ethyl 3-hydroxybenzoate

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: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:

Conditions: temp:80.01; pressure:0.00; stir:

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 was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int c) and ethyl 3-hydroxybenzoate (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. White solid (32%). MS (Turbo Spray): m/z=539.2 [M+H].

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a solution of 3-hydroxy-benzoic acid ethyl ester (10.14 g, 0.061 mol) in CH2Cl2 (200 mL) cooled to −78° C. was condensed isobutylene (150 mL) followed by addition of triflic acid (1.08 mL, 0.061 mol). The reaction mixture was allowed to warm to −20° C. When a solution was obtained and tlc indicated loss of starting material, the reaction was quenched with Et3N (6.8 mL, 0.049 mol) and left to warm to ambient temperature. The solution was concentrated and the residue chromatographed on an ISCO combiflash eluting with 0-10% EtoAc/hexane to give 12.91 g (95%) of the title compound. When a solution was obtained left to warm to ambient temperature The solution was concentrated the residue chromatographed on an ISCO combiflash eluting with 0-10% EtoAc/hexane

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

Procedure: To a solution of ethyl-3-hydroxybenzoate (5.0 g, 30 mmol) in acetone (250 ml) at rt was added 1-bromo-3-chloro-propane (5.67 g, 36 mmol) and K2CO3 (12.4 g, 90 mmol). The resulting suspension was heated to reflux where it was maintained for 25 h. After this time, the mixture was concentrated under reduced pressure and the resulting solid was partitioned between H2O and EtOAc. The organic phase was separated and the aqueous phase was extracted with additional EtOAc. The combined organic fractions were washed with 1N HCl and brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide the crude product. Purification by chromatography on silica eluting with 5% EtOAc/hexane gave 3-(3-chloro-propoxy)-benzoic acid ethyl ester as a colourless oil (5.0 g, 68%). The resulting suspension was heated to reflux where it was maintained for 25 h After this time, the mixture was concentrated under reduced pressure the resulting solid was partitioned between H2O and EtOAc The organic phase was separated the aqueous phase was extracted with additional EtOAc The combined organic fractions were washed with 1N HCl and brine dried (Na2SO4) filtered concentrated under reduced pressure to provide the crude product Purification by chromatography on silica eluting with 5% EtOAc/hexane