2,2-difluoropropane-1,3-diol

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

Procedure: A mixture of 2,2-difluoropropane-1,3-diol (1 g, 8.9 mmol), benzyloxyacetaldehyde (1.34 g, 8.9 mmol), p-toluenesulfonic acid monohydrate (154 mg, 0.81 mmol) and toluene (20 ml) was heated under reflux by a condenser equipped with a Dean-Stark apparatus for one hour. The resultant mixture was stirred at room temperature overnight and then the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and silica gel was added thereto. The resultant mixture was concentrated to dryness and subjected to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=10/1) to obtain the title compound (930 mg, 42.8%). was heated under reflux by a condenser equipped with a Dean-Stark apparatus for one hour the reaction mixture was concentrated under reduced pressure The residue was dissolved in ethyl acetate silica gel was added The resultant mixture was concentrated to dryness subjected to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=10/1)

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

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

Procedure: To a solution of 5 g (44.6 mmol) 2,2-difluoropropane-1,3-diol (prepared as described in J. Med. Chem. 1994, 37, 1857-1864) in DCM (50 mL) was added triethylamine (18.6 mL, 133.83 mmol) and methane sulphonyl chloride (6.9 mL, 89.22 mmol) at 0° C. and stirred for 1 h at 0° C. Thereafter the reaction mixture was quenched with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 2,2-difluoropropane-1,3-diyl dimethanesulfonate (9 g, 84%) which was used immediately in the next step. Thereafter the reaction mixture was quenched with water extracted with DCM The organic layer was dried over anhydrous sodium sulphate concentrated

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

Procedure: To a solution of 5 g (44.6 mmol) 2,2-difluoropropane-1,3-diol (prepared as described in J. Med. Chem. 1994, 37, 1857-1864) in DCM (50 mL) was added triethylamine (18.6 mL, 133.83 mmol) and methane sulphonyl chloride (6.9 mL, 89.22 mmol) at 0° C. and stirred for 1 h at 0° C. Thereafter the reaction mixture was quenched with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 2,2-difluoropropane-1,3-diyl dimethanesulfonate (9 g, 84%) which was used immediately in the next step. Thereafter the reaction mixture was quenched with water extracted with DCM The organic layer was dried over anhydrous sodium sulphate concentrated

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

Procedure: A mixture of 2,2-difluoropropane-1,3-diol (1 g, 8.9 mmol), benzyloxyacetaldehyde (1.34 g, 8.9 mmol), p-toluenesulfonic acid monohydrate (154 mg, 0.81 mmol) and toluene (20 ml) was heated under reflux by a condenser equipped with a Dean-Stark apparatus for one hour. The resultant mixture was stirred at room temperature overnight and then the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and silica gel was added thereto. The resultant mixture was concentrated to dryness and subjected to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=10/1) to obtain the title compound (930 mg, 42.8%). was heated under reflux by a condenser equipped with a Dean-Stark apparatus for one hour the reaction mixture was concentrated under reduced pressure The residue was dissolved in ethyl acetate silica gel was added The resultant mixture was concentrated to dryness subjected to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=10/1)

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

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

Procedure: A mixture of 2,2-difluoropropane-1,3-diol (1 g, 8.9 mmol), benzyloxyacetaldehyde (1.34 g, 8.9 mmol), p-toluenesulfonic acid monohydrate (154 mg, 0.81 mmol) and toluene (20 ml) was heated under reflux by a condenser equipped with a Dean-Stark apparatus for one hour. The resultant mixture was stirred at room temperature overnight and then the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and silica gel was added thereto. The resultant mixture was concentrated to dryness and subjected to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=10/1) to obtain the title compound (930 mg, 42.8%). was heated under reflux by a condenser equipped with a Dean-Stark apparatus for one hour the reaction mixture was concentrated under reduced pressure The residue was dissolved in ethyl acetate silica gel was added The resultant mixture was concentrated to dryness subjected to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=10/1)

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

Procedure: A suspension of 2,2-difluoropropane-1,3-diol (Compound 59I, 6.0 g, 53.5 mmol), 4-fluorophenylboronic acid (1.5 g, 10.7 mmol) and K2CO3 (11.0 g, 80.3 mmol) in DMF (50 mL) was treated with benzyl bromide (8.9 mL, 74.9 mmol). The reaction mixture was stirred at RT for 72 h, diluted with ethyl acetate (200 mL) and washed with water (5×100 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give yellow oil which was purified by column chromatography (SiO2, 20% ethyl acetate/hexanes) to give 5 g (50%) of the desired product as an oil. 1H NMR (500 MHz, CDCl3) δ 7.38-7.34 (m, 5H), 4.70 (s, 2H), 3.89-3.88 (m, 2H), 3.77 (t, J=12.6 Hz, 2H). washed with water (5×100 mL) The organic layer was dried over Na2SO4 filtered concentrated to give yellow oil which was purified by column chromatography (SiO2, 20% ethyl acetate/hexanes)

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

Procedure: 3,3-Difluoro-3,4-dihydro-2H-thieno[3,4-b][1,4]-dioxepine-6,8-dicarboxylic acid diethyl ester was synthesized by adding dropwise 3.4 mL (17.2 mmol) of azodicarboxylic acid diisopropyl ester (ADC) to a mixture of 1.77 g (6.67 mmol) of 3,4-dihydroxythiophen-2,5-dicarboxylic acid diethyl ester, 748 mg of 2,2-difluoro-1,3-propanediol and 4.3 mL of tributylphosphine in 12 mL of absolute tetrahydrofuran under argon at 20° C. with ice-cooling. After completion of the addition of ADC the resulting mixture was allowed to stand at room temperature for 4 days. The tetrahydrofuran was then distilled off and the residue heated for 12.5 hours at 100° C. after which it was dissolved in ethyl acetate. The ethyl acetate solution was washed three times with saturated sodium bicarbonate solution, then with deionized water, dried with anhydrous magnesium sulphate, concentrated and the residue chromatographically purified on a kieselgel 60 column with heptane/ethyl acetate as eluant. 335 mg (corresponding to a yield of 15%) of the desired product was obtained with a melting point of 121–122° C., as characterized by: 3,3-Difluoro-3,4-dihydro-2H-thieno[3,4-b][1,4]-dioxepine-6,8-dicarboxylic acid diethyl ester was synthesized cooling The tetrahydrofuran was then distilled off was dissolved in ethyl acetate The ethyl acetate solution was washed three times with saturated sodium bicarbonate solution with deionized water, dried with anhydrous magnesium sulphate concentrated the residue chromatographically purified on a kieselgel 60 column with heptane/ethyl acetate as eluant

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

Procedure: To a solution of 2,2-difluoropropane-1,3-diol (2.5 g, 22.3 mmol) in CH2Cl2 (100 mL) is added triethylamine (14.3 mL, 111.5 mmol) followed by 4-methyl-benzenesulfonyl chloride (12.8 g, 66.9 mmol). The reaction mixture is stirred for 16 h at room temperature. Water (35 mL) is added and the organic layer is separated and washed with more water (2×35 mL). The organic layer is concentrated and the crude compound is purified by flash column chromatography using EtOAc in heptane to afford the title compound (6.7 g, 71%). the organic layer is separated washed with more water (2×35 mL) The organic layer is concentrated the crude compound is purified by flash column chromatography

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

Procedure: A mixture of 2,2-difluoropropane-1,3-diol (1 g, 8.9 mmol), benzyloxyacetaldehyde (1.34 g, 8.9 mmol), p-toluenesulfonic acid monohydrate (154 mg, 0.81 mmol) and toluene (20 ml) was heated under reflux by a condenser equipped with a Dean-Stark apparatus for one hour. The resultant mixture was stirred at room temperature overnight and then the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and silica gel was added thereto. The resultant mixture was concentrated to dryness and subjected to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=10/1) to obtain the title compound (930 mg, 42.8%). was heated under reflux by a condenser equipped with a Dean-Stark apparatus for one hour the reaction mixture was concentrated under reduced pressure The residue was dissolved in ethyl acetate silica gel was added The resultant mixture was concentrated to dryness subjected to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=10/1)

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

Procedure: To a solution of 5 g (44.6 mmol) 2,2-difluoropropane-1,3-diol (prepared as described in J. Med. Chem. 1994, 37, 1857-1864) in DCM (50 mL) was added triethylamine (18.6 mL, 133.83 mmol) and methane sulphonyl chloride (6.9 mL, 89.22 mmol) at 0° C. and stirred for 1 h at 0° C. Thereafter the reaction mixture was quenched with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 2,2-difluoropropane-1,3-diyl dimethanesulfonate (9 g, 84%) which was used immediately in the next step. Thereafter the reaction mixture was quenched with water extracted with DCM The organic layer was dried over anhydrous sodium sulphate concentrated