CN106117200A - 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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- CN106117200A CN106117200A CN201610480815.3A CN201610480815A CN106117200A CN 106117200 A CN106117200 A CN 106117200A CN 201610480815 A CN201610480815 A CN 201610480815A CN 106117200 A CN106117200 A CN 106117200A
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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
Abstract
The invention discloses prevention or the preparation method for the treatment of joint replacement phlebothrombosis medicine Eliquis, the method includes: 1) will be to methoxyl group phenylhydrazine and glyoxylic acid ethyl ester cuprous bromide catalytic reaction in the presence of a base, reaction terminates to filter, filtrate adds borane dimethyl sulphide complex, then adds the compound shown in Formulas I and be stirred hybrid reaction and obtain reactant mixture L；2) by step 1) the reactant mixture L that obtains stirs in acid condition；3) by step 1) 1 (4 methoxyphenyl) 7 oxo 6 [4 (2 oxo-piperidine 1 base 3) phenyl] 4 of obtaining, 5,6,7 tetrahydrochysene 1H pyrazoles [3,4 c] pyridine 3 Ethyl formates carry out ammonolysis and obtain Eliquis；
Description
Technical field
The invention belongs to pharmaceutical synthesis field, in particular it relates to prevention or treatment joint replacement phlebothrombosis medicine Ah piperazine
The preparation method of husky class
Background technology
Eliquis (Apixaban), chemical entitled 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-piperidine-
1-base 3) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine-3-carboxamides, it is used for preventing and treat hip joint or knee joint
The vein bolt thromboembolism occurred in joint replacement.Eliquis is to be developed jointly by Mei-Shi Guibao company when hundred and Pfizer
The direct inhibitor of novel Xa factor, concrete structure is as follows:
Synthetic method currently, with respect to Eliquis is reported a lot, but all there is also many problems in these methods.
WO2010/030983 discloses the synthetic method of a kind of Eliquis, and the method P-nethoxyaniline is for initial former
Expect then to be condensed with chloro ethyl acetoacetate by diazotising, diazo-reaction condition harsh (stringent low-temperature) and have safety
Risk, is not suitable for industrialized production, and this nonreactive yield is relatively low；The method use iodo former due to annulation
Material, therefore intermediate product A have to purification, complex steps；It addition, the method final step and ammonia high temperature (120 in ethylene glycol
DEG C) ammonolysis obtains the yield of Eliquis and only have about 27%, seriously constrain the industrial applications of the method, specifically synthesize road
Line is as follows:
CN103626759B discloses the preparation method of the intermediate of a kind of Eliquis, and the method is molten with dichloromethane
Agent, under reflux conditions, under the effect of organic base, reacts compound 3 and 4；The continuation being subsequently adding mineral acid is anti-
Answer thus obtain the intermediate of Eliquis.But the method does not provide preparation method and this compound of compound 4
In commercially available product the most common, price is higher so that this process costs is higher.Additionally the method there is also response time length and
The problem that yield is general.Concrete synthetic route is as follows:
Therefore, this area still needs to a kind of low cost, mild condition, yield height, the preparation side of the simple Eliquis of step
Method.
Summary of the invention
It is an object of the invention to overcome in the existing method preparing Eliquis that yield is low, condition is harsh and step
The defect that loaded down with trivial details, cost is high, it is provided that a kind of low cost, mild condition, yield are high and step simple antithrombotic reagent Ah piperazine is husky
The preparation method of class.
To achieve these goals, the present invention provides prevention or the system for the treatment of joint replacement phlebothrombosis medicine Eliquis
Preparation Method, the method comprises 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, adds borane dimethyl sulphide complex, then adds the compound shown in Formulas I and be stirred hybrid reaction extremely in filtrate
Compound reaction shown in Formulas I completely, obtains reactant mixture L；
2) by step 1) the reactant mixture L that obtains stirs in acid condition, obtains 1-(4-methoxyphenyl)-7-oxygen
Generation-6-[4-(2-oxo-piperidine-1-base 3) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] Nicotinicum Acidum ethyl ester；
3) by step 1) 1-(4-the methoxyphenyl)-7-oxo-6-[4-(2-oxo-piperidine-1-base 3) phenyl] that obtains-
4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] Nicotinicum Acidum 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, Formulas I
The consumption 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 improve yield and the efficiency of ammonolysis further, glyoxylic acid ethyl ester with to methoxyl group phenylhydrazine,
The consumption mol ratio of the compound shown in alkali, cuprous bromide, borane dimethyl sulphide complex, Formulas I be 1:1.5:2:0.1～
0.2:1.6:0.8.
In the present invention, inventor has found that while that conventional alkaline also can complete reaction, but the more by-product of yield is the most, excellent
Selection of land, described alkali is piperidines or nafoxidine.
Preferably, step 1) catalytic reaction in also include addMolecular 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, step 1) temperature of catalytic reaction is 35～45 DEG C, borane dimethyl sulphide complex and Formulas I institute
The addition temperature of the compound shown is 20～25 DEG C, and the temperature mixing hybrid reaction is 60～80 DEG C, catalytic reaction and stirring mixing
The solvent of reaction is DMF.
Preferably, step 1) DMF solution that feed postition is dropping compound shown in Formulas I of the compound shown in Formulas I.
In the present invention, step 2) reactant mixture L stirs in acid condition in order to remove step 1) product
In morpholine molecule, acid condition can be add acid solution, such as hydrochloric acid, phosphoric acid, acetic acid etc..Step 2) preferably at low temperature
Under carry out, such as-10～10 DEG C.
In the present invention, step 3) ammonolysis be not particularly limited, ammonolysis method of the prior art can be used,
Such as method in CN104628724A, detailed process can be: by 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxygen
For piperidin-1-yl 3) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] Nicotinicum Acidum ethyl ester is added sequentially to ethanol
In rustless steel pressure still, airtight, it is passed through ammonia, is heated to 60 DEG C, holding pressure is 0.3Mpa, reacts 8 hours, stopped reaction.Instead
Answer still to open after being cooled to room temperature, filter, filter cake washing with alcohol, dried Eliquis white solid.
Obtaining impact in order to avoid air etc. to reacting, to improve reaction yield and efficiency further, described haptoreaction is with de-
Hydrogen reaction is all carried out in the presence of protective gas, and described protective gas is nitrogen, helium or argon.
In the present invention, reaction is monitored following the tracks of by the method that this area can be used conventional, such as TLC, LCMS,
GCMS etc., react complete finger TLC monitor not excess raw material disappeared or in LCMS, GCMS not excess raw material residue be less than
2%.
The Eliquis that the method for the present invention obtains, can be prepared as respectively with reference to this area routine techniques means as required
Plant the Eliquis of crystal formation.
The concrete route that the present invention prepares the method for Eliquis is as follows:
Compared with prior art, using the method preparing Eliquis that the present invention provides, use mild condition, it is right to use
Methoxybenzene trap is initiation material, and " one kettle way " generates pyrazole ring product, and technique is simpler, and cost is substantially reduced, and keeps away
Exempt from the diazo-reaction that prior art is widely used；And yield is also greatly improved.
Other features and advantages of the present invention will be described in detail in detailed description of the invention part subsequently.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is expanded on further.But these embodiments be only limitted to illustrate the present invention and not
It it is the further restriction to protection scope of the present invention.
Embodiment 1
1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-piperidine-1-base 3) phenyl]-4,5,6,7-tetrahydrochysene-1H-
The preparation of pyrazoles [3,4-c] Nicotinicum Acidum ethyl ester
1) under nitrogen protection, will be to methoxyl group phenylhydrazine 20.7g (150mmol), glyoxylic acid ethyl ester 10.2g (100mmol), alkali
17g (piperidines),Molecular sieve 10.2g and cuprous bromide 2.8g (20mmol) joins in flask 40 DEG C and carries out catalytic reaction,
Reaction terminate after, filter, 20 DEG C in filtrate add borane dimethyl sulphide complex (2.0M in THF, containing borine dimethyl
Thioether complex 12.2g) and Formulas I shown in compound (DMF solution, containing the compound 28.4g shown in Formulas I), then heat up
It is stirred hybrid reaction to 80 DEG C to react completely to the compound shown in Formulas I, obtains reactant mixture L；
2) by step 1) the reactant mixture L that obtains adds stirring reaction 2.5 hours, dichloro in 100ml 4MHCl frozen water
Methane extracts, and organic facies concentrates, washes three times, then re-crystallizing in ethyl acetate, is dried and to obtain 1-(4-methoxyphenyl)-7-oxygen
Generation-6-[4-(2-oxo-piperidine-1-base 3) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] Nicotinicum Acidum ethyl ester
34.2g, yield is 87.4%, purity 99.41% (HPLC).
Embodiment 2
1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-piperidine-1-base 3) phenyl]-4,5,6,7-tetrahydrochysene-1H-
The preparation of pyrazoles [3,4-c] Nicotinicum Acidum ethyl ester
1) under nitrogen protection, will be to methoxyl group phenylhydrazine 19.3g (140mmol), glyoxylic acid ethyl ester 10.2g (100mmol), alkali
25.5g (piperidines),Molecular sieve 8.2g and cuprous bromide 1.4g (10mmol) joins in flask 35 DEG C, and to carry out catalysis anti-
Should, reaction terminate after, filter, 20 DEG C in filtrate add borane dimethyl sulphide complex (2.0M in THF, containing borine two
Dimethyl sulfide complex 13.7g) and Formulas I shown in compound (DMF solution, containing the compound 24.9g shown in Formulas I), then
It is warming up to 60 DEG C and is stirred hybrid reaction to the compound reaction shown in Formulas I completely, obtain reactant mixture L；
2) by step 1) the reactant mixture L that obtains adds stirring reaction 2.5 hours, dichloro in 100ml 4MHCl frozen water
Methane extracts, and organic facies concentrates, washes three times, then re-crystallizing in ethyl acetate, is dried and to obtain 1-(4-methoxyphenyl)-7-oxygen
Generation-6-[4-(2-oxo-piperidine-1-base 3) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] Nicotinicum Acidum ethyl ester
28.6g, yield is 83.7%, purity 99.61% (HPLC).
Embodiment 3
1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-piperidine-1-base 3) phenyl]-4,5,6,7-tetrahydrochysene-1H-
The preparation of pyrazoles [3,4-c] Nicotinicum Acidum ethyl ester
1) under nitrogen protection, will be to methoxyl group phenylhydrazine 16.6g (120mmol), glyoxylic acid ethyl ester 10.2g (100mmol), alkali
17.8g (nafoxidine),Molecular sieve 13.3g and cuprous bromide 2.2g (15mmol) joins in flask 45 DEG C and urges
Changing reaction, after reaction terminates, filter, 25 DEG C add borane dimethyl sulphide complex (2.0M in THF, boracic in filtrate
Alkane dimethyl sulfide complex 11.4g) and Formulas I shown in compound (DMF solution, containing the compound 31.9g shown in Formulas I),
Then heat to 70 DEG C and be stirred hybrid reaction to the compound reaction shown in Formulas I completely, obtain reactant mixture L；
2) by step 1) the reactant mixture L that obtains adds stirring reaction 2.5 hours, dichloromethane in 100ml4MHCl frozen water
Alkane extract, organic facies concentrate, washing three times, then re-crystallizing in ethyl acetate, be dried 1-(4-methoxyphenyl)-7-oxo-
6-[4-(2-oxo-piperidine-1-base 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 methoxyphenyl)-7-oxo-6-[4-(2-oxo-piperidine-1-base 3) phenyl]-4 in embodiment 1,
The preparation of 5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] Nicotinicum Acidum ethyl esters, except that, do not useMolecular sieve, dry
Dry 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-piperidine-1-base 3) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazoles
[3,4-c] Nicotinicum Acidum ethyl ester 31.7g, yield is 81.0%, purity 99.10% (HPLC).
Embodiment 5
The preparation of Eliquis
By 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-piperidine-1-base 3) phenyl]-4,5,6,7-tetrahydrochysene-
1H-pyrazoles [3,4-c] Nicotinicum Acidum ethyl ester 4.9g, 150ml ethanol is added sequentially in stainless steel pressure still, airtight, is passed through
Ammonia, is warming up to 60 DEG C, keeps pressure at 0.3Mpa, reacts 8 hours, stopped reaction, be cooled to room temperature, open reactor, mistake
Filter, filter cake washing with alcohol, it is dried to obtain Eliquis 4.2g, yield 91.7%, purity 98.41% (HPLC).
Comparative example 1
Such as 1-(4-the methoxyphenyl)-7-oxo-6-[4-(2-oxo-piperidine-1-base 3) phenyl]-4 in embodiment 1,
The preparation of 5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] Nicotinicum Acidum ethyl esters, except that, do not use cuprous bromide, be dried
Obtain 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-piperidine-1-base 3) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazoles
[3,4-c] Nicotinicum Acidum ethyl ester 24.1g, yield is 61.7%, purity 99.70% (HPLC).
Comparative example 2
Such as 1-(4-the methoxyphenyl)-7-oxo-6-[4-(2-oxo-piperidine-1-base 3) phenyl]-4 in embodiment 1,
The preparation of 5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] Nicotinicum Acidum ethyl esters, except that, do not use borine dimethyl disulfide
Ether complexes, is dried to obtain 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-piperidine-1-base 3) phenyl]-4,5,6,7-
Tetrahydrochysene-1H-pyrazoles [3,4-c] Nicotinicum Acidum ethyl ester 13.9g, yield is 35.7%, purity 99.70% (HPLC).
The preferred embodiment of the present invention described in detail above, but, the present invention is not limited in above-mentioned embodiment
Detail, in the technology concept of the present invention, technical scheme can be carried out multiple simple variant, this
A little simple variant belong to protection scope of the present invention.
It is further to note that each the concrete technical characteristic described in above-mentioned detailed description of the invention, at not lance
In the case of shield, can be combined by any suitable means, in order to avoid unnecessary repetition, the present invention to various can
The compound mode of energy illustrates the most separately.Additionally, any group can also be carried out between the various different embodiment of the present invention
Closing, as long as it is without prejudice to the thought of the present invention, it should be considered as content disclosed in this invention equally.
Claims (8)
1. prevention or the preparation method for the treatment of joint replacement phlebothrombosis medicine Eliquis, it is characterised in that the 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
Liquid adds borane dimethyl sulphide complex, then adds the compound shown in Formulas I and be stirred hybrid reaction to Formulas I institute
The compound reaction shown completely, obtains reactant mixture L；
2) by step 1) the reactant mixture L that obtains stirs in acid condition, obtain 1-(4-methoxyphenyl)-7-oxo-
6-[4-(2-oxo-piperidine-1-base 3) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] Nicotinicum Acidum ethyl ester；
3) by step 1) 1-(4-the methoxyphenyl)-7-oxo-6-[4-(2-oxo-piperidine-1-base 3) phenyl]-4,5 that obtains,
6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] Nicotinicum Acidum ethyl ester carries out ammonolysis and obtains Eliquis；
Preparation method the most according to claim 1, it is characterised in that glyoxylic acid ethyl ester with to methoxyl group phenylhydrazine, alkali, bromination
The consumption mol ratio of the compound shown in cuprous, borane dimethyl sulphide complex, Formulas I be 1:1.2～1.5:2～3:0.1～
0.2:1.5～1.8:0.7～0.9.
Preparation method the most according to claim 2, it is characterised in that glyoxylic acid ethyl ester with to methoxyl group phenylhydrazine, alkali, bromination
The consumption mol ratio of the compound shown in cuprous, borane dimethyl sulphide complex, Formulas I is 1:1.5:2:0.2:1.6:0.8.
4. according to the method described in claim 1-3, it is characterised in that described alkali is piperidines or nafoxidine.
Method the most according to claim 1, it is characterised in that step 1) catalytic reaction in also include addMolecule
Sieve；By weight, describedThe addition of molecular sieve is 0.8～1.3 times of glyoxylic acid ethyl ester weight.
Method the most according to claim 1, it is characterised in that step 1) temperature of catalytic reaction is 35～45 DEG C, borine
The addition temperature of the compound shown in dimethyl sulfide complex and Formulas I is 20～25 DEG C, mix the temperature of hybrid reaction be 60～
80 DEG C, the solvent of catalytic reaction and stirring hybrid reaction is DMF.
Method the most according to claim 1, it is characterised in that step 1) feed postition of the compound shown in Formulas I is for dripping
Add the DMF solution of the compound shown in Formulas I.
8. according to the method described in claim 1-7, it is characterised in that stirring hybrid reaction is carried out in the presence of protective gas,
Described protective gas is nitrogen, helium or argon.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111253392A (en) * | 2019-12-17 | 2020-06-09 | 哈尔滨珍宝制药有限公司 | Method for preparing apixaban |
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|---|---|---|---|---|
| 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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111253392A (en) * | 2019-12-17 | 2020-06-09 | 哈尔滨珍宝制药有限公司 | Method for preparing apixaban |
| CN111253392B (en) * | 2019-12-17 | 2021-06-11 | 哈尔滨珍宝制药有限公司 | Method for preparing apixaban |
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