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A kind of preparation method of (2r,3s)-1-chloro-3-tert-butoxyamido-4-phenyl-2-butanol

A kind of tert-butoxyamido, phenyl technology, applied in the preparation of -1-chloro-3-tert-butoxyamido-4-phenyl-2-butanol, the field of anti-AIDS drug amprenavir intermediates , can solve the problems of unsuitability for industrial production, difficult separation of products, harsh reaction conditions, etc., to achieve safe yield, improve production efficiency, and achieve the effect of industrialization

Inactive Publication Date: 2017-08-25
SHANGHAI INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] Aiming at the above technical problems in the prior art, the present invention provides a method for preparing (2R,3S)-1-chloro-3-tert-butoxyamido-4-phenyl-2-butanol, the The preparation method of this (2R,3S)-1-chloro-3-tert-butoxyamido-4-phenyl-2-butanol needs to solve the harsh reaction conditions of the preparation method in the prior art, the product is not easy to separate, and the Technical issues suitable for industrial production

Method used

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  • A kind of preparation method of (2r,3s)-1-chloro-3-tert-butoxyamido-4-phenyl-2-butanol
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  • A kind of preparation method of (2r,3s)-1-chloro-3-tert-butoxyamido-4-phenyl-2-butanol

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Step 1: (S)-2-(Dibenzylamino)-3-phenyl-propionic acid benzyl ester 2

[0040] L-phenylalanine 1 (20.0g, 121.1mmol), K 2 CO 3 (60.0g, 434.8mmol), H 2 The mixture of O (90ml), EtOH (45ml), and BnCl (45.2g, 394.7mmol) was heated to 90°C, and the reaction was stopped after 15h. After the reaction, the aqueous layer was removed, 100ml of n-hexane was added to the organic layer and washed with 500ml of water, dried, filtered, and spin-dried to obtain light yellow liquid compound 2 (50.6g, 96%). 1 H-NMR (300MHz, CDCl 3 ):δ3.20(dd,2H,J=8.4,14.4Hz,Ph CH 2 C),3.60(d,2H,J=15.0Hz,2Ph CHb N),3.80(dd,1H,J=8.5,8.5Hz,N CH ),4.00(d,2H,J=15.0Hz,2PhCHb N),5.20(d,1H,J=13.5Hz,Ph CHb O),5.30(d,1H,J=13.5Hz,Ph CHb O),7.50-7.00(m,20H,4PhH)ppm. 13 C-NMR (125MHz, CDCl 3 ):δ35.6,54.3,62.3,66.0,126.2,126.9,128.1,128.2,128.4,128.5,128.6,129.4,135.9,138.0,139.2,172.0ppm.MS(ESI,m / z):436.0(MH + ).

[0041] Step 2: N,N-Dibenzyl-L-phenylalanine 3

[0042] (S)-2-(Dibenzylamino)-3-phenyl-pr...

Embodiment 2

[0056] Step 1: (S)-2-(Dibenzylamino)-3-phenyl-propionic acid benzyl ester 2

[0057] Dissolve L-phenylalanine 1 (50.0g, 302.7mmol), NaOH (20.0g, 500.0mmol), BnCl (294.9g, 908.7mmol) in 250ml of water and 200ml of EtOH, heat to reflux at 90°C, N 2 Reacted at this temperature for 10 h under protection. After the reaction was completed, toluene (2×250ml) was added, and several layers were washed with water and saturated brine in sequence, dried, filtered, and spin-dried to obtain light yellow liquid compound 2 (121.3g, 92 %).

[0058] The second step: (S)-N,N-dibenzyl-L-phenylalanine 3

[0059] With embodiment 1.

[0060] Step 3: Bn-mixed anhydride 4

[0061] A 500ml glass reactor was equipped with a 250ml addition funnel, stirrer, thermometer and cooling bath. Dissolve (S)-N,N-dibenzyl-L-phenylalanine 3 (50.0g, 130.9mmol) in dichloromethane (200ml), and add N-methylmorpholine at one time while stirring (16.0 g), the clear, colorless solution was transferred to an addition f...

Embodiment 3

[0073] Step 1: (S)-2-(Dibenzylamino)-3-phenyl-propionic acid benzyl ester 2

[0074] L-phenylalanine 1 (20.0g, 122.7mmol), K 2 CO3 (60.0g, 606mmol), H 2 The mixture of O (90ml), EtOH (45ml), and BnCl (50.0g, 393.7mmol) was heated to 80°C, and the reaction was stopped after 48h. After the reaction, the aqueous layer was removed, 100ml of n-hexane was added to the organic layer and washed with 500ml of water, dried, filtered, and spin-dried to obtain light yellow liquid compound 2 (51.7g, 96.8%).

[0075] The second step: (S)-N,N-dibenzyl-L-phenylalanine 3

[0076] With embodiment 1.

[0077] Step 3: Bn-mixed anhydride 4

[0078] A 250ml glass reactor was equipped with a 250ml addition funnel, stirrer, thermometer and cooling bath. Dissolve (S)-N,N-dibenzyl-L-phenylalanine 3 (25.0g, 0.065mol) in dichloromethane (100ml), and add N-methylmorpholine in one go while stirring (8.78 g), the clear, colorless solution was transferred to an addition funnel. A solution of ethyl chl...

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Abstract

The invention provides a preparation method for (2R,3S)-1-chlorine-3-tert-butoxycarbonylamino-4-phenyl-2-butanol. The preparation method comprises the steps that L-phenylalanine is taken as raw materials, protected by adopting benzyl, esterified and then catalyzed through NMM to generate a mixed anhydride compound, the mixed anhydride compound reacts with diazomethane to generate diazoketone, a reduction reaction and palladium carbon reduction are performed, and finally the intermediate (2R,3S)-1-chlorine-3-tert-butoxycarbonylamino-4-phenyl-2-butanol is obtained. According to the preparation method, the low-cost benzyl is adopted to protect amidogen, the synthetic route is reasonable, the operation technology is simple, safe and high in yield, industrialization can be well achieved, and the production efficiency is improved.

Description

technical field [0001] The invention belongs to the field of organic chemistry, and in particular relates to an anti-AIDS drug amprenavir intermediate, specifically a (2R,3S)-1-chloro-3-tert-butoxyamido-4-phenyl- Process for the preparation of 2-butanol. 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-chloro-3-tert-butoxyamido-4-phenyl-2-butanol is an important synthetic intermediate for the preparation of amprenavir, and its molecular formula is as follows: [0003] [0004] The preparation method of (2R,3S)-1-chloro-3-tert-butoxyamido-4-phenyl-2-butanol with industrial application value according to literature reports mainly contains the following types: [0005] The first method (Tetrahedron Lett.1995, 36 (31), 5453-5456) uses L-phenylalanine a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C271/16C07C269/04
Inventor 余焓廉翔韩生李亮
Owner SHANGHAI INST OF TECH
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