[4-(bromomethyl)phenyl] acetate

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

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

Procedure: By following the procedure of Example 1, Step A, but substituting equimolar amounts of 6-[2-(2,4-dichloro-6-hydroxyphenyl)ethyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one and 4-(bromomethyl)phenol acetate for the 4,6-dichlorosalicylaldehyde and benzyl bromide used therein, the title compound is obtained.

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

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

Procedure: N-Bromosuccinimide (60.0 g.) was added in portions during 40 minutes to a solution of 4-acetoxytoluene (50.0 g.) and 2,2'-azobis(2-methylpropionitrile) (10 mg.) in carbon tetrachloride (300 ml.) heated under reflux and illuminated by a high energy tungsten lamp (275 watt). Heating and illumination were continuted for 80 minutes after the addition was complete. The mixture was then cooled and filtered. The solid residue was washed with carbon tetrachloride (100 ml.) and the combined filtrate and washings were evaporated to give 4-acetoxybenzyl bromide as a syrupy solid, which was dissolved, without further purification, in ethanol (300 ml.). 1,2,3,6-Tetrahydropyridine (83.0 g.) was then added to the solution during 10 minutes. The subsequent mixture was left at 20°-25° C. for 16 hours, and then evaporated. Water (300 ml.) was added to the residue obtained and the subsequent mixture was acidified to pH2 with dilute hydrochloric acid, and then extracted with ether (2×100 ml.) and the extracts discarded. The aqueous phase was basified to pH9 (sodium hydroxide solution) and extracted with ether (3×100 ml.). The extracts were washed with water (2×50 ml.), dried (MgSO4) and evaporated. The residue was dissolved in acetone (200 ml.), the solution obtained was filtered, and the filtrate acidified to pH2 with ethereal hydrogen chloride. There was thus obtained 1-(4-hydroxybenzyl)-1,2,3,6-tetrahydropyridine hydrochloride which was recrystallised from methanol/ethyl acetate to give pure material (34.6 g.), m.p. 234°-236° C. heated under reflux illuminated by a high energy tungsten lamp (275 watt) Heating after the addition The mixture was then cooled filtered The solid residue was washed with carbon tetrachloride (100 ml.) the combined filtrate and washings were evaporated

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

Procedure: To a solution of 28 mg of 4-acetoxybenzyl bromide in 1.5 mL of CHCl3 was added 30 mg of Ketoconazole and the mixture was stirred for 16 h at room temperature. The solvent was evaporated in vacuo. Column chromatography on silica gel(Wakogel C-200, solvent:CH2Cl2/MeOH=10/1) gave 1-(4-acetoxybenzyl)-3-[(2R*,4S*)-4-[4-(4-acetyl pi perazin-1-yl)phenoxymethyl]-2-(2,4-dichlorophenyl)-[1,3]dioxolan-2-yl methyl]-3H-imidazol-1-ium bromide (32 mg, 76%, as colorless oil); MALDI-TOF-MS m/z 679 (M--Br)+; 1H-NMR(CDCl3) δ2.14(3H,s), 2.28(3H,s), 3.05(4H,m), 3.60~3.89(8H,m), 4.33(1H,m), 4.80(2H,s), 5.37(1H,d,J=14.5 Hz), 5.61(1H,d,J=14.5 Hz), 6.78(2H,d,J=9.1 Hz), 6.92, (2H,d,J=9.1 Hz), 7.03(2H,d,J=8.6 Hz), 7.24~7.63(7H,m), 10.1(1H,s). The solvent was evaporated in vacuo

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

Procedure: By following the procedure of Example 1, Step A, but substituting equimolar amounts of 6-[2-(2,4-dichloro-6-hydroxyphenyl)ethyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one and 4-(bromomethyl)phenol acetate for the 4,6-dichlorosalicylaldehyde and benzyl bromide used therein, the title compound is obtained.

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

Procedure: An ethanol solution of potassium hydroxide (16.6 g. in 400 ml.) was added to a stirred solution of indoline-2,3-dione (isatin) (43.6 g.) in dimethyl sulphoxide (400 ml.). After 10 minutes a solution of 4-acetoxybenzyl bromide (76.3 g.) in dimethyl sulphoxide (40 ml.) was added. The mixture was stirred for 72 hours and then poured into ice/water (~1000 ml.). The gum which first formed slowly crystallised. The solid which formed was recrystallised from methanol (500 ml.) to give 1-(4-acetoxybenzyl)indoline-2,3-dione as a solid, m.p. 159°-161° C. The gum which first formed slowly crystallised The solid which formed was recrystallised from methanol (500 ml.)

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

Procedure: To the solution of 4-hydroxymethylphenol acetate (2.50 g, 15.0 mmol) and carbon tetrabromide (5.97 g, 18.0 mmol) in 40 ml of methylene chloride was added triphenylphosphine (4.73 g, 180 mmol) under nitrogen. The resultant mixture was stirred for 3 hours. The product was purified by flash chromatography using heptane/ethyl acetate (90/10-80/20) as eluent in a yield of 79%. The product was purified by flash chromatography

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

Procedure: To the solution of 4-hydroxymethylphenol acetate (2.50 g, 15.0 mmol) and carbon tetrabromide (5.97 g, 18.0 mmol) in 40 ml of methylene chloride was added triphenylphosphine (4.73 g, 180 mmol) under nitrogen. The resultant mixture was stirred for 3 hours. The product was purified by flash chromatography using heptane/ethyl acetate (90/10-80/20) as eluent in a yield of 79%. The product was purified by flash chromatography

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

Procedure: By following the procedure of Example 1, Step A, but substituting equimolar amounts of 6-[2-(2,4-dichloro-6-hydroxyphenyl)ethyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one and 4-(bromomethyl)phenol acetate for the 4,6-dichlorosalicylaldehyde and benzyl bromide used therein, the title compound is obtained.

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

Procedure: By following the procedure of Example 1, Step A, but substituting equimolar amounts of 6-[2-(2,4-dichloro-6-hydroxyphenyl)ethyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one and 4-(bromomethyl)phenol acetate for the 4,6-dichlorosalicylaldehyde and benzyl bromide used therein, the title compound is obtained.

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

Procedure: N-Bromosuccinimide (60.0 g.) was added in portions during 40 minutes to a solution of 4-acetoxytoluene (50.0 g.) and 2,2'-azobis(2-methylpropionitrile) (10 mg.) in carbon tetrachloride (300 ml.) heated under reflux and illuminated by a high energy tungsten lamp (275 watt). Heating and illumination were continuted for 80 minutes after the addition was complete. The mixture was then cooled and filtered. The solid residue was washed with carbon tetrachloride (100 ml.) and the combined filtrate and washings were evaporated to give 4-acetoxybenzyl bromide as a syrupy solid, which was dissolved, without further purification, in ethanol (300 ml.). 1,2,3,6-Tetrahydropyridine (83.0 g.) was then added to the solution during 10 minutes. The subsequent mixture was left at 20°-25° C. for 16 hours, and then evaporated. Water (300 ml.) was added to the residue obtained and the subsequent mixture was acidified to pH2 with dilute hydrochloric acid, and then extracted with ether (2×100 ml.) and the extracts discarded. The aqueous phase was basified to pH9 (sodium hydroxide solution) and extracted with ether (3×100 ml.). The extracts were washed with water (2×50 ml.), dried (MgSO4) and evaporated. The residue was dissolved in acetone (200 ml.), the solution obtained was filtered, and the filtrate acidified to pH2 with ethereal hydrogen chloride. There was thus obtained 1-(4-hydroxybenzyl)-1,2,3,6-tetrahydropyridine hydrochloride which was recrystallised from methanol/ethyl acetate to give pure material (34.6 g.), m.p. 234°-236° C. heated under reflux illuminated by a high energy tungsten lamp (275 watt) Heating after the addition The mixture was then cooled filtered The solid residue was washed with carbon tetrachloride (100 ml.) the combined filtrate and washings were evaporated