Preparation method of Darunavir intermediate

A technology of darunavir and intermediates, applied in the field of heterocyclic chemistry, can solve the problems of low yield of active esters, expensive active reagents, etc., and achieve high reaction activity, high industrial application and economic value, and high reaction yield. Effect

Active Publication Date: 2012-08-01
ZHEJIANG JIUZHOU PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The purpose of the present invention is to overcome in above-mentioned prior art, (3R, 3aS, 6aR)-hexahydrofuro[2,3-b] furan-3-alcohol active reagent used expensive pr...

Method used

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  • Preparation method of Darunavir intermediate
  • Preparation method of Darunavir intermediate
  • Preparation method of Darunavir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Embodiment 1: the preparation of formula 3 compound

[0064]

[0065] Triphosgene (5.86g, 0.02mol) was dissolved in 20ml of dichloromethane, raised to 50°C, (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]furan-3-ol (2.60g, 0.02 mol) and triethylamine (3.00g, 0.0.03mol) were mixed and dissolved in 25ml of dichloromethane, added dropwise to the reactor, after the dropwise addition was completed, the reaction was continued for 3 hours, TLC detected that the raw materials disappeared, and a quantitative crude compound of formula 3 was obtained.

Embodiment 2

[0066] Embodiment 2: the preparation of formula 6-1 compound

[0067]

[0068] The compound of formula 3 (3.8g, 0.02mol) obtained in Example 1 was dissolved in 30ml of tetrahydrofuran, and added dropwise to N-hydroxyl

[0069] Add triethylamine (2.02g, 0.02mol) to a 45ml tetrahydrofuran solution of succinimide (2.3g, 0.02mol), add dropwise, reflux, react for 2 hours, TLC detects that the raw materials disappear, add aqueous solution of salt water to extract , and concentrated the upper layer to obtain 5.4 g of the compound of formula 6-1, with a yield of 99.6%.

Embodiment 3

[0070] Embodiment 3: the preparation of formula 6-2 compound

[0071]

[0072] The compound of formula 3 (3.8g, 0.02mol) obtained in Example 1 was added dropwise in 45ml of dichloromethane solution of N-hydroxyphthalimide (3.26g, 0.02mol), and pyridine (1.58g , 0.02mol) was added dropwise, refluxed, and reacted for 1.5 hours. TLC detected that the raw materials disappeared, added water for liquid extraction, and concentrated the lower layer to obtain 6.3g of the compound of formula 6-2, with a yield of 98.7%.

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Abstract

The invention relates to the technical field of heterocyclic chemistry, especially relates to a condensed ring system containing oxygen atoms as the only heterocycle atoms, concretely discloses a preparation method of a Darunavir intermediate. The method comprises the following steps: obtaining a compound of formula (3) by using (3R,3aS,6aR)-hexahydro-furo[2,3-b]furan-3-ol as a raw material to react with triphosgene under alkaline conditions, then directly reacting with a compound of formula (7) to obtain a compound of formula (8); or obtaining a compound of formula (3) to react with an N-hydroxyl compound to prepare active ester, and then reacting with the compound of formula (7) to obtain the compound of formula (8).

Description

technical field [0001] The invention relates to the technical field of heterocyclic chemistry, in particular to the technical field of heterocyclic chemistry in which a condensed ring system contains an oxygen atom as the only heterocyclic atom. Background technique [0002] Darunavir, a non-peptide HIV protease inhibitor developed for Johnson & Johnson’s Icelandic branch Tibotec, was launched in the United States on June 23, 2006. It is clinically based on its ethanol solvent Compound is used, and its structural formula is as follows: [0003] [0004] Regarding the preparation method of darunavir, there are not many existing synthetic routes. According to the current literature, it is mainly prepared by the following formula 8 through hydrogenation reduction. The structural formula of the compound of formula 8 is as follows: [0005] [0006] The common synthetic route of present formula 8 compound is as follows: [0007] Route 1: The route announced in the PCT pat...

Claims

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Application Information

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IPC IPC(8): C07D493/04
Inventor 李明亮张斌张现毅高红军车大庆
Owner ZHEJIANG JIUZHOU PHARM CO LTD
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