ethyl 3-cyclopropyl-2,2-difluoropropanoate

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:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of ethyl 3-cyclopropyl-2,2-difluoropropanoate (43.5 g, 0.244 mol), prepared as in Example 1, in absolute ethanol (100 mL) was added drop wise to a stirred slurry of sodium borohydride (9.45 g, 0.25 mol) in absolute ethanol (150 mL). The temperature of the mixture was allowed to rise to 35° C., whereupon cooling (ice/acetone bath) was applied and the temperature was maintained at 5° C. by controlling the rate of addition of the ester over 2 hours. The mixture then was stirred in an ice bath for 3 hours and then for 17 hours at room temperature. The reaction was quenched at 0° C. with 2M hydrochloric acid (180 mL) and the mixture was stirred for 30 minutes. The resulting homogenous mixture was poured into water (1000 mL) and extracted with diethyl ether (4×300 mL). The combined extracts were washed with 2M hydrochloric acid, water, 10% aqueous sodium bicarbonate and brine, dried over magnesium sulfate and filtered. The solvent was removed from the filtrate under reduced pressure. Distillation of the residue under reduced pressure gave 3-cyclopropyl-2,2-difluoro-1-propanol (28.3 g, 85% over 2 steps), as a colorless oil, b.p. 48-50° C./5 mbar. 1H-NMR (400 MHz, CDCl3): δ=6:15-0.23 (m, 2H), 0.49-0.60 (m, 2H), 0.77-0.90 (m, 1H), 1.77 (bs, 1H), 1.80-1.90 (m, 2H), 3.83 (t, J=14 Hz, 2H); 1H-NMR (400 MHz, CD3SOCD3): δ=0.08-0.28 (m, 2H), 0.39-0.55 (m, 2H), 0.70-0.86 (m, 1H), 1.70-1.87 (m, 2H), 3.53-3.73 (m, 2H), 5.36 (t, J=4 Hz, 1H). to rise to 35° C. for 17 hours at room temperature The reaction was quenched at 0° C. with 2M hydrochloric acid (180 mL) the mixture was stirred for 30 minutes The resulting homogenous mixture was poured into water (1000 mL) extracted with diethyl ether (4×300 mL) The combined extracts were washed with 2M hydrochloric acid, water, 10% aqueous sodium bicarbonate and brine dried over magnesium sulfate filtered The solvent was removed from the filtrate under reduced pressure Distillation of the residue under reduced pressure

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Zinc-copper (Zn—Cu) couple (1.6 Kg, 800 mol %) and dichloromethane (7.5 L) was charged into a dry 20.0 L, 4-neck round bottomed flask, fitted with an over head stirrer, a thermo socket and a condenser under a nitrogen atmosphere. Trifluoroacetic acid (235 mL, 100 mol %) was added to the above Zn—Cu couple at ambient temperature via addition funnel over 30 minutes. Diiodomethane (860 mL; 2.86 Kg; 10.7 mol; 352 mol %) was added to above the Zn—Cu couple at ambient temperature via addition funnel over 1.5 hours. The reaction temperature was raised to reflux and then ethyl 2,2-difluoropent-4-enoate (500 g; 3.05 mol) in dichloromethane (500 mL) was added slowly via addition funnel over 30 minutes at reflux. The reaction temperature was maintained for 40-60 hours at reflux. Progress of the reaction was monitored by GC analysis which showed about 93% conversion to product based on relative area % of the peaks corresponding to product and starting material. The reaction mass was cooled to 0-5° C. and 5% dilute hydrochloric acid (500 mL) was added then the solution was filtered and washed with dichloromethane (1500 mL). The filtrate was washed with a solution of 5% aqueous hydrochloric acid (500 mL), water (1000 mL) followed by a solution of brine (1000 mL). The organic layer was concentrated under vacuum at 35° C./260-360 mm Hg to provide crude ethyl 3-cyclopropyl-2,2-difluoropropanoate (740 g), which was 79% pure by GC analysis. The crude product was then subjected to an oxidative work-up as described below to remove residual starting material (5% by area as determined by GC analysis). fitted with an over head stirrer The reaction temperature was raised to reflux at reflux The reaction temperature was maintained for 40-60 hours at reflux the solution was filtered washed with dichloromethane (1500 mL) The filtrate was washed with a solution of 5% aqueous hydrochloric acid (500 mL), water (1000 mL) The organic layer was concentrated under vacuum at 35° C./260-360 mm Hg

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of diethyl zinc (500 mL, 1.0 M in hexanes) in methylene chloride (700 mL) was chilled to −10° C. under nitrogen in a cooling bath. A solution of trifluoroacetic acid (57 g, 0.5 mol) in methylene chloride (50 mL) was added dropwise over 1 hour 45 minutes. The mixture was stirred for 30 minutes at −5° C. A solution of diiodomethane (133.9 g, 0.5 mol) in methylene chloride (50 mL) was added to the mixture over a period of 20 minutes. The mixture became homogenous upon stirring for 30 minutes at 0° C. A solution of ethyl 2,2-difluoropent-4-enoate (40 g, 0.244 mol) in methylene chloride (50 mL) was added dropwise over a period of 25 minutes and the cooling bath was removed. The mixture was stirred for 1 hour at room temperature and then for 15 hours at reflux. The reaction was quenched by addition of saturated aqueous ammonium chloride (500 mL) and stirring for 30 minutes. The biphasic mixture was poured into 500 mL of saturated aqueous ammonium chloride and the organic layer was separated. The aqueous layer was extracted with methylene chloride (3×300 mL) and the combined organic extracts were dried over magnesium sulfate and filtered. The solvent was removed from the filtrate under reduced pressure to afford ethyl 3-cyclopropyl-2,2-difluoropropanoate (43.5 g, quant), as light yellow oil, which was used in the Example 4 without further purification. 1H-NMR (400 MHz, CDCl3): δ=0.12-0.22 (m, 2H), 0.49-0.59 (m, 2H), 0.75-0.91 (m, 1H), 1.37 (t, J=8 Hz, 3H), 1.95-2.05 (m, 2H), 4.34 (q, J=8 Hz, 2H). upon stirring for 30 minutes at 0° C the cooling bath was removed The mixture was stirred for 1 hour at room temperature for 15 hours at reflux The reaction was quenched by addition of saturated aqueous ammonium chloride (500 mL) stirring for 30 minutes The biphasic mixture was poured into 500 mL of saturated aqueous ammonium chloride the organic layer was separated The aqueous layer was extracted with methylene chloride (3×300 mL) the combined organic extracts were dried over magnesium sulfate filtered The solvent was removed from the filtrate under reduced pressure

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

Procedure: A fifth aspect of this invention is a process for the preparation of ethyl 3-cyclopropyl-2,2-difluoropropanoate, which process comprises: (a) reacting bromomethylcyclopropane with 2-carboethoxy-1,3-dithiane in the presence of strong base to give ethyl 2-(cyclopropylmethyl)-1,3-dithiane-2-carboxylate; (b) reacting the ethyl 2-(cyclopropylmethyl)-1,3-dithiane-2-carboxylate with N-bromosuccinimide to give ethyl 3-cyclopropyl-2-oxopropanoate; and (c) reacting the ethyl 3-cyclopropyl-2-oxopropanoate with a fluorinating agent.

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

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