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A new process for the synthesis of darunavir intermediates

A darunavir and intermediate technology, applied in the field of new synthetic technology, can solve the problems of low selectivity and uneconomical reduction of carbonyl group, and achieve the effect of increasing reaction yield and reducing production cost

Active Publication Date: 2017-02-15
CHONGQING SHENGHUAXI PHARMA CO LTD +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage is that the selectivity of carbonyl reduction is low, the isomer ratio is 3:1, and the required configuration product is purified and separated by column chromatography
The reductive amination reaction requires the use of expensive platinum oxide as a catalyst, which is also uneconomical in industrial production

Method used

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  • A new process for the synthesis of darunavir intermediates
  • A new process for the synthesis of darunavir intermediates
  • A new process for the synthesis of darunavir intermediates

Examples

Experimental program
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Embodiment 1

[0025] Embodiment 1 Preparation of N-tert-butoxycarbonyl-L-phenylalanine phenyl ester

[0026] N-tert-butoxycarbonyl-L--phenylalanine 50g, dichloromethane 800ml, stirred and dissolved, added 26 grams of phenol, 3 grams of 4-dimethylaminopyridine, 39 grams of dicyclohexyl carboximide, 20 React at about ℃ for 5 hours, filter, evaporate the filtrate to dryness, add 100ml of ethanol, heat up to dissolve, slowly cool down to 20-30℃, gradually solids precipitate, then add 50ml of water, cool down to 0℃, and crystallize for 1 hour to obtain a solid 58 grams (yield 90.2%, purity 95%).

Embodiment 2

[0027] Example 2 Preparation of N-tert-butoxycarbonyl-L-phenylalanine p-nitrophenyl ester

[0028] N-tert-butoxycarbonyl-L--phenylalanine 50g, dichloromethane 800ml, stir to dissolve, add 39g p-nitrophenol, DMAP 3g, DCC 39g, react at 20°C for 5 hours, filter, and evaporate the filtrate to dryness , add 100ml of ethanol, heat up to dissolve, slowly cool down to 20-30°C, and gradually solids precipitate out, then add 50ml of water, cool down to 0°C, crystallize for 1 hour, and obtain 62 grams of solid (yield 86.5%, purity 93% ).

Embodiment 3

[0029] Example 3 Preparation of (S)-3-tert-butoxycarbonylamino-1-nitro-4-phenyl 2-butanone

[0030] Mix 46 grams of potassium tert-butoxide and 200ml of DMSO, stir and cool down to about 10°C, add 30ml of nitromethane dropwise, raise the temperature to 20-25°C after the addition, react for 1 hour to form a suspension, and then add N-tert-butyl 162 grams of oxycarbonyl-L-phenylalanine phenyl ester was incubated at 20-25° C. for 4-5 hours. During the reaction, the reaction liquid gradually dissolved. Then cool the reaction solution to 0-10°C with ice water, add 500ml of water dropwise, adjust the pH to 3-4 with concentrated hydrochloric acid, and crystallize at 0-10°C for 2 hours, filter, wash the filter cake with water, and decompress the filter cake after draining After drying, 132.9 g of (S)-3-tert-butoxycarbonylamino-1-nitro-4-phenyl 2-butanone was obtained (90.8% yield, 96% purity).

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Abstract

The invention provides a novel synthesis process of Darunavir intermediate, N-tertbutyloxycarbonyl-L-phenylalanine is used as a raw material, esterification, condensation, reduction, hydrogenation and reduction amination, and other reactions are carried out for preparing the key intermediate of Darunavir: (2R,3S)-3-(tert-butyloxycarbonyl)amino-1-[(2-methyl propyl)amino]-4-phenyl-2-butanol. The new synthesis process of Darunavir intermediate has the advantages of mild reaction condition, simple operation, and high reaction selectivity and yield, and the process is suitable for industrial production.

Description

technical field [0001] The invention relates to a new synthesis process of darunavir intermediate, which belongs to the technical field of chemical industry. Background technique [0002] Darunavir is a second-generation protease inhibitor anti-AIDS drug developed by Johnson & Johnson, which was first launched in the United States in July 2006. Since the launch of darunavir, the global usage has gradually increased, and as of 2012, the global sales have reached 1.5 billion US dollars. [0003] There are many synthetic methods of darunavir reported in the literature, most of which require the synthesis of the key intermediate (2R,3S)-3-tert-butoxycarbonylamino-1-[(2-methylpropyl)amino]-4- Phenyl 2-butanol (compound 1), its structural formula is as follows: [0004] [0005] The synthetic route bibliographical report of compound 1 mainly contains the following several: [0006] Route 1 (Journal of Medicinal Chemistry, 1994 , vol. 37, p. 1758 -1768): [0007] [0008]...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C271/20C07C269/06
Inventor 何亮曾秀秀
Owner CHONGQING SHENGHUAXI PHARMA CO LTD
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