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Method for synthesizing anti-aids drug amprenavir intermediate

An anti-AIDS, intermediate technology, applied in the direction of organic chemistry, can solve the problem of high cost, achieve the effect of high yield, safe operation and cheap raw materials

Inactive Publication Date: 2007-09-19
XIAMEN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] Catalyst used Pd(OH) 2 more expensive

Method used

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  • Method for synthesizing anti-aids drug amprenavir intermediate
  • Method for synthesizing anti-aids drug amprenavir intermediate
  • Method for synthesizing anti-aids drug amprenavir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Step 1 (S)-2-(Dibenzylamino)-3-phenyl-propionic acid benzyl ester 2

[0036] L-phenylalanine 1 (20.0g, 122.7mmol), K 2 CO 3 (60.0g, 606mmol), H 2 The mixture of O (90 mL), EtOH (45 mL), and BnCl (50.0 g, 393.7 mmol) was heated to 90° C., and the reaction was stopped after 15 h. After the reaction, the aqueous layer was removed, and 100 mL of n-hexane was added to the organic layer, washed with 500 mL of water, dried, filtered, and spin-dried to obtain light yellow liquid compound 2 (51.2 g, 96%). 1 H-NMR (CDCl 3 , 500MHz): δ3.20 (dd, J=8.4, 14.4Hz, 2H, PhCH 2 C), 3.60 (d, J=15.0Hz, 2H, 2PhCHaHbN), 3.80 (dd, J=8.5, 8.5Hz, 1H, NCH), 4.00 (d, J=15.0Hz, 2H, 2PhCHaHbN), 5.20(d , J=13.5Hz, 1H, PhCHaHbO), 5.30 (d, J=13.5Hz, 1H, PhCHaHbO), 7.50~7.00 (m, 20H, 4PhH) ppm. 13 C-NMR (CDCl 3 , 125MHz): 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 ( M H + ).

[0037] Step 2 (S)-tert-butyl 4...

Embodiment 2

[0054] Step 1 (S)-2-(Dibenzylamino)-3-phenyl-propionic acid benzyl ester 2

[0055] L-phenylalanine (50.0g, 302.1mmol), NaOH (24.2g, 605.0mmol) and K 2 CO 3 Dissolve in 500ml of water, heat to 97°C, slowly add BnBr (219.0ml, 1210mmol) dropwise to the above solution, react at this temperature for 10h under nitrogen protection, add toluene (2×250ml) after the reaction is complete, The organic layer was washed with water and saturated brine successively, dried, filtered, and spin-dried to obtain light yellow liquid compound 2 (124.8 g, 95%).

[0056] Step 2 (S)-tert-butyl 4-(dibenzylamino)-3-oxo-5-phenylpentanoate 3

[0057] With embodiment 1.

[0058] Step 3 (S)-tert-butyl 4-(dibenzylamino)-2-bromo-3-oxo-5-phenylpentanoate 4

[0059] Copper bromide (0.9g, 4.0mmol), compound 3 (0.44g, 1.0mmol) and Et 3 N (1.7mL, 1.2g, 12mmol) was dissolved in ethyl acetate (4mL), and the reaction was stopped after stirring for 40h at room temperature. After the reaction, water (10 mL) was a...

Embodiment 3

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

[0074] With embodiment 1.

[0075] Step 2 (S)-tert-butyl 4-(dibenzylamino)-3-oxo-5-phenylpentanoate 3

[0076] With embodiment 1.

[0077] Step 3 (S)-tert-butyl 4-(dibenzylamino)-2-bromo-3-oxo-5-phenylpentanoate 4

[0078] With embodiment 1.

[0079] Step 4 (S)-1-bromo-3-(dibenzylamino)-4-phenyl-2-butanone 5

[0080] Dissolve (S)-4-(dibenzylamino)-2-bromo-3-oxo-5-phenylpentanoic acid tert-butyl ester 4 solution (0.522g, 1mmol) in dilute sulfuric acid (4mL, 15% ), and stop the reaction after stirring at room temperature for 15h. After the reaction, 10 mL of water was added to the system and extracted with EtOAc (3×10 mL), the organic layers were combined, dried, filtered, and spin-dried to obtain white solid 5 (0.23 g, 56%).

[0081] Step 5 (2S,3S)-1-bromo-3-(dibenzylamino)-4-phenyl-2-butanol 6

[0082] Put (S)-1-bromo-3-(dibenzylamino)-4-phenyl-2-butanone 5 solution (4.22g, 10mmol, in 20mL EtOH...

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Abstract

A method for synthesizing anti - AIDS medicine amprenavir intermediate is related to a synthesis method of a compound, especially for 4-amido-N-((2R,3S)-3-amido-2-hydroxy-4-phenylbutyl)-N-isobutylbenzenesulfamide (amprenavir intermediate), including taking the L-phenylalanine as material, adopting the benzyl protection and esterification, reaction of bromine with CuBr2 / DMF, Pd carbon deoxidization to synthesize amprenavir intermediate. We choose the economic means of protecting the amido by benzyl so as to avoid using the benzyl chloroformate. The copper bromide for halogenated use can be reacted in room temperature so as to avoid using the expensive reagent such as chlorobromomethane and chloroiodomethane and produce no pollution to the air. The debenzylation hydrogenation is finished by Pd / C so as to avoid using the expensive palladium dydroxide. The method uses cheaper materials and has a higher yield, which is suitable for commercial process.

Description

technical field [0001] The present invention relates to a kind of synthetic method of compound, especially synthetic 4-amino-N-((2R, 3S)-3-amino-2-hydroxyl-4-phenylbutyl)-N-isobutylbenzenesulfamide ( Amprenavir intermediate) method. Background technique [0002] (2S,3S)-3-(Dibenzylamino)-3-benzyloxypropylene 7 and 4-amino-N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl) -N-isobutylbenzenesulfamide 10 is the synthetic intermediate of the anti-AIDS drug amprenavir, and its molecular formula is as follows: [0003] [0004] The method of the synthetic compound 7 that has reported industrial application value mainly contains the following several kinds: [0005] (1) Using (S)-2-(dibenzylamino)-3-phenyl-propanal as raw material, compound 7 (J.Org.Chem.1997,62,8902) was obtained through two-step reaction, synthetic route as follows: [0006] [0007] (2) Using (S)-2-(dibenzylamino)-3-phenyl-propanal as raw material, compound 7 (J.Org.Chem.1996, 61, 3635) was obtained through ...

Claims

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Application Information

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IPC IPC(8): C07C311/40
Inventor 郑剑峰石国宗苏贞夏靳立人
Owner XIAMEN UNIV
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