CN102757388A - Preparation method of high-purity etravirine - Google Patents
Preparation method of high-purity etravirine Download PDFInfo
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- CN102757388A CN102757388A CN2012102295111A CN201210229511A CN102757388A CN 102757388 A CN102757388 A CN 102757388A CN 2012102295111 A CN2012102295111 A CN 2012102295111A CN 201210229511 A CN201210229511 A CN 201210229511A CN 102757388 A CN102757388 A CN 102757388A
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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 the preparation method of a kind of high purity Ying Jiaweilin.
Background technology
Ying Jiaweilin (ingavirin, chemical name: 5-((2-(1 hydrogen-imidazol-4 yl) ethyl) amino)-5-oxopentanoic acid) is to influenza virus, the active drug of adenovirus infection.
Application number is to have mentioned compound 5-((2-(1 hydrogen-imidazol-4 yl) ethyl) amino)-5-oxopentanoic acid first in the patented claim of WO9901103), promptly Ying Jiaweilin has effect preferably to virus.Document T. A. Kromova; G. A. Zheltukhina. Pharmaceutical Chemistry Journal. Vol. 39, and No. 3,2005 has reported the compound method of Ying Jiaweilin: be raw material with the histamine dihydrochloric acid; DMF is a solvent, obtains Ying Jiaweilin with the Pyroglutaric acid reaction.We find that through test the Ying Jiaweilin purity that the aftertreatment of this method obtains is not high, and 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 objective of the invention is to provides the preparation method of a kind of high purity Ying Jiaweilin to the deficiency that exists in the prior art.This preparation method is skillfully constructed, flow process is simple, and prepared Ying Jiaweilin purity reaches more than 99.9%, meets each item medicinal standard.
For realizing above-mentioned purpose, the technical solution adopted for the present invention to solve the technical problems is:
The preparation method of a kind of high purity Ying Jiaweilin may further comprise the steps:
A, under-40 ℃ of-150 ℃ of temperature, with the Ying Jiaweilin dissolving crude product in solvent;
B, under-40 ℃ of-150 ℃ of temperature, add poor solvent in the mixture with the steps A gained;
C, the mixture of step B gained is separated out the Ying Jiaweilin solid under-80 ℃ of-150 ℃ of temperature;
D, with the Ying Jiaweilin solids constituent of step C gained from obtaining required high purity Ying Jiaweilin.
As optimal way, in the said steps A, solvent is selected from water, alcohol, DMSO 99.8MIN., ether, N, one or more in dinethylformamide or the organic bases.
Further preferred, said alcohol is C1-C5 alcohol.
As optimal way, in the said steps A, the volume ratio of Ying Jiaweilin bullion quality and solvent is 1:2 ~ 1:50.
Further preferred, in the said steps A, the volume ratio of Ying Jiaweilin bullion quality and solvent is 1:4 ~ 1:10.
As optimal way, in the said steps A, the temperature during dissolving is 20 ℃-40 ℃.
As optimal way, among the said step B, poor solvent is selected from one or more in alcohols, ester class, ethers, hydro carbons or the aromatics.
Further preferred, said alcohol is C1-C5 alcohol.
As optimal way, among the said step B, the volume ratio of solvent for use is 0.5:1 ~ 50:1 in poor solvent and the steps A.
Further preferred, among the said step B, the volume ratio of solvent for use is 1:1 ~ 10:1 in poor solvent and the steps A.
As optimal way, among the said step B, the adding poor solvent is that the temperature of mixture remains on 20 ℃-40 ℃.
As optimal way, among the said step C, separate out temperature and be-10 ℃-10 ℃.
As optimal way, among the said step C, the mode of separating out is stirring and crystallizing or static crystallization.
As optimal way, among the said step D, isolating method is filtration or centrifugal.
Further preferred, in the said filtering separation, obtain filter cake after the filtration, with filter cake with solvent wash after, drying under reduced pressure 2h-24h under 30 ℃ of-120 ℃ of temperature obtains required high purity Ying Jiaweilin.
The contriver is through a large amount of experiments; The preparation method of the at last surprised Ying Jiaweilin that discovery the present invention put down in writing can drop to impurity such as the triethylamine in the Ying Jiaweilin bullion, histamine dihydrochloric acid, Pyroglutaric acid, pentanedioic acid below the ICH requirement; Single Control of Impurities meets medicinal standard in per mille.HPLC records its purity and reaches (peak area normalization method) more than 99.9%, and other routine inspections also meet medicinal requirements.
Beneficial effect of the present invention is: the present invention is skillfully constructed, flow process is simple, and prepared Ying Jiaweilin purity reaches more than 99.8%, and single impurity all is lower than 0.1%, meets each item medicinal standard.
Embodiment
Disclosed all characteristics in this specification sheets, or the step in disclosed all methods or the process except mutually exclusive characteristic and/or the step, all can make up by any way.
Comparative Examples: get 0.366g (3.3mmoL) histamine, join among the 5mLDMF, add 0.376g (3.3mmoL) Pyroglutaric acid down, stir 23h down, filter, collect filter cake,, obtain 0.51g Ying Jiaweilin with 2mL water recrystallization in 20 ℃ in stirring.
Experimental result: the solid that obtains has serious triethylamine taste, and it is 95.25% that HPLC detects its purity, and the inside contains the histamine peak, is about 4%, m.p.187-189 ℃.
Embodiment 1: 2.98g Ying Jiaweilin bullion, 50mL methyl alcohol are joined in the flask; Drip 25mL triethylamine to solid under stirring and dissolve, slowly add 360mL ETHYLE ACETATE then, be cooled to 0 ℃ of stirring and crystallizing 2h; Filter; Filter cake is collected filter cake with the washing of 100mL ETHYLE ACETATE, and 60 ℃ of drying under reduced pressure got white solid 1.94g in 5 hours.
It is 99.91% that experimental result: HPLC detects its purity, and no histamine peak, single impurity be less than 0.1%, m.p.194.6 ~ 195.0 ℃.
Embodiment 2: 2.98g Ying Jiaweilin bullion, 50mLDMSO are joined in the flask; Drip 25mL triethylamine to solid under stirring and dissolve, slowly add 360mL ETHYLE ACETATE then, be cooled to 0 ℃ of stirring and crystallizing 2h; Filter; Filter cake is collected filter cake with the washing of 100mL ETHYLE ACETATE, and 60 ℃ of drying under reduced pressure got white solid 1.82g in 5 hours.
It is 99.81% that experimental result: HPLC detects its purity, and no histamine peak, single impurity be less than 0.1%, m.p.194.4 ~ 195.0 ℃
Embodiment 3: 2.98g Ying Jiaweilin bullion, 25mLDMSO and 25mL methyl alcohol are joined in the flask; Drip 25mL triethylamine to solid under stirring and dissolve, slowly add 360mL ETHYLE ACETATE then, be cooled to 0 ℃ of stirring and crystallizing 2h; Filter; Filter cake is collected filter cake with the washing of 100mL ETHYLE ACETATE, and 60 ℃ of drying under reduced pressure got white solid 2.1g in 5 hours.
It is 99.77% that experimental result: HPLC detects its purity, no histamine peak, and single impurity is less than 0.1%.m.p.194.5~195.0℃
Embodiment 4: 2.0g Ying Jiaweilin bullion, 15mL water are joined in the flask, drip 70mL acetone under stirring, be cooled to 0 ℃ of stirring and crystallizing 2h, filter, filter cake is collected filter cake with the washing of 100mL ETHYLE ACETATE, and 60 ℃ of drying under reduced pressure got white solid 1.2g in 5 hours.
It is 99.89% that experimental result: HPLC detects its purity, and no histamine peak, single impurity be less than 0.1%, m.p.194.6 ~ 195.1 ℃.
Embodiment 5: 2.0g Ying Jiaweilin bullion, 15mL water are joined in the flask, drip 70mL acetone under stirring, be cooled to 0 ℃ of stirring and crystallizing 2h, filter, filter cake is collected filter cake with the washing of 100mL ETHYLE ACETATE, and 60 ℃ of drying under reduced pressure got white solid 1.2g in 5 hours.
It is 99.90% that experimental result: HPLC detects its purity, and no histamine peak, single impurity be less than 0.1%, m.p.194.6 ~ 195.0 ℃.
Embodiment 6: 2.98g Ying Jiaweilin bullion, 50mL methyl alcohol are joined in the flask; Drip 25mL triethylamine to solid under stirring and dissolve, slowly add 360mL acetone then, be cooled to 0 ℃ of stirring and crystallizing 2h; Filter; Filter cake is used the 100mL washing with acetone, collects filter cake, and 60 ℃ of drying under reduced pressure got white solid 2.21g in 5 hours.
It is 99.86% that experimental result: HPLC detects its purity, and no histamine peak, single impurity be less than 0.1%, m.p.194.4 ~ 194.8 ℃.
Embodiment 7: 3.0g Ying Jiaweilin bullion, 20mL methyl alcohol, 40mL ethanol are joined in the flask; Drip 25mL triethylamine to solid under stirring and dissolve, slowly add 360mL acetone then, be cooled to 0 ℃ of stirring and crystallizing 2h; Filter; Filter cake is used the 100mL washing with acetone, collects filter cake, and 60 ℃ of drying under reduced pressure got white solid 2.12g in 5 hours.
It is 99.92% that experimental result: HPLC detects its purity, and no histamine peak, single impurity be less than 0.1%, m.p.194.6 ~ 194.9 ℃.
We can find that preparation method of the present invention can drop to the impurity of Ying Jiaweilin bullion below ICH requires from the experimental result of the Comparative Examples and the embodiment of the invention, and the purity that HPLC detects is apparently higher than Comparative Examples, and steady quality.
The present invention is not limited to aforesaid embodiment.The present invention expands to any new feature or any new combination that discloses in this manual, and the arbitrary new method that discloses or step or any new combination of process.
Claims (15)
1. the preparation method of a high purity Ying Jiaweilin is characterized in that may further comprise the steps:
A, under-40 ℃ of-150 ℃ of temperature, with the Ying Jiaweilin dissolving crude product in solvent;
B, under-40 ℃ of-150 ℃ of temperature, add poor solvent in the mixture with the steps A gained;
C, the mixture of step B gained is separated out the Ying Jiaweilin solid under-80 ℃ of-150 ℃ of temperature;
D, with the Ying Jiaweilin solids constituent of step C gained from obtaining required high purity Ying Jiaweilin.
2. the preparation method of a kind of high purity Ying Jiaweilin according to claim 1, it is characterized in that: in the said steps A, solvent is selected from water, alcohol, DMSO 99.8MIN., ether, N, one or more in dinethylformamide or the organic bases.
3. the preparation method of a kind of high purity Ying Jiaweilin according to claim 2, it is characterized in that: said alcohol is C
1-C
5Alcohol.
4. the preparation method of a kind of high purity Ying Jiaweilin according to claim 1, it is characterized in that: in the said steps A, the volume ratio of Ying Jiaweilin bullion quality and solvent is 1:2 ~ 1:50.
5. the preparation method of a kind of high purity Ying Jiaweilin according to claim 4, it is characterized in that: in the said steps A, the volume ratio of Ying Jiaweilin bullion quality and solvent is 1:4 ~ 1:10.
6. the preparation method of a kind of high purity Ying Jiaweilin according to claim 1, it is characterized in that: in the said steps A, the temperature during dissolving is 20 ℃-40 ℃.
7. the preparation method of a kind of high purity Ying Jiaweilin according to claim 1, it is characterized in that: among the said step B, poor solvent is selected from one or more in alcohols, ester class, ethers, hydro carbons or the aromatics.
8. the preparation method of a kind of high purity Ying Jiaweilin according to claim 7, it is characterized in that: said alcohol is C
1-C
5Alcohol.
9. the preparation method of a kind of high purity Ying Jiaweilin according to claim 1, it is characterized in that: among the said step B, the volume ratio of solvent for use is 0.5:1 ~ 50:1 in poor solvent and the steps A.
10.1 the preparation method of a kind of high purity Ying Jiaweilin according to claim 9 is characterized in that: among the said step B, the volume ratio of solvent for use is 1:1 ~ 10:1 in poor solvent and the steps A.
11. the preparation method of a kind of high purity Ying Jiaweilin according to claim 1 is characterized in that: among the said step B, the adding poor solvent is that the temperature of mixture remains on 20 ℃-40 ℃.
12. the preparation method of a kind of high purity Ying Jiaweilin according to claim 1 is characterized in that: among the said step C, separate out temperature and be-10 ℃-10 ℃.
13. the preparation method of a kind of high purity Ying Jiaweilin according to claim 1 is characterized in that: among the said step C, the mode of separating out is stirring and crystallizing or static crystallization.
14. the preparation method of a kind of high purity Ying Jiaweilin according to claim 1 is characterized in that: among the said step D, isolating method is filtration or centrifugal.
15. the preparation method of a kind of high purity Ying Jiaweilin according to claim 14; It is characterized in that: in the said filtering separation, obtain filter cake after the filtration, with filter cake with solvent wash after; Drying under reduced pressure 2h-24h under 30 ℃ of-120 ℃ of temperature obtains required high purity Ying Jiaweilin.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN105418512A (en) * | 2014-09-19 | 2016-03-23 | 江苏正大丰海制药有限公司 | Single crystal of ingavirin, preparation method and pharmaceutical composition of ingavirin |
| CN106257276A (en) * | 2015-06-19 | 2016-12-28 | 江苏正大丰海制药有限公司 | A kind of ingavirin and the method for detecting impurities of preparation thereof |
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 |
-
2012
- 2012-07-04 CN CN201210229511.1A patent/CN102757388B/en active Active
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 |
|---|
| 北京师范大学化学系有机教研组: "《有机化学实验》", 31 January 1998 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN105418512A (en) * | 2014-09-19 | 2016-03-23 | 江苏正大丰海制药有限公司 | Single crystal of ingavirin, preparation method and pharmaceutical composition of ingavirin |
| 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 |
| CN106257276A (en) * | 2015-06-19 | 2016-12-28 | 江苏正大丰海制药有限公司 | A kind of ingavirin and the method for detecting impurities of preparation thereof |
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