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Preparation method for (2R,3S)-1-chlorine-3-tert-butoxycarbonylamino-4-phenyl-2-butanol

A technology of tert-butoxyamido and phenyl, applied in the preparation of -1-chloro-3-tert-butoxyamido-4-phenyl-2-butanol, the field of anti-AIDS drug amprenavir intermediates , can solve problems such as not suitable for industrial production, difficult separation of products, harsh reaction conditions, etc., to achieve safe yield, improve production efficiency, and realize the effect of industrialization

Inactive Publication Date: 2015-12-16
SHANGHAI APPLIED TECHNOLOGIES COLLEGE
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  • 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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  • Preparation method for (2R,3S)-1-chlorine-3-tert-butoxycarbonylamino-4-phenyl-2-butanol
  • Preparation method for (2R,3S)-1-chlorine-3-tert-butoxycarbonylamino-4-phenyl-2-butanol
  • Preparation method for (2R,3S)-1-chlorine-3-tert-butoxycarbonylamino-4-phenyl-2-butanol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] The first step: (S)-2-(Dibenzylamino)-3-phenyl-propionic acid benzyl ester 2

[0040] Add L-phenylalanine 1 (20.0g, 121.1mmol), K 2 CO 3 (60.0g, 434.8mmol), H 2 The mixture of O (90ml), EtOH (45ml), BnCl (45.2g, 394.7mmol) was heated to 90°C, and the reaction was stopped after 15h. After the reaction, the water layer was removed, and 100 ml of n-hexane was added to the organic layer and washed with 500 ml of water, dried, filtered, and spin-dried to obtain a pale yellow liquid compound 2 (50.6 g, 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 CHaHb N), 3.80(dd,1H,J=8.5,8.5Hz,N CH ), 4.00(d,2H,J=15.0Hz,2Ph CHaHb N), 5.20 (d, 1H, J = 13.5 Hz, Ph CHaHb O),5.30(d,1H,J=13.5Hz,Ph CHaHb 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] The second step: N,N-dibenzyl-L-phenylalanine 3

[00...

Embodiment 2

[0056] The first step: (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 90°C and reflux, N 2 The reaction was carried out at this temperature for 10 hours under protection. After the reaction was completed, toluene (2×250ml) was added. Several layers were washed successively with water and saturated brine, dried, filtered, and spin-dried to obtain a pale yellow liquid compound 2 (121.3g, 92 %).

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

[0059] The same as in Example 1.

[0060] The third step: 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), add N-methylmorpholine at once while stirring (16.0 g), transfer the clear, colorless solut...

Embodiment 3

[0073] The first step: (S)-2-(Dibenzylamino)-3-phenyl-propionic acid benzyl ester 2

[0074] Add L-phenylalanine 1 (20.0g, 122.7mmol), K 2 CO 3 (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 water layer was removed, and 100 ml of n-hexane was added to the organic layer and washed with 500 ml of water, dried, filtered, and spin-dried to obtain a pale yellow liquid compound 2 (51.7 g, 96.8%).

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

[0076] The same as in Example 1.

[0077] The third step: 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), add N-methylmorpholine all at once while stirring (8.78g), transfer the clear, colorless solution to the addition funnel. The reactor w...

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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 particularly relates to an anti-AIDS drug amprenavir intermediate, specifically a (2R, 3S)-1-chloro-3-tert-butoxyamido-4-phenyl- Preparation method of 2-butanol. Background technique [0002] Amprenavir can block the division of protein precursors necessary for HIV maturation, thereby interfering with the maturation process of the virus, and causing the protein precursors 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. Its molecular formula is as follows: [0003] [0004] According to literature reports, the preparation methods of (2R,3S)-1-chloro-3-tert-butoxyamido-4-phenyl-2-butanol with industrial application value mainly include the following: [0005] The first method (Tetrahedron Lett. 1995, 36(31), 5453-5456) uses L-phenylalanine as a raw material and undergoes...

Claims

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Application Information

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IPC IPC(8): C07C271/16C07C269/04
Inventor 余焓廉翔韩生李亮
Owner SHANGHAI APPLIED TECHNOLOGIES COLLEGE
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