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Chiral synthesis method of (R)-1-(3, 5-di (trifluoromethyl) phenyl] ethanol

A technology of trifluoromethyl and ethanol, applied in the field of chemistry, can solve the problems of high price of oxazolborane, low product yield, complicated operation and the like, and achieve the effects of low cost, high yield and simple operation

Active Publication Date: 2015-04-15
LUNAN PHARMA GROUP CORPORATION
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Problems solved by technology

[0003] Chinese invention patent application publication specification CN1436178A discloses (2R,2-α-R,3a)-2-[1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4 The synthetic method of -fluorophenyl)-1,4-oxazine, this technical scheme reports catalytic reduction of 3,5-bis(trifluoromethyl)acetophenone with coordination metal catalyst, operation is more loaded down with trivial details, the product obtained low yield
E.J.Corey et al reported the use of oxazole boron in "A stable and easily prepared catalyst for the enantioselective reduction of ketones. Alkanes are used as catalysts to catalyze the reduction of 3,5-bis(trifluoromethyl)acetophenone, but oxazoboridine is more expensive and more toxic

Method used

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  • Chiral synthesis method of (R)-1-(3, 5-di (trifluoromethyl) phenyl] ethanol
  • Chiral synthesis method of (R)-1-(3, 5-di (trifluoromethyl) phenyl] ethanol

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Embodiment 1

[0021] The chiral synthesis method of embodiment 1 (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol

[0022] a) Biocatalytic reduction of formula Ⅰ with baker's yeast

[0023] Put 20g of baker's yeast into the reaction bottle, add 700ml of pure water and 40g of sucrose, and stir vigorously at 33-36°C for 3 hours. Then 20 g of 3,5-bis(trifluoromethyl)acetophenone was added, and the reaction was continued to be vigorously stirred, and the end point of the reaction was monitored by TLC.

[0024] The aqueous solution was filtered with celite. The obtained yeast filter cake was washed with 100ml of methyl tert-butyl ether; after the aqueous layer was saturated with sodium chloride, the diatomaceous earth filter was used to remove the gelatinous liquid, and the filtrate was extracted with 140ml of methyl tert-butyl ether. The organic layers were combined and washed successively with 200 ml of pure water and 200 ml of saturated brine. Dry over anhydrous magnesium sulfate for 2 hours,...

Embodiment 2

[0031] Example 2.b) Inversion of the configuration of the by-product formula III obtained in step a)

[0032] 2.0g (7.75mmol) of (s)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol obtained in step a) of Example 1, namely the compound of formula III, 4.0g (15.5mmol) of triphenyl Dissolve phosphine and 1.16g (9.27mmol) of benzoic acid in 25ml of ether, cool down to about 0°C, under nitrogen protection, slowly add 2.48ml (15.5mmol) of diethyl azodicarboxylate, naturally warm to room temperature, Stirring was continued for 1 hour, and the reaction solution was concentrated under reduced pressure until no solvent flowed out. Then add 60ml of methanol to dissolve, then add 28ml (28mmol) of 1M potassium hydroxide aqueous solution and stir at room temperature for 1 hour, add dilute hydrochloric acid to adjust the pH to 7.5, concentrate under reduced pressure until no solvent flows out, the residue is dissolved in methanol, and the insoluble matter is removed by filtration. Add n-hexane to...

Embodiment 3

[0033] Example 3. The chiral synthesis method of (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol

[0034] Immobilized yeast cells, i.e. immobilization of baker's yeast:

[0035]Slowly add 20g of baker's yeast into 200ml of rapidly stirred pure water; then slowly add 10g of sodium alginate into 200ml of rapidly stirred pure water to make two solutions, when both solutions become homogeneous viscous liquid When they are combined, they are added dropwise to 660ml of calcium chloride aqueous solution (10% m / v) to form gelatinous pellets. The pellets were washed three times with 500 ml of pure water and immediately used for the reduction of Formula I.

[0036] a) Biocatalytic reduction of formula Ⅰ by immobilized baker's yeast

[0037] Put about 200g of the prepared pellets into a reaction flask, add 700ml of pure water and 40g of sucrose, and stir vigorously at 33-36°C for 3 hours. Then 20 g of 3,5-bis(trifluoromethyl)acetophenone was added, and the reaction was continued to be v...

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Abstract

The invention belongs to the technical field of chemistry, and in particular relates to a chiral synthesis method of (R)-1-(3, 5-di (trifluoromethyl) phenyl] ethanol, and the prepared compound is a key intermediate for the production of aprepitant. The technical scheme includes two reaction steps, namely a) biological catalytic reduction of formula I by use of bread yeast, and b) configuration reversion of byproduct formula III prepared by the step a) to obtain formula II, and the technical scheme can also include the preparation of immobilized yeast cells, namely bread yeast immobilization. The method is biological asymmetric reduction, has the advantages of low cost, simple operation, high yield, mild reaction conditions, great implementation value, and suitability for industrial production.

Description

technical field [0001] The invention belongs to the field of chemical technology, in particular to a chiral synthesis method of (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol, the prepared compound is used for producing aprepitant key intermediates. Background technique [0002] Aprepitant is the first approved clinical application of neurokinin-1 (NK-1) receptor antagonists. This product was developed by Merck (Merck) and was launched in the United States in March 2003 under the trade name of Emend. The approved indication is to be used in combination with other antiemetic drugs to prevent acute or delayed vomiting caused by cancer chemotherapy. Optically active (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol is a key intermediate for the preparation of aprepitant. [0003] Chinese invention patent application publication specification CN1436178A discloses (2R,2-α-R,3a)-2-[1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4 The synthetic method of -fluorophenyl)-1,4-oxazine, th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P7/22C07C33/46C07C29/00C12R1/865
CPCC07C29/00C12P7/22C07C33/46
Inventor 赵志全白文钦王友国冯晓亮
Owner LUNAN PHARMA GROUP CORPORATION
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