2,2,2-trifluoroethane-1,1-diol

Conditions: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3A Molecular sieves (27.04 g) were heated at 120° C. under vacuum for 20 hours and added to a solution of 2-methyl-1-nitropropane (13.0 g) in methyl tert-butyl ether (420 ml). The mixture was stirred for 5 minutes, potassium carbonate (64.5 g) added and the mixture stirred a further 30 minutes. The mixture was cooled to 15° C. and fluoral hydrate (22.0 g) was added over 30 minutes. The reaction mixture was stirred at ambient temperature for 16 hours, then cooled to 15° C. and water (270 ml) added. After stirring for 5 minutes at ambient temperature, the organic phase was separated and washed with 10% aqueous potassium carbonate, 2M hydrochloric acid solution and water. Solvent was then removed by evaporation under reduced pressure at a temperature below 40° C. and the oil azeotroped dry with isopropyl alcohol at a temperature below 50° C. to give 4-methyl-3-nitro-1,1,1-trifluoro-2-pentanol (21.3 g) as an oil which was used without further purification. the mixture stirred a further 30 minutes The reaction mixture was stirred at ambient temperature for 16 hours cooled to 15° C. After stirring for 5 minutes at ambient temperature the organic phase was separated washed with 10% aqueous potassium carbonate, 2M hydrochloric acid solution and water Solvent was then removed by evaporation under reduced pressure at a temperature below 40° C. the oil azeotroped dry with isopropyl alcohol at a temperature below 50° C.

Conditions: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3A Molecular sieves (27.04 g) were heated at 120° C. under vacuum for 20 hours and added to a solution of 2-methyl-1-nitropropane (13.0 g) in methyl tert-butyl ether (420 ml). The mixture was stirred for 5 minutes, potassium carbonate (64.5 g) added and the mixture stirred a further 30 minutes. The mixture was cooled to 15° C. and fluoral hydrate (22.0 g) was added over 30 minutes. The reaction mixture was stirred at ambient temperature for 16 hours, then cooled to 15° C. and water (270 ml) added. After stirring for 5 minutes at ambient temperature, the organic phase was separated and washed with 10% aqueous potassium carbonate, 2M hydrochloric acid solution and water. Solvent was then removed by evaporation under reduced pressure at a temperature below 40° C. and the oil azeotroped dry with isopropyl alcohol at a temperature below 50° C. to give 4-methyl-3-nitro-1,1,1-trifluoro-2-pentanol (21.3 g) as an oil, which was used without further purification. the mixture stirred a further 30 minutes The reaction mixture was stirred at ambient temperature for 16 hours cooled to 15° C. After stirring for 5 minutes at ambient temperature the organic phase was separated washed with 10% aqueous potassium carbonate, 2M hydrochloric acid solution and water Solvent was then removed by evaporation under reduced pressure at a temperature below 40° C. the oil azeotroped dry with isopropyl alcohol at a temperature below 50° C.

Conditions: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3A Molecular sieves (27.04 g) were heated at 120° C. under vacuum for 20 hours and added to a solution of 2-methyl-1-nitropropane (13.0 g) in methyl tert-butyl ether (420 ml). The mixture was stirred for 5 minutes, potassium carbonate (64.5 g) added and the mixture stirred a further 30 minutes. The mixture was cooled to 15° C. and fluoral hydrate (22.0 g) was added over 30 minutes. The reaction mixture was stirred at ambient temperature for 16 hours, then cooled to 15° C. and water (270 ml) added. After stirring for 5 minutes at ambient temperature, the organic phase was separated and washed with 10% aqueous potassium carbonate, 2M hydrochloric acid solution and water. Solvent was then removed by evaporation under reduced pressure at a temperature below 40° C. and the oil azeotroped dry with isopropyl alcohol at a temperature below 50° C. to give 4-methyl-3-nitro-1,1,1-trifluoro-2-pentanol (21.3 g) as an oil, which was used without further purification. the mixture stirred a further 30 minutes The reaction mixture was stirred at ambient temperature for 16 hours cooled to 15° C. After stirring for 5 minutes at ambient temperature the organic phase was separated washed with 10% aqueous potassium carbonate, 2M hydrochloric acid solution and water Solvent was then removed by evaporation under reduced pressure at a temperature below 40° C. the oil azeotroped dry with isopropyl alcohol at a temperature below 50° C.

Conditions: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3A Molecular sieves (27.04 g) were heated at 120° C. under vacuum for 20 hours and added to a solution of 2-methyl-1-nitropropane (13.0 g) in methyl tert-butyl ether (420 ml). The mixture was stirred for 5 minutes, potassium carbonate (64.5 g) added and the mixture stirred a further 30 minutes. The mixture was cooled to 15° C. and fluoral hydrate (22.0 g) was added over 30 minutes. The reaction mixture was stirred at ambient temperature for 16 hours, then cooled to 15° C. and water (270 ml) added. After stirring for 5 minutes at ambient temperature, the organic phase was separated and washed with 10% aqueous potassium carbonate, 2M hydrochloric acid solution and water. Solvent was then removed by evaporation under reduced pressure at a temperature below 40° C. and the oil azeotroped dry with isopropyl alcohol at a temperature below 50° C. to give 4-methyl-3-nitro-1,1,1-trifluoro-2-pentanol (21.3 g) as an oil, which was used without further purification. the mixture stirred a further 30 minutes The reaction mixture was stirred at ambient temperature for 16 hours cooled to 15° C. After stirring for 5 minutes at ambient temperature the organic phase was separated washed with 10% aqueous potassium carbonate, 2M hydrochloric acid solution and water Solvent was then removed by evaporation under reduced pressure at a temperature below 40° C. the oil azeotroped dry with isopropyl alcohol at a temperature below 50° C.

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

Procedure: To a mixture of ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate and 2,2,2-trifluoroethane-1,1-diol in CH2Cl2 (242 μL) at 0° C. was added sodium cyanoborohydride (32.0 mg, 0.509 mmol). The reaction mixture was allowed to stir for 16 hours and then neutralized with 2M aqueous sodium carbonate and extracted with ethyl acetate (×3). The combined organic fractions were dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. The combined fractions containing the desired product were concentrated until only the water layer remained. The water layer was neutralized with saturated aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate (×3). The combined organic fractions were dried over sodium sulfate, filtered and concentrated under reduced pressure to give ethyl 4-{3-[(2,2,2-trifluoroethyl)amino]phenyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C17H16F3N4O2 [M+H]+: 365, found 365. 1H NMR (600 MHz, DMSO-D6) δ 12.92 (s, 1H), 8.87 (s, 1H), 8.25 (s, 1H), 7.21 (t, 1H, J=7.63 Hz), 7.00 (s, 1H), 6.86 (m, 2H), 6.37 (m, 1H), 3.94 (m, 2H), 3.83 (q, 2H, J=7.04 Hz), 0.81 (t, 3H, J=7.04 Hz). extracted with ethyl acetate (×3) The combined organic fractions were dried with sodium sulfate filtered concentrated under reduced pressure The residue was purified by reverse phase HPLC The combined fractions containing the desired product were concentrated until only the water layer the mixture was extracted with ethyl acetate (×3) The combined organic fractions were dried over sodium sulfate filtered concentrated under reduced pressure

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

Procedure: A mixture of 2,2,2-trifluoroethane-1,1-diol (75% aq solution, 20 g, 0.13 mol), CH3NO2 (24 g, 0.39 mol) and Na2CO3 (0.85 g, 8 mmol) was stirred overnight at RT. Water (50 mL) was added and the mixture was extracted with diethyl ether (3×30 mL) and dried over Na2SO4. After concentrating the organic extract at low temperature and under reduced pressure, P2O5 (20.0 g, 0.14 mol) was added to the residue oil, which was distilled at atmospheric pressure to give a green-yellow oil (4 g, 50% purity, 10% yield). Boiling point 85-90° C.; 1H NMR (400 MHz, CDCl3) δ ppm 7.09-7.17 (m, 1H), 7.50 (dd, J=2.0 Hz, 12.0 Hz, 1H). the mixture was extracted with diethyl ether (3×30 mL) dried over Na2SO4 After concentrating the was added to the residue oil, which was distilled at atmospheric pressure to give a green-yellow oil (4 g, 50% purity, 10% yield)

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

Procedure: A mixture of 2,2,2-trifluoroethane-1,1-diol (75% aq solution, 20 g, 0.13 mol), CH3NO2 (24 g, 0.39 mol) and Na2CO3 (0.85 g, 8 mmol) was stirred overnight at RT. Water (50 mL) was added and the mixture was extracted with diethyl ether (3×30 mL) and dried over Na2SO4. After concentrating the organic extract at low temperature and under reduced pressure, P2O5 (20.0 g, 0.14 mol) was added to the residue oil, which was distilled at atmospheric pressure to give a green-yellow oil (4 g, 50% purity, 10% yield). Boiling point 85-90° C.; 1H NMR (400 MHz, CDCl3) δ ppm 7.09-7.17 (m, 1H), 7.50 (dd, J=2.0 Hz, 12.0 Hz, 1H). the mixture was extracted with diethyl ether (3×30 mL) dried over Na2SO4 After concentrating the was added to the residue oil, which was distilled at atmospheric pressure to give a green-yellow oil (4 g, 50% purity, 10% yield)

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

Procedure: A mixture of 2,2,2-trifluoroethane-1,1-diol (75% aq solution, 20 g, 0.13 mol), CH3NO2 (24 g, 0.39 mol) and Na2CO3 (0.85 g, 8 mmol) was stirred overnight at RT. Water (50 mL) was added and the mixture was extracted with diethyl ether (3×30 mL) and dried over Na2SO4. After concentrating the organic extract at low temperature and under reduced pressure, P2O5 (20.0 g, 0.14 mol) was added to the residue oil, which was distilled at atmospheric pressure to give a green-yellow oil (4 g, 50% purity, 10% yield). Boiling point 85-90° C.; 1H NMR (400 MHz, CDCl3) δ ppm 7.09-7.17 (m, 1 H), 7.50 (dd, J=2.0 Hz, 12.0 Hz, 1 H). the mixture was extracted with diethyl ether (3×30 mL) dried over Na2SO4 After concentrating the was added to the residue oil, which was distilled at atmospheric pressure to give a green-yellow oil (4 g, 50% purity, 10% yield)

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

Procedure: A mixture of 2,2,2-trifluoroethane-1,1-diol (75% aq solution, 20 g, 0.13 mol), CH3NO2 (24 g, 0.39 mol) and Na2CO3 (0.85 g, 8 mmol) was stirred overnight at RT. Water (50 mL) was added and the mixture was extracted with diethyl ether (3×30 mL) and dried over Na2SO4. After concentrating the organic extract at low temperature and under reduced pressure, P2O5 (20.0 g, 0.14 mol) was added to the residue oil, which was distilled at atmospheric pressure to give a green-yellow oil (4 g, 50% purity, 10% yield). Boiling point 85-90° C.; 1H NMR (400 MHz, CDCl3) δ ppm 7.09-7.17 (m, 1 H), 7.50 (dd, J=2.0 Hz, 12.0 Hz, 1 H). the mixture was extracted with diethyl ether (3×30 mL) dried over Na2SO4 After concentrating the was added to the residue oil, which was distilled at atmospheric pressure to give a green-yellow oil (4 g, 50% purity, 10% yield)

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

Procedure: A mixture of 2,2,2-trifluoroethane-1,1-diol (75% aq solution, 20 g, 0.13 mol), CH3NO2 (24 g, 0.39 mol) and Na2CO3 (0.85 g, 8 mmol) was stirred overnight at RT. Water (50 mL) was added and the mixture was extracted with diethyl ether (3×30 mL) and dried over Na2SO4. After concentrating the organic extract at low temperature and under reduced pressure, P2O5 (20.0 g, 0.14 mol) was added to the residue oil, which was distilled at atmospheric pressure to give a green-yellow oil (4 g, 50% purity, 10% yield). Boiling point 85-90° C.; 1H NMR (400 MHz, CDCl3) δ ppm 7.09-7.17 (m, 1H), 7.50 (dd, J=2.0 Hz, 12.0 Hz, 1H). the mixture was extracted with diethyl ether (3×30 mL) dried over Na2SO4 After concentrating the was added to the residue oil, which was distilled at atmospheric pressure to give a green-yellow oil (4 g, 50% purity, 10% yield)

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

Procedure: A suspension of (carbethoxyethylidene)triphenylphosphorane (400 g, 1.10 mole) in tetrahydrofuran (600 mL) was treated with aqueous fluoral hydrate (71.5% w/w, 180 g, 1.10 mole) over a period of 4 hours. During the addition the reaction temperature rose to 45° C. and all of the solid dissolved to give a clear brown solution. The mixture was allowed to stand for 15 hours and was then heated under reflux for 3.5 hours. The solution was distilled at 2,700 Pa until the temperature in the distillation flask reached 140° C., giving ethyl (E)-2-methyl-4,4,4-trifluorobut-2-enoate as a solution in tetrahydrofuran (Solution A, 0.75 L, containing a maximum of 201 g of alkene); NMR (270 MHz, CDCl3): 1.3 (t, 3H, J=7Hz), 2.1 (br, s, 3H), 4.3 (q, 2H, J=7Hz) and 6.7 (m, 1H), (plus signals due to tetrahydrofuran). During the addition the reaction temperature rose to 45° C. all of the solid dissolved to give a clear brown solution was then heated under reflux for 3.5 hours The solution was distilled at 2,700 Pa until the temperature in the distillation flask reached 140° C.

Conditions: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3A Molecular sieves (27.04 g) were heated at 120° C. under vacuum for 20 hours and added to a solution of 2-methyl-1-nitropropane (13.0 g) in methyl tert-butyl ether (420 ml). The mixture was stirred for 5 minutes, potassium carbonate (64.5 g) added and the mixture stirred a further 30 minutes. The mixture was cooled to 15° C. and fluoral hydrate (22.0 g) was added over 30 minutes. The reaction mixture was stirred at ambient temperature for 16 hours, then cooled to 15° C. and water (270 ml) added. After stirring for 5 minutes at ambient temperature, the organic phase was separated and washed with 10% aqueous potassium carbonate, 2M hydrochloric acid solution and water. Solvent was then removed by evaporation under reduced pressure at a temperature below 40° C. and the oil azeotroped dry with isopropyl alcohol at a temperature below 50° C. to give 4-methyl-3-nitro-1,1,1-trifluoro-2-pentanol (21.3 g) as an oil which was used without further purification. the mixture stirred a further 30 minutes The reaction mixture was stirred at ambient temperature for 16 hours cooled to 15° C. After stirring for 5 minutes at ambient temperature the organic phase was separated washed with 10% aqueous potassium carbonate, 2M hydrochloric acid solution and water Solvent was then removed by evaporation under reduced pressure at a temperature below 40° C. the oil azeotroped dry with isopropyl alcohol at a temperature below 50° C.