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Preparation method of dolutegravir

A technology of dolutegravir and concentration, which is applied in the field of preparation of dolutegravir, can solve the problems of affecting bioavailability and poor solubility, and achieve the effects of excellent ultrafine effect, lower temperature, and excellent dispersion and stability effect

Active Publication Date: 2022-03-22
JIANGSU YUXIANG CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although dolutegravir has excellent performance, its solubility in water is too poor, thus affecting its bioavailability

Method used

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  • Preparation method of dolutegravir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] (1) In the reaction kettle, add the solvent DMF, dissolve the original powder of dolutegravir in DMF, and prepare the DMF solution of dolutegravir, wherein the concentration of dolutegravir is 30mg / ml.

[0028] (2) In another reaction kettle, prepare an aqueous solution of polyvinyl alcohol PVA1788 with a concentration of 1%.

[0029] (3) Turn on the strong stirring of the polyvinyl alcohol aqueous solution, control the temperature at 0°C, and quickly pump the DMF solution of dolutegravir into the liquid level of the polyvinyl alcohol aqueous solution through the high-pressure delivery pump, and the flow rate at the outlet pipe greater than 3 m / s. Continue vigorous stirring for 60 min. Obtain dolutegravir suspension. Wherein the volume ratio of polyvinyl alcohol aqueous solution to the DMF solution of dolutegravir is 5:1.

[0030] (4) The suspension is subjected to solid-liquid separation, and the dolutegravir powder can be obtained after drying. The obtained dolute...

Embodiment 2

[0032] (1) In the reaction kettle, add the solvent DMF, dissolve the original powder of dolutegravir in DMF, and prepare the DMF solution of dolutegravir, wherein the concentration of dolutegravir is 70mg / ml.

[0033] (2) In another reaction kettle, prepare an aqueous solution of polyvinyl alcohol PVA2488 with a concentration of 3%.

[0034] (3) Turn on the strong stirring of the polyvinyl alcohol aqueous solution, control the temperature at 20°C, and quickly pump the DMF solution of dolutegravir into the liquid level of the polyvinyl alcohol aqueous solution through the high-pressure delivery pump, and the flow rate at the outlet pipe greater than 3 m / s. Continue vigorous stirring for 30 min. Obtain dolutegravir suspension. Wherein the volume ratio of polyvinyl alcohol aqueous solution to the DMF solution of dolutegravir is 50:1.

[0035] (4) The suspension is subjected to solid-liquid separation, and the dolutegravir powder can be obtained after drying. The obtained dolu...

Embodiment 3

[0037] (1) In the reaction kettle, add the solvent DMF, dissolve the original powder of dolutegravir in DMF, and prepare the DMF solution of dolutegravir, wherein the concentration of dolutegravir is 50mg / ml.

[0038] (2) In another reaction kettle, prepare an aqueous solution of polyvinyl alcohol PVA1788 with a concentration of 2%.

[0039] (3) Turn on the strong stirring of the polyvinyl alcohol aqueous solution, control the temperature at 10°C, and quickly pump the DMF solution of dolutegravir into the liquid level of the polyvinyl alcohol aqueous solution through the high-pressure delivery pump, and the flow rate at the outlet pipe greater than 3 m / s. Continue vigorous stirring for 45 min. Obtain dolutegravir suspension. Wherein the volume ratio of polyvinyl alcohol aqueous solution to the DMF solution of dolutegravir is 25:1.

[0040] (4) The suspension is subjected to solid-liquid separation, and the dolutegravir powder can be obtained after drying. The obtained dolu...

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Abstract

The invention discloses a preparation method of dolutegravir, which comprises the following steps: adding a solvent dimethyl formamide (DMF) into a reaction kettle, dissolving dolutegravir raw powder into the DMF to prepare a DMF solution of dolutegravir, preparing a polyvinyl alcohol aqueous solution in another reaction kettle, starting strong stirring and mixing of the polyvinyl alcohol aqueous solution, and then carrying out solid-liquid separation and drying. According to the dolutegravir superfine powder and the preparation method thereof, the polyvinyl alcohol aqueous solution is adopted, on one hand, the polyvinyl alcohol aqueous solution can greatly reduce the temperature for separating out crystals, on the other hand, the polyvinyl alcohol aqueous solution has a particularly excellent dispersion stabilizing effect, superfine nanocrystals are obtained and are not prone to coalescence, and the prepared dolutegravir superfine powder has the particle size D90 smaller than 1.0 micron, preferably 0.3-0.7 micron, and the particle size D90 is smaller than 1.0 micron. The method is much smaller than traditional processes and literature reports.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry, and in particular relates to a preparation method of dolutegravir. Background technique [0002] AIDS has developed into a serious global public health and social problem. Integrase (Integrase) plays an important role in the HIV-1 virus replication process. There is no functional analogue of integrase in the human body, and this enzyme has gradually become an ideal target for anti-HIV drugs. In recent years, several such HIV inhibitors such as raltegravir, elvitegravir, dolutegravir, cabotegravir, and bictegravir have been successfully marketed or entered clinical practice. [0003] Dolutegravir is an anti-human immunodeficiency virus type 1 (HIV-1) infection drug developed by ViiV Healthcare, a subsidiary of GlaxoSmithKline (GSK). Prevents the transfer of viral DNA strands to the host DNS and can be used in combination with other antiretroviral drugs. Both in vivo and in vitro studi...

Claims

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Application Information

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IPC IPC(8): C07D498/14
CPCC07D498/14
Inventor 张治国程云涛徐官根李思远王金程红伟
Owner JIANGSU YUXIANG CHEM
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