CN107955003A - The sweep-out method of specific impurities S4 in a kind of 2 building-up process of Eliquis intermediate - Google Patents
The sweep-out method of specific impurities S4 in a kind of 2 building-up process of Eliquis intermediate Download PDFInfo
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- CN107955003A CN107955003A CN201711455479.8A CN201711455479A CN107955003A CN 107955003 A CN107955003 A CN 107955003A CN 201711455479 A CN201711455479 A CN 201711455479A CN 107955003 A CN107955003 A CN 107955003A
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- triethylamine
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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 the sweep-out method of specific impurities S4 in 2 building-up process of Eliquis intermediate a kind of, it comprises the following steps：Heat up after compound 1, compound 2 and triethylamine are sequentially added in ethyl acetate solvent, the equivalent proportion of ethyl acetate and compound 1, compound 2 and triethylamine is 4.0~6.0：1：1.1~1.5：3.0~5.0；After above-mentioned solution is warming up to 80 ± 5 DEG C, reaction is stirred at reflux, triethylamine is persistently added in reflux course, the amount for the triethylamine added is 1 with the equivalent proportion of compound 1:1.0~2.0；After being cooled to 10 DEG C after above-mentioned back flow reaction 4h, the dilute sulfuric acid of 2~6M is added dropwise at temperature control≤30 DEG C, intermediate 2 is obtained by filtration after 2h is then stirred at room temperature, the equivalent proportion of the dilute sulfuric acid and triethylamine is 1:1.The present invention is not in the case where changing organic base species used in reaction, by adding organic base, it is suppressed that the generation of impurity S4 in reaction process, impurity content are only 0.00%~0.02%, so as to effectively control the content of impurity S4.
Description
Technical field
The invention belongs to medicinal chemicals synthesis technical field, more particularly to Eliquis bulk pharmaceutical chemicals intermediate building-up process
In caused specific impurities removing.
Background technology
Eliquis intermediate 1- (4- methoxyphenyls) -7- oxos -6- [4- (2- oxo-piperidine -1- bases) phenyl] -
4,5,6,7- tetrahydrochysene -1H- pyrazolos [3,4-C] pyridine-3-carboxylic acid ethyl ester（Intermediate 2）Building-up process in, impurity can be produced
S4, that is, 1- (4- chloros phenyl) -7- oxos -6- [4- (2- oxo-piperidine -1- bases) phenyl] -4,5,6,7- tetrahydrochysene -1H- pyrazolos
[3,4-C] pyridine-3-carboxylic acid ethyl ester, impurity S4 are difficult to clean off by conventional purification methods such as recrystallizations, and can be follow-up
Reaction is continued to participate in reaction, ultimately generates impurity 1- (4- chloros phenyl) -7- oxos -6 [4- (2- oxo-piperidine -1- bases) benzene
Base] -4,5,6,7- tetrahydrochysene -1H- pyrazoles [3,4-c] pyridine-3-carboxamide（Impurity B MS-591329）, which passes through recrystallization
It is difficult to clean off Deng conventional purification method, retains in Eliquis bulk pharmaceutical chemicals finished product, the quality of bulk pharmaceutical chemicals is had an impact.Cause
This, realizes that the removing to impurity S4 is very necessary in intermediate building-up process.
In CN1639147A, certain equivalent is added using when reaction starts to feed intake the step of synthetic intermediate 2
The method of organic bases triethylamine, on the one hand promotes reaction to be carried out to positive direction, the hydrochloric acid on the other hand generated by neutralization reaction,
To suppress the generation of impurity S4.By testing correlation technique, find due to reaction temperature（80℃）With the boiling point 89.5 of triethylamine
It is DEG C close, the partial loss of triethylamine in reaction reflux course can be caused, causes to be unable to complete neutralization hydrochloric acid, so as to be difficult to effectively
The generation of the impurity is controlled, effectively controlling to the impurity is still can not achieve by increasing triethylamine when feeding intake.
The content of the invention
The present invention provides the sweep-out method of specific impurities S4 in 2 building-up process of Eliquis intermediate a kind of, existing to solve
The problem of with the presence of technology.
The present invention reaction process be：
Wherein compound 1 is：5,6- dihydros -3- (4- morpholinyls) -1- [4- (2- oxo -1- piperidyls) phenyl] -2 (1H)-pyrroles
Pyridine ketone, compound 2 are：[(4- methoxyphenyls) diazanyl] ethyl chloroacetate.
The present invention seeks to what is be achieved through the following technical solutions：
A. 5,6- dihydros -3- (4- morpholinyls) -1- [4- (2- oxo -1- piperidyls) benzene is sequentially added in ethyl acetate solvent
Base] heat up after -2 (1H)-pyridones, [(4- methoxyphenyls) diazanyl] ethyl chloroacetate and triethylamine, ethyl acetate and 5,6-
Dihydro -3- (4- morpholinyls) -1- [4- (2- oxo -1- piperidyls) phenyl] -2 (1H)-pyridones, [(4- methoxyphenyls) hydrazine
Base] equivalent proportion of ethyl chloroacetate and triethylamine is 4.0~6.0:1:1.1~1.5:3.0~5.0；
B. after above-mentioned solution being warming up to 80 ± 5 DEG C, reaction is stirred at reflux, triethylamine is persistently added in reflux course, is added
Triethylamine amount and 5,6- dihydros -3- (4- morpholinyls) -1- [4- (2- oxo -1- piperidyls) phenyl] -2 (1H)-pyridones
Equivalent proportion be 1:1.0~2.0；
C. after being cooled to 10 DEG C after above-mentioned back flow reaction 4h, the dilute sulfuric acid of 2~6M is added dropwise at temperature control≤30 DEG C, then in room temperature
Filtered after lower stirring 2h, the total yield of dilute sulfuric acid and triethylamine ratio is 1 in the step a, step b:Dilute sulphur in 1, the step a
The equivalent proportion of acid and triethylamine is 4:5~7:The equivalent proportion of dilute sulfuric acid and triethylamine is 2 in 3, the step b:1~7:1.
The technological progress that the present invention obtains：
Compared with prior art, advantages of the present invention is mainly reflected at following 2 points：
First, the impurity S4 the present invention be directed to be produced in Eliquis intermediate building-up process is designed, and is effectively removed
Impurity S4 in intermediate 2.Impurity S4 is the accessory substance produced in 2 building-up process of Eliquis intermediate, because its structure is with
Mesosome 2 is very close, and polarity spectrum is little, therefore is difficult to effectively remove it using conventional recrystallization method.And impurity S4 exists
It may proceed to the impurity B MS-591329 being converted into Eliquis bulk pharmaceutical chemicals finished product in subsequent reactions, the impurity is also difficult in finished product
To remove, so as to be impacted to product quality.Therefore realize that the removing to impurity S4 is very in intermediate building-up process
It is necessary.The method that CN1639147A is the triethylamine that certain equivalent is added when reacting and starting is offered according to original text, is tried repeatedly
Verify it is bright, after conventional recrystallization purifying gained intermediate 2 in S4 content be 0.08~0.13%, content is higher.Therefore,
The method offered according to original text is difficult to effective control to impurity S4.
For the above situation, the present invention analyzes reaction mechanism, in CN1639147A, synthetic intermediate 2
Step using the method for the organic bases triethylamine that certain equivalent is added when reaction starts to feed intake, on the one hand promotes reaction to just
Direction carries out, the hydrochloric acid on the other hand generated by neutralization reaction, to suppress the generation of impurity S4.By testing correlation technique,
It was found that due to reaction temperature（80±5℃）It is close with 89.5 DEG C of the boiling point of triethylamine, triethylamine in reaction reflux course can be caused
Partial loss, cause to be unable to complete neutralization hydrochloric acid, so as to be difficult to the generation for effectively controlling the impurity.When beginning is reacted
Excessive triethylamine is added, still cannot effectively control the content of S4.Therefore, except step a react start when add certain equivalent
Triethylamine outside, add the triethylamine of certain equivalent in batches in stepb, triethylamine in reaction process is kept enough amounts
To neutralize by-product hydrochloric acid, so as to suppress the generation of S4.Through repetition test, testing result proves the content control using this method S4
System limits 0.03% 0.00%~0.02%, less than report as defined in ICH, is completely removed substantially.
Second, the method for the present invention is simple and easy to do, beneficial to operation.Do not changing the situation of organic base species used in reaction
Under, the innovation of the invention for passing through organic base feed postition, it is suppressed that the generation of impurity S4 in reaction process.It is other relative to groping
The organic base of species explores the other process conditions of change to reduce for the content of S4, and this method is very easy, is easy to grasp
Make.
Embodiment
With reference to embodiment, the invention will be further described.
Embodiment 1：A. 300ml ethyl acetate, 50.0g compounds 1,39.7g chemical combination are sequentially added in glass reaction bottle
Thing 2, heats up after adding 42.7g triethylamines；
B. by above-mentioned solution to reaction 4h is stirred at reflux after 80 ± 5 DEG C, persistently adding triethylamine at twice in reflux course is total to
14.2g；
C. react and complete after above-mentioned back flow reaction 4h, be then cooled to the dilute sulfuric acid that 2M is added dropwise at 10 DEG C, then temperature control≤30 DEG C
281ml, after dripping, separates out 2 solid of intermediate after 2h is stirred at room temperature, then refilters to obtain intermediate 2.
Embodiment 2：The present embodiment difference from Example 1 is that the equivalent of addition compound 2 is 1.5.
A. 300ml ethyl acetate, 50.0g compounds 1,54.2g compounds 2 are sequentially added in glass reaction bottle, then is added
Heat up after entering 42.7g triethylamines；
B. by above-mentioned solution to reaction 4h is stirred at reflux after 80 ± 5 DEG C, persistently adding triethylamine at twice in reflux course is total to
14.2g；
C. react and complete after above-mentioned back flow reaction 4h, be then cooled to the dilute sulfuric acid that 2M is added dropwise at 10 DEG C, then temperature control≤30 DEG C
281ml, after dripping, is stirred at room temperature acidolysis completion precipitation 2 solid of intermediate after 2h, then refilters to obtain intermediate 2.
Embodiment 3：The present embodiment difference from Example 1 is that the equivalent of addition triethylamine is 5.0 when reaction starts.
A. 300ml ethyl acetate, 50.0g compounds 1,39.7g compounds 2 are sequentially added in glass reaction bottle, then is added
Heat up after entering 71.2g triethylamines；
B. by above-mentioned solution to reaction 4h is stirred at reflux after 80 ± 5 DEG C, persistently adding triethylamine at twice in reflux course is total to
14.2g；
C. react and complete after above-mentioned back flow reaction 4h, be then cooled to the dilute sulfuric acid that 2M is added dropwise at 10 DEG C, then temperature control≤30 DEG C
422ml, after dripping, is stirred at room temperature acidolysis completion precipitation 2 solid of intermediate after 2h, then refilters to obtain intermediate 2.
Embodiment 4：The present embodiment difference from Example 1 is that the equivalent that triethylamine is added in reaction is changed to by 1.0
2.0。
A. 300ml ethyl acetate, 50.0g compounds 1,39.7g compounds 2 are sequentially added in glass reaction bottle, then is added
Heat up after entering 42.7g triethylamines；
B. by above-mentioned solution to reaction 4h is stirred at reflux after 80 ± 5 DEG C, persistently adding triethylamine at twice in reflux course is total to
28.4g；
C. react and complete after above-mentioned back flow reaction 4h, be then cooled to the dilute sulfuric acid that 2M is added dropwise at 10 DEG C, then temperature control≤30 DEG C
351ml, after dripping, is stirred at room temperature acidolysis completion precipitation 2 solid of intermediate after 2h, then refilters to obtain intermediate 2.
Claims (1)
1. the sweep-out method of specific impurities S4, its feature are comprising the following steps in a kind of 2 building-up process of Eliquis intermediate：
A. 5,6- dihydros -3- (4- morpholinyls) -1- [4- (2- oxo -1- piperidyls) benzene is sequentially added in ethyl acetate solvent
Base] heat up after -2 (1H)-pyridones, [(4- methoxyphenyls) diazanyl] ethyl chloroacetate and triethylamine, ethyl acetate and 5,6-
Dihydro -3- (4- morpholinyls) -1- [4- (2- oxo -1- piperidyls) phenyl] -2 (1H)-pyridones, [(4- methoxyphenyls) hydrazine
Base] equivalent proportion of ethyl chloroacetate and triethylamine is 4.0~6.0:1:1.1~1.5:3.0~5.0；
B. after above-mentioned solution being warming up to 80 ± 5 DEG C, reaction is stirred at reflux, triethylamine is persistently added in reflux course, is added
Triethylamine amount and 5,6- dihydros -3- (4- morpholinyls) -1- [4- (2- oxo -1- piperidyls) phenyl] -2 (1H)-pyridones
Equivalent proportion be 1:1.0~2.0；
C. after being cooled to 10 DEG C after above-mentioned back flow reaction 4h, the dilute sulfuric acid of 2~6M is added dropwise at temperature control≤30 DEG C, then in room temperature
Filtered after lower stirring 2h, the total yield of dilute sulfuric acid and triethylamine ratio is 1 in the step a, step b:Dilute sulphur in 1, the step a
The equivalent proportion of acid and triethylamine is 4:5~7:The equivalent proportion of dilute sulfuric acid and triethylamine is 2 in 3, the step b:1~7:1.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109627242A (en) * | 2018-12-29 | 2019-04-16 | 江苏豪森药业集团有限公司 | The preparation method of Eliquis |
| CN110372698A (en) * | 2019-08-09 | 2019-10-25 | 新乡双鹭药业有限公司 | A kind of synthetic method of Eliquis impurity |
Citations (2)
| 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 |
| CN103626759A (en) * | 2012-08-24 | 2014-03-12 | 上海医药工业研究院 | Preparation method of apixaban intermediate |
-
2017
- 2017-12-28 CN CN201711455479.8A patent/CN107955003A/en active Pending
Patent Citations (2)
| 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 |
| CN103626759A (en) * | 2012-08-24 | 2014-03-12 | 上海医药工业研究院 | Preparation method of apixaban intermediate |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109627242A (en) * | 2018-12-29 | 2019-04-16 | 江苏豪森药业集团有限公司 | The preparation method of Eliquis |
| CN110372698A (en) * | 2019-08-09 | 2019-10-25 | 新乡双鹭药业有限公司 | A kind of synthetic method of Eliquis impurity |
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