CN102757388B - Preparation method of high-purity etravirine - Google Patents
Preparation method of high-purity etravirine Download PDFInfo
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- CN102757388B CN102757388B CN201210229511.1A CN201210229511A CN102757388B CN 102757388 B CN102757388 B CN 102757388B CN 201210229511 A CN201210229511 A CN 201210229511A CN 102757388 B CN102757388 B CN 102757388B
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Abstract
The invention discloses a preparation method of high-purity etravirine, which comprises the following steps: A. dissolving a crude etravirine product in a solvent at -40-150 DEG C; B. adding a poor solvent into the mixture obtained in the step A at -40-150 DEG C; C. precipitating an etravirine solid from the mixture obtained in the step B at -80-150 DEG C; and D. separating the etravirine solid obtained in the step C to obtain the required high-purity etravirine. The preparation method disclosed by the invention has the advantages of ingenious concept and simple process; and the purity of the prepared etravirine is up to higher than 99.9%, and the prepared etravirine conforms to various medicine standards.
Description
Technical field
The invention belongs to technical field of pharmaceutical chemistry, relate to a kind of preparation method of high-purity etravirine.
Background technology
Ingavirin (ingavirin, chemical name: 5-((2-(1 hydrogen-imidazol-4 yl) ethyl) is amino)-5-oxopentanoic acid) is for influenza virus, the active drug of adenovirus infection.
Application number is refer to compound 5-((2-(1 hydrogen-imidazol-4 yl) ethyl) is amino)-5-oxopentanoic acid in the patent application of WO9901103 first), i.e. ingavirin, has good effect to virus.Document T. A. Kromova, G. A. Zheltukhina. Pharmaceutical Chemistry Journal. Vol. 39, No. 3,2005 reports the synthetic method of ingavirin: take histamine dihydrochloric acid as raw material, DMF is solvent, is obtained by reacting ingavirin with Pyroglutaric acid.We are found by test, and the ingavirin purity that the aftertreatment of the method obtains is not high, and the impurity such as triethylamine, histamine dihydrochloric acid, Pyroglutaric acid, pentanedioic acid are contained in the inside, have a strong impact on its quality product.
Summary of the invention
The object of the invention is to for the deficiencies in the prior art, a kind of preparation method of high-purity etravirine is provided.This preparation method is skillfully constructed, flow process simple, and prepared ingavirin purity reaches more than 99.9%, meets every medicinal standard.
For achieving the above object, the technical solution adopted for the present invention to solve the technical problems is:
A preparation method for high-purity etravirine, comprises the following steps:
A, at-40 DEG C of-150 DEG C of temperature, by ingavirin dissolving crude product in a solvent;
B, at-40 DEG C of-150 DEG C of temperature, add poor solvent by the mixture of steps A gained;
C, the mixture of step B gained is separated out ingavirin solid at-80 DEG C of-150 DEG C of temperature;
D, by the ingavirin solid of step C gained be separated obtain required high-purity etravirine.
As optimal way, in described steps A, solvent be selected from water, alcohol, dimethyl sulfoxide (DMSO), ether, DMF or organic bases one or more.
Further preferably, described alcohol is C1-C5 alcohol.
As optimal way, in described steps A, the volume ratio of ingavirin crude product quality and solvent is 1:2 ~ 1:50.
Further preferably, in described steps A, the volume ratio of ingavirin crude product quality and solvent is 1:4 ~ 1:10.
As optimal way, in described steps A, temperature during dissolving is 20 DEG C-40 DEG C.
As optimal way, in described step B, poor solvent be selected from alcohols, ester class, ethers, hydro carbons or aromatics one or more.
Further preferably, described alcohol is C1-C5 alcohol.
As optimal way, in described step B, in poor solvent and steps A, the volume ratio of solvent for use is 0.5:1 ~ 50:1.
Further preferably, in described step B, in poor solvent and steps A, the volume ratio of solvent for use is 1:1 ~ 10:1.
As optimal way, in described step B, adding poor solvent is that the temperature of mixture remains on 20 DEG C-40 DEG C.
As optimal way, in described step C, Precipitation Temperature is-10 DEG C-10 DEG C.
As optimal way, in described step C, precipitation mode is stirring and crystallizing or static crystallization.
As optimal way, in described step D, the method for separation is filtration or centrifugal.
Further preferably, in described filtering separation, obtain filter cake after filtration, after filter cake solvent wash, drying under reduced pressure 2h-24h at 30 DEG C of-120 DEG C of temperature, obtains required high-purity etravirine.
Contriver is through a large amount of experiments, the impurity such as the triethylamine in ingavirin crude product, histamine dihydrochloric acid, Pyroglutaric acid, pentanedioic acid can be dropped to below ICH requirement by the preparation method of the finally surprised ingavirin described in discovery the present invention, single Control of Impurities, within thousandth, meets medicinal standard.HPLC records its purity and reaches more than 99.9% (areas of peak normalization method), and other routine inspections also meet medicinal requirements.
Beneficial effect of the present invention is: the present invention is skillfully constructed, flow process simple, and prepared ingavirin purity reaches more than 99.8%, and single impurity, all lower than 0.1%, meets every medicinal standard.
Embodiment
All features disclosed in this specification sheets, or the step in disclosed all methods or process, except mutually exclusive feature and/or step, all can combine by any way.
Comparative example: get 0.366g(3.3mmoL) histamine, join in 5mLDMF, under stirring, add 0.376g (3.3mmoL) Pyroglutaric acid, at 20 DEG C, stir 23h, filter, collect filter cake, with 2mL water recrystallization, obtain 0.51g ingavirin.
Experimental result: the solid obtained has serious triethylamine taste, it is 95.25% that HPLC detects its purity, and the inside, containing histamine peak, is about 4%, m.p.187-189 DEG C.
Embodiment 1: 2.98g ingavirin crude product, 50mL methyl alcohol are joined in flask, stir lower dropping 25mL triethylamine to dissolution of solid, then 360mL ethyl acetate is slowly added, be cooled to 0 DEG C of stirring and crystallizing 2h, filter, filter cake 100mL ethyl acetate washing, collects filter cake, and 60 DEG C of drying under reduced pressure obtain white solid 1.94g in 5 hours.
It is 99.91% that experimental result: HPLC detects its purity, and without histamine peak, single impurity is less than 0.1%, m.p.194.6 ~ 195.0 DEG C.
Embodiment 2: 2.98g ingavirin crude product, 50mLDMSO are joined in flask, stir lower dropping 25mL triethylamine to dissolution of solid, then 360mL ethyl acetate is slowly added, be cooled to 0 DEG C of stirring and crystallizing 2h, filter, filter cake 100mL ethyl acetate washing, collects filter cake, and 60 DEG C of drying under reduced pressure obtain white solid 1.82g in 5 hours.
It is 99.81% that experimental result: HPLC detects its purity, and without histamine peak, single impurity is less than 0.1%, m.p.194.4 ~ 195.0 DEG C
Embodiment 3: 2.98g ingavirin crude product, 25mLDMSO and 25mL methyl alcohol are joined in flask, stir lower dropping 25mL triethylamine to dissolution of solid, then 360mL ethyl acetate is slowly added, be cooled to 0 DEG C of stirring and crystallizing 2h, filter, filter cake 100mL ethyl acetate washing, collects filter cake, and 60 DEG C of drying under reduced pressure obtain white solid 2.1g in 5 hours.
It is 99.77% that experimental result: HPLC detects its purity, and without histamine peak, single impurity is less than 0.1%.m.p.194.5~195.0℃
Embodiment 4: join in flask by 2.0g ingavirin crude product, 15mL water, drips 70mL acetone under stirring, is cooled to 0 DEG C of stirring and crystallizing 2h, filters, and filter cake 100mL ethyl acetate washing, collects filter cake, and 60 DEG C of drying under reduced pressure obtain white solid 1.2g in 5 hours.
It is 99.89% that experimental result: HPLC detects its purity, and without histamine peak, single impurity is less than 0.1%, m.p.194.6 ~ 195.1 DEG C.
Embodiment 5: join in flask by 2.0g ingavirin crude product, 15mL water, drips 70mL acetone under stirring, is cooled to 0 DEG C of stirring and crystallizing 2h, filters, and filter cake 100mL ethyl acetate washing, collects filter cake, and 60 DEG C of drying under reduced pressure obtain white solid 1.2g in 5 hours.
It is 99.90% that experimental result: HPLC detects its purity, and without histamine peak, single impurity is less than 0.1%, m.p.194.6 ~ 195.0 DEG C.
Embodiment 6: 2.98g ingavirin crude product, 50mL methyl alcohol are joined in flask, stir lower dropping 25mL triethylamine to dissolution of solid, then 360mL acetone is slowly added, be cooled to 0 DEG C of stirring and crystallizing 2h, filter, filter cake 100mL washing with acetone, collects filter cake, and 60 DEG C of drying under reduced pressure obtain white solid 2.21g in 5 hours.
It is 99.86% that experimental result: HPLC detects its purity, and without histamine peak, single impurity is less than 0.1%, m.p.194.4 ~ 194.8 DEG C.
Embodiment 7: 3.0g ingavirin crude product, 20mL methyl alcohol, 40mL ethanol are joined in flask, stir lower dropping 25mL triethylamine to dissolution of solid, then 360mL acetone is slowly added, be cooled to 0 DEG C of stirring and crystallizing 2h, filter, filter cake 100mL washing with acetone, collects filter cake, and 60 DEG C of drying under reduced pressure obtain white solid 2.12g in 5 hours.
It is 99.92% that experimental result: HPLC detects its purity, and without histamine peak, single impurity is less than 0.1%, m.p.194.6 ~ 194.9 DEG C.
From the experimental result of comparative example and the embodiment of the present invention, we can find that the impurity of ingavirin crude product can drop to below ICH requires by preparation method of the present invention, and the purity that HPLC detects is apparently higher than comparative example, and steady quality.
The present invention is not limited to aforesaid embodiment.The present invention expands to any new feature of disclosing in this manual or any combination newly, and the step of the arbitrary new method disclosed or process or any combination newly.
Claims (7)
1. the preparation method of a high-purity etravirine, it is characterized in that comprising the following steps: 2.98g ingavirin crude product, 50mL methyl alcohol are joined in flask, stir lower dropping 25mL triethylamine to dissolution of solid, then 360mL ethyl acetate is slowly added, be cooled to 0 DEG C of stirring and crystallizing 2h, filter, filter cake 100mL ethyl acetate is washed, collect filter cake, 60 DEG C of drying under reduced pressure obtain white solid in 5 hours.
2. the preparation method of a high-purity etravirine, it is characterized in that comprising the following steps: 2.98g ingavirin crude product, 50mLDMSO are joined in flask, stir lower dropping 25mL triethylamine to dissolution of solid, then 360mL ethyl acetate is slowly added, be cooled to 0 DEG C of stirring and crystallizing 2h, filter, filter cake 100mL ethyl acetate is washed, collect filter cake, 60 DEG C of drying under reduced pressure obtain white solid in 5 hours.
3. the preparation method of a high-purity etravirine, it is characterized in that comprising the following steps: 2.98g ingavirin crude product, 25mLDMSO and 25mL methyl alcohol are joined in flask, stir lower dropping 25mL triethylamine to dissolution of solid, then 360mL ethyl acetate is slowly added, be cooled to 0 DEG C of stirring and crystallizing 2h, filter, filter cake 100mL ethyl acetate is washed, collect filter cake, 60 DEG C of drying under reduced pressure obtain white solid in 5 hours.
4. the preparation method of a high-purity etravirine, it is characterized in that comprising the following steps: 2.0g ingavirin crude product, 15mL water are joined in flask, stir lower dropping 70mL acetone, be cooled to 0 DEG C of stirring and crystallizing 2h, filter, filter cake 100mL ethyl acetate washing, collects filter cake, and 60 DEG C of drying under reduced pressure obtain white solid in 5 hours.
5. the preparation method of a high-purity etravirine, it is characterized in that comprising the following steps: 2.0g ingavirin crude product, 15mL water are joined in flask, stir lower dropping 70mL acetone, be cooled to 0 DEG C of stirring and crystallizing 2h, filter, filter cake 100mL ethyl acetate washing, collects filter cake, and 60 DEG C of drying under reduced pressure obtain white solid in 5 hours.
6. the preparation method of a high-purity etravirine, it is characterized in that comprising the following steps: 2.98g ingavirin crude product, 50mL methyl alcohol are joined in flask, stir lower dropping 25mL triethylamine to dissolution of solid, then 360mL acetone is slowly added, be cooled to 0 DEG C of stirring and crystallizing 2h, filter, filter cake 100mL washing with acetone, collect filter cake, 60 DEG C of drying under reduced pressure obtain white solid in 5 hours.
7. the preparation method of a high-purity etravirine, it is characterized in that comprising the following steps: 3.0g ingavirin crude product, 20mL methyl alcohol, 40mL ethanol are joined in flask, stir lower dropping 25mL triethylamine to dissolution of solid, then 360mL acetone is slowly added, be cooled to 0 DEG C of stirring and crystallizing 2h, filter, filter cake 100mL washing with acetone, collect filter cake, 60 DEG C of drying under reduced pressure obtain white solid in 5 hours.
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| CN103288742A (en) * | 2013-06-04 | 2013-09-11 | 四川百利药业有限责任公司 | Preparation method for high-purity ingavirin raw material |
| CN103382179A (en) * | 2013-06-05 | 2013-11-06 | 四川百利药业有限责任公司 | Ingavirin polymorph and its preparation method |
| CN105418512B (en) * | 2014-09-19 | 2018-05-01 | 江苏正大丰海制药有限公司 | Monocrystalline, preparation method and its pharmaceutical composition of ingavirin |
| CN106257276B (en) * | 2015-06-19 | 2018-06-26 | 江苏正大丰海制药有限公司 | A kind of method for detecting impurities of ingavirin and its preparation |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1020179A2 (en) * | 1997-07-04 | 2000-07-19 | Vladimir Evgenievich Nebolsin | Peptide derivatives or pharmaceutically acceptable salts thereof, method for producing the same, use of said derivatives and pharmaceutical composition |
| CN101243053A (en) * | 2005-06-15 | 2008-08-13 | 本国药品上市股份公司 | N-acylic aminoacid derivatives, method for the production thereof, pharmacological composition and the use in the form of anti-allergic, anti-inflammatory and hypolipidemic agents |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1020179A2 (en) * | 1997-07-04 | 2000-07-19 | Vladimir Evgenievich Nebolsin | Peptide derivatives or pharmaceutically acceptable salts thereof, method for producing the same, use of said derivatives and pharmaceutical composition |
| CN101243053A (en) * | 2005-06-15 | 2008-08-13 | 本国药品上市股份公司 | N-acylic aminoacid derivatives, method for the production thereof, pharmacological composition and the use in the form of anti-allergic, anti-inflammatory and hypolipidemic agents |
Non-Patent Citations (1)
| Title |
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| 北京师范大学化学系有机教研组.重结晶.《有机化学实验》.1998,12-14. * |
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