1-ethoxy-2,2-difluoroethanol

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-((9-hydroxy-9H-fluoren-9-yl)carbonyl)-N-(2-aminomethyl-5-chlorobenzyl)-L-prolinamide (65 mg, 0.14 mmol) in anhydrous toluene (1.0 mL) at 0° C. was added difluoroacetaldehyde ethylhemiacetal (20 mg, 0.16 mmol, 1.1 eq). The mixture was heated to 100° C. under nitrogen atmosphere for 40 min and was then treated with MgSO4. Heating was continued for another 2 h. The mixture was then cooled to room temperature and diluted with CH2Cl2. The solution was dried over MgSO4, filtered and concentrated to an orange oil which yielded N-(5-chloro-2-{[(2,2-difluoroethylidene)amino]-methyl}benzyl-1-[(9-hydroxy-9-H-fluoren-9-yl)carbonyl]-L-prolinamide as a foam on prolonged drying under high vacuum. (66 mg, 90%). Heating The mixture was then cooled to room temperature The solution was dried over MgSO4 filtered concentrated to an orange oil which

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

Procedure: A mixture of (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentan-2-amine (8.5 g, 36.8 mmol) and difluoroacetaldehyde ethyl hemiacetal (5.0 g, 39.7 mmol) in benzene was refluxed with a Dean-stark trap overnight. Solvent was removed in vacuo. The residue was passed through a short silica column and eluted with hexanes:EtOAc (10:1) to give the title compound as a pale yellow oil. was refluxed with a Dean-stark trap overnight Solvent was removed in vacuo eluted with hexanes:EtOAc (10:1)

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

Procedure: A mixture of (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentan-2-amine (8.5 g, 36.8 mmol) and difluoroacetaldehyde ethyl hemiacetal (5.0 g, 39.7 mmol) in benzene was refluxed with a Dean-stark trap overnight. Solvent was removed in vacuo. The residue was passed through a short silica column and eluted with hexanes:EtOAc (10:1) to give the title compound as a pale yellow oil. was refluxed with a Dean-stark trap overnight Solvent was removed in vacuo eluted with hexanes:EtOAc (10:1)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-ethoxy-2,2-difluoroethanol (60 g, 0.47 mol), CH3NO2 (32.9 g, 0.56 mol) and Na2CO3 (3 g) was stirred at 60° C. for 3 hrs, then at rt overnight. The mixture was diluted with water (40 mL), extracted with tert-butyl methyl ether (200 mL) and the organic layer was dried over Na2SO4 and concentrated under low temperature to give the title compound, which was used for next step directly. at rt overnight extracted with tert-butyl methyl ether (200 mL) the organic layer was dried over Na2SO4 concentrated under low temperature

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-ethoxy-2,2-difluoroethanol (60 g, 0.47 mol), CH3NO2 (32.9 g, 0.56 mol) and Na2CO3 (3 g) was stirred at 60° C. for 3 hrs, then at rt overnight. The mixture was diluted with water (40 mL), extracted with tert-butyl methyl ether (200 mL) and the organic layer was dried over Na2SO4 and concentrated under low temperature to give the title compound, which was used for next step directly. at rt overnight extracted with tert-butyl methyl ether (200 mL) the organic layer was dried over Na2SO4 concentrated under low temperature

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

Procedure: A solution of 3 g (22.5 mmol) of 1-amino-2,2-diethoxyethane, 3.1 g (24.8 mmol) of difluoroacetaldehyde ethyl hemiacetal and 1 pellet of solid NaOH in 44 ml of toluene was heated at 120° C. with a Dean-Stark trap for 1.5 hours. The mixture was left to stand until it had cooled to room temperature and was concentrated in vacuo. The residue was diluted with 80 ml of methanol, and 3.4 g (90 mmol) of sodium borohydride were added in small quantities. The reaction mixture was then stirred overnight, concentrated in vacuo and partitioned between ethyl acetate and water. The organic phase was isolated, dried (MgSO4) and concentrated in vacuo. 3.7 g of crude substance were obtained as a colorless oil. The residue was subjected to a flash chromatography on 40 g of SiO2 (elution with DCM/MeOH, gradient 1-8%). 3.1 g of the desired amine were obtained as a colorless oil. The mixture was left was concentrated in vacuo were added in small quantities concentrated in vacuo partitioned between ethyl acetate and water The organic phase was isolated dried (MgSO4) concentrated in vacuo 3.7 g of crude substance were obtained as a colorless oil

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

Procedure: A mixture of (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentan-2-amine (8.5 g, 36.8 mmol) and difluoroacetaldehyde ethyl hemiacetal (5.0 g, 39.7 mmol) in benzene was refluxed with a Dean-stark trap overnight. Solvent was removed in vacuo. The residue was passed through a short silica column and eluted with hexanes:EtOAc (10:1) to give the title compound as a pale yellow oil. was refluxed with a Dean-stark trap overnight Solvent was removed in vacuo eluted with hexanes:EtOAc (10:1)

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

Procedure: A mixture of (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentan-2-amine (8.5 g, 36.8 mmol) and difluoroacetaldehyde ethyl hemiacetal (5.0 g, 39.7 mmol) in benzene was refluxed with a Dean-stark trap overnight. Solvent was removed in vacuo. The residue was passed through a short silica column and eluted with hexanes:EtOAc (10:1) to give the title compound as a pale yellow oil. was refluxed with a Dean-stark trap overnight Solvent was removed in vacuo eluted with hexanes:EtOAc (10:1)

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

Procedure: A solution of 3 g (22.5 mM) of 1-amino-2,2-diethoxyethane, 3.1 g (24.8 mM) of difluoroacetaldehyde ethyl hemiacetal and 1 pellet of solid NaOH in 44 ml of toluene was heated at 120° C. with a Dean-Stark trap for 1.5 hours. The mixture is left to stand until it has cooled to room temperature and is concentrated in vacuo. The residue is diluted with 80 ml of methanol, and 3.4 g (90 mM) of sodium borohydride were added in small quantities. The reaction mixture is then stirred overnight, concentrated in vacuo and partitioned between ethyl acetate and water. The organic phase is isolated, dried (MgSO4) and concentrated in vacuo. 3.7 g of crude substance are obtained as a colorless oil. The residue is subjected to a flash chromatography on 40 g of SiO2 (elution with DCM/MeOH, gradient 1-8%). 3.1 g of the desired amine were obtained as a colorless oil. The mixture is left is concentrated in vacuo The residue is diluted with 80 ml of methanol, and 3.4 g (90 mM) of sodium borohydride were added in small quantities concentrated in vacuo partitioned between ethyl acetate and water The organic phase is isolated dried (MgSO4) concentrated in vacuo 3.7 g of crude substance are obtained as a colorless oil

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A sealed suspension of 3-hydroxy-1-methypyridin-4(1H)-one (1.00 g, 8.0 mmol) and potassium carbonate (0.11 g, 0.8 mmol) in 2.4 mL of difluoroacetaldehyde ethyl hemiacetal was heated to 50° C. for 18 h. The volatile components were evaporated under reduced pressure. The residue was dissolved in 3 mL of de-ionized water then cooled in an ice-water bath, and the pH was adjusted to 5-6 with a 1N HCl solution. The precipitate was collected by suction filtration and dried. Thus, the title compound Apo7078 was obtained (410 mg) as a white solid. Yield=25%; 1H NMR (400 MHz, CD3OD) δ (ppm): 7.62 (d, J=7.1 Hz, 1H), 6.41 (d, J=7.1 Hz, 1H), 6.30 (dt, 3J=55.8 Hz, 2J=5.1 Hz, 1H), 5.45 (dt, 2J=5.1 Hz, 3J=11.4 Hz, 1H), 3.96 (s, 3H); MS m/z 206 [M+1], 188 (100%). The volatile components were evaporated under reduced pressure The residue was dissolved in 3 mL of de-ionized water then cooled in an ice-water bath The precipitate was collected by suction filtration dried

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-((9-hydroxy-9H-fluoren-9-yl)carbonyl)-N-(2-aminomethyl-5-chlorobenzyl)-L-prolinamide (65 mg, 0.14 mmol) in anhydrous toluene (1.0 mL) at 0° C. was added difluoroacetaldehyde ethylhemiacetal (20 mg, 0.16 mmol, 1.1 eq). The mixture was heated to 100° C. under nitrogen atmosphere for 40 min and was then treated with MgSO4. Heating was continued for another 2 h. The mixture was then cooled to room temperature and diluted with CH2Cl2. The solution was dried over MgSO4, filtered and concentrated to an orange oil which yielded N-(5-chloro-2-{[(2,2-difluoroethylidene)amino]-methyl}benzyl-1-[(9-hydroxy-9-H-fluoren-9-yl)carbonyl]-L-prolinamide as a foam on prolonged drying under high vacuum. (66 mg, 90%). Heating The mixture was then cooled to room temperature The solution was dried over MgSO4 filtered concentrated to an orange oil which

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

Procedure: A mixture of (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentan-2-amine (8.5 g, 36.8 mmol) and difluoroacetaldehyde ethyl hemiacetal (5.0 g, 39.7 mmol) in benzene was refluxed with a Dean-stark trap overnight. Solvent was removed in vacuo. The residue was passed through a short silica column and eluted with hexanes:EtOAc (10:1) to give the title compound as a pale yellow oil. was refluxed with a Dean-stark trap overnight Solvent was removed in vacuo eluted with hexanes:EtOAc (10:1)