2-(2,4-difluorophenyl)ethanol

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

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

Procedure: The title compound or its salt was prepared by a procedure similar to that described for E11 starting from 2-(2,4-difluorophenyl)ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.

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

Procedure: The title compound or its salt was prepared by a procedure similar to that described for E11 starting from 2-(2,4-difluorophenyl)ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.

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

Procedure: To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (20 mg, 0.043 mmol), 2-(2,4-difluorophenyl)ethanol (33.7 mg, 0.213 mmol) and Ph3P-resin (33.6 mg, 0.128 mmol) in THF (2 mL) was added DEAD (0.020 mL, 0.128 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (0.854 mL, 0.854 mmol) in MeOH (1 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(5-(4-(2,4-difluorophenethoxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid (8.6 mg, 0.015 mmol, 34.7% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.53-7.45 (m, 1H), 7.28-7.15 (m, 2H), 7.11-6.90 (m, 4H), 5.82 (s, 1H), 4.31-4.18 (m, 2H), 3.08 (t, J=6.6 Hz, 2H), 2.84-2.76 (m, 1H), 2.43 (s, 3H), 2.17 (d, J=10.6 Hz, 1H), 2.05 (s, 3H), 1.49 (br. s., 1H), 1.34-1.27 (m, 1H), 1.17 (d, J=12.5 Hz, 1H), 1.12 (s, 9H), 1.02 (d, J=12.8 Hz, 1H), 0.85 (s, 3H), 0.60 (s, 3H). LCMS (M+H)=581.5. mixture was filtered to remove polymer concentrated Mixture was then cooled purified by prep-HPLC

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

Procedure: To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (20 mg, 0.043 mmol), 2-(2,4-difluorophenyl)ethanol (33.7 mg, 0.213 mmol) and Ph3P-resin (33.6 mg, 0.128 mmol) in THF (2 mL) was added DEAD (0.020 mL, 0.128 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (0.854 mL, 0.854 mmol) in MeOH (1 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(5-(4-(2,4-difluorophenethoxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid (8.6 mg, 0.015 mmol, 34.7% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.53-7.45 (m, 1H), 7.28-7.15 (m, 2H), 7.11-6.90 (m, 4H), 5.82 (s, 1H), 4.31-4.18 (m, 2H), 3.08 (t, J=6.6 Hz, 2H), 2.84-2.76 (m, 1H), 2.43 (s, 3H), 2.17 (d, J=10.6 Hz, 1H), 2.05 (s, 3H), 1.49 (br. s., 1H), 1.34-1.27 (m, 1H), 1.17 (d, J=12.5 Hz, 1H), 1.12 (s, 9H), 1.02 (d, J=12.8 Hz, 1H), 0.85 (s, 3H), 0.60 (s, 3H). LCMS (M+H)=581.5. mixture was filtered to remove polymer concentrated Mixture was then cooled purified by prep-HPLC

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

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

Procedure: Lithium aluminum hydride (65 g) was suspended in dry THF (1.5 L) under a nitrogen atmosphere and this mixture was then treated with a solution of 2,4-difluorophenylacetic acid (169 g) in dry THF (1 L) over a period of 90 min at 0° C. The reaction mixture was stirred for 70 min at 0° C. and then quenched dropwise with the slow addition of 20% w/v KOH(aq) (340 mL) at 0° C. The inorganic salts were then filtered over Hi flo (200 g) and MgSO4 (200 g), washed with ethyl acetate (200 g), and the filtrate concentrated in vacuo to provide the 2,4-difluorophenethyl alcohol. This alcohol was brominated and converted to its Grignard salt in the same manner described for COMPOUNDS I and II respectively. This 0.5M solution of 2,4difluorophenethyl magnesium bromide was used in the following transformation to generate EXAMPLE 4. quenched dropwise with the slow addition of 20% at 0° C The inorganic salts were then filtered over Hi flo (200 g) and MgSO4 (200 g) washed with ethyl acetate (200 g) the filtrate concentrated in vacuo

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

Procedure: Lithium aluminum hydride (65 g) was suspended in dry THF (1.5 L) under a nitrogen atmosphere and this mixture was then treated with a solution of 2,4-difluorophenylacetic acid (169 g) in dry THF (1 L) over a period of 90 min at 0° C. The reaction mixture was stirred for 70 min at 0° C. and then quenched dropwise with the slow addition of 20% w/v KOH(aq) (340 mL) at 0° C. The inorganic salts were then filtered over Hi flo (200 g) and MgSO4 (200 g), washed with ethyl acetate (200 g), and the filtrate concentrated in vacuo to provide the 2,4-difluorophenethyl alcohol. This alcohol was brominated and converted to its Grignard salt in the same manner described for COMPOUNDS I and II respectively. This 0.5M solution of 2,4difluorophenethyl magnesium bromide was used in the following transformation to generate EXAMPLE 4. quenched dropwise with the slow addition of 20% at 0° C The inorganic salts were then filtered over Hi flo (200 g) and MgSO4 (200 g) washed with ethyl acetate (200 g) the filtrate concentrated in vacuo

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

Procedure: Lithium aluminum hydride (65 g) was suspended in dry THF (1.5 L) under a nitrogen atmosphere and this mixture was then treated with a solution of 2,4-difluorophenylacetic acid (169 g) in dry THF (1 L) over a period of 90 min at 0° C. The reaction mixture was stirred for 70 min at 0° C. and then quenched dropwise with the slow addition of 20% w/v KOH(aq) (340 mL) at 0° C. The inorganic salts were then filtered over Hi flo (200 g) and MgSO4 (200 g), washed with ethyl acetate (200 g), and the filtrate concentrated in vacuo to provide the 2,4-difluorophenethyl alcohol. This alcohol was brominated and converted to its Grignard salt in the same manner described for COMPOUNDS I and II respectively. This 0.5M solution of 2,4difluorophenethyl magnesium bromide was used in the following transformation to generate EXAMPLE 4. quenched dropwise with the slow addition of 20% at 0° C The inorganic salts were then filtered over Hi flo (200 g) and MgSO4 (200 g) washed with ethyl acetate (200 g) the filtrate concentrated in vacuo

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3.63 g of 2,4-difluorophenethyl alcohol were reacted with 2.17 g of chloroacetic acid in a manner analogous to that described in Example 1(a), except that the reaction mixture was heated at 120° C. for 1 hour, to give 2.7 g (54%) of 2-(2,4-difluorophenyl)ethoxyacetic acid in the form of an oil which was homogeneous according to chromatography.

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

Procedure: Methanesulphonyl chloride (3.3 ml; 0.043 mol) and triethylamine (5.9 ml; 0.043 mol) were added to a solution of 2-(2,4-difluorophenyl)ethanol (6.4 g; 0.0426 mol) in dichloromethane (100 ml). The solution was cooled for 1 h at 0° C. and then brought to room temperature for 1 h. The reaction mixture was then treated by washing, successively, with 5N sulphuric acid (20 ml), water (50 ml), a 5% solution of NaHCO3 (50 ml) and water (50 ml). The organic phase was then dried over Na2SO4, filtered and concentrated at reduced pressure. The residue was taken up twice in CCl4, thus obtaining 6.42 g of 2-(2,4-difluorophenyl)ethyl methanesulphonate. The reaction mixture was then treated by washing The organic phase was then dried over Na2SO4 filtered concentrated at reduced pressure

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

Procedure: The title compound or its salt was prepared by a procedure similar to that described for E11 starting from 2-(2,4-difluorophenyl)ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.