CN105440040B - The purification process of Buddhist nun is replaced according to Shandong - Google Patents
The purification process of Buddhist nun is replaced according to Shandong Download PDFInfo
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- CN105440040B CN105440040B CN201510984875.4A CN201510984875A CN105440040B CN 105440040 B CN105440040 B CN 105440040B CN 201510984875 A CN201510984875 A CN 201510984875A CN 105440040 B CN105440040 B CN 105440040B
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- shandong
- buddhist nun
- solvent
- purification process
- finished product
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention discloses a kind of purification process that Buddhist nun is replaced according to Shandong, it includes step 1) and will be dissolved according to Shandong for Buddhist nun's crude product in middle polar organic solvent, adds column chromatography and is mixed with silica gel, stirs, filters, gained filtrate is concentrated to dryness to obtain replaces Buddhist nun's semi-finished product according to Shandong.The present invention's carries out impurity separation for the purification process of Buddhist nun according to Shandong in simple silica gel absorption method, and what is obtained after purification can reach 99.5% according to Shandong for Buddhist nun's semi-finished product purity；Carry out that step 2) recrystallization separation can obtain purity more than 99.8% again replaces Buddhist nun's finished product according to Shandong.The present invention's can effectively remove for the purification process of Buddhist nun that the impurity replaced according to Shandong in Buddhist nun's crude product, purification process be simple and high income according to Shandong, be applicable to industrial production.
Description
Technical field
The present invention relates to the purification process of compound, more particularly to a kind of purification process that Buddhist nun is replaced according to Shandong.
Background technology
Buddhist nun (Ibrutinib) is replaced according to Shandong, it is chemical entitled：1- [(3R) -3- [4- amino -3- (4- Phenoxyphenyls) -1H-
Pyrazolo [3,4-D] pyrimidine -1- bases] -1- piperidyls] -2- propylene -1- ketone, molecular formula is：C25H24N6O2, molecular weight is：
440.50 No. CAS is：936563-96-1, structural formula are as follows：
It is the bruton's tyrosine kinase that Johnson Co. researches and develops jointly with U.S.'s pharmacy circulation company to replace Buddhist nun according to Shandong
(BTK) inhibitor.2 months 2013, the medicine obtained FDA " breakthrough sex therapy " qualification, and is obtained on November 13rd, 2013
City ratifies, as the single medicine of jacket cell lymph cancer, suitable for the jacket cell lymph treated before with other means
Cancer patient, trade name " Imbruvca ".
There is no the special report that Buddhist nun's purification process is replaced according to Shandong in existing literature, and conventional purification process is recrystallization,
Recrystallization solvent is generally ethyl acetate, toluene, methanol etc..Prior art readily available 95% replaces Buddhist nun according to Shandong, but will
It is further purified to obtain 99% or higher when replacing Buddhist nun according to Shandong, in general purification process is often extremely difficult to Expected Results.
The method of the compound commonly used in the prior art for obtaining high-purity for example has silica gel column chromatography method.Silica gel column layer
The separation principle of analysis is different according to absorption affinity of the material on silica gel and separated, generally the larger material of polarity
Easily be not easy by silica gel absorption, the weaker material of polarity by silica gel absorption, whole chromatography process be total material Adsorption and desorption,
Adsorb again, desorption process again.Silica gel column chromatography method is used to need to consider post effect to reach different material Adsorption and desorption, inhale again
Attached, desorption ability difference, and separation process needs constantly addition eluting solvent and detects product stream artificial situation in real time, not only needs again
Substantial amounts of eluting solvent is wanted, is easily introduced new impurity；And purifying dosage is seldom, the operating time is very long, cumbersome right every time
Operating personnel require higher, and hardly possible is applied to industrialized production.
Therefore it is badly in need of proposing new technical scheme to optimizing for the purification process of Buddhist nun according to Shandong.
The content of the invention
The present invention is directed to technical problem existing for prior art and replaces Buddhist nun pure according to Shandong, and it is an object of the present invention to provide one kind can effectively improve
The purification process that Buddhist nun is replaced according to Shandong easy to operate for being suitable for industrial-scale production of degree.
The present invention's includes according to Shandong for the purification process of Buddhist nun：
Step 1) will be dissolved in middle polar organic solvent according to Shandong for Buddhist nun's crude product, is added column chromatography and is mixed with silica gel, stirring, mistake
Filter, gained filtrate is concentrated to dryness to obtain replaces Buddhist nun's semi-finished product according to Shandong.
Buddhist nun's dissolving crude product polar organic solvent in suitable is replaced according to Shandong described in step 1), then can be in solution with silica gel
Most impurity effectively adsorbed and target substance according to Shandong for Buddhist nun not by silica gel absorption, then using customary filtration methods and
What method for concentration obtained high-purity replaces Buddhist nun's semi-finished product according to Shandong.In the method, do not occur Adsorption and desorption in silica gel column chromatography,
Adsorb again, desorption process again so that this method eliminate largely to the unfriendly organic solvent of environment, the operating time,
With the requirement to operating personnel, and 99.5% high-purity is reached, suitable for industrial-scale production.
The middle polar organic solvent is dichloromethane and/or ethyl acetate.The middle polar organic solvent：It is described according to Shandong
Weight ratio for Buddhist nun's crude product is 10~20:1；The preferred dichloromethane of middle polar organic solvent；Dissolving adsorption process can heat up
To 30~40 DEG C and stir 10~30 minutes, make to be completely dissolved for Buddhist nun according to Shandong.
To prevent from separating out for Buddhist nun according to Shandong, it can be filtered while hot after dissolving absorption, filter cake can be cleaned with ethyl acetate during filtering, will
Being washed out according to Shandong for Buddhist nun on filter cake surface, also has small part of the absorption on silica gel according to Shandong for Buddhist nun while is eluted out certainly；
The ethyl acetate of preferably 60~77 DEG C of filter cake is cleaned, can effectively be washed out according to Shandong for Buddhist nun without eluting impurity, reaches and preferably divides
From effect.
The mesh number of the column chromatography silica gel is 100~300 mesh preferably 200~300 mesh, 200~300 thinner purposes
Column chromatography silica gel has preferable impurity absorption effect；The dosage of the column chromatography silica gel should be suitable, and amount that should be enough is to protect
Removal of impurity is demonstrate,proved, the increase of solvent load and the reduction according to Shandong for Buddhist nun's yield, institute caused by also avoiding dosage excessive
State column chromatography silica gel：It is described to be controlled according to Shandong for the weight ratio of Buddhist nun's crude product 1~2：1.
The present invention for the purification process of Buddhist nun can be 95~98% to be purified for Buddhist nun's crude product according to Shandong to purity according to Shandong, warp
What step 1) silica gel absorption obtained after purification can reach 99.5% according to Shandong for Buddhist nun's semi-finished product purity, it is described according to Shandong for Buddhist nun's semi-finished product also
It can be further purified through recrystallization, concrete operations are
Step 2) dissolves what step 1) obtained according to Shandong for highly polar organic solvent in Buddhist nun's semi-finished product use, is added dropwise after dissolved clarification anti-
Solvent, solid is separated out, filtered, be dried to obtain and replace Buddhist nun's finished product according to Shandong.
In step 2), the middle intensive polar solvent is to having certain deliquescent middle polarity or highly polar according to Shandong for Buddhist nun
Solvent, one or several kinds of the middle intensive polar solvent in esters solvent, alcohols solvent and ketones solvent.
The esters solvent includes ethyl acetate, isopropyl acetate and n-propyl acetate；The alcohols solvent include methanol,
Ethanol and isopropanol；The ketones solvent is acetone.
Different anti-solvents is selected for different kinds of liquid solvents, anti-solvent corresponding with the esters solvent is n-hexane
And/or normal heptane, anti-solvent corresponding with the alcohols solvent and the similar solvent is water.
In step 2), the dosage of highly polar organic solvent and the anti-solvent should be suitable in described, highly polar in described to have
Solvent：It is described according to Shandong for Buddhist nun's semi-finished product weight ratio be 10~15:1, the anti-solvent：Highly polar organic solvent in described
Weight ratio is 0.5~1:1.
Highly polar organic solvent dissolves in the case where being heated to reflux temperature in being used in step 2) according to Shandong for Buddhist nun's semi-finished product, is cooled to
Solid is separated out at 0~30 DEG C preferably 0~20 DEG C.
It is further purified through step 2) recrystallization, what is obtained can reach 99.8% according to Shandong for Buddhist nun's finished product purity.
The positive effect of the present invention：The silica gel column chromatography side of industrialized production need not be not suitable for greatly using operation difficulty
Method is purified, and is only purified in solvent dissolving with silica gel absorption and recrystallization method is purified, and purge process is easy to operate,
The impurity replaced according to Shandong in Buddhist nun's crude product can be effectively removed, finally can reach more than 99.80%, Er Qieshou according to Shandong for Buddhist nun's finished product purity
Rate is high, suitable for industrialized production.
It is described further below with reference to specific embodiment, to be fully understood from the purpose of the present invention, feature and effect.
Embodiment
Replace Buddhist nun's crude product in the silica gel absorption of embodiment 1~4 purifying Shandong
It will be put into according to Shandong for Buddhist nun's crude product in reaction bulb, addition dichloromethane, after stirring and dissolving, add 200~300 purposes
Column chromatography silica gel, 30~40 DEG C are warming up to, after stirring half an hour, filtered while hot, filter cake is floated with 70~77 DEG C of ethyl acetate
Wash, gained filtrate is concentrated to dryness, and get Yi Lu replaces Buddhist nun's semi-finished product.
Embodiment 1~4 purifies to obtain through column chromatography with silica gel absorption replaces Buddhist nun's semi-finished product, raw material dosage purity, reaction according to Shandong
Kettle volume, solvent, silica gel and its dosage and purification result are as shown in table 1.
The silica gel absorption of table 1 purifies parameter list
Conclusion：Purity 95.2~97% purifies according to Shandong for Buddhist nun's crude product by easy silica gel absorption, according to Shandong for the pure of Buddhist nun
Degree is increased dramatically, and reaches 99.5% according to Shandong for Buddhist nun's semi-finished product purity.By embodiment 1~4 obtain according to Shandong for Buddhist nun half into
Product (99.5%~99.6%) can further recrystallization purifying, such as example 5 below~11.
Embodiment 5~11
Will be according to Shandong in Buddhist nun's semi-finished product input reaction bulb, highly polar organic solvent is warming up to backflow in addition, stirs to clear
Clearly, anti-solvent is added dropwise to, is finished, after T DEG C of stirring half an hour, cool crystallization, after being cooled to 0~20 DEG C, filtering, drying
Buddhist nun's finished product is replaced according to Shandong.Design parameter is as shown in table 2.
The embodiment 5~11 of table 2 is according to Shandong for Buddhist nun's semi-finished product recrystallization method purifying parameter
Embodiment 5~11 replaces Buddhist nun's finished product to be obtained according to Shandong for Buddhist nun's semi-finished product as raw material through further recrystallization purifying according to Shandong.
As a result as shown in table 2, according to Shandong for Buddhist nun's finished product purity be promoted to 99.8% and more than.
Claims (11)
- A kind of 1. purification process that Buddhist nun is replaced according to Shandong, it is characterised in that including：Step 1) will be dissolved in middle polar organic solvent according to Shandong for Buddhist nun's crude product, is added column chromatography and is mixed with silica gel, stirs, filters, Gained filtrate is concentrated to dryness to obtain replaces Buddhist nun's semi-finished product according to Shandong, and described according to Shandong is 95%~98% for the purity of Buddhist nun's crude product, the post Silica gel for chromatography：It is described according to Shandong for Buddhist nun's crude product weight ratio be 1~2：1.
- 2. the purification process of Buddhist nun is replaced according to Shandong as claimed in claim 1, it is characterised in that：Step 1) will be dissolved according to Shandong for Buddhist nun's crude product In middle polar organic solvent, add column chromatography and mixed with silica gel, be warming up to 30~40 DEG C, stir 10~30 minutes, filter while hot, Filter cake is cleaned with 60~77 DEG C of ethyl acetate, and gained filtrate is concentrated to dryness to obtain replaces Buddhist nun's semi-finished product according to Shandong.
- 3. the purification process of Buddhist nun is replaced according to Shandong as claimed in claim 1 or 2, it is characterised in that：In step 1), the middle polarity has Solvent is dichloromethane and/or ethyl acetate；The middle polar organic solvent：It is described according to Shandong for Buddhist nun's crude product weight ratio be 10 ~20:1；The mesh number of the column chromatography silica gel is 100~300 mesh.
- 4. the purification process of Buddhist nun is replaced according to Shandong as claimed in claim 3, it is characterised in that：In step 1), the column chromatography silicon The mesh number of glue is 200~300 mesh.
- 5. the purification process of Buddhist nun is replaced according to Shandong as claimed in claim 1 or 2, it is characterised in that：It also includes step2) dissolved what step 1) obtained according to Shandong for highly polar organic solvent in Buddhist nun's semi-finished product use, anti-solvent is added dropwise after dissolved clarification, analyses Go out solid, filter, be dried to obtain and replace Buddhist nun's finished product according to Shandong.
- 6. the purification process of Buddhist nun is replaced according to Shandong as claimed in claim 5, it is characterised in that：It is highly polar in described to have in step 2) One or several kinds of the solvent in esters solvent, alcohols solvent and ketones solvent.
- 7. the purification process of Buddhist nun is replaced according to Shandong as claimed in claim 6, it is characterised in that：Esters solvent described in step 2) is second Acetoacetic ester, isopropyl acetate and/or n-propyl acetate, the anti-solvent are n-hexane and/or normal heptane.
- 8. the purification process of Buddhist nun is replaced according to Shandong as claimed in claim 6, it is characterised in that：Alcohols solvent described in step 2) is first Alcohol, ethanol and/or isopropanol, the ketones solvent are acetone, and the anti-solvent is water.
- 9. the purification process of Buddhist nun is replaced according to Shandong as claimed in claim 5, it is characterised in that：Used in step 2) according to Shandong for Buddhist nun's semi-finished product In highly polar organic solvent dissolved in the case where being heated to reflux temperature, be cooled at 0~30 DEG C and separate out solid.
- 10. the purification process of Buddhist nun is replaced according to Shandong as claimed in claim 9, it is characterised in that：It is cooled at 0~20 DEG C and separates out admittedly Body.
- 11. the purification process of Buddhist nun is replaced according to Shandong as claimed in claim 5, it is characterised in that：It is highly polar in described in step 2) to have Solvent：It is described according to Shandong for Buddhist nun's semi-finished product weight ratio be 10~15:1, the anti-solvent：Highly polar organic solvent in described Weight ratio is 0.5~1:1.
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| CN201510984875.4A CN105440040B (en) | 2015-12-23 | 2015-12-23 | The purification process of Buddhist nun is replaced according to Shandong |
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| CN201510984875.4A CN105440040B (en) | 2015-12-23 | 2015-12-23 | The purification process of Buddhist nun is replaced according to Shandong |
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| CN105440040B true CN105440040B (en) | 2018-03-13 |
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Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20220093389A (en) | 2012-06-04 | 2022-07-05 | 파마싸이클릭스 엘엘씨 | Crystalline forms of a bruton's tyrosine kinase inhibitor |
| KR20170033358A (en) | 2014-08-07 | 2017-03-24 | 파마싸이클릭스 엘엘씨 | Novel formulations of a bruton's tyrosine kinase inhibitor |
| DK3265084T3 (en) | 2015-03-03 | 2024-02-12 | Pharmacyclics Llc | Pharmaceutical formulations of Bruton's tyrosine kinase inhibitor |
| CN106083860A (en) * | 2016-06-23 | 2016-11-09 | 艾美科健（中国）生物医药有限公司 | A kind of synthesis and purifying process replacing Buddhist nun's intermediate according to Shandong |
| CN106117214A (en) * | 2016-06-29 | 2016-11-16 | 上海创诺医药集团有限公司 | According to Shandong for Buddhist nun's novel crystal forms and preparation method thereof |
| CN106831788B (en) * | 2017-01-22 | 2020-10-30 | 鲁南制药集团股份有限公司 | Ibutotinib refining method |
| CN108467389A (en) * | 2018-06-27 | 2018-08-31 | 苏州市贝克生物科技有限公司 | The purification process of Afatinib |
| CN108707154A (en) * | 2018-07-10 | 2018-10-26 | 刘凤娟 | A kind of drug solvent for the treatment of cancer closes object and preparation method thereof |
| CN108727387B (en) * | 2018-07-25 | 2021-03-16 | 天津大学 | Ibrutinib isopropyl acetate solvent compound and preparation method thereof |
| CN113214261A (en) * | 2020-01-21 | 2021-08-06 | 尚科生物医药（上海）有限公司 | Purification method of ibrutinib crystal form A |
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| CN104557946A (en) * | 2015-02-04 | 2015-04-29 | 王立强 | Preparation method of ibrutinib |
| CN104557945A (en) * | 2015-01-27 | 2015-04-29 | 安润医药科技（苏州）有限公司 | Synthesis method of ibrutinib |
| WO2015071432A1 (en) * | 2013-11-14 | 2015-05-21 | Sandoz Ag | Pharmaceutical compositions of ibrutinib |
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2015
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| WO2015071432A1 (en) * | 2013-11-14 | 2015-05-21 | Sandoz Ag | Pharmaceutical compositions of ibrutinib |
| CN105085529A (en) * | 2014-05-15 | 2015-11-25 | 广东东阳光药业有限公司 | Novel crystal form of ibrutinib and preparation method thereof |
| CN104557945A (en) * | 2015-01-27 | 2015-04-29 | 安润医药科技（苏州）有限公司 | Synthesis method of ibrutinib |
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