]-N-(2,2,2-trifluoro-1-phenylethyl)benzamide as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.90 (s, 1H), 7.84 (s, 1H), 7.65 (s, 1H), 7.61-7.55 (m, 2H), 7.46-7.40 (m, 3H), 7.34-7.24 (m, 3H), 7.20-7.15 (m, 2H), 6.04-5.96 (m, 1H), 4.72 (A of AB, d, J=13.8 Hz, 1H), 4.68 (B of AB, d, J=13.8 Hz, 1H), 3.71 (t, J=7.1 Hz, 2H), 3.45 (A of AB, d, J=10.0 Hz, 1H), 3.40 (B of AB, d, J=10.0 Hz, 1H), 3.08 (A of AB, d, J=13.4 Hz, 1H), 2.96 (s, 3H), 2.87 (B of AB, d, J=13.4 Hz, 1H), 1.51-1.41 (m, 2H), 1.25 (s, 3H), 0.90 (t, J=7.4 Hz, 3H). the reaction was purified by preparative HPLC (5->95% CH3CN/H2O, 0.1% added TFA

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of α-(trifluoromethyl)benzylazide (849 mf, 4.22 mmol) in ether (10 mL), lithium aluminum hydride (160 mg, 12.7 mmol) was added. The reaction mixture was stirred at room temerature for 2 hours. Then 0.46 ml H2O, 0.51 mL of 15% NaOH and 1.06 mL of H2O were added. The solid was filtered. The liquid was concentrated under reduced pressure to give desired product (647 mg, 88%). EI-MS m/z 176 (M+). The solid was filtered The liquid was concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of α-(trifluoromethyl)benzylazide (849 mf, 4.22 mmol) in ether (10 mL), lithium aluminum hydride (160 mg, 12.7 mmol) was added. The reaction mixture was stirred at room temerature for 2 hours. Then 0.46 ml H2O, 0.51 mL of 15% NaOH and 1.06 mL of H2O were added. The solid was filtered. The liquid was concentrated under reduced pressure to give desired product (647 mg, 88%). EI-MS m/z 176 (M+). The solid was filtered The liquid was concentrated under reduced pressure

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-borono-2-fluorobenzoic acid (54 mg, 0.294 mmol) in DCM (1468 μL) was cooled to 0° C. Then ghosez reagent N,N,3-trimethylbut-2-en-2-amine (65.8 μL, 0.587 mmol) was added and the whole mixture was stirred at rt for 20 min. The mixture was added into a mixture of TEA (246 μL, 1.762 mmol), 2,2,2-trifluoro-1-phenylethanamine (59.1 mg, 0.338 mmol) and DCM (1468 μL). The reaction was stirred at room temperature for 2 h. To the reaction mixture was added EtOAc, and washed with sat. sodium bicarbonate, water, and dried over Na2SO4. Filtered and concentrated to provide the crude product which was taken to the next step without further purification. LCMS (m/z): 342.2 (MH+), 0.84 min. was added The reaction was stirred at room temperature for 2 h washed with sat. sodium bicarbonate, water dried over Na2SO4 Filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: L-Tartaric acid (36 g, 240.0 mmol) was added to a solution of 2,2,2-trifluoro-1-phenylethanamine (40 g, 228.57 mmol) in isopropanol (400 mL). The solution was heated to reflux for 30 min. The mixture was cooled and the solid was collected by filtration. The material was diluted with Na2CO3/H2O and the aqueous mixture was extracted with methylene chloride (3×100 mL). The combined organic extracts were dried over K2CO3 and concentrated under reduced pressure to afford (1R)-2,2,2-trifluoro-1-phenylethanamine (12.5 g, 31% yield) as a white solid. The solution was heated to reflux for 30 min The mixture was cooled the solid was collected by filtration The material was diluted with Na2CO3/H2O the aqueous mixture was extracted with methylene chloride (3×100 mL) The combined organic extracts were dried over K2CO3 concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 8.2 g ammonium thiocyanate are dissolved in 54 ml water and the resulting solution is cooled to about 0°. The temperature is kept to this temperature during the addition of a solution of 11.5 ml benzoyl chloride in 10.5 ml acetone thereto. The temperature of the reaction mixture is let to revert to about 30° then the mixture is heated to reflux for 10 mn. A solution of α-phenyl trifluoroethylamine in 110 ml acetone is thereafter added portionwise for 1 hour while heating the mixture at reflux. The heating is maintained for a further period of 11/2 hour then let to revert to ambient temperature. The solvent is distilled off. The dry residue is taken up in 250 ml water. The aqueous solution is extracted 3 times with 200 ml ether. The organic phases are united, washed with water until the washings are free of chlorine ions, filtered and dried on sodium sulphate. The solvent is evaporated off, under reduced pressure and 34.1 g of raw product are recovered. The compound is purified by recrystallizing it from hexane. The pure N-(α-phenyl trifluoroethyl) N'-benzoyl thio Urea melts at 55°-60°. the resulting solution is cooled to about 0° to revert to about 30° the mixture is heated to reflux for 10 mn while heating the mixture at reflux to revert to ambient temperature The solvent is distilled off The aqueous solution is extracted 3 times with 200 ml ether washed with water until the washings filtered dried on sodium sulphate The solvent is evaporated off, under reduced pressure and 34.1 g of raw product are recovered The compound is purified by recrystallizing it from hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 8.2 g ammonium thiocyanate are dissolved in 54 ml water and the resulting solution is cooled to about 0°. The temperature is kept to this temperature during the addition of a solution of 11.5 ml benzoyl chloride in 10.5 ml acetone thereto. The temperature of the reaction mixture is let to revert to about 30° then the mixture is heated to reflux for 10 mn. A solution of α-phenyl trifluoroethylamine in 110 ml acetone is thereafter added portionwise for 1 hour while heating the mixture at reflux. The heating is maintained for a further period of 11/2 hour then let to revert to ambient temperature. The solvent is distilled off. The dry residue is taken up in 250 ml water. The aqueous solution is extracted 3 times with 200 ml ether. The organic phases are united, washed with water until the washings are free of chlorine ions, filtered and dried on sodium sulphate. The solvent is evaporated off, under reduced pressure and 34.1 g of raw product are recovered. The compound is purified by recrystallizing it from hexane. The pure N-(α-phenyl trifluoroethyl) N'-benzoyl thio Urea melts at 55°-60°. the resulting solution is cooled to about 0° to revert to about 30° the mixture is heated to reflux for 10 mn while heating the mixture at reflux to revert to ambient temperature The solvent is distilled off The aqueous solution is extracted 3 times with 200 ml ether washed with water until the washings filtered dried on sodium sulphate The solvent is evaporated off, under reduced pressure and 34.1 g of raw product are recovered The compound is purified by recrystallizing it from hexane

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (163 mg, 0.674 mmol), 2,2,2-trifluoro-1-phenylethanamine (624 mg, 3.56 mmol, 5.3 equiv) and p-toluenesulfonic acid monohydrate (321 mg, 1.69 mmol, 2.5 equiv) in n-BuOH (3 mL) was heated at 110° C. for 2 h and treated with additional p-toluenesulfonic acid monohydrate (321 mg, 1.69 mmol, 2.5 equiv), then heated at 110° C. for 1½ h. After cooling, the solid reaction mixture was treated with MeCN, sonicated and filtered. The filtrated was concentrated and purified by silica gel column chromatography (EtOAc/Heptane 0 to 30%) to give (4S)-4-isopropyl-3-(2-(2,2,2-trifluoro-1-phenylethylamino)pyrimidin-4-yl)oxazolidin-2-one (65 mg) in 25% yield. HRMS(B) m/z 381.1545 (M+H)+. Anal. RP-HPLC tR=4.31//4.46 min (1.0 mL/min flow rate with gradient from 5% to 15% acetonitrile with 0.05% formic acid in 5.00 min and then 15% to 95% acetonitrile with 0.05% formic acid from 5.00 min to 9.50 min, aqueous phase modified with 0.1% formic acid. Silica gel column chromatography separated the two diastereomers (S)-4-isopropyl-3-(2-((R)-2,2,2-trifluoro-1-phenylethylamino)pyrimidin-4-yl)oxazolidin-2-one and (S)-4-isopropyl-3-(2-((S)-2,2,2-trifluoro-1-phenylethylamino)pyrimidin-4-yl)oxazolidin-2-one. After cooling the solid reaction mixture sonicated filtered The filtrated was concentrated purified by silica gel column chromatography (EtOAc/Heptane 0 to 30%)