Synthetic method of 2,2-bis (trifluoroethyl) propanol

Abstract

The invention relates to a synthetic method of 2,2-bis (trifluoroethyl) propanol and mainly solves the technical problem that the existing synthetic method is lack of industrialization prospect. The method includes subjecting dibenzyl ester malonate and trifluoroethyl triflate to a step-by-step reaction in the presence of an alkalization agent to obtain 2,2-bis (trifluoroethyl) dibenzyl ester malonate 2; reducing the composition 2 through lithium aluminum hydride to obtain 2,2-bis (trifluoroethyl)-1,3-propylene glycol; and using tosyl to protect one hydroxyl and then using sodium borohydride for reduction to obtain the 2,2-bis (trifluoroethyl) propanol. The 2,2-bis (trifluoroethyl) propanol can be prepared quickly and conveniently through the method.

Description

technical field

[0001] The invention relates to a method for synthesizing an important pharmaceutical intermediate 2,2-bistrifluoroethylpropanol. Background technique

[0002] 2,2-bistrifluoroethylpropanol is an important pharmaceutical intermediate, which can be widely used in the design of drug molecules; one of its hydroxyl groups can react with many other drug template molecules to synthesize various drugs with different requirements. drug molecule. The derivatives of 2,2-bistrifluoroethylpropanol have been reported in a small number of literatures, and the Journal of Medicinal Chemistry (J. Med. Chem. 2012, 55, 3827? 3836) reported that this type of compound has the ability to block the sugar transport of tumor cells The activity of the channel is a kind of promising anti-tumor prodrug. Therefore, 2,2-bistrifluoroethylpropanol has important research value. Contents of the invention

[0003] The object of the present invention is to provide a novel synthetic method ...

Examples

Embodiment 1

[0021] dibenzyl malonate 1 (40 g, 0.14 mol) was dissolved in 200 mL of anhydrous tetrahydrofuran, cooled to 0 ℃, and sodium hydride (8.5 g, 0.21 mol) was slowly added under nitrogen protection. Stir at 25°C for 30 minutes, then cool to 0°C, add trifluoroethyl trifluoromethanesulfonate (39.2 g, 0.17 mol), stir at 0°C for 10 minutes, stir at 15-25°C, adjust to 1N hydrochloric acid after 12 hours When the pH value reached 5, it was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated, and purified by column with petroleum ether / ethyl acetate at a volume ratio of 30:1 to obtain 2-trifluoroethane as a colorless oil dibenzyl malonate 2 (20 g, yield 39 %).

Embodiment 2

[0023] dibenzyl malonate 1 (40 g, 0.14 mol) was dissolved in 200 mL of anhydrous tetrahydrofuran, cooled to 0 ℃, and sodium hydride (8.5 g, 0.21 mol) was slowly added under nitrogen protection. Stir at 25°C for 30 minutes, then cool to 0°C, add trifluoroethyl trifluoromethanesulfonate (39.2 g, 0.17 mol), stir at 0°C for 10 minutes, reflux at 40-50°C, and cool to 0°C after 12 hours , adjusted the pH value to 5 with 1N hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated, and purified by column purification with petroleum ether / ethyl acetate at a volume ratio of 30:1 to obtain a colorless oily Dibenzyl 2-trifluoroethylmalonate 2 (25 g, yield 48%).

Embodiment 3

[0025] dibenzyl malonate 1 (40 g, 0.14 mol) was dissolved in 200 mL of anhydrous tetrahydrofuran, cooled to 0 ℃, and sodium hydride (8.5 g, 0.21 mol) was slowly added under nitrogen protection. Stir at 25°C for 30 minutes, then cool to 0°C, add trifluoroethyl trifluoromethanesulfonate (39.2 g, 0.17 mol), stir at 0°C for 10 minutes, reflux at 40-50°C, and cool to 0°C after 36 hours , adjusted the pH value to 5 with 1N hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated, and purified by column purification with petroleum ether / ethyl acetate at a volume ratio of 30:1 to obtain a colorless oily Dibenzyl 2-trifluoroethylmalonate 2 (40 g, yield 78%).

[0026] H NMR spectrum CDCl 3 400MHz,d 7.28-7.38 (10H, m, Ar-H), 5.12-5.22 (4H, Bn-H), 3.77-3.80 (1H, t, -CH-), 2.83-2.92 (2H, m, -CH 2 -CF 3 ).

[0027] 2,2-Dibenzyl trifluoroethyl malonate 3 synthesis

technical field

[0001] The invention relates to a method for synthesizing an important pharmaceutical intermediate 2,2-bistrifluoroethylpropanol. Background technique

[0002] 2,2-bistrifluoroethylpropanol is an important pharmaceutical intermediate, which can be widely used in the design of drug molecules; one of its hydroxyl groups can react with many other drug template molecules to synthesize various drugs with different requirements. drug molecule. The derivatives of 2,2-bistrifluoroethylpropanol have been reported in a small number of literatures, and the Journal of Medicinal Chemistry (J. Med. Chem. 2012, 55, 3827? 3836) reported that this type of compound has the ability to block the sugar transport of tumor cells The activity of the channel is a kind of promising anti-tumor prodrug. Therefore, 2,2-bistrifluoroethylpropanol has important research value. Contents of the invention

[0003] The object of the present invention is to provide a novel synthetic method ...

Examples

Embodiment 1

[0021] dibenzyl malonate 1 (40 g, 0.14 mol) was dissolved in 200 mL of anhydrous tetrahydrofuran, cooled to 0 ℃, and sodium hydride (8.5 g, 0.21 mol) was slowly added under nitrogen protection. Stir at 25°C for 30 minutes, then cool to 0°C, add trifluoroethyl trifluoromethanesulfonate (39.2 g, 0.17 mol), stir at 0°C for 10 minutes, stir at 15-25°C, adjust to 1N hydrochloric acid after 12 hours When the pH value reached 5, it was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated, and purified by column with petroleum ether / ethyl acetate at a volume ratio of 30:1 to obtain 2-trifluoroethane as a colorless oil dibenzyl malonate 2 (20 g, yield 39 %).

Embodiment 2

[0023] dibenzyl malonate 1 (40 g, 0.14 mol) was dissolved in 200 mL of anhydrous tetrahydrofuran, cooled to 0 ℃, and sodium hydride (8.5 g, 0.21 mol) was slowly added under nitrogen protection. Stir at 25°C for 30 minutes, then cool to 0°C, add trifluoroethyl trifluoromethanesulfonate (39.2 g, 0.17 mol), stir at 0°C for 10 minutes, reflux at 40-50°C, and cool to 0°C after 12 hours , adjusted the pH value to 5 with 1N hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated, and purified by column purification with petroleum ether / ethyl acetate at a volume ratio of 30:1 to obtain a colorless oily Dibenzyl 2-trifluoroethylmalonate 2 (25 g, yield 48%).

Embodiment 3

[0025] dibenzyl malonate 1 (40 g, 0.14 mol) was dissolved in 200 mL of anhydrous tetrahydrofuran, cooled to 0 ℃, and sodium hydride (8.5 g, 0.21 mol) was slowly added under nitrogen protection. Stir at 25°C for 30 minutes, then cool to 0°C, add trifluoroethyl trifluoromethanesulfonate (39.2 g, 0.17 mol), stir at 0°C for 10 minutes, reflux at 40-50°C, and cool to 0°C after 36 hours , adjusted the pH value to 5 with 1N hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated, and purified by column purification with petroleum ether / ethyl acetate at a volume ratio of 30:1 to obtain a colorless oily Dibenzyl 2-trifluoroethylmalonate 2 (40 g, yield 78%).

[0026] H NMR spectrum CDCl 3 400MHz,d 7.28-7.38 (10H, m, Ar-H), 5.12-5.22 (4H, Bn-H), 3.77-3.80 (1H, t, -CH-), 2.83-2.92 (2H, m, -CH 2 -CF 3 ).

[0027] 2,2-Dibenzyl trifluoroethyl malonate 3 synthesis

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