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A kind of method for preparing anti-AIDS medicine amprenavir intermediate

An anti-AIDS and intermediate technology, which is used in the preparation of -1,2-epoxy-3-tert-butoxyamido-4-phenylbutane, and the field of anti-AIDS drug amprenavir intermediates, which can Solve the problems of not large-scale industrial production, low erythro configuration selectivity, low reaction temperature, etc., to achieve the effects of low cost, easy industrial production, and simple reaction

Active Publication Date: 2018-05-22
SHANGHAI INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0016] The above two methods are similar, but the more expensive reagents dihalomethane and LiAlH are used in the reaction 4 , where LiAlH 4 Operating process than NaBH 4 There are many dangers, and the reaction temperature is very low, and there is also the problem of low selectivity of the erythro configuration in the reduction reaction step, which is not an ideal condition for large-scale industrial production

Method used

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  • A kind of method for preparing anti-AIDS medicine amprenavir intermediate
  • A kind of method for preparing anti-AIDS medicine amprenavir intermediate
  • A kind of method for preparing anti-AIDS medicine amprenavir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Step 1 (S)-2-(tert-butoxyamido)-3-phenyl-propionic acid tert-butyl ester 2

[0039] L-phenylalanine 1 (40.5g, 245.4mmol), K 2 CO 3 (170.0g, 1.23mol), H 2 The mixture of O (180ml), EtOH (90ml), and BocCl (82.6g, 613.5mol) was heated to 90°C, and the reaction was stopped after 15 hours. After the reaction, the water layer was removed, 150ml of n-hexane was added to the organic layer and washed with 800ml of water, dried, filtered, and spin-dried to obtain light yellow liquid compound 2 (83.4g, 93%).

[0040] Step 2 (S)-4-(tert-butoxyamido)-3-keto-5-phenylpentanoic acid tert-butyl ester 3

[0041] To a solution of LDA (60ml, freshly prepared) was added tert-butyl acetate (8ml, 20mmol) at -45°C. After 0.5 hour, compound 2 (7.3 g, 20 mmol, in 30 ml THF) was added to the system, and the reaction was terminated after 1 hour. The aqueous layer was extracted with EtOAc (2×80ml), and several layers were combined, dried, filtered, and spin-dried to give a pale yellow liquid, ...

Embodiment 2

[0051] Step 1 (S)-2-(tert-butoxyamido)-3-phenyl-propionic acid tert-butyl ester 2

[0052] L-phenylalanine 1 (121.5g, 736.2mmol), NaOH (58.9g, 1.47mol) K 2 CO 3 dissolved in H 2 In O (800ml), heated to 95°C, N 2 Under protection, BocCl (298 g, 2.21 mol) was slowly added into the system, and after the dropwise addition was completed, the reaction was continued at this temperature for 10 h. After the reaction, toluene (3×250ml) was added, and the organic layer was washed with water and saturated brine, dried, filtered, and spin-dried to obtain compound 2 (259.0g, 96.2%) as a pale yellow liquid.

[0053] Step 2 (S)-4-(tert-butoxyamido)-3-keto-5-phenylpentanoic acid tert-butyl ester 3

[0054] With embodiment 1.

[0055] Step 3 (S)-4-(tert-butoxyamido)-2-chloro-3-keto-5-phenylpentanoic acid tert-butyl ester 4

[0056] Copper chloride (1.4g, 8.0mmol), compound 3 solution (0.7g, 2.2mmol) and triethylamine (3.4ml, 2.4g, 24mmol) were dissolved in ethyl acetate (8ml), at room tem...

Embodiment 3

[0064] Step 1 (S)-2-(tert-butoxyamido)-3-phenyl-propionic acid tert-butyl ester 2

[0065] With embodiment 1.

[0066] Step 2 (S)-4-(tert-butoxyamido)-3-keto-5-phenylpentanoic acid tert-butyl ester 3

[0067] With embodiment 1.

[0068] Step 3 (S)-4-(tert-butoxyamido)-2-chloro-3-keto-5-phenylpentanoic acid tert-butyl ester 4

[0069] With embodiment 1.

[0070] Step 4 (S)-1-chloro-3-(tert-butoxyamido)-4-phenyl-2-butanone 5

[0071] Compound 4 (3.5 g, 10 mmol) was dissolved in dilute sulfuric acid (25 ml, 15%), and the reaction was stopped after stirring overnight at room temperature. After the reaction, 30ml of water was added to the system, and extracted with ethyl acetate (3×20ml), the fractions were combined, dried, filtered, and spin-dried to obtain light yellow solid compound 5 (2.0g, 68.3%).

[0072] Step 5 (2R,3S)-1-chloro-3-(tert-butoxyamido)-4-phenyl-2-butanol 6

[0073] Compound 5 solution (7.4g, 25mmol, in 40ml EtOH) was placed in an ice bath at -3°C, NaBH was...

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Abstract

The invention discloses a method for preparing an amprenavir midbody serving as anti-AIDS medicine. According to the method, L-phenylalanine serves as raw materials, tertiary butyl is adopted for protection and esterification, CuCl<2> / DMF cholro and sodium borohydride serve as reducing agents, binaphthol phosphamidon compounds obtained through complexation of ruthenium trichloride and (+)-B-chlorodiisopinocampherylborane serve as catalysts, and a target product, namely (2R, 3S)-1, 2-epoxy group-3- amine tert-butoxide group-4-phenylbutane, is synthesized in an efficient and asymmetrical mode. By means of the method, the binaphthol phosphamidon compounds obtained through complexation of ruthenium trichloride and (+)-B-chlorodiisopinocampherylborane serve as the catalysts, the proportion of erythro form structures in the reduction reaction product is greatly raised, waste of raw materials is avoided, meanwhile, the separation cost is decreased, and the method is economic, safe and more suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of organic chemistry, in particular to an anti-AIDS drug amprenavir intermediate, specifically (2R,3S)-1,2-epoxy-3-tert-butoxyamido-4-benzene The preparation method of butane. Background technique [0002] Amprenavir can block the splitting of the protein precursor necessary for HIV maturation, thereby interfering with the maturation process of the virus, causing the protein precursor to release immature, non-infectious virus molecules. (2R,3S)-1,2-epoxy-3-tert-butoxyamido-4-phenylbutane is an important synthetic intermediate for the preparation of amprenavir, and its molecular structural formula is: [0003] [0004] According to literature reports, there are mainly the following methods for synthesizing compound 7 with industrial application value. [0005] One is to use (S)-2-(dibenzylamino)-3-phenyl-propionaldehyde as raw material, and obtain compound 3 (J.Org.Chem.1997,62,8902) through two-step reaction. The...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D303/36C07D301/26
CPCC07D301/26C07D303/36
Inventor 廉翔余焓韩生李亮张兴华
Owner SHANGHAI INST OF TECH