CN110372665A - A kind of preparation method of Eliquis pyridone impurity - Google Patents
A kind of preparation method of Eliquis pyridone impurity Download PDFInfo
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- CN110372665A CN110372665A CN201910733938.7A CN201910733938A CN110372665A CN 110372665 A CN110372665 A CN 110372665A CN 201910733938 A CN201910733938 A CN 201910733938A CN 110372665 A CN110372665 A CN 110372665A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of preparation methods of Eliquis pyridone impurity, including two steps: first step condensation and cyclization reaction: 1- (4- aminophenyl) -5, -2 (1H) - pyridone of 6- dihydro -3- (4- morpholine) and compound 5-Chlorovaleryl Chloride are by condensation and cyclization reaction preparation 5,6- dihydro -3- (4- morpholinyl) -1- [4- (2- oxo -1- piperidyl) phenyl] -2 (1H) - pyridones；The reaction of second step dehydrogenation oxidation: APSB-1 is reacted by the chloro- 5,6- dicyanoquinone dehydrogenation oxidation of 2,3- bis- is made object；It is an object of the invention to provide a kind of efficient, high yield, high-purity method for preparing Eliquis pyridone impurity for the first time, it can be studied for the related substance of Eliquis and substance and quality assurance are provided, declared registration for subsequent correlation and strong data support is provided.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, are related to a kind of Eliquis key intermediate impurity (i.e. Eliquis
Pyridone impurity) efficient, high yield, the preparation method of high-purity.
Background technique
Eliquis (Apixaban) is a kind of oral Selective activation X factor inhibitors, is applied by Pfizer and U.S.A when hundred
Your treasured is developed jointly.Obtain the import drug permit that state food and drug administration issues in January, 2013, in
In April, 2013 is formally in Discussion on Chinese Listed.
Eliquis is new oral anticoagulant, and compared to other drugs, it has effectively prevention venous thromboembolism
Disease does not increase bleeding risk simultaneously, is not necessarily to routine monitoring coagulation function, also adjusts without dosage, is clinically mainly used for preventing
With the drug for the treatment of thrombus.
The main synthetic route of Eliquis have been reported (1.Monatshefte fuer Chemie, 2017,148,
1477；2.US20170015663；3.WO2017013079；4.EP3064497；5.WO2016035007；6.CN101967145
Deng) it is as follows: mainly by compound SM-1 (1- (4- aminophenyl) -5,6- dihydro -3- (4- morpholine) -2 (1H)-pyridine
Ketone) and compound SM-2 (5-Chlorovaleryl Chloride) condensation and cyclization generation key intermediate APSB-1 (5,6- dihydro -3- (4- morpholine
Base) -1- [4- (2- oxo -1- piperidyl) phenyl] -2 (1H)-pyridones), then with SM-3 ([(4- methoxyphenyl) diazanyl]
Ethyl chloroacetate) reaction generation intermediate A PSB-2 (1- (4- methoxyphenyl) -7- oxo -6- [4- (2- oxo-piperidine -1-
Base) phenyl] -4,5,6,7- tetrahydro -1H- pyrazolo [3,4-c] pyridine-3-carboxylic acid ethyl esters), ammonolysis finally, which is carried out, with formamide obtains
To Eliquis.Dihydro pyrrole during preparing key intermediate APSB-1 by SM-1 and SM-2 reaction, in APSB-1 structure
Pyridine ketone ring is easy to oxidative dehydrogenation and generates pyridone impurity.
Impurity of the drug is most important in pharmaceutical process research, so to the above-mentioned miscellaneous Quality Research of Eliquis pyridone
It is very necessary.But there is not document report for the preparation of Eliquis pyridone impurity at present.
Summary of the invention
The present invention provides a kind of preparation methods of Eliquis pyridone impurity, it is characterised in that: including two steps:
First step condensation and cyclization reaction: 1- (4- aminophenyl) -5,6- dihydro -3- (4- morpholine) -2 (1H)-pyridone (letter
Claim SM-1) and compound 5-Chlorovaleryl Chloride (abbreviation SM-2) by condensation and cyclization reaction prepare 5,6- dihydro -3- (4- morpholinyl) -
1- [4- (2- oxo -1- piperidyl) phenyl] -2 (1H)-pyridones (abbreviation APSB-1)；
The reaction of second step dehydrogenation oxidation: APSB-1 passes through chloro- 5,6- dicyanoquinone (abbreviation DDQ) dehydrogenation oxidation of 2,3- bis-
It reacts and object is made, reaction equation is as follows:
The preparation method of a kind of Eliquis pyridone impurity, it is characterised in that: in condensation and cyclization reaction
SM-1:SM-2 mass ratio=1:0.69；
SM-1: triethylamine: sodium ethoxide mass ratio=1:0.46:1.29；
Reaction temperature is 10-30 DEG C.
The preparation method of a kind of Eliquis pyridone impurity, it is characterised in that: in dehydrogenation oxidation reaction
APSB-1:DDQ mass ratio=1:1.28；
Reaction temperature is 50-150 DEG C.
The preparation method of a kind of Eliquis pyridone impurity, it is characterised in that the reaction of dehydrogenation oxidation reaction is molten
Agent is methylene chloride, dioxane, dimethylbenzene, chlorobenzene.
The preparation method of a kind of Eliquis pyridone impurity, it is characterised in that the reaction of dehydrogenation oxidation reaction is molten
Agent is dioxane.
It is an object of the invention to provide for the first time it is a kind of efficiently, high yield, high-purity prepare Eliquis pyridone
The method of impurity.Impurity studies the most important thing in being new drug research now and declaring and works, the necessary thoroughly research of impurity, synthesis
The pyridone impurity of preparation can be studied for the related substance of Eliquis and provide substance and quality assurance, for subsequent related Shen
Report registration provides strong data and supports.
Specific embodiment
It will be helpful to understand the present invention by specific example below, but this is not as limitation of the present invention.
Embodiment 1:
150mL methylene chloride, 1.6g triethylamine and 3.5g raw material SM-1 are added into tetra- mouthfuls of reaction flasks of 250mL.Under ice bath
Dropwise addition 2.4g raw material SM-2, is added dropwise and finishes, and controls interior warm 10-30 DEG C insulated and stirred 1 hour, then by 4.5g sodium ethoxide solid, adds
Enter in reaction flask.10-30 DEG C of insulated and stirred is warming up to react 2 hours.Drinking water 100mL is added after having reacted, stirs 30 minutes
After pour into layering in separatory funnel, upper layer aqueous is extracted one time with 100mL methylene chloride, is merged lower layer's organic phase and is concentrated to get
APSB-1 solid 5.2g.
Above-mentioned APSB-1 solid 5.2g will be added in 250mL reaction flask, chloro- 5, the 6- dicyanoquinone of 2,3- bis- is added
Methylene chloride 150mL is added in 6.67g, and nitrogen is replaced three times, is warming up to 50 DEG C and flows back 24 hours, is down to room temperature after having reacted, adds
Enter 150mL saturated sodium carbonate solution, layering is primary with 150mL methylene chloride aqueous layer extracted, merges organic layer, and anhydrous sodium sulfate is dry
It is dry, it is concentrated to give solid, column chromatography (petroleum ether: ethyl acetate=3:1-1:5) isolates and purifies to obtain faint yellow solid pyridone impurity
3.1g.HPLC:99.02%；ESI-MS m/z=353.9 ([M+H]+), 376.0 ([M+Na]+), 707.2 ([2M+H]+),
729.1([2M+Na]+)；1H-NMR(CDCl3, 400MHz): δ ppm:7.38-7.44 (m, 4H), 7.15-7.24 (m, 2H),
6.37-6.41 (m, 1H), 3.92-3.98 (m, 4H), 3.70-3.73 (t, 2H), 3.35-3.36 (m, 4H), 2.66-2.69 (m,
2H), 2.00-2.01 (m, 4H).
Embodiment 2:
150mL methylene chloride, 1.6g triethylamine and 3.5g raw material SM-1 are added into tetra- mouthfuls of reaction flasks of 250mL.Under ice bath
Dropwise addition 2.4g raw material SM-2, is added dropwise and finishes, and controls interior warm 10-30 DEG C insulated and stirred 1 hour, then by 4.5g sodium ethoxide solid, adds
Enter in reaction flask.10-30 DEG C of insulated and stirred is warming up to react 2 hours.Drinking water 100mL is added after having reacted, stirs 30 minutes
After pour into layering in separatory funnel, upper layer aqueous is extracted one time with 100mL methylene chloride, is merged lower layer's organic phase and is concentrated to get
APSB-1 solid 5.1g.
Above-mentioned APSB-1 solid 5.1g will be added in 100mL reaction flask, chloro- 5, the 6- dicyanoquinone of 2,3- bis- is added
Dioxane 50mL is added in 6.54g, and nitrogen is replaced three times, is warming up to 110 DEG C and flows back 24 hours, room temperature is down to after having reacted, will
Above-mentioned reaction solution pours into 150mL ice water, and a large amount of solids are precipitated filtration dryings and obtain solid, column chromatography (petroleum ether: ethyl acetate=
3:1-1:5) isolate and purify to obtain faint yellow solid pyridone impurity 3.6g.HPLC:97.69%；ESI-MS m/z=353.9 ([M+
H]+),376.0([M+Na]+),707.2([2M+H]+),729.1([2M+Na]+)；1H-NMR(CDCl3, 400MHz): δ ppm:
7.38-7.44 (m, 4H), 7.15-7.24 (m, 2H), 6.37-6.41 (m, 1H), 3.92-3.98 (m, 4H), 3.70-3.73 (t,
2H), 3.35-3.36 (m, 4H), 2.66-2.69 (m, 2H), 2.00-2.01 (m, 4H).
Embodiment 3:
150mL methylene chloride, 1.6g triethylamine and 3.5g raw material SM-1 are added into tetra- mouthfuls of reaction flasks of 250mL.Under ice bath
Dropwise addition 2.4g raw material SM-2, is added dropwise and finishes, and controls interior warm 10-30 DEG C insulated and stirred 1 hour, then by 4.5g sodium ethoxide solid, adds
Enter in reaction flask.10-30 DEG C of insulated and stirred is warming up to react 2 hours.Drinking water 100mL is added after having reacted, stirs 30 minutes
After pour into layering in separatory funnel, upper layer aqueous is extracted one time with 100mL methylene chloride, is merged lower layer's organic phase and is concentrated to get
APSB-1 solid 5.2g.
Above-mentioned APSB-1 solid 5.2g will be added in 250mL reaction flask, chloro- 5, the 6- dicyanoquinone of 2,3- bis- is added
Dimethylbenzene 150mL is added in 6.67g, and nitrogen is replaced three times, is warming up to 150 DEG C and flows back 24 hours, is down to room temperature after having reacted, adds
Enter 150mL saturated sodium carbonate solution, layering is primary with 150mL ethyl acetate aqueous layer extracted, merges organic layer, and anhydrous sodium sulfate is dry
It is dry, it is concentrated to give solid, column chromatography (petroleum ether: ethyl acetate=3:1-1:5) isolates and purifies to obtain faint yellow solid pyridone impurity
3.4g.HPLC:98.37%；ESI-MS m/z=353.9 ([M+H]+), 376.0 ([M+Na]+), 707.2 ([2M+H]+),
729.1([2M+Na]+)；1H-NMR(CDCl3, 400MHz): δ ppm:7.38-7.44 (m, 4H), 7.15-7.24 (m, 2H),
6.37-6.41 (m, 1H), 3.92-3.98 (m, 4H), 3.70-3.73 (t, 2H), 3.35-3.36 (m, 4H), 2.66-2.69 (m,
2H), 2.00-2.01 (m, 4H).
Embodiment 4:
150mL methylene chloride, 1.6g triethylamine and 3.5g raw material SM-1 are added into tetra- mouthfuls of reaction flasks of 250mL.Under ice bath
Dropwise addition 2.4g raw material SM-2, is added dropwise and finishes, and controls interior warm 10-30 DEG C insulated and stirred 1 hour, then by 4.5g sodium ethoxide solid, adds
Enter in reaction flask.10-30 DEG C of insulated and stirred is warming up to react 2 hours.Drinking water 100mL is added after having reacted, stirs 30 minutes
After pour into layering in separatory funnel, upper layer aqueous is extracted one time with 100mL methylene chloride, is merged lower layer's organic phase and is concentrated to get
APSB-1 solid 5.2g.
Above-mentioned APSB-1 solid 5.2g will be added in 250mL reaction flask, chloro- 5, the 6- dicyanoquinone of 2,3- bis- is added
Chlorobenzene 150mL is added in 6.67g, and nitrogen is replaced three times, is warming up to 150 DEG C and flows back 24 hours, room temperature is down to after having reacted, is added
150mL saturated sodium carbonate solution, layering is primary with 150mL ethyl acetate aqueous layer extracted, merges organic layer, and anhydrous sodium sulfate is dry
It is dry, it is concentrated to give solid, column chromatography (petroleum ether: ethyl acetate=3:1-1:5) isolates and purifies to obtain faint yellow solid pyridone impurity
3.6g.HPLC:98.68%；ESI-MS m/z=353.9 ([M+H]+),376.0([M+Na]+),707.2([2M+H]+),
729.1([2M+Na]+)；1H-NMR(CDCl3, 400MHz): δ ppm:7.38-7.44 (m, 4H), 7.15-7.24 (m, 2H),
6.37-6.41 (m, 1H), 3.92-3.98 (m, 4H), 3.70-3.73 (t, 2H), 3.35-3.36 (m, 4H), 2.66-2.69 (m,
2H), 2.00-2.01 (m, 4H).
Claims (5)
1. a kind of preparation method of Eliquis pyridone impurity, it is characterised in that: including two steps:
The reaction of first step condensation and cyclization: 1- (4- aminophenyl) -5,6- dihydro -3- (4- morpholine) -2 (1H)-pyridone is (referred to as
SM-1) and compound 5-Chlorovaleryl Chloride (abbreviation SM-2) is by condensation and cyclization reaction preparation 5,6- dihydro -3- (4- morpholinyl) -1-
[4- (2- oxo -1- piperidyl) phenyl] -2 (1H)-pyridones (abbreviation APSB-1)；
The reaction of second step dehydrogenation oxidation: APSB-1 is reacted by chloro- 5,6- dicyanoquinone (abbreviation DDQ) dehydrogenation oxidation of 2,3- bis-
Object is made, reaction equation is as follows:
2. a kind of preparation method of Eliquis pyridone impurity according to claim 1, it is characterised in that: condensation and cyclization
In reaction
SM-1:SM-2 mass ratio=1:0.69；
SM-1: triethylamine: sodium ethoxide mass ratio=1:0.46:1.29；
Reaction temperature is 10-30 DEG C.
3. a kind of preparation method of Eliquis pyridone impurity according to claim 1, it is characterised in that: dehydrogenation oxidation
In reaction
APSB-1:DDQ mass ratio=1:1.28；
Reaction temperature is 50-150 DEG C.
4. a kind of preparation method of Eliquis pyridone impurity according to claim 1, it is characterised in that dehydrogenation oxidation
The reaction dissolvent of reaction is methylene chloride, dioxane, dimethylbenzene, chlorobenzene.
5. a kind of preparation method of Eliquis pyridone impurity according to claim 1, it is characterised in that dehydrogenation oxidation
The reaction dissolvent of reaction is dioxane.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111116553A (en) * | 2019-12-10 | 2020-05-08 | 北京鑫开元医药科技有限公司 | Preparation method of dihydropyridone derivatives |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111116553A (en) * | 2019-12-10 | 2020-05-08 | 北京鑫开元医药科技有限公司 | Preparation method of dihydropyridone derivatives |
| CN111116553B (en) * | 2019-12-10 | 2022-02-08 | 北京鑫开元医药科技有限公司 | Preparation method of dihydropyridone derivatives |
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Application publication date: 20191025 |