(2,6-difluorophenyl)methanol

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

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

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

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 332 g of 2,6-difluorobenzaldehyde were placed under nitrogen in a 0.7 1 autoclave and admixed with 6.4 g of 5% strength by weight palladium-on-carbon (catalyst from Heraeus type K-0227, containing 50% by weight of water). The autoclave was closed and purged with nitrogen. 50 bar of hydrogen were then injected and the contents of the autoclave were heated to 80° C. Hydrogenation was carried out for a total of 4 hours while stirring. After cooling and venting, the reaction mixture was filtered through Celite® filter aid, the autoclave was rinsed with 50 g of isopropanol and the filter cake was washed with 150 g of isopropanol. The solvent was distilled from the combined filtrates and washings and the crude product mixture was subsequently distilled off. 288 g of 2,6-difluorobenzyl alcohol were obtained (90% of theory). The autoclave was closed purged with nitrogen was carried out for a total of 4 hours After cooling the reaction mixture was filtered through Celite® filter aid the autoclave was rinsed with 50 g of isopropanol the filter cake was washed with 150 g of isopropanol The solvent was distilled from the combined filtrates and washings the crude product mixture was subsequently distilled off

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

Procedure: Particularly preferably, 2,6-dichlorobenzaldehyde is used in the process of the invention and 2-fluoro-6-chlorobenzaldehyde, 2-fluoro-6-chlorobenzyl alcohol, 2,6-difluorobenzaldehyde or 2,6-difluorobenzyl alcohol is obtained or 2,4-dichlorobenzaldehyde is used and 2,4-difluoro-benzaldehyde or 2,4-difluorobenzyl alcohol is obtained or 3,4-dichloro-benzaldehyde is used and 3-chloro-4-fluorobenzaldehyde or 3-chloro-4-fluorobenzyl alcohol is obtained.

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

Procedure: Acetyl chloride (1.13 mL, 15.8 mmol) was added dropwise to a solution of 2,6-difluorobenzyl alcohol (1.76 g, 12.2 mmol) and triethylamine (3.43 mL, 24.4 mmol) in DCM (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was diluted with water and extracted with DCM (3×20 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as a colourless oil (1.72 g, 76%). 1H NMR 400 MHz δ (CDCl3): 7.37-7.28 (1H, m), 6.96-6.88 (2H, m), 5.20 (2H, s), 2.08 (3H, s). extracted with DCM (3×20 mL) The combined organic fractions were washed with brine dried (MgSO4) concentrated in vacuo The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane)

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

Procedure: Acetyl chloride (1.13 mL, 15.8 mmol) was added dropwise to a solution of 2,6-difluorobenzyl alcohol (1.76 g, 12.2 mmol) and triethylamine (3.43 mL, 24.4 mmol) in DCM (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was diluted with water and extracted with DCM (3×20 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as a colourless oil (1.72 g, 76%). 1H NMR 400 MHz δ (CDCl3): 7.37-7.28 (1H, m), 6.96-6.88 (2H, m), 5.20 (2H, s), 2.08 (3H, s). extracted with DCM (3×20 mL) The combined organic fractions were washed with brine dried (MgSO4) concentrated in vacuo The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane)

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

Procedure: The title compound (cis/trans=22/78) was prepared as a white powder in 58.3% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=24/76) and 2,6-difluorobenzyl alcohol.

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 332 g of 2,6-difluorobenzaldehyde were placed under nitrogen in a 0.7 1 autoclave and admixed with 6.4 g of 5% strength by weight palladium-on-carbon (catalyst from Heraeus type K-0227, containing 50% by weight of water). The autoclave was closed and purged with nitrogen. 50 bar of hydrogen were then injected and the contents of the autoclave were heated to 80° C. Hydrogenation was carried out for a total of 4 hours while stirring. After cooling and venting, the reaction mixture was filtered through Celite® filter aid, the autoclave was rinsed with 50 g of isopropanol and the filter cake was washed with 150 g of isopropanol. The solvent was distilled from the combined filtrates and washings and the crude product mixture was subsequently distilled off. 288 g of 2,6-difluorobenzyl alcohol were obtained (90% of theory). The autoclave was closed purged with nitrogen was carried out for a total of 4 hours After cooling the reaction mixture was filtered through Celite® filter aid the autoclave was rinsed with 50 g of isopropanol the filter cake was washed with 150 g of isopropanol The solvent was distilled from the combined filtrates and washings the crude product mixture was subsequently distilled off

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

Procedure: Particularly preferably, 2,6-dichlorobenzaldehyde is used in the process of the invention and 2-fluoro-6-chlorobenzaldehyde, 2-fluoro-6-chlorobenzyl alcohol, 2,6-difluorobenzaldehyde or 2,6-difluorobenzyl alcohol is obtained or 2,4-dichlorobenzaldehyde is used and 2,4-difluoro-benzaldehyde or 2,4-difluorobenzyl alcohol is obtained or 3,4-dichloro-benzaldehyde is used and 3-chloro-4-fluorobenzaldehyde or 3-chloro-4-fluorobenzyl alcohol is obtained.

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

Procedure: Acetyl chloride (1.13 mL, 15.8 mmol) was added dropwise to a solution of 2,6-difluorobenzyl alcohol (1.76 g, 12.2 mmol) and triethylamine (3.43 mL, 24.4 mmol) in DCM (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was diluted with water and extracted with DCM (3×20 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as a colourless oil (1.72 g, 76%). 1H NMR 400 MHz δ (CDCl3): 7.37-7.28 (1H, m), 6.96-6.88 (2H, m), 5.20 (2H, s), 2.08 (3H, s). extracted with DCM (3×20 mL) The combined organic fractions were washed with brine dried (MgSO4) concentrated in vacuo The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane)

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