CN108164526A - A kind of preparation method of Eliquis impurity B - Google Patents
A kind of preparation method of Eliquis impurity B Download PDFInfo
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- CN108164526A CN108164526A CN201611124585.3A CN201611124585A CN108164526A CN 108164526 A CN108164526 A CN 108164526A CN 201611124585 A CN201611124585 A CN 201611124585A CN 108164526 A CN108164526 A CN 108164526A
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- preparation
- impurity
- eliquis
- reaction
- thf
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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)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses the invention discloses a kind of Eliquis（Apixaban）The preparation method of impurity B obtains Eliquis impurity B by alkylated reaction, amine transesterification（APIX‑Impurity B）, reaction solution improves yield and purity by the modes such as concentrating, purifying.It is easy to operate in the technical matters, purity is high.Pay attention to the research of quality control standard product reference substance simultaneously, it has also become the pith that drug Conformance Assessment is strict with has good market application value.Quality control for medicine for cardiovascular system Eliquis provides qualified reference substance.
Description
Technical field
The invention belongs to chemical fields, and in particular to a kind of preparation method of Eliquis impurity B.
Background technology
Eliquis（Apixaban, ELIQUIS) be a kind of oral Ⅹ factor inhibitors of Selective activation, by Pfizer with
Bristol Myers Squibb is developed jointly.Thrombus can be prevented and treated, the adverse reaction of bleeding is far smaller than old medicine.It is to face in more than 50 years
Main anticoagulant to be applied in bed practice.Eliquis impurity B is wherein important impurity, at present should without related data report
The synthesis of impurity, while be also that Eliquis carries out the impurity reference substance that quality analysis must have qualification.
Invention content
" range " disclosed herein is in the form of lower and upper limit.Can be respectively one or more lower limits and one
Or multiple upper limits.Given range is defined by selecting a lower limit and a upper limit.Selected lower and upper limit limit
The boundary of special range is determined.All ranges that can be defined in this way comprising and can combine, i.e., any lower limit
It can combine to form a range with any upper limit.For example, listing 60 ~ 150 ranges for special parameter, it is interpreted as 60 ~ 110
Range with 80 ~ 120 is also what is expected.
It is tied under DIPEA and DMF environment by contrast experiment by starting material SM-1 and SM-2 in step 1 of the present invention
Fruit, it is 80 DEG C to determine optimal reaction temperature, reaction time 8h.Reaction solution purifies to obtain target product by filtering, column chromatography.
By analyzing multigroup experimental result in step 1 of the present invention, it is 1 to select reactant molar ratio:1, reaction result is shown
Reaction is abundant.
It is DMF that solvent is selected in step 1 of the present invention, is laboratory common solvents, environmentally friendly small toxicity.Select DIPEA organic
Alkali is conducive to fully react.
It by step 1 reaction product in step 2 of the present invention, is reacted under the conditions of THF/NH3, keeps 80 DEG C of temperature, instead
It is 8h between seasonable.
Reactant molar ratio preferably 1 is used in step 2 of the present invention:3, the solvent tetrahydrochysene of the preferred middle polarity of reaction dissolvent
Furans has the characteristics that low toxicity, low boiling point, good fluidity.
Specific embodiment
Content for a better understanding of the present invention is described further with reference to specific embodiment, but not only office of the invention
It is limited to this.
Embodiment 1：The preparation of Eliquis impurity B intermediate product
1g SM-1 are added in 20mL round-bottomed flasks, sequentially add 0.8 mL DIPEA and 500 mg SM-2.By mixture temperature
Degree is increased to 80 DEG C, is stirred to react 8h.It shows what product was formed by thin-layer chromatography test, after reaction cools down reaction solution
To room temperature, filtering, column chromatography purify to obtain the desired intermediate TM-1 of 1g, purity 96%（Yield 85%）.
Embodiment 2：The preparation of Eliquis impurity B
1 g step 1 products obtained therefrom TM-1 is taken to be dissolved in 6mL THF/NH3 in 20mL round-bottomed flasks, mixture temperature is risen to
80 DEG C, react 8h.To the end of reaction, reaction solution is cooled to room temperature, shows what product was formed by thin-layer chromatography test.Reaction
Liquid is evaporated under reduced pressure, and column chromatography purifies to obtain 0.8g target product APXB-Impurity B, purity 97%（Yield 92%）.
Claims (6)
1. a kind of preparation method of tropsch imatinib related impurities, which is characterized in that including following reaction route：SM-1 is anti-with SM-2
Should, target product TM-1 is obtained by concentrating, purifying by reaction solution, by product TM-1 obtained above in THF/NH3Under the conditions of
Reaction, prepares target product APXB-ImpurityB。
2. the preparation method of Eliquis impurity B according to claim 1, which is characterized in that organic solvent in step 1
Methanol, ethyl alcohol, n-butanol, dichloromethane, N,N-dimethylformamide（DMF）, n,N-dimethylacetamide etc., preferably DMF.
3. the preparation method of Eliquis impurity B according to claim 1, which is characterized in that alkali described in step 1 is
Potassium carbonate, sodium hydroxide, sodium carbonate, potassium hydroxide, n,N-diisopropylethylamine（DIPEA）Deng preferably DIPEA.
4. the preparation method of Eliquis impurity B according to claim 1, which is characterized in that reactant rubs in step 1
You are than being 1：1~4；Reaction temperature is 60 DEG C ~ 150 DEG C, preferably 80 DEG C；Reaction time is 6 ~ 14h, preferably 8h.
5. the preparation method of Eliquis impurity B according to claim 1, which is characterized in that organic solvent in step 2
Methanol, ethyl alcohol, n-butanol, dichloromethane, N,N-dimethylformamide（DMF）, DMAC N,N' dimethyl acetamide, tetrahydrofuran
（THF）, water and said combination etc., preferably THF.
6. the preparation method of Eliquis impurity B according to claim 1, which is characterized in that reactant rubs in step 2
You are than being 1：2 ~ 7 reaction temperatures are 60 DEG C ~ 150 DEG C, preferably 80 DEG C；Reaction time is 6 ~ 14h, preferably 8h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611124585.3A CN108164526A (en) | 2016-12-08 | 2016-12-08 | A kind of preparation method of Eliquis impurity B |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611124585.3A CN108164526A (en) | 2016-12-08 | 2016-12-08 | A kind of preparation method of Eliquis impurity B |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108164526A true CN108164526A (en) | 2018-06-15 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611124585.3A Pending CN108164526A (en) | 2016-12-08 | 2016-12-08 | A kind of preparation method of Eliquis impurity B |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108164526A (en) |
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2016
- 2016-12-08 CN CN201611124585.3A patent/CN108164526A/en active Pending
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| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20180615 |