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Method for preparing (R)-3,5-bis(trifluoromethyl)benzene-ethanol

A technology of trifluoromethyl and phenethyl alcohol is applied in the field of preparing chiral pharmaceutical intermediates by asymmetric catalytic hydrogenation, and can solve the problems of high production cost, large amount of coenzyme added, low initial concentration and the like

Active Publication Date: 2013-08-07
GUANGXI XINJING TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Grasa et al. (Journal of Organometallic Chemistry, 2006, 691: 2332-2334.) at room temperature and under the action of [(diphosphine) ruthenium dichloride (diamine compound)] novel catalyst, using isopropanol as a solvent, to obtain (R)-3,5-bis(trifluoromethyl)phenylethanol Gelo-Puiic et al. (Tetra-hedronAsymmetry, 2006,17:2000-2005.) with a conversion rate of 95% adopt Lactobacillus kefir (Lactobacillus kefir ) and Aspergillus niger, reducing 3,5-bis(trifluoromethyl)acetophenone to obtain (R)-3,5-bis(trifluoromethyl)phenylethanol product with ee value as high as 99% , the biggest disadvantage of this method is that a large amount of coenzyme needs to be added, and the initial concentration of the reactant is too low, which seriously affects industrial production
[0007] Among these methods reported in the literature, both chemical synthesis and biosynthesis use 3,5-bis(trifluoromethyl)acetophenone as a raw material, and the separation of chemical catalysts is difficult and expensive
However, the production efficiency of the biological method is relatively low, and the amount of coenzyme added is large
Industrial production costs are relatively high

Method used

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  • Method for preparing (R)-3,5-bis(trifluoromethyl)benzene-ethanol
  • Method for preparing (R)-3,5-bis(trifluoromethyl)benzene-ethanol

Examples

Experimental program
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Effect test

example 1

[0031] Complexation steps:

[0032] 0.0082g catalyst [RuCl 2 (C 10 h 14 ) 2 ] 2 and the chiral phosphine ligand (S,S)-C 6 P 2 (NH) 2 Put it into a (catalyst: ligand = 1:2) 100 mL round bottom flask, add 50 mL of tetrahydrofuran, and stir magnetically at 0° C. for 10 min to fully complex the catalyst and the ligand.

[0033] Reaction steps:

[0034] Add tetrahydrofuran 400mL (organic solvent: substrate = 20: 1) in 2500mL reactor, behind 20mL substrate 3,5-bis (trifluoromethyl) acetophenone and 0.82g KOH (base: catalyst = 100: 1) Put it into the reaction kettle, then add 50 mL of the above-mentioned complexed catalyst and ligand mixed solution, and replace the reaction kettle with hydrogen for 3 times to ensure that the reaction is carried out under anaerobic conditions. Turn on the stirring, set the stirring rate to 600r / min, and the hydrogen pressure to 2MPa. Afterwards, the temperature was raised to 100°C and kept at a constant temperature, and the reaction was carr...

example 2

[0039] Complexation steps:

[0040] 0.0082g catalyst Ir[(COD)Cl] 2 and the chiral ligand (S,S)-C 6 P 2 (NH) 2 (catalyst: ligand = 1: 1) was put into a 100mL round-bottomed flask, 50mL of toluene was added, and magnetically stirred at 10°C under normal pressure for 20min to fully dissolve and complex the catalyst and the ligand;

[0041] Reaction steps:

[0042] In 2500mL reactor, add toluene 2000mL (organic solvent: substrate=100: 1), behind 20mL substrate 3,5-bis(trifluoromethyl) acetophenone and 0.082g KOH (base: catalyst=10: 1) Put it into the reaction kettle, then add 50 mL of the above-mentioned complexed catalyst and ligand mixed solution, and replace the reaction kettle with hydrogen for 3 times to ensure that the reaction is carried out under anaerobic conditions. Stirring was started, the stirring rate was set to 600r / min, and the hydrogen pressure was 2.5MPa. Afterwards, the temperature was raised to 45°C and kept at a constant temperature, and the reaction was...

example 3

[0047] Complexation steps:

[0048] 0.0082g catalyst Ir[(COD)Cl] 2 Put the chiral ligand BINAP (catalyst: ligand = 1: 1.2) into a 100mL round bottom flask, add 50mL of absolute ethanol, and stir magnetically at 20°C for 30min to fully dissolve and complex the catalyst and the ligand;

[0049] Reaction steps:

[0050] In 2500mL reactor, add dehydrated alcohol 600mL (organic solvent: substrate=30: 1), behind 20mL substrate 3,5-bis(trifluoromethyl) acetophenone and 0.164gNaOH (base: catalyst=20 : 1) add in the reactor, then add 50mL of the catalyst and ligand mixed solution that the above-mentioned complexation is completed, replace 3 times with hydrogen in the reactor, to guarantee that the reaction is carried out under anaerobic conditions. Turn on the stirring, set the stirring rate to 600r / min, and the hydrogen pressure to 3MPa. Afterwards, the temperature was raised to 50°C and kept at a constant temperature, and the reaction was carried out for 6h.

[0051] Separation s...

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Abstract

The present invention provides a method for preparing (R)-3,5-bis(trifluoromethyl)benzene-ethanol by using 3,5-bis(trifluoromethyl)acetophenone as a raw material, through asymmetric-hydrogenation catalytic reduction. The method of the invention belongs to the technical field of asymmetric catalytic hydrogenation synthesis of chiral pharmaceutical intermediates. In the method, [RuCl2(C10H14)2]2 or Ir[(COD)Cl]2 is used as a catalyst, and BINAP or (S, S)-C6P2 (NH) 2 is used as a chiral phosphine ligand to form a complex catalyst, in an oxygen-free sealed high-pressure hydrogenation reaction system, the substrate 3,5-bis(trifluoromethyl)acetophenone is catalyzed to prepare (R)-3,5-bis(trifluoromethyl)benzene-ethanol.

Description

technical field [0001] The invention relates to a method for preparing a chiral pharmaceutical intermediate by asymmetric catalytic hydrogenation, specifically, (R)-3 is prepared by asymmetric hydrogenation catalytic reduction of 3,5-bis(trifluoromethyl)acetophenone as a raw material , the method of 5-bis(trifluoromethyl)phenethyl alcohol. Background technique [0002] Chiral hydroxy alcohols are an important class of pharmaceutical and chemical intermediates, widely used in pharmaceuticals, food, spices and pesticides and other fields. The chemical formula of (R)-3,5-bis(trifluoromethyl)phenethyl alcohol is C 9 h 8 f 6 O, English name: (R)-3,5-bis(trifluoromethyl)benzene-ethanol, its structural formula is as follows: [0003] [0004] Physical and chemical properties: CAS: 127852-28-2; Molecular weight: 258.16; Density: 1.376g / mL; Boiling point: 175.8°C; Flash point: 60.1°C. [0005] (R)-3,5-bis(trifluoromethyl)phenethyl alcohol is a key intermediate in the synthesi...

Claims

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Application Information

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IPC IPC(8): C07C33/46C07C29/143
Inventor 蒲国荣孙果宋韦志明黄科润黄平穆允玲袁芳爱周龙昌向忠权
Owner GUANGXI XINJING TECH
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