3-bromo-3,3-difluoroprop-1-ene

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

Procedure: The title compound was prepared as a pale yellow oil in 70.4% yeild in a similar procedure to that described in Referential Example 9 by using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 3-bromo-3,3-difluoro-1-propene.

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

Procedure: A heterogenous solution of acid-washed zinc powder (4.74 g, 72,5 mmol), 3-pentanone (3.84 ml, 36.4 mmol), and dry THF (25 ml) was cooled to 0° C. in an ice-water bath, and a mixture of 3-bromo-3,3-difluoropropene (6.00 g, 38.2 mmol) in dry THF (10 ml) was slowly added. The reaction mixture was allowed to stand at room temperature overnight. Then, aqueous hydrochloric acid (5%, 30 ml) was added to the reaction mixture, which was stirred for 5 minutes. Excess zinc was removed by filtration and washed with ether. The organic phase was washed with saturated sodium bicarbonate solution, water (twice), dried over MgSO4 and concentrated. This oil was dissolved in dichloromethane (50 ml), and triethylamine (7.05 ml, 50.8 mmol) and 4-(N,N-dimethylamino)-pyridine (250 mg) are added. The reaction mixture was cooled to 0° C. and trimethylsilyl chloride (6.42 ml, 50.8 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted twice with ether. The combined organic layers were washed several times with water, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography (50 g silica gel; 2% EtOAc in petroleum ether as eluant) to give the compound as a colourless oil, δ 0.13 (s, 9H), 0.89 (m, 6H), 1.5-1.8 (m, 4H), 5.43 (m, 1H), 5.63 (m, 1H), 5.92-6.13 (m, 1H). was slowly added Excess zinc was removed by filtration washed with ether The organic phase was washed with saturated sodium bicarbonate solution, water (twice), dried over MgSO4 concentrated This oil was dissolved in dichloromethane (50 ml) the mixture was stirred at room temperature overnight extracted twice with ether The combined organic layers were washed several times with water dried over MgSO4 evaporated in vacuo The residue was purified by chromatography (50 g silica gel; 2% EtOAc in petroleum ether as eluant)

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

Procedure: To a solution of 5.0 g 4-Methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazole-5-carbaldehyde (derived from [4-Methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-methanol according to the method described for 4-Methyl-2-(trans-1,4-trifluoromethyl-cyclohexyl)-thiazole-5-carbaldehyde) and 4.33 g 3-bromo-3,3-difluorpropene in 25 ml dimethylformamide. 2.11 g Indium were added and the resulting suspension was stirred in an ultrasonic bath for three hours. Then 20 ml 1N HCL were added and the mixture stirred at room temperature for thirty minutes. The mixture was extracted three times with portions of 50 ml ethyl acetate. The combined organic layers were dried over MgSO4. The solvent was evaporated in vacuo. The resulting residue was purified by reversed phase HPLC to obtain 4.67 g 2,2-Difluoro-1-[4-methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-but-3-en-1-ol as a colorless lyophilisate. Then 20 ml 1N HCL were added the mixture stirred at room temperature for thirty minutes The mixture was extracted three times with portions of 50 ml ethyl acetate The combined organic layers were dried over MgSO4 The solvent was evaporated in vacuo The resulting residue was purified by reversed phase HPLC

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

Procedure: To a solution of 5.0 g 4-Methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazole-5-carbaldehyde (derived from [4-Methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-methanol according to the method described for 4-Methyl-2-(trans-1,4-trifluoromethyl-cyclohexyl)-thiazole-5-carbaldehyde) and 4.33 g 3-bromo-3,3-difluorpropene in 25 ml dimethylformamide. 2.11 g Indium were added and the resulting suspension was stirred in an ultrasonic bath for three hours. Then 20 ml 1N HCL were added and the mixture stirred at room temperature for thirty minutes. The mixture was extracted three times with portions of 50 ml ethyl acetate. The combined organic layers were dried over MgSO4. The solvent was evaporated in vacuo. The resulting residue was purified by reversed phase HPLC to obtain 4.67 g 2,2-Difluoro-1-[4-methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-but-3-en-1-ol as a colorless lyophilisate. Then 20 ml 1N HCL were added the mixture stirred at room temperature for thirty minutes The mixture was extracted three times with portions of 50 ml ethyl acetate The combined organic layers were dried over MgSO4 The solvent was evaporated in vacuo The resulting residue was purified by reversed phase HPLC

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

Procedure: To a solution of 5.0 g 4-Methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazole-5-carbaldehyde (derived from [4-Methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-methanol according to the method described for 4-Methyl-2-(trans-1,4-trifluoromethyl-cyclohexyl)-thiazole-5-carbaldehyde) and 4.33 g 3-bromo-3,3-difluorpropene in 25 ml dimethylformamide. 2.11 g Indium were added and the resulting suspension was stirred in an ultrasonic bath for three hours. Then 20 ml 1N HCL were added and the mixture stirred at room temperature for thirty minutes. The mixture was extracted three times with portions of 50 ml ethyl acetate. The combined organic layers were dried over MgSO4. The solvent was evaporated in vacuo. The resulting residue was purified by reversed phase HPLC to obtain 4.67 g 2,2-Difluoro-1-[4-methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-but-3-en-1-ol as a colorless lyophilisate. Then 20 ml 1N HCL were added the mixture stirred at room temperature for thirty minutes The mixture was extracted three times with portions of 50 ml ethyl acetate The combined organic layers were dried over MgSO4 The solvent was evaporated in vacuo The resulting residue was purified by reversed phase HPLC

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (30.0 g) in N,N-dimethylformamide (300 ml) were added potassium carbonate (36.2 g) and 3-bromo-3,3-difluoropropene (16 ml), and the mixture was stirred at 60° C. for 4.5 hours. To the reaction mixture was added water, and the mixture was extracted with n-hexane/ethyl acetate (1/1) solution. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1) to give the titled compound (33.5 g). the mixture was extracted with n-hexane/ethyl acetate (1/1) solution The organic layer was dried over anhydrous sodium sulfate concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of pyrrolidine-1,3-dicarboxylic acid-1-tert-butyl ester (3.40 g) in N,N-dimethylformamide (34 ml) were added potassium carbonate (4.37 g) and 3-bromo-3,3-difluoropropene (1.93 ml), and the mixture was stirred at 60° C. for 6 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1) to give the titled compound (3.73 g). the mixture was extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1)

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

Procedure: 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (0.511 g, 1.92 mmol), 3-bromo-3,3-difluoro-propene (0.4977 g, 3.07 mmol), indium (0.357 g, 3.07 mmol) and sodium iodide (0.0142 g, 0.096 mmol) were combined in DMF (5 mL) and stirred at room temperature overnight. The reaction mixture was submitted to standard aqueous workup to afford the title compound, which was taken to the next step without further purification.

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

Procedure: 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (0.511 g, 1.92 mmol), 3-bromo-3,3-difluoro-propene (0.4977 g, 3.07 mmol), indium (0.357 g, 3.07 mmol) and sodium iodide (0.0142 g, 0.096 mmol) were combined in DMF (5 mL) and stirred at room temperature overnight. The reaction mixture was submitted to standard aqueous workup to afford the title compound, which was taken to the next step without further purification.

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

Procedure: To a solution of 1.0 g 4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbaldehyde and 868 mg 3-bromo-3,3-difluorpropene in 10 ml dimethylformamide 425 mg Indium were added and the resulting suspension was stirred in an ultrasonic bath for two hours. Then 20 ml 1 N hydrochloric acid were added and the mixture stirred at room temperature for thirty minutes. The mixture was extracted three times with portions of 50 ml ethyl acetate. The combined organic layers were dried over MgSO4. The solvent was evaporated in vacuo. The resulting residue was purified by reversed phase HPLC to obtain 740 mg 2,2-Difluoro-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-but-3-en-1-ol as a colorless lyophilisate. the mixture stirred at room temperature for thirty minutes The mixture was extracted three times with portions of 50 ml ethyl acetate The combined organic layers were dried over MgSO4 The solvent was evaporated in vacuo The resulting residue was purified by reversed phase HPLC

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

Procedure: The title compound was prepared as a pale yellow oil in 70.4% yeild in a similar procedure to that described in Referential Example 9 by using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 3-bromo-3,3-difluoro-1-propene.

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

Procedure: A heterogenous solution of acid-washed zinc powder (4.74 g, 72,5 mmol), 3-pentanone (3.84 ml, 36.4 mmol), and dry THF (25 ml) was cooled to 0° C. in an ice-water bath, and a mixture of 3-bromo-3,3-difluoropropene (6.00 g, 38.2 mmol) in dry THF (10 ml) was slowly added. The reaction mixture was allowed to stand at room temperature overnight. Then, aqueous hydrochloric acid (5%, 30 ml) was added to the reaction mixture, which was stirred for 5 minutes. Excess zinc was removed by filtration and washed with ether. The organic phase was washed with saturated sodium bicarbonate solution, water (twice), dried over MgSO4 and concentrated. This oil was dissolved in dichloromethane (50 ml), and triethylamine (7.05 ml, 50.8 mmol) and 4-(N,N-dimethylamino)-pyridine (250 mg) are added. The reaction mixture was cooled to 0° C. and trimethylsilyl chloride (6.42 ml, 50.8 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted twice with ether. The combined organic layers were washed several times with water, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography (50 g silica gel; 2% EtOAc in petroleum ether as eluant) to give the compound as a colourless oil, δ 0.13 (s, 9H), 0.89 (m, 6H), 1.5-1.8 (m, 4H), 5.43 (m, 1H), 5.63 (m, 1H), 5.92-6.13 (m, 1H). was slowly added Excess zinc was removed by filtration washed with ether The organic phase was washed with saturated sodium bicarbonate solution, water (twice), dried over MgSO4 concentrated This oil was dissolved in dichloromethane (50 ml) the mixture was stirred at room temperature overnight extracted twice with ether The combined organic layers were washed several times with water dried over MgSO4 evaporated in vacuo The residue was purified by chromatography (50 g silica gel; 2% EtOAc in petroleum ether as eluant)