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Method for preparing (2S, 3R)-2-benzyloxy-3-pentanol as intermediate of posaconazole

A technology of posaconazole and benzyloxy, which is applied in the field of preparation of the intermediate-2-benzyloxy-3-pentanol, which can solve the unfavorable production cost of posaconazole raw materials and the difficulty of chiral inducers low cost, low impurity, and low cost of raw materials

Inactive Publication Date: 2014-07-23
JINAN KANGHE MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Both of the above approaches can achieve highly selective asymmetric addition of Grignard reagents to ketones, but they also have significant disadvantages
The chiral inducer required by the first route is not easy to obtain, so the price is quite expensive, and its source has become the biggest defect; the second route requires the metal compound and the Grignard reagent to react with the Grignard reagent. Swap, quite cumbersome to operate, difficult to control, and poor atom economy
[0011] Posaconazole is a drug with a large specification, and the cost of its raw material accounts for the proportion of the entire production cost, and the high price of intermediates is bound to be detrimental to the production cost of posaconazole raw material. Therefore, it is necessary to choose a An asymmetric addition method that can be implemented to reduce the cost of the product and increase its economic value

Method used

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  • Method for preparing (2S, 3R)-2-benzyloxy-3-pentanol as intermediate of posaconazole
  • Method for preparing (2S, 3R)-2-benzyloxy-3-pentanol as intermediate of posaconazole
  • Method for preparing (2S, 3R)-2-benzyloxy-3-pentanol as intermediate of posaconazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1: Preparation of (2S)-2-benzyloxy-3-pentanone

[0033]

[0034] Add 8g (0.2mol) of sodium hydroxide powder and 118ml of toluene to the reaction flask, add 1.5g of tetrabutylammonium iodide under stirring, then add 11.8g (0.1mol) of S-ethyl lactate dropwise under temperature control below 10°C, dropwise After finishing, continue to insulate and stir for 20 min. 12.6 g (0.1 mol) of benzyl chloride was added dropwise at a temperature controlled below 10°C. After the drop was completed, the reaction was stirred at a temperature of 0°C to 10°C for about 30 hours. Filtrate, distill the filtrate to remove the solvent under reduced pressure, and add the residue dropwise to a tetrahydrofuran solution of ethylmagnesium bromide (1M, 110ml) prepared in advance and cooled to below -10°C to keep the temperature at -10°C to -5°C, about After 0.5h dropwise addition, continue to maintain the temperature for 6 hours, stop the reaction, extract the reaction with saturated am...

Embodiment 2

[0035] Example 2: Preparation of (2S)-2-benzyloxy-3-pentanone

[0036]

[0037]Add 8g (0.2mol) of sodium hydroxide powder and 118ml of toluene to the reaction flask, add 1.5g of tetrabutylammonium bromide under stirring, then add 11.8g (0.1mol) of S-ethyl lactate dropwise under temperature control below 10°C, dropwise After finishing, continue to insulate and stir for 20 min. 11.3 g (0.09 mol) of benzyl chloride was added dropwise at a temperature controlled below 10°C. After the drop was complete, the reaction was stirred at a temperature of 0°C to 10°C for about 30 hours. Filtrate, distill the filtrate to remove the solvent under reduced pressure, and add the residue dropwise to a tetrahydrofuran solution of ethylmagnesium bromide (1M, 110ml) prepared in advance and cooled to below -10°C to keep the temperature at -10°C to -5°C, about After 0.5 h of dropwise addition, continue to maintain the temperature for 10 hours, stop the reaction, extract the reaction with satura...

Embodiment 3

[0038] Example 3: Preparation of (2S)-2-benzyloxy-3-pentanone

[0039]

[0040] Add 3.6 g (0.15 mol) of sodium hydride, 50 ml of tetrahydrofuran, and 25 ml of DMF into the reaction flask, add 11.8 g (0.1 mol) of S-ethyl lactate dropwise under stirring in an ice bath, and continue to insulate and stir for 30 min. 12.6 g (0.1 mol) of benzyl chloride was added dropwise at a temperature controlled below 10°C. After the drop was complete, the reaction was stirred at a temperature of 0°C to 10°C for about 20 hours. Filtrate, distill the filtrate to remove the solvent under reduced pressure, and add the residue dropwise to a tetrahydrofuran solution of ethylmagnesium bromide (1M, 110ml) prepared in advance and cooled to below -10°C to keep the temperature at -10°C to -5°C, about After 0.5h dropwise addition, continue to maintain the temperature for 6 hours, stop the reaction, extract the reaction with saturated ammonium chloride, extract with ethyl acetate, wash the organic phas...

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PUM

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Abstract

The invention relates to a method for preparing (2S, 3R)-2-benzyloxy-3-pentanol as an intermediate of posaconazole, The method comprises the following steps of directly protecting hydroxyl group of S-ethyl lactate with the benzyl chloride, carrying out a Grignard reaction to obtain (2S)-2-benzyloxy-3-pentanone and directly carrying out a chiral reduction with BH3 to obtain (2S, 3R)-2-benzyloxy-3-pentanol in the presence of a chiral catalyst, wherein the S-ethyl lactate, which is wide in source and low in cost, is used as a starting material. The method disclosed by the invention has the advantages of reduction in reaction steps, improved yield, effectively saved cost, low cost of raw materials, environmental protection, less pollution, wide source of S-ethyl lactate as the starting material, low price, relatively mild reaction conditions, high yield and greatly reduced cost. The products prepared by the method has high optical selectivity, ee values greater than 99%, purity greater than 99% and less impurities and can be used directly without purification.

Description

Technical field [0001] The present invention is a chemical synthesis field, which involves a preparation method for the intermediate (2S, 3R) -2-cymbal alcohol for synthesis of Poposodazole. technical background [0002] Posaconazole (POSACONAZOLE, product name NOXAFIL, CAS registration number 171228-49-2, chemical name: 4- [4- [4- [(3r, 5r) -5- (2,4- (2,4-Disfluorophenyl) -5- (1,2,4-triazol-1-base methyl) oxygen hybrid ring-3-base] Phenoxyl] phenzide-1-base]-2- [(2S, 3S) -2-hydroxy-3-base] -1,2,4-triazol-3-ketone) is the third-generation antifungal medicine developed by SChering-Plough Pharmaceutical Co., Ltd., 2005, 2005In December, it was listed in Germany for the first time, listed in the UK in March 2006, and on September 18, 2006, the FDA was approved.Pohakangazole has a wide range of antibacterial spectra. For Candida, Milkcernite, Podmococcus, Sydophyll, bisophyteriophytis, sickle, and yeast.Non -white rosary strains, including fluoropatomazole, new type of crushing bacte...

Claims

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Application Information

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IPC IPC(8): C07C43/178C07C41/26
CPCC07C41/26C07C45/54C07C67/31C07C43/1782C07C49/255C07C69/734
Inventor 张颖刘元鑫刘鹏孙丽梦李洪爽孙健王学斌曲延伟朱玉正杨延昆
Owner JINAN KANGHE MEDICAL TECH
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