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Preparation method of anti-AIDs drug intermediates

A technology of anti-AIDS and intermediates, which is applied in the field of preparation of anti-AIDS drug intermediates, can solve the problems of high price, high price and infeasibility of reducing agents, and achieve simple product refining methods, high total yield and low price Effect

Active Publication Date: 2014-05-07
JIANGXI DONGBANG PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

US2002 / 0013499 A1, Chen, P. (Tetrahedron Lett. 1997,38, 3175) uses sodium borohydride reduction, the solvent is toluene and ethanol, under this condition (2S,3S)-1-chloro-2-hydroxy The yield of -3-tert-butoxyamido-4-phenylbutane (Ⅱ) is greater than 80%, and its isomers only account for a small proportion, which is unfavorable for (2R,3S)-chlorobutane (Ⅲ ) separation and purification; US5847144, EP0963972A2, WO2011 / 060302 A1 disclose the preparation method using aluminum isopropoxide as reducing agent and isopropanol as solvent, the isomer (2S, 3S)- The yield of 1-chloro-2-hydroxy-3-tert-butoxyamido-4-phenylbutane (Ⅱ) was 89-95%, while another isomer (2R,3S)-1- Chloro-2-hydroxy-3-tert-butoxyamido-4-phenylbutane (Ⅲ) only accounts for about 5%, so it is difficult to purify and obtain (2R,3S)-chloroalkane (Ⅲ), causing waste
[0006]US2002 / 0072621 A1 and EP1081133 A1 reported using lithium tri-tert-butoxy aluminum hydride as a reducing agent and diethyl ether as a reaction solvent, wherein the selection of isomers The property is (2S,3S)-1-chloro-2-hydroxyl-3-tert-butoxyamido-4-phenylbutane (Ⅱ): (2R,3S)-1-chloro-2-hydroxyl-3- tert-butoxyamido-4-phenylbutane (Ⅲ)=13:87, the yield is 92%. Although the selectivity of (2R,3S)-chloroalkane (Ⅲ) is large by this method, it is beneficial to Preparation of isomer (2R,3S)-chloroalkane (III), but no isolation of isomer (2S,3S)-1-chloro-2-hydroxy-3-tert-butoxyamido-4-phenyl Butane (II) is wasteful from economic considerations, and the reducing agent used is too expensive and the cost is too high to be suitable for industrial production; Takayuki Hamada also reported a method (J. Org. Chem. 2004, 69, 7391-7394), using chiral rhodium compound Rh(R,R)-Tsdpen as catalyst, HCOOH / N(C2H5)3 sub> is the solvent, then (2S,3S)-1-chloro-2-hydroxyl-3-tert-butoxyamido-4-phenylbutane (Ⅱ): (2R,3S)-1-chloro-2- Hydroxy-3-tert-butoxyamido-4-phenylbutane (Ⅲ)=10:90, the yield is 95%, but this catalyst is not easy to obtain, expensive, high production cost, and not suitable for industrial production; WO2006 / 016116 reported a series of reduction conditions, the best of which was Ru(S-Xyl-P-Phos)Cl2(dmf)2 as catalyst, D Alcohol is used as a solvent, and hydrogen gas of 10 atmospheres needs to be introduced, and the selectivity of (2S,3S)-1-chloro-2-hydroxyl-3-tert-butoxyamido-4-phenylbutane (Ⅱ): ( 2R,3S)-1-chloro-2-hydroxy-3-tert-butoxyamido-4-phenylbutane (Ⅲ)=4:94, the total yield is 98%, but this method can only be separated ( 2R,3S)-1-chloro-2-hydroxyl-3-tert-butoxyamido-4-phenylbutane (Ⅲ), and the generated (2S,3S)-1-chloro-2-hydroxyl-3- tert-butoxyamido-4-phenylbutane (Ⅱ) is difficult to separate and purify
At the same time, the price of the reducing agent is very high, and this method is not feasible from the perspective of industrial production
[0007] To sum up, if the common reduction method is adopted, the selectivity of the reaction is mainly biased towards (2S,3S)-1-chloro-2-hydroxyl -3-tert-butoxyamido-4-phenylbutane (II), its proportion is more than 90%, so for its isomer (III), due to its low content, it is necessary to purify and synthesize Utilization brings greater difficulty; and if rare metal chiral catalysts are used, although the selectivity can be turned to (2R,3S)-1-chloro-2-hydroxyl-3-tert-butoxyamido-4-phenylbutane (Ⅲ), but its isomer (Ⅱ) cannot be separated and purified, and its production cost is too high, which is not conducive to industrial production
None of the above methods can simultaneously separate two optical isomers in the same reduction reaction, which causes great waste in production

Method used

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  • Preparation method of anti-AIDs drug intermediates

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Experimental program
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Embodiment １

[0026] Add 400 ml of isopropanol to a 1000 ml reaction bottle, then add 50 g of ketone (I) and 5 g of calcium chloride, control the temperature between 20 and 60 °C, and slowly add 10 g of sodium borohydride; after the addition is complete , and then continue to stir and react for 4 hours. After the reaction is completed, lower the temperature to 0-5°C and keep it warm for 1-5 hours, and filter with suction to obtain 45 g of white solid wet material (crude product) and methanol mother liquor 1. the

[0027] Add 400 ml of isopropanol to a 1000ml reaction bottle, then add 45 g of the above-mentioned white solid wet material, heat up to about 70°C, after dissolving, keep warm for 30 minutes, slowly cool down to -10~30°C, keep warm for 5 hours, pump Filter and dry to obtain the first batch of (2S,3S)-1-chloro-2-hydroxy-3-tert-butoxyamido-4-phenylbutane (II) 28.5 g pure product and mother liquor 2. the

[0028] The above mother liquor 1 and mother liquor 2 were combined and disti...

Embodiment 2

[0031] Add 400 ml of anhydrous methanol to a 1000 ml reaction bottle, then add 50 g of ketone (I) and 5 g of calcium chloride, control the temperature between 20 and 60 °C, and slowly add 10 g of sodium borohydride; after the addition is complete , and then continue to stir and react for 5-10 hours. After the reaction is completed, lower the temperature to 0-5° C. and keep the temperature for 1-5 hours, and suction filter to obtain 50 g of white solid wet material and methanol mother liquor 1. The refining method was the same as in Example 1, and about 33.0 g of (2S,3S)-1-chloro-2-hydroxyl-3-tert-butoxyamido-4-phenylbutane (II) was obtained, with a yield of 65.5%, HPLC purity About 99.7%, about 14.0 g of (2R,3S)-1-chloro-2-hydroxy-3-tert-butoxyamido-4-phenylbutane (Ⅲ) was obtained, the yield was 27.8%, and the HPLC purity was about 99.5%, the total yield is 93.3%.

Embodiment 3

[0033] Add 400 ml of anhydrous methanol to a 1000 ml reaction bottle, then add 50 g of ketone (I) and 5 g of zinc chloride, control the temperature at about 20-60 °C, and slowly add 10 g of sodium borohydride; after the addition is complete, Continue to stir and react for 8 hours. After the reaction is completed, lower the temperature to 0-5° C. and keep the temperature for 5 hours, and filter with suction to obtain 49 g of white solid wet material and methanol mother liquor 1. The refining method was the same as in Example 1, and 35.0 g of (2S,3S)-1-chloro-2-hydroxy-3-tert-butoxyamido-4-phenylbutane (II) was obtained, the yield was 69.5%, and the purity was detected by HPLC. About 99.5%, about 11.5g of (2R,3S)-1-chloro-2-hydroxy-3-tert-butoxyamido-4-phenylbutane (Ⅲ) was obtained, the yield was 22.8%, and the HPLC purity was about It was 99.5%, and the total yield was 92.3%.

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Abstract

The invention discloses a preparation method of anti-AIDs drug intermediates, particularly relates to the synthesis of compounds (2S, 3S)-1-chloro-2-hydroxy-3-tert-butyl-O-amido-4-phenyl butane and (2R, 3S)-1- chloro-2-hydroxy-3- tert-butyl-O-amido-4-phenyl butane and a separation and purification method of the two compounds. The separation and purification method specifically comprises the following steps: adding a reducing agent, an additive and a solvent into (3S)-1-chloro-3-tert-butyl-O-amido-4-phenyl-2-butanone serving as a raw material and carrying out reduction reaction for 1-20h at 0-65 DEG C to obtain the anti-AIDs drug intermediates, wherein the addition of the reducing agent is 5%-40% of the weight of the raw material and the addition of the additive is 10%-40% of the weight of the raw material; and carrying out separation and purification by crystallizing and re crystallizing to obtain the two compounds, wherein the optical purity of each of the two compounds is higher than 99.5%, meeting the requirement of medicinal intermediates.

Description

technical field [0001] The invention belongs to the technical field of drugs for treating AIDS among drugs for treating major infectious diseases, and relates to a method for preparing an intermediate of an anti-AIDS drug, in particular to the compound (2S, 3S)-1-chloro-2-hydroxy-3-tert-butyl Preparation method of oxyamido-4-phenylbutane and (2R,3S)-1-chloro-2-hydroxyl-3-tert-butoxyamido-4-phenylbutane. Background technique [0002] AIDS is a clinical syndrome in which human immunodeficiency virus (HIV) infection leads to deficiencies in human defense functions (especially cell-mediated immune dysfunction), and is prone to opportunistic infections and tumors. HIV protease has become an important target for the treatment of AIDS Target. Currently, a variety of protease inhibitors are already on the market. In December 1995, the US FDA approved the first HIV protease inhibitor Saquinavir (Saquinavir) for the treatment of AIDS. In June 2003, the US FDA approved another new dr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C271/16C07C269/06
Inventor 吕恒佳李雪峰刘苏友周宏勤蒋达元朱中华汪家永
Owner JIANGXI DONGBANG PHARMA