CN114213432B - Preparation method of dolutegravir - Google Patents
Preparation method of dolutegravir Download PDFInfo
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- CN114213432B CN114213432B CN202111654700.9A CN202111654700A CN114213432B CN 114213432 B CN114213432 B CN 114213432B CN 202111654700 A CN202111654700 A CN 202111654700A CN 114213432 B CN114213432 B CN 114213432B
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- dolutegravir
- polyvinyl alcohol
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
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Abstract
The invention discloses a preparation method of dolutegravir, which comprises the following steps of adding dimethyl formamide DMF (dimethyl formamide) serving as a solvent into a reaction kettle, dissolving original dolutegravir powder in the DMF to prepare a DMF solution of dolutegravir, preparing a polyvinyl alcohol aqueous solution in another reaction kettle, starting strong stirring and mixing the polyvinyl alcohol aqueous solution, and then carrying out solid-liquid separation and drying. The invention adopts the polyvinyl alcohol aqueous solution, on one hand, the polyvinyl alcohol aqueous solution can greatly reduce the temperature of precipitated crystals, and on the second hand, the polyvinyl alcohol aqueous solution has particularly excellent dispersion stability effect, so that the superfine nano crystals are obtained and are not easy to coalesce, and the prepared dolutegravir ultrafine powder has the particle size D90 of less than 1.0 micron, preferably 0.3-0.7 micron which is far less than that of the traditional process and the literature reports.
Description
Technical Field
The invention belongs to the technical field of organic chemistry, and particularly relates to a preparation method of dolutegravir.
Background
Aids has developed into a serious global public health and social problem. Integrase (Integrase) plays an important role in the replication process of HIV-1 virus, and functional analogues of Integrase do not exist in human bodies, and the Integrase also gradually becomes an ideal target of anti-HIV drugs. In recent years, a plurality of HIV inhibitors such as raltegravir (raltegravir), elviteravir (elviteravir), doluteravir, caboteravir, bictegravir and the like have been successfully marketed or entered into the clinic.
Dolutegravir (dolutegravir) is an anti-human immunodeficiency virus type 1 (HIV-1) infection drug developed by ViiV Healthcare under the flag of Glatiramer Stacker (GSK), is a2 nd generation HIV integrase inhibitor, can prevent the transfer of viral DNA chains to host DNS, and can be used in combination with other antiretroviral drugs. In-vitro and in-vivo experimental studies show that dolutegravir has stronger anti-HIV-1 virus activity, and clinical studies show that compared with the 1 st generation HIV integrase inhibitor Letergevir and Etigevir, the dolutegravir has better safety, drug effect and tolerance, has few adverse reactions, does not influence the curative effect and pharmacokinetic parameters of a combined drug, can obviously prolong the service life of AIDS patients, and is a new anti-AIDS drug with good clinical application prospect. The expiration date of the dolutegravir patent is 2027 years, and the structural formula is shown as follows.
Dolutegravir, while excellent in performance, is too poorly soluble in water, thereby affecting its bioavailability. When administered in suspension form, it is severely limited by its dissolution or solubility. Dolutegravir sodium is almost insoluble in buffer solution, belongs to low-solubility drugs, and is not applicable to bioequivalence test exemption.
The micro powder form of the medicine can greatly improve the bioavailability of the medicine. The dolutegravir product is easy to crystallize, and the obtained powder generally has the particle size of more than 20 microns. Therefore, the development of a suitable dolutegravir micro powder preparation process can greatly promote the development of related industries at present.
Disclosure of Invention
The invention provides a preparation method of dolutegravir capable of obtaining dolutegravir powder with extremely low particle size, aiming at the problems to be solved in the prior art.
The technical scheme adopted by the invention is as follows:
the preparation method of dolutegravir is characterized by comprising the following steps:
1) Adding a solvent dimethylformamide DMF (dimethyl formamide) into a reaction kettle, and dissolving dolutegravir raw powder in the DMF to prepare a DMF solution of dolutegravir;
2) Preparing a polyvinyl alcohol aqueous solution in another reaction kettle;
3) Starting strong stirring of a polyvinyl alcohol aqueous solution, controlling the temperature to be 0-20 ℃, rapidly pumping a DMF (dimethyl formamide) solution of dolutegravir into the polyvinyl alcohol aqueous solution through a high-pressure delivery pump, and stirring strongly for 30-60 min to obtain a dolutegravir suspension;
4) And carrying out solid-liquid separation on the suspension, and drying to obtain dolutegravir powder.
As a further improvement, the concentration of the dolutegravir in the DMF solution of moderate dolutegravir in the step 1) is 30mg/ml-70mg/ml.
As a further improvement, in the step 2 of the invention, the concentration of the prepared polyvinyl alcohol aqueous solution is 1% -3%.
As a further improvement, the polyvinyl alcohol provided by the invention is one of PVA1788 or PVA 2488.
As a further improvement, the volume ratio of the polyvinyl alcohol aqueous solution to the dolutegravir DMF solution is 5-50.
As a further improvement, the DMF solution of dolutegravir provided by the invention is rapidly pumped below the liquid level of the polyvinyl alcohol aqueous solution by a high-pressure delivery pump, and the flow velocity at an outlet pipe is more than 3 m/s.
As a further improvement, the dolutegravir powder prepared by the invention has the particle size D90 of less than 1.0 micron.
As a further improvement, the particle size D90 in the present invention is preferably 0.3 to 0.7. Mu.m.
The invention adopts the process of recrystallization by an anti-solvent method to obtain dolutegravir powder, and has the following technical effects:
1) The aqueous solution of polyvinyl alcohol, especially the aqueous solution of PVA1788 or PVA2488, has especially excellent ultramicro effect. On one hand, the temperature of precipitated crystals can be greatly reduced by the polyvinyl alcohol aqueous solution, and on the second hand, the polyvinyl alcohol aqueous solution has a particularly excellent dispersion stabilizing effect, and ultrafine nanocrystals are obtained and are not easy to coalesce.
2) The DMF solution of dolutegravir is quickly pumped below the liquid level of the polyvinyl alcohol aqueous solution by a high-pressure delivery pump, and the flow velocity at an outlet pipe is more than 3 m/s. Generally, in the conventional anti-solvent recrystallization process, the solution is slowly dripped, and the effect is not good; and the high-pressure pump is adopted to quickly add the mixture below the liquid level, so that the effect is excellent. And the flow velocity is more than 3 m/s, so that the flow of the fluid can be effectively controlled to be in a completely developed high-speed turbulent flow state, and the ultramicro effect can be realized.
3) The novel process is applied as a core and key technology for realizing the preparation of the dolutegravir ultrafine powder, the dolutegravir ultrafine powder is prepared by the process, and the particle size D90 is less than 1.0 micron, preferably 0.3-0.7 micron which is far less than that of the traditional process and the literature reports.
Detailed Description
The technical solution of the present invention is further illustrated by the following specific examples:
example 1
(1) Adding a solvent DMF into a reaction kettle, dissolving dolutegravir raw powder in the DMF to prepare a DMF solution of dolutegravir, wherein the concentration of the dolutegravir is 30mg/ml.
(2) In another reaction kettle, an aqueous solution of polyvinyl alcohol PVA1788 with a concentration of 1% is prepared.
(3) And (2) starting strong stirring of the polyvinyl alcohol aqueous solution, controlling the temperature to be 0 ℃, rapidly pumping the DMF solution of the dolutegravir into the position below the liquid level of the polyvinyl alcohol aqueous solution through a high-pressure delivery pump, and enabling the flow velocity at an outlet pipe to be more than 3 m/s. Stirring vigorously for 60min. Obtaining dolutegravir suspension. Wherein the volume ratio of the polyvinyl alcohol aqueous solution to the dolutegravir DMF solution is 5:1.
(4) And carrying out solid-liquid separation on the suspension, and drying to obtain dolutegravir powder. The obtained dolutegravir powder has a particle size D90 of 0.7 microns.
Example 2
(1) Adding a solvent DMF into a reaction kettle, and dissolving the dolutegravir raw powder in the DMF to prepare a dolutegravir DMF solution, wherein the concentration of the dolutegravir is 70mg/ml.
(2) In another reaction kettle, an aqueous solution of polyvinyl alcohol PVA2488 with the concentration of 3 percent is prepared.
(3) And (2) starting strong stirring of the polyvinyl alcohol aqueous solution, controlling the temperature to be 20 ℃, rapidly pumping the DMF solution of the dolutegravir into the position below the liquid level of the polyvinyl alcohol aqueous solution through a high-pressure delivery pump, and enabling the flow velocity at an outlet pipe to be more than 3 m/s. Stirring vigorously for 30min. Obtaining dolutegravir suspension. Wherein the volume ratio of the polyvinyl alcohol aqueous solution to the dolutegravir DMF solution is 50.
(4) And carrying out solid-liquid separation on the suspension, and drying to obtain dolutegravir powder. The obtained dolutegravir powder has a particle size D90 of 0.5 micron.
Example 3
(1) Adding a solvent DMF into a reaction kettle, dissolving dolutegravir raw powder in the DMF to prepare a DMF solution of dolutegravir, wherein the concentration of the dolutegravir is 50mg/ml.
(2) In another reaction kettle, an aqueous solution of polyvinyl alcohol PVA1788 with a concentration of 2% is prepared.
(3) Starting strong stirring of a polyvinyl alcohol aqueous solution, controlling the temperature to be 10 ℃, rapidly pumping the DMF solution of dolutegravir into the position below the liquid level of the polyvinyl alcohol aqueous solution through a high-pressure delivery pump, and enabling the flow velocity at an outlet pipe to be more than 3 m/s. Stirring vigorously for 45min. Obtaining dolutegravir suspension. Wherein the volume ratio of the polyvinyl alcohol aqueous solution to the dolutegravir DMF solution is 25.
(4) And carrying out solid-liquid separation on the suspension, and drying to obtain dolutegravir powder. The obtained dolutegravir powder has a particle size D90 of 0.3 micron.
Comparative example 1
(1) Adding a solvent DMF into a reaction kettle, dissolving dolutegravir raw powder in the DMF to prepare a DMF solution of dolutegravir, wherein the concentration of the dolutegravir is 50mg/ml.
(2) In another reaction kettle, water is added.
(3) Starting strong stirring, controlling the temperature to be 10 ℃, rapidly pumping the DMF solution of the dolutegravir into the position below the liquid level of water through a high-pressure delivery pump, and enabling the flow speed at an outlet pipe to be more than 3 m/s. Stirring vigorously for 45min. Obtaining dolutegravir suspension. Wherein the volume ratio of water to dolutegravir in DMF is 25.
(4) And carrying out solid-liquid separation on the suspension, and drying to obtain dolutegravir powder. The obtained dolutegravir powder has a particle size D90 of 8.0 microns.
It can be seen that, compared with the comparative example 1 and the example 3, the particle size distribution of the product is remarkably increased due to the fact that the polyvinyl alcohol aqueous solution is not used for effective dispersion stabilization, and the particle size D90 of the obtained dolutegravir powder is 8.0 microns.
Comparative example 2
(1) Adding a solvent DMF into a reaction kettle, dissolving dolutegravir raw powder in the DMF to prepare a DMF solution of dolutegravir, wherein the concentration of the dolutegravir is 50mg/ml.
(2) In another reaction kettle, water is added.
(3) Starting strong stirring, dropping the DMF solution of the dolutegravir into the water under the condition of controlling the temperature to be 10 ℃, and continuing strong stirring for 45min. Obtaining dolutegravir suspension. Wherein the volume ratio of water to dolutegravir in DMF is 25.
(4) And carrying out solid-liquid separation on the suspension, and drying to obtain dolutegravir powder. The resulting dolutegravir powder had a particle size D90 of 18.0 microns.
It can be seen that, in comparison with comparative example 2, in comparative example 1, the grain size D90 of the obtained dolutegravir powder is significantly increased due to the fact that the anti-solvent is not rapidly pumped into the position below the liquid level by the high-pressure delivery pump and the traditional dropping manner is adopted, and the grain size D90 of the obtained dolutegravir powder is 18.0 microns.
Finally, it should also be noted that the above list is only a specific implementation example of the present invention. It is obvious that the invention is not limited to the above embodiment examples, but that many variations are possible. All modifications which can be derived or suggested by a person skilled in the art from the disclosure of the present invention are to be considered within the scope of the invention.
Claims (8)
1. The preparation method of dolutegravir is characterized by comprising the following steps:
1) Adding a solvent dimethylformamide DMF into a reaction kettle, and dissolving dolutegravir raw powder in the DMF to prepare a DMF solution of dolutegravir;
2) Preparing a polyvinyl alcohol aqueous solution in another reaction kettle;
3) Starting strong stirring of a polyvinyl alcohol aqueous solution, controlling the temperature to be 0-20 ℃, rapidly pumping a DMF (dimethyl formamide) solution of dolutegravir into the polyvinyl alcohol aqueous solution through a high-pressure delivery pump, and stirring strongly for 30-60 min to obtain a dolutegravir suspension;
4) And carrying out solid-liquid separation on the suspension, and drying to obtain dolutegravir powder.
2. The process for preparing dolutegravir according to claim 1, wherein the concentration of dolutegravir in the DMF solution of moderate dolutegravir in step 1) is 30mg/ml-70mg/ml.
3. The preparation method of dolutegravir according to claim 1 or 2, wherein in step 2, the concentration of the prepared polyvinyl alcohol aqueous solution is 1% -3%.
4. The preparation method of dolutegravir according to claim 1, wherein the polyvinyl alcohol is one of PVA1788 or PVA 2488.
5. The preparation method of dolutegravir according to claim 3, wherein the volume ratio of the polyvinyl alcohol aqueous solution to the DMF solution of dolutegravir is 5-50.
6. The preparation method of dolutegravir according to claim 1, 2, 4 or 5, characterized in that the DMF solution of dolutegravir is pumped rapidly under the liquid level of the aqueous solution of polyvinyl alcohol by a high pressure delivery pump, and the flow rate at the outlet pipe is more than 3 m/s.
7. The preparation method of dolutegravir according to claim 6, characterized in that the prepared dolutegravir powder has a particle size D90 of less than 1.0 μm.
8. The process for preparing dolutegravir according to claim 7, characterized in that the particle size D90 is preferably 0.3-0.7 μm.
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Citations (10)
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| WO2013038407A1 (en) * | 2011-09-14 | 2013-03-21 | Mapi Pharma Ltd. | Amorphous form of dolutegravir |
| WO2015120110A2 (en) * | 2014-02-07 | 2015-08-13 | Auspex Pharmaceuticals, Inc. | Novel pharmaceutical formulations |
| WO2015118460A1 (en) * | 2014-02-07 | 2015-08-13 | Mylan Laboratories Ltd. | Crystalline forms of dolutegravir sodium |
| WO2017029642A2 (en) * | 2015-08-19 | 2017-02-23 | Laurus Labs Private Limited | Novel polymorphs of dolutegravir and salts thereof |
| CN107074875A (en) * | 2014-07-29 | 2017-08-18 | 斯洛文尼亚莱柯制药股份有限公司 | Novel hydrates of dolutegravir sodium |
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2021
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Patent Citations (10)
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| WO2013038407A1 (en) * | 2011-09-14 | 2013-03-21 | Mapi Pharma Ltd. | Amorphous form of dolutegravir |
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| WO2015118460A1 (en) * | 2014-02-07 | 2015-08-13 | Mylan Laboratories Ltd. | Crystalline forms of dolutegravir sodium |
| CN107074875A (en) * | 2014-07-29 | 2017-08-18 | 斯洛文尼亚莱柯制药股份有限公司 | Novel hydrates of dolutegravir sodium |
| CN107428778A (en) * | 2015-01-16 | 2017-12-01 | 斯洛文尼亚莱柯制药股份有限公司 | The method for preparing Du Lutewei and Capote Wei and the like |
| WO2017029642A2 (en) * | 2015-08-19 | 2017-02-23 | Laurus Labs Private Limited | Novel polymorphs of dolutegravir and salts thereof |
| EP3661940A1 (en) * | 2017-09-07 | 2020-06-10 | Cipla Limited | New polymorphs of dolutegravir sodium |
| CN109293675A (en) * | 2018-11-19 | 2019-02-01 | 遵义医学院 | A kind of improved Du Lutewei preparation process |
| CN109528659A (en) * | 2018-12-31 | 2019-03-29 | 京山瑞生制药有限公司 | A kind of preparation method of Florfenicol Ultramicro-powder |
| CN110396099A (en) * | 2019-05-22 | 2019-11-01 | 博诺康源(北京)药业科技有限公司 | The synthetic method of diastereoisomer impurity in a kind of Du Lutewei raw material |
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