CN106117200B - Prevention or the preparation method for the treatment of joint replacement phlebothrombosis medicine Eliquis - Google Patents
Prevention or the preparation method for the treatment of joint replacement phlebothrombosis medicine Eliquis Download PDFInfo
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- CN106117200B CN106117200B CN201610480815.3A CN201610480815A CN106117200B CN 106117200 B CN106117200 B CN 106117200B CN 201610480815 A CN201610480815 A CN 201610480815A CN 106117200 B CN106117200 B CN 106117200B
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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
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Abstract
The invention discloses the preparation method for preventing or treating joint replacement phlebothrombosis medicine Eliquis, this method includes：1) will to methoxyl group phenylhydrazine and glyoxylic acid ethyl ester, cuprous bromide catalytic reaction, reaction terminate filtering, borane dimethyl sulphide complex compound are added in filtrate in the presence of a base, then add the compound shown in Formulas I and be stirred hybrid reaction and obtain reactant mixture L；2) the reactant mixture L that step 1) obtains is stirred in acid condition；3) 1 (4 methoxyphenyl) 7 oxo 6 [4 (base 3 of 2 oxo-piperidine 1) phenyl] 4 obtained step 1), 5, the Ethyl formate of 6,7 tetrahydrochysene 1H pyrazoles [3,4 c] pyridine 3 carries out ammonolysis and obtains Eliquis；
Description
Technical field
The invention belongs to pharmaceutical synthesis field, in particular it relates to prevent or treat joint replacement phlebothrombosis medicine Ah piperazine
The preparation method of husky class
Background technology
Eliquis (Apixaban), entitled 1- (4- the methoxyphenyls) -7- oxos -6- of chemistry [4- (2- oxo-piperidines -
1- bases 3) phenyl] -4,5,6,7- tetrahydrochysene -1H- pyrazoles [3,4-c] pyridine-3-carboxamides, for preventing and treating hip joint or knee
The vein bolt embolism occurred in joint replacement.Eliquis is by Mei-Shi Guibao companies when hundred and Pfizer's joint development
The direct inhibitor of new Xa factor, concrete structure is as follows：
At present, the synthetic method report on Eliquis is a lot, but the problem of many all also be present in these methods.
WO2010/030983 discloses a kind of synthetic method of Eliquis, and this method P-nethoxyaniline is former for starting
Material is condensed by diazotising and then with chloro ethyl acetoacetate, and diazo-reaction condition harshness and has safety at (stringent low-temperature)
Risk, be not suitable for industrialized production, and the nonreactive yield is relatively low；Because annulation is former using iodo in this method
Material, therefore intermediate product A has to purify, complex steps；In addition, this method final step and ammonia are in ethylene glycol high temperature (120
DEG C) the ammonolysis yield that obtains Eliquis only has 27% or so, the industrial applications of this method are seriously constrained, specifically synthesize road
Line is as follows：
CN103626759B discloses a kind of preparation method of the intermediate of Eliquis, and this method is using dichloromethane to be molten
Agent, under reflux conditions, in the presence of organic base, compound 3 and 4 is reacted；Then the continuation for adding inorganic acid is anti-
Should be so as to obtaining the intermediate of Eliquis.But this method does not have the preparation method and the compound for providing compound 4
Uncommon in commercially available product, price is higher so that the process costs are higher.Other this method also exist the reaction time it is long and
The problem of yield is general.Specific synthetic route is as follows：
Therefore, this area still needs to the preparation side of the simple Eliquis of a kind of low cost, mild condition, high income, step
Method.
The content of the invention
It is an object of the invention to overcome in the existing method for preparing Eliquis, yield is low, condition is harsh and step
Cumbersome, the defects of cost is high, there is provided a kind of cost is low, mild condition, high income and the simple antithrombotic reagent Ah piperazine of step are husky
The preparation method of class.
To achieve these goals, the present invention provides the system of prevention or treatment joint replacement phlebothrombosis medicine Eliquis
Preparation Method, this method comprise the following steps：
1) will be to methoxyl group phenylhydrazine and glyoxylic acid ethyl ester cuprous bromide catalytic reaction in the presence of a base, after reaction terminates, mistake
Filter, borane dimethyl sulphide complex compound is added in filtrate, the compound shown in Formulas I is then added and is stirred hybrid reaction extremely
Compound reaction shown in Formulas I is complete, obtains reactant mixture L；
2) the reactant mixture L that step 1) obtains is stirred in acid condition, obtains 1- (4- methoxyphenyls) -7- oxygen
Generation -6- [4- (2- oxo-piperidine -1- bases 3) phenyl] -4,5,6,7- tetrahydrochysene -1H- pyrazoles [3,4-c] Nicotinicum Acidum ethyl ester；
3) 1- (4- the methoxyphenyls) -7- oxos -6- [4- (2- oxo-piperidine -1- bases 3) phenyl] obtained step 1) -
4,5,6,7- tetrahydrochysene -1H- pyrazoles [3,4-c] Nicotinicum Acidums ethyl ester carries out ammonolysis and obtains Eliquis；
Preferably, glyoxylic acid ethyl ester with to methoxyl group phenylhydrazine, alkali, cuprous bromide, borane dimethyl sulphide complex compound, Formulas I
The dosage mol ratio of shown compound is 1：1.2~1.5：2~3：0.1~0.2：1.5~1.8：0.7~0.9.
In the present invention, in order to further improve the yield of ammonolysis and efficiency, glyoxylic acid ethyl ester with to methoxyl group phenylhydrazine,
Alkali, cuprous bromide, borane dimethyl sulphide complex compound, the dosage mol ratio of compound shown in Formulas I are 1：1.5：2：0.1~
0.2：1.6：0.8.
In the present invention, inventor has found that while that conventional alkali can also be completed to react, but the more accessory substance of yield is also more, excellent
Selection of land, the alkali are piperidines or nafoxidine.
Preferably, also include adding in the catalytic reaction of step 1)Molecular sieve.It is further preferred that by weight, institute
StateThe addition of molecular sieve is 0.8~1.3 times of glyoxylic acid ethyl ester weight.
Under preferable case, the temperature of step 1) catalytic reaction is 35~45 DEG C, borane dimethyl sulphide complex compound and Formulas I institute
The addition temperature for the compound shown is 20~25 DEG C, and the temperature for mixing hybrid reaction is 60~80 DEG C, catalytic reaction and is stirred
The solvent of reaction is DMF.
Preferably, the feed postition of the compound shown in step 1) Formulas I is the DMF solution that the compound shown in Formulas I is added dropwise.
In the present invention, step 2) reactant mixture L is stirred in acid condition, in order to removes step 1) product
In morpholine molecule, acid condition can be to add acid solution, such as hydrochloric acid, phosphoric acid, acetic acid etc..Step 2) is preferably in low temperature
Lower progress, such as -10~10 DEG C.
In the present invention, the ammonolysis of step 3) is not particularly limited, and can use ammonolysis method of the prior art,
Such as the method in CN104628724A, detailed process can be：By 1- (4- methoxyphenyls) -7- oxos -6- [4- (2- oxygen
For piperidin-1-yl 3) phenyl] -4,5,6,7- tetrahydrochysene -1H- pyrazoles [3,4-c] Nicotinicum Acidum ethyl esters are added sequentially to ethanol
It is closed in stainless steel pressure kettle, ammonia is passed through, is heated to 60 DEG C, holding pressure is 0.3Mpa, is reacted 8 hours, stops reaction.Instead
Answer kettle to be opened after being cooled to room temperature, filter, filter cake is washed with ethanol, and Eliquis white solid is obtained after drying.
In order to avoid air etc. must influence on reacting, reaction yield and efficiency are further improved, the haptoreaction and de-
Hydrogen reaction is carried out all in the presence of protective gas, and the protective gas is nitrogen, helium or argon gas.
In the present invention, the conventional method in this area can be used to be monitored tracking to reacting, such as TLC, LCMS,
GCMS etc., reaction finish refer to TLC monitor not excess raw material disappeared or LCMS, GCMS in not excess raw material residue be less than
2%.
The Eliquis that the method for the present invention obtains, can be prepared into respectively with reference to this area conventional technical means as needed
The Eliquis of kind crystal formation.
The specific route that the present invention prepares the method for Eliquis is as follows：
Compared with prior art, using the method provided by the invention for preparing Eliquis, using mild condition, using pair
Methoxybenzene trap is initiation material, and " one kettle way " generation pyrazole ring product, technique is simpler, and cost substantially reduces, and keeps away
The widely used diazo-reaction of prior art is exempted from；And yield also greatly improves.
Other features and advantages of the present invention will be described in detail in subsequent specific embodiment part.
Embodiment
With reference to specific embodiment, the present invention is expanded on further.But these embodiments be only limitted to explanation the present invention without
It is the further restriction to protection scope of the present invention.
Embodiment 1
1- (4- methoxyphenyls) -7- oxos -6- [4- (2- oxo-piperidine -1- bases 3) phenyl] -4,5,6,7- tetrahydrochysenes -1H-
The preparation of pyrazoles [3,4-c] Nicotinicum Acidum ethyl ester
1), will be to methoxyl group phenylhydrazine 20.7g (150mmol), glyoxylic acid ethyl ester 10.2g (100mmol), alkali under nitrogen protection
17g (piperidines),Molecular sieve 10.2g and cuprous bromide 2.8g (20mmol) is added to 40 DEG C of progress catalytic reactions in flask,
After reaction terminates, filtering, 20 DEG C add borane dimethyl sulphide complex compound (2.0M in THF, dimethyl containing borine into filtrate
Thioether complex compound 12.2g) and Formulas I shown in compound (DMF solution, containing the compound 28.4g shown in Formulas I), then heat up
It is complete to the 80 DEG C of compound being stirred shown in hybrid reaction to Formulas I reactions, obtain reactant mixture L；
2) the reactant mixture L for obtaining step 1) adds stirring reaction 2.5 hours, dichloro in 100ml 4MHCl frozen water
Methane extracts, organic phase concentration, washing three times, then re-crystallizing in ethyl acetate, dry 1- (4- methoxyphenyls) -7- oxygen
Generation -6- [4- (2- oxo-piperidine -1- bases 3) phenyl] -4,5,6,7- tetrahydrochysene -1H- pyrazoles [3,4-c] Nicotinicum Acidum ethyl ester
34.2g, yield 87.4%, purity 99.41% (HPLC).
Embodiment 2
1- (4- methoxyphenyls) -7- oxos -6- [4- (2- oxo-piperidine -1- bases 3) phenyl] -4,5,6,7- tetrahydrochysenes -1H-
The preparation of pyrazoles [3,4-c] Nicotinicum Acidum ethyl ester
1), will be to methoxyl group phenylhydrazine 19.3g (140mmol), glyoxylic acid ethyl ester 10.2g (100mmol), alkali under nitrogen protection
25.5g (piperidines),Molecular sieve 8.2g and cuprous bromide 1.4g (10mmol) be added in flask 35 DEG C be catalyzed it is anti-
Should, after reaction terminates, filtering, 20 DEG C add borane dimethyl sulphide complex compound (2.0M in THF, containing borine two into filtrate
Dimethyl sulfide complex compound 13.7g) and Formulas I shown in compound (DMF solution, containing the compound 24.9g shown in Formulas I), then
It is complete to be warming up to the 60 DEG C of compound being stirred shown in hybrid reaction to Formulas I reactions, obtains reactant mixture L；
2) the reactant mixture L for obtaining step 1) adds stirring reaction 2.5 hours, dichloro in 100ml 4MHCl frozen water
Methane extracts, organic phase concentration, washing three times, then re-crystallizing in ethyl acetate, dry 1- (4- methoxyphenyls) -7- oxygen
Generation -6- [4- (2- oxo-piperidine -1- bases 3) phenyl] -4,5,6,7- tetrahydrochysene -1H- pyrazoles [3,4-c] Nicotinicum Acidum ethyl ester
28.6g, yield 83.7%, purity 99.61% (HPLC).
Embodiment 3
1- (4- methoxyphenyls) -7- oxos -6- [4- (2- oxo-piperidine -1- bases 3) phenyl] -4,5,6,7- tetrahydrochysenes -1H-
The preparation of pyrazoles [3,4-c] Nicotinicum Acidum ethyl ester
1), will be to methoxyl group phenylhydrazine 16.6g (120mmol), glyoxylic acid ethyl ester 10.2g (100mmol), alkali under nitrogen protection
17.8g (nafoxidine),Molecular sieve 13.3g and cuprous bromide 2.2g (15mmol) is added in flask 45 DEG C and urged
Change reaction, after reaction terminates, filtering, 25 DEG C add borane dimethyl sulphide complex compound (2.0M in THF, boracic into filtrate
Alkane dimethyl sulfide complex 11.4g) and Formulas I shown in compound (DMF solution, containing the compound 31.9g shown in Formulas I),
It is complete to then heat to the 70 DEG C of compound being stirred shown in hybrid reaction to Formulas I reactions, obtains reactant mixture L；
2) the reactant mixture L for obtaining step 1) adds stirring reaction 2.5 hours, dichloromethane in 100ml4MHCl frozen water
Alkane extracts, organic phase concentration, washing three times, then re-crystallizing in ethyl acetate, dry 1- (4- methoxyphenyls) -7- oxos -
6- [4- (2- oxo-piperidine -1- bases 3) phenyl] -4,5,6,7- tetrahydrochysene -1H- pyrazoles [3,4-c] Nicotinicum Acidum ethyl ester 36.5g,
Yield is 83.1%, purity 99.42% (HPLC).
Embodiment 4
Such as 1- (4- the methoxyphenyls) -7- oxos -6- [4- (2- oxo-piperidine -1- bases 3) phenyl] -4 in embodiment 1,
The preparation of 5,6,7- tetrahydrochysene -1H- pyrazoles [3,4-c] Nicotinicum Acidum ethyl esters, except that, without usingMolecular sieve, do
It is dry to obtain 1- (4- methoxyphenyls) -7- oxos -6- [4- (2- oxo-piperidine -1- bases 3) phenyl] -4,5,6,7- tetrahydrochysene -1H- pyrazoles
[3,4-c] Nicotinicum Acidum ethyl ester 31.7g, yield 81.0%, purity 99.10% (HPLC).
Embodiment 5
The preparation of Eliquis
By 1- (4- methoxyphenyls) -7- oxos -6- [4- (2- oxo-piperidine -1- bases 3) phenyl] -4,5,6,7- tetrahydrochysenes -
1H- pyrazoles [3,4-c] Nicotinicum Acidum ethyl ester 4.9g, 150ml ethanol is added sequentially in stainless steel pressure kettle, closed, is passed through
Ammonia, 60 DEG C are warming up to, keep pressure to be reacted in 0.3Mpa, reaction 8 hours, stopping, being cooled to room temperature, open reactor, mistake
Filter, filter cake washs with ethanol, dry Eliquis 4.2g, yield 91.7%, purity 98.41% (HPLC).
Comparative example 1
Such as 1- (4- the methoxyphenyls) -7- oxos -6- [4- (2- oxo-piperidine -1- bases 3) phenyl] -4 in embodiment 1,
The preparation of 5,6,7- tetrahydrochysene -1H- pyrazoles [3,4-c] Nicotinicum Acidum ethyl esters, except that, without using cuprous bromide, dry
Obtain 1- (4- methoxyphenyls) -7- oxos -6- [4- (2- oxo-piperidine -1- bases 3) phenyl] -4,5,6,7- tetrahydrochysene -1H- pyrazoles
[3,4-c] Nicotinicum Acidum ethyl ester 24.1g, yield 61.7%, purity 99.70% (HPLC).
Comparative example 2
Such as 1- (4- the methoxyphenyls) -7- oxos -6- [4- (2- oxo-piperidine -1- bases 3) phenyl] -4 in embodiment 1,
The preparation of 5,6,7- tetrahydrochysene -1H- pyrazoles [3,4-c] Nicotinicum Acidum ethyl esters, except that, without using borine dimethyl disulfide
Ether complexes, dry 1- (4- methoxyphenyls) -7- oxos -6- [4- (2- oxo-piperidine -1- bases 3) phenyl] -4,5,6,7-
Tetrahydrochysene -1H- pyrazoles [3,4-c] Nicotinicum Acidum ethyl ester 13.9g, yield 35.7%, purity 99.70% (HPLC).
The preferred embodiment of the present invention described in detail above, still, the present invention are not limited in above-mentioned embodiment
Detail, in the range of the technology design of the present invention, a variety of simple variants can be carried out to technical scheme, this
A little simple variants belong to protection scope of the present invention.
It is further to note that each particular technique feature described in above-mentioned embodiment, in not lance
In the case of shield, can be combined by any suitable means, in order to avoid unnecessary repetition, the present invention to it is various can
The combination of energy no longer separately illustrates.In addition, any group can also be carried out between a variety of embodiments of the present invention
Close, as long as it without prejudice to the thought of the present invention, it should equally be considered as content disclosed in this invention.
Claims (5)
1. prevention or the preparation method for the treatment of joint replacement phlebothrombosis medicine Eliquis, it is characterised in that this method includes
Following steps：
1）Methoxyl group phenylhydrazine and glyoxylic acid ethyl ester cuprous bromide catalytic reaction in the presence of a base after reaction terminates, will be filtered, filter
Borane dimethyl sulphide complex compound is added in liquid, the compound shown in Formulas I is then added and is stirred hybrid reaction to Formulas I institute
The compound reaction shown is complete, obtains reactant mixture L；Glyoxylic acid ethyl ester with to methoxyl group phenylhydrazine, alkali, cuprous bromide, borine two
The dosage mol ratio of compound shown in Dimethyl sulfide complex compound, Formulas I is 1：1.2~1.5：2~3：0.1~0.2：1.5~1.8：0.7
~0.9；
2）By step 1）Obtained reactant mixture L is stirred in acid condition, obtain 1- (4- methoxyphenyls) -7- oxos -
6- [4- (2- oxo-piperidine -1- bases 3) phenyl] -4,5,6,7- tetrahydrochysene -1H- pyrazoles [3,4-c] Nicotinicum Acidum ethyl ester；
3）By step 1）Obtained 1- (4- methoxyphenyls) -7- oxos -6- [4- (2- oxo-piperidine -1- bases 3) phenyl] -4,5,
6,7- tetrahydrochysene -1H- pyrazoles [3,4-c] Nicotinicum Acidums ethyl ester carries out ammonolysis and obtains Eliquis；
The alkali is piperidines or nafoxidine；Step 1）The temperature of catalytic reaction is 35 ~ 45 DEG C, borane dimethyl sulphide complex compound
Addition temperature with the compound shown in Formulas I is 20 ~ 25 DEG C, and the temperature for mixing hybrid reaction is 60 ~ 80 DEG C, catalytic reaction and stirring
The solvent of hybrid reaction is DMF；
。
2. according to the method for claim 1, it is characterised in that glyoxylic acid ethyl ester with to methoxyl group phenylhydrazine, alkali, protobromide
Copper, borane dimethyl sulphide complex compound, the dosage mol ratio of compound shown in Formulas I are 1：1.5：2：0.2：1.6：0.8.
3. according to the method for claim 1, it is characterised in that step 1）Catalytic reaction in also include add 4 molecules
Sieve；By weight, the addition of 4 molecular sieve is 0.8 ~ 1.3 times of glyoxylic acid ethyl ester weight.
4. according to the method for claim 1, it is characterised in that step 1）The feed postition of compound shown in Formulas I is drop
Add the DMF solution of the compound shown in Formulas I.
5. according to the method described in any one in claim 1-4, it is characterised in that be stirred reaction and deposited in protective gas
In lower progress, the protective gas is nitrogen, helium or argon gas.
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| CN201610480815.3A CN106117200B (en) | 2016-06-27 | 2016-06-27 | Prevention or the preparation method for the treatment of joint replacement phlebothrombosis medicine Eliquis |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1639147A (en) * | 2001-12-10 | 2005-07-13 | 布里斯托尔-迈尔斯斯奎布公司 | Synthesis of 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones |
| WO2014072884A1 (en) * | 2012-11-12 | 2014-05-15 | Alembic Pharmaceuticals Limited | Process for the synthesis of apixaban |
| CN104892601A (en) * | 2015-06-09 | 2015-09-09 | 江苏中邦制药有限公司 | Preparation method of antithrombotic drug Apixaban |
| CN105254630A (en) * | 2015-11-16 | 2016-01-20 | 江苏康缘药业股份有限公司 | Preparing method for apixaban |
-
2016
- 2016-06-27 CN CN201610480815.3A patent/CN106117200B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1639147A (en) * | 2001-12-10 | 2005-07-13 | 布里斯托尔-迈尔斯斯奎布公司 | Synthesis of 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones |
| WO2014072884A1 (en) * | 2012-11-12 | 2014-05-15 | Alembic Pharmaceuticals Limited | Process for the synthesis of apixaban |
| CN104892601A (en) * | 2015-06-09 | 2015-09-09 | 江苏中邦制药有限公司 | Preparation method of antithrombotic drug Apixaban |
| CN105254630A (en) * | 2015-11-16 | 2016-01-20 | 江苏康缘药业股份有限公司 | Preparing method for apixaban |
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