CN107663205A - A kind of process for purification of Eliquis - Google Patents
A kind of process for purification of Eliquis Download PDFInfo
- Publication number
- CN107663205A CN107663205A CN201610609546.6A CN201610609546A CN107663205A CN 107663205 A CN107663205 A CN 107663205A CN 201610609546 A CN201610609546 A CN 201610609546A CN 107663205 A CN107663205 A CN 107663205A
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- Prior art keywords
- eliquis
- activated carbon
- organic solvent
- purification
- solvent
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to pharmaceutical synthesis field, is related to a kind of process for purification of high-purity Eliquis.The process for purification of Eliquis of the present invention comprises the steps of：Eliquis crude product is added in organic solvent, by heating stirring to being completely dissolved, activated carbon decolorizing, natural cooling crystallization, filtration drying obtains the Eliquis of high-purity.The exquisite method technical process of the present invention is simple and convenient to operate, low production cost, product purity height, process stabilizing, suitable industrialized production.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, and in particular to a kind of process for purification of Eliquis.
Background technology
Eliquis is a kind of anticoagulant declared jointly by Pfizer company and Bristol-Myers Squibb Co., directly
Connect and act on factor Xa, include DVT (deepvenousthrombosis, DVT) and pulmonary embolism for treating
Phlebothrombosis disease including (pulmonaryembolism, PE), the adverse reaction of bleeding are less than old medicine warfarin.2011 5
Month, European Union ratifies direct inhibitor Eliquis (trade name Eliquis) listing of oral Xa factor, for select a time hip joint or
The adult patients of replacement knee in arthroplasty, to prevent venous thronbosis (venousthrombembolicevents, VTE).
Obtain EMA approvals in November, 2012, FDA and PMDA approvals are obtained in December, 2012 respectively, for preventing atrial fibrillation patients apoplexy.
CN105503859 discloses a kind of purification process of Eliquis in the prior art, and this method passes through Ah piperazine is husky
Class's crude product DMF thermosol cold analysis, the solid after precipitation flow back mashing to purify to obtain Ah piperazine with organic solvent
Husky class's finished product.
By the research to Eliquis purification process in the prior art, still need to develop that a kind of technical process is simple, behaviour
Make convenience, low production cost, product purity height, process stabilizing, suitable industrialized production refined Eliquis method.
The content of the invention
In view of the deficiencies of the prior art, the present invention provides a kind of technical process is simple and convenient to operate, low production cost,
Product purity height, process stabilizing, be adapted to industrialized production refined Eliquis method.
The present invention relates to a kind of process for purification of high-purity Eliquis, it comprises the following steps：
(1) first step is dissolved, and Eliquis is dissolved in organic solvent, heating stirring to dissolving；
(2) second step decolourizes, and adds activated carbon backflow, and heat filtering collects filtrate；
(3) the 3rd step cooling crystallizations, filtrate are heated to flowing back, and naturally cool to precipitation white solid, stirring and crystallizing；
(4) the 4th step filtration dryings, filtering filter cake are washed with non-polar solven, drain and be dried under reduced pressure.
Preferably, the organic solvent described in step (1) is dichloromethane and alcohols mixed solvent, and the alcohols solvent is excellent
Select isopropanol, the tert-butyl alcohol；
Preferably, the mass ratio of solvent organic solvent and Eliquis described in step (1) is 5:1~10:1；
Preferably, it is 40~60 DEG C that dissolved clarification temperature is heated described in step (1).
Preferably, discoloration method is activated carbon decolorizing described in step (2), maintains the reflux for 0.1~1h, and activated carbon dosage is
The 1%-10% of the quality of Eliquis.
Preferably, cooling crystallization temperature described in step (3) is -5~10 DEG C, and the crystallization time is 5~24h.
Preferably, filtration drying process is described in step (4)：Filtering, 2~5 times of Eliquis quality of filter cake
N-hexane or normal heptane washing, drain filter cake, are dried under reduced pressure.
The beneficial effects of the present invention are：
Step (2) of the present invention is decolourized using activated carbon, and decolorizing effect is notable and can also effectively remove some impurity.
This subtractive process is further circulated, is more beneficial for improving refining effect, reaches strict quality standard.
It can be refined yield by product purity in Eliquis up to 99.5% more than and be not less than 90% by the inventive method.
Embodiment
In order that technical problem solved by the invention and beneficial effect are more clearly understood, it is with reference to embodiments, right
The present invention is further elaborated.
Embodiment one
By 20g Eliquis crude product and 90ml dichloromethane with 10ml isopropanols input reaction bulb, being warming up to 40 DEG C, solid is complete
Portion's dissolved clarification, activated carbon 0.5g is added, flow back 20min, is incubated 40 DEG C of filterings, collects filtrate.Filtrate is reheated to backflow,
Stop heating cooling to 0 DEG C, stirring and crystallizing 12 hours is filtered, and filter cake is washed with 50ml n-hexanes, done in 40 DEG C of vacuum
Dry 12 hours, obtain 18.9g Eliquis fine work.
Embodiment two
By 20g Eliquis crude product and 180ml dichloromethane with 20ml isopropanols input reaction bulb, being warming up to 42 DEG C, solid
Whole dissolved clarifications, activated carbon 0.5g is added, flow back 30min, insulation filtering, collects filtrate.Filtrate is reheated to backflow, stopped
Heating is cooled to 0 DEG C, and stirring and crystallizing 12 hours, filtering, filter cake is washed with 50ml n-hexanes, in 60 DEG C of vacuum drying 12
Hour, obtain 18.1g Eliquis fine work.
Embodiment three
By 20g Eliquis crude product and 150ml dichloromethane with 10ml tert-butyl alcohols input reaction bulb, being warming up to 40 DEG C, solid
Whole dissolved clarifications, activated carbon 0.5g is added, flow back 1h, is incubated 40 DEG C of filterings, collects filtrate.Filtrate is reheated to backflow, stopped
Only heating is cooled to 0 DEG C, and stirring and crystallizing 12 hours, filtering, filter cake is washed with 50ml normal heptanes, in 40 DEG C of vacuum drying
12 hours, obtain 18.3g Eliquis fine work.
The Eliquis refining effect data comparison of table 1
| Purity（HPLC） | Yield | |
| Embodiment 1 | 99.86% | 94.5% |
| Embodiment 2 | 99.61% | 90.5% |
| Embodiment 3 | 99.51% | 91.5% |
Claims (9)
1. a kind of process for purification of high-purity Eliquis, it is characterised in that it comprises the following steps：(1) first step dissolves,
Eliquis is dissolved in organic solvent, heating stirring to dissolving；(2) second step decolourizes, and adds activated carbon backflow, heat filtering
Collect filtrate；(3) the 3rd step cooling crystallizations, filtrate are heated to flowing back, and naturally cool to precipitation white solid, stirring and crystallizing；
(4) the 4th step filtration dryings, filtering filter cake are washed with non-polar solven, drain and be dried under reduced pressure.
2. according to the method for claim 1, it is characterised in that organic solvent described in step (1) is dichloromethane and alcohol
Class mixed solvent.
3. according to the method for claim 2, it is characterised in that the alcohols solvent is selected from isopropanol, the tert-butyl alcohol.
4. according to the method for claim 2, it is characterised in that the mass ratio of organic solvent and Eliquis in step (1)
For 5:1~10:1.
5. according to the method for claim 1, it is characterised in that it is 40~60 DEG C that dissolved clarification temperature is heated described in step (1).
6. according to the method for claim 1, it is characterised in that discoloration method described in step (2) is activated carbon decolorizing,
0.1~1h is maintained the reflux for, activated carbon dosage is the 1%-10% of the quality of Eliquis.
7. according to the method for claim 1, it is characterised in that cooling crystallization temperature described in step (3) is -5~10 DEG C.
8. according to the method for claim 1, it is characterised in that the cooling crystallization time described in step (3) is 5~24h.
9. according to the method for claim 1, it is characterised in that the filtration drying process described in step (4), the non-pole
Property solvent washing be selected from n-hexane or normal heptane, 40~60 DEG C of drying temperature.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610609546.6A CN107663205A (en) | 2016-07-29 | 2016-07-29 | A kind of process for purification of Eliquis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610609546.6A CN107663205A (en) | 2016-07-29 | 2016-07-29 | A kind of process for purification of Eliquis |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107663205A true CN107663205A (en) | 2018-02-06 |
Family
ID=61114589
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610609546.6A Pending CN107663205A (en) | 2016-07-29 | 2016-07-29 | A kind of process for purification of Eliquis |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107663205A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110615788A (en) * | 2019-10-17 | 2019-12-27 | 江西国药有限责任公司 | Preparation process of high-purity apixaban |
-
2016
- 2016-07-29 CN CN201610609546.6A patent/CN107663205A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110615788A (en) * | 2019-10-17 | 2019-12-27 | 江西国药有限责任公司 | Preparation process of high-purity apixaban |
| CN110615788B (en) * | 2019-10-17 | 2021-07-06 | 江西国药有限责任公司 | Preparation process of high-purity apixaban |
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Legal Events
| Date | Code | Title | Description |
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| PB01 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20180206 |
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| WD01 | Invention patent application deemed withdrawn after publication |