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Method for preparing prezista dehydrate crystal form

A dihydrate and crystal form technology, applied in the field of chemical synthesis, can solve the problems of poor thermal stability of darunavir hydrate, poor thermal stability of hydrate, uncertain water metering ratio, etc., and achieve suitable drying time and temperature , low price, less solvent effect

Inactive Publication Date: 2018-12-21
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

US patent US20180170945 discloses several solvates of darunavir and acids (benzenesulfonic acid, sulfuric acid, naphthalenesulfonic acid, toluenesulfonic acid, acetic acid, etc.), darunavir methyl ethyl ketone solvate, methyl tetrahydrofuran Solvate, methyl acetate solvate, ethyl formate solvate, hydrate (containing about 6-12 parts of water) and preparation method thereof, wherein the preparation of hydrate crystal form adopts the method of suspending crystal in aqueous solution , the crystallization time is greater than 9 days, and the water content in the prepared hydrate is uncertain (the water content is 0.66%, 16.3%, and more than 16.3%), and the crystallization process conditions (mainly the crystallization time ) is related to drying conditions, and the prepared hydrate has poor thermal stability, and dehydration begins at room temperature
Patent EP2521728 discloses darunavir hydrate, amorphous form and preparation method thereof, wherein the preparation method of the hydrate crystal form is in a mixed solvent of a water-soluble solvent (such as methanol, ethanol, isopropanol) and water In the method of suspension and crystallization, the crystallization time is longer than 10 hours, and the water content in the hydrate is about 5.5-7.5%. Poor stability, dehydration begins at 30°C
The literature (European Journal of Pharmaceutical Sciences, 2009, 38:489-497) also mentions a preparation method of a hydrate crystal form, which is a crystal transformation under high humidity conditions (about 90% RH), but the crystal transformation time is long, It takes more than 1 month, and the obtained darunavir hydrate also has the problems of poor thermal stability and uncertain water ratio
[0006] In the preparation process of darunavir hydrate in the prior art, there are technical defects such as long preparation time, poor reproducibility, uncertain stoichiometric ratio of water in the prepared hydrate crystal form, and poor thermal stability.

Method used

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  • Method for preparing prezista dehydrate crystal form
  • Method for preparing prezista dehydrate crystal form
  • Method for preparing prezista dehydrate crystal form

Examples

Experimental program
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Embodiment 1

[0041] Example 1: Preparation of Darunavir Dihydrate Crystal Form

[0042] Add 10 grams of darunavir into 15 mL of acetonitrile, heat to the boiling point, stir until it is completely dissolved, continue to reflux for 10 minutes, stop stirring, and naturally cool down to about 5-10°C (ice-water bath), continue crystallization 2 hours, suction filtration, and vacuum drying at 40° C. to obtain 9.4 g of the crystalline form of darunavir dihydrate with a yield of 94%.

Embodiment 2

[0043] Example 2: Preparation of Darunavir Dihydrate Crystal Form

[0044] Add 20 grams of darunavir into a mixed solvent of 40 mL of acetonitrile and water (where the water is 2 mL), heat to the boiling point, stir until it is completely dissolved, continue to reflux for 10 min, stop stirring, and naturally cool down to about 0- Continue crystallization at 5°C for 3 hours, filter with suction, and dry under vacuum at 40°C to obtain 18.9 g of the crystalline form of darunavir dihydrate with a yield of 94.5%.

Embodiment 3

[0045] Example 3: Preparation of Darunavir Dihydrate Crystal Form

[0046] Add 20 grams of darunavir into a mixed solvent of 40 mL of acetonitrile and water (1 mL of water), heat to the boiling point, stir until it is completely dissolved, continue to reflux for 20 min, stop stirring, and naturally cool down to about 5- Continue crystallization at 10°C (ice-water bath) for 5 hours, filter with suction, and dry under vacuum at 40°C to obtain 18.2 g of the crystalline form of darunavir dihydrate with a yield of 91%.

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Abstract

The invention relates to a method for preparing a prezista dehydrate crystal form which has good crystallinity, and contains two kinds of stable crystal water. The invention discloses a preparation method for the prezista dehydrate crystal form, wherein a solvent mixture of a low-boiling-point organic solvent and little water is adopted to dissolve, and natural cooling and crystallization are performed after heating reflux, so that the technical defects such as long preparation time, unset crystal water content and unstable heat in a preparation process for the prezista dehydrate crystal formare solved. The production process provided by the invention is simple to operate, and is low in cost; and the prepared prezista dehydrate crystal form is good in crystallinity, good in stability, andis very suitable for industrial production.

Description

Background technique [0001] The invention relates to the technical field of chemical synthesis, in particular to a method for preparing a crystal form of darunavir dihydrate. [0002] Darunavir (structural formula as shown in formula I), also known as Darunavir, is a new non-peptide antiretroviral protease inhibitor for the treatment of AIDS, which is produced by Tabotec ( Tibobec) pharmaceutical company successfully developed it for the first time, and it has been listed in the United States, the European Union and other countries and regions under the trade name Prezista. It is currently the most bioavailable among the six protease inhibitors (saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir), and it works by blocking infection from infected host cells The process by which new, mature virions are released from the surface acts by inhibiting the viral protease. [0003] [0004] US Patent US6248775 and its family patent EP0715618 disclose darunavir and its pr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/04
CPCC07B2200/13C07D493/04
Inventor 胡秀荣沈洁汤谷平
Owner ZHEJIANG UNIV