CN106831788A - Yi Bu replaces Buddhist nun's process for purification - Google Patents
Yi Bu replaces Buddhist nun's process for purification Download PDFInfo
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- CN106831788A CN106831788A CN201710054191.3A CN201710054191A CN106831788A CN 106831788 A CN106831788 A CN 106831788A CN 201710054191 A CN201710054191 A CN 201710054191A CN 106831788 A CN106831788 A CN 106831788A
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- buddhist nun
- purification
- replaces buddhist
- cloth
- ethyl acetate
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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 present invention relates to pharmaceutical synthesis field, and in particular to be that her cloth improved replaces Buddhist nun's process for purification.Her cloth of the present invention is that her cloth is carried out into column chromatography for separation for Buddhist nun's crude product for Buddhist nun's process for purification, inserts has the silica gel in document to be changed to macroporous absorbent resin, and eluant, eluent is ethyl acetate and petroleum ether, and the process for purification yield is very high and non-degradable, low production cost, is adapted to industrialized production.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, and in particular to be that her cloth a kind of replaces Buddhist nun's process for purification.
Background technology
Yi Bu replaces Buddhist nun, chemical entitled 1- [(3R) -3- [4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d]
Pyrimidine -1- bases] -1- piperidyls] -2- propylene -1- ketone, it is to be developed by Pharmacyclics companies and Johson ＆ Johnson's joint research and development,
In November, 2013 accelerates approval listing through FDA (Food and Drug Adminstration), and trade name Imbruvica is general entitled
Ibrutinib.Yi Bu is a kind of pioneering new drug of oral entitled bruton's tyrosine kinase (BTK) inhibitor for Buddhist nun, mainly
For treating a kind of rare aggressive leukemia --- lymphoma mantle cell (MCL).The medicine by with target protein Btk activity site
Cysteine residues optionally suppress BTK in covalent bond irreversibility ground, so as to effectively prevent tumour from being moved to from B cell
It is adapted to the lymphoid tissue of tumour growth environment.It is previous to have analyst it is predicted that the year sale peak of all indications of Ibrutinib
Value will reach about 5,000,000,000 dollars, and its maximum sales quota may be from chronic lymphocytic leukemia indication (CLL),
And the indication is also waiting FDA to ratify at present.
The preparation method that her cloth various replace Buddhist nun is disclosed in the prior art, and wherein CN101610676A is disclosed with 4- benzene oxygen
Yl benzoic acid is initiation material, is condensed with malononitrile after chlorination, then obtains Pyrazol intermediate with anhydrous hydrazine cyclization, afterwards and first
Acid amides cyclization obtains 4- amino-pyrazols simultaneously [3,4-d] pyrimidine parent nucleus, through light prolong reaction with chiral alcohol be condensed, take off Boc protection groups and
Product is obtained after the step such as acrylated, synthetic route is as follows：
The synthetic route is tediously long, and step is various, and it is low (34%) that light prolongs reactions steps yield, and total recovery only has 8.1%, and uses
To the triphenyl phosphorus resin that costliness is not easy to obtain, most can just obtain her cloth through chromatogram purification afterwards and replace Buddhist nun so that route industry chemical conversion
This height, complex operation.
With the bromo- 4- amino-pyrazols of 3-, simultaneously [3,4-d] pyrimidine, for initiation material, is passed through the route of CN103121999A reports successively
The coupling of suzuki reaction and 4- phenoxy groups phenyl boric acid, under conditions of cesium carbonate is alkali and chiral alcohol condensation, by trifluoroacetyl group
Protection, takes off Boc protection groups, and her cloth is obtained after the step such as acrylated and de- trifluoroacetyl group protection for Buddhist nun, and synthetic route is as follows
It is shown：
The synthetic route is tediously long, wherein the suzuki reaction with PdCl2 (PhCN) 2 as catalyst is difficult to repeat, and catalyst
Consumption is big；Cesium carbonate is needed 24 hours for the condensation step of alkali, and the reaction time is long；Protection deprotection steps to amino extend reaction
Route, reduces route total recovery, total recovery be 21.5% (with the bromo- 4- amino-pyrazols of 3- simultaneously [3,4-d] pyrimidine for starting is former
Material), the technique is unsuitable for being amplified production.
WO2014022390A1 report with 4- amino-pyrazols simultaneously [3,4-d] pyrimidine be initiation material, through iodo prepare in
Iodo- 1H- pyrazolos [3, the 4-d] pyrimidine -4- amine of mesosome 3-, after successively through suzuki reaction and 4- phenoxy groups phenyl boric acid coupling, through light
Prolong to react and be condensed with chiral alcohol, then most Buddhist nun is replaced through acrylated her cloth that obtains final product afterwards into salt after the de- Boc protections of hydrochloric acid, synthesize road
Line is as follows：
The suzuki reaction used catalyst tetra-triphenylphosphine palladium consumption of the route is high, and the inventory of relative substrate is worked as 0.2
Amount, the reaction time is up to 24 hours；Light prolongs that the reactions steps time is long, and yield is low (38%), and route total recovery only has 9.3%, and
Industrialization need to be unsuitable for through chromatogram purification.
Her cloth in patent WO2002080926 for the synthesis of Buddhist nun's analog describe with 3- iodo -4- amino-pyrazols simultaneously [3,
4-d] pyrimidine is raw material, light first occurs with 3- hydroxyl-1- t-butoxycarbonylpiperidins prolongs reaction and obtains 1-piperidines substituent, afterwards with
There is suzuki reaction and obtain various different analogs in different boric acid, synthetic route is as follows：
In the route, with 3- iodo -4- amino-pyrazols, simultaneously [3,4-d] pyrimidine is that raw material generation light prolongs reaction, the iodo
Raw material high cost, and light prolongs reactions steps yield and there was only 25%.
Patent WO2014/022390A1 reports the process for purification that her cloth replaces Buddhist nun.The process for purification is as filling out with silica gel
Filling material carries out column chromatography for separation, and eluant, eluent is methyl alcohol：Dichloromethane.The method yield is low, and analytical effect is poor, is not suitable for industry
Metaplasia is produced.
The content of the invention
In view of the deficiencies in the prior art, of the invention to carry out column chromatography for separation as fill material with macroporous absorbent resin, wash
De- agent is ethyl acetate and petroleum ether, significantly improves separating effect, improves purity and yield, is adapted to industrialized production.
Technical scheme is summarized as follows：
Added after macroporous absorbent resin and organic solvent are well mixed in large pore resin absorption column, be compacted with compression pump,
Her cloth is dissolved loading for Buddhist nun's crude product with a small amount of above-mentioned organic solvent again, is eluted with eluant ethyl acetate and petroleum ether, led to
TLC detections are crossed, purer eluent is collected, concentrated under reduced pressure be dried to obtain her pure cloth and replace Buddhist nun.
Mass ratio meter, the macroporous absorbent resin：Yi Bu replaces Buddhist nun crude product=20~30：1.
The organic solvent is preferably dichloromethane.
The eluant, eluent can also be ethyl acetate with n-hexane, ethyl acetate and pentane, methyl alcohol and petroleum ether, acetic acid
Ethyl ester and dichloromethane, ethyl acetate and chloroform, methyl alcohol and chloroform, absolute ethyl alcohol and petroleum ether, absolute ethyl alcohol with
Dichloromethane, absolute ethyl alcohol and chloroform, methyl alcohol and n-hexane, methyl alcohol and normal heptane.
The eluant ethyl acetate is 1 with the volume ratio of petroleum ether:100~230；Preferably 1:200.
The blade diameter length ratio of pillar is 1 in the column chromatography for separation:8~10.
The flow velocity eluted in the column chromatography for separation is 20~30ml/min.
Temperature is 40~45 DEG C when the eluent of the collection is concentrated under reduced pressure.
The temperature of the drying steps is 40~45 DEG C, and drying mode is vacuum drying.
The advantage of this technique：Separating effect is significantly improved, purity improves yield up to more than 99.89, yield is up to 80%
More than, production cost is reduced, it is adapted to industrialized production.
Specific embodiment
With reference to specific embodiment is implemented, the present invention is further illustrated.It should be understood that these embodiments are merely to illustrate this
Invention rather than limitation the scope of the present invention.Empirical tests methods described is applied to any preparation method gained concentration of prior art
Liquid, different degrees of raising can be obtained using the refined rear purity of the application method.
Used raw material or reagent are commercially available in embodiment；Concentrate described in following embodiments 1~6 by
CN105985344A is prepared, if through drying crude product purity about 85%.
Embodiment 1
Macroporous adsorbent resin column chromatography
To adding dichloromethane to dissolve in concentrate, loading large pore resin absorption column, resin model is HP20, resin column footpath
Height compares 1:8, flow velocity is 25ml/min, and it is 1 with petroleum ether ratio that ethyl acetate is used after end of the sample:200 solution rinse resin column, lead to
TLC detections are crossed, purer eluent is collected, is concentrated under reduced pressure, thickening temperature is 40-45 DEG C, collects solid, sabot, in temperature
Spend to be vacuum dried 12-14h under the conditions of 45 DEG C, obtain solid, HPLC：99.92%, yield 85%.
Embodiment 2
Macroporous adsorbent resin column chromatography
To adding dichloromethane to dissolve in concentrate, loading large pore resin absorption column, resin model is HP20, resin column footpath
Height compares 1:10, flow velocity is 30ml/min, and it is 1 with petroleum ether ratio that ethyl acetate is used after end of the sample:100 solution rinse resin column,
Detected by TLC, collect purer eluent, be concentrated under reduced pressure, thickening temperature is 40-45 DEG C, collection solid, sabot,
Temperature obtains solid, HPLC to be vacuum dried 12-14h under the conditions of 45 DEG C：99.90%, yield 84%.
Embodiment 3
Macroporous adsorbent resin column chromatography
To adding dichloromethane to dissolve in concentrate, loading large pore resin absorption column, resin model is HP20, resin column footpath
Height compares 1:10, flow velocity is 20ml/min, and it is 1 with petroleum ether ratio that ethyl acetate is used after end of the sample:230 solution rinse resin column,
Detected by TLC, collect purer eluent, be concentrated under reduced pressure, thickening temperature is 40~45 DEG C, collection solid, sabot,
Temperature is 12~14h of vacuum drying under the conditions of 40 DEG C, obtains solid, HPLC：99.92%, yield 85%.
Embodiment 4
Macroporous adsorbent resin column chromatography
To adding dichloromethane to dissolve in concentrate, loading large pore resin absorption column, resin model is HP20, resin column footpath
Height compares 1:10, flow velocity is 20ml/min, and it is 1 with petroleum ether ratio that ethyl acetate is used after end of the sample:300 solution rinse resin column,
Detected by TLC, collect purer eluent, be concentrated under reduced pressure, thickening temperature is 40~45 DEG C, collection solid, sabot,
Temperature is 12~14h of vacuum drying under the conditions of 45 DEG C, obtains solid, HPLC：99.85%, yield 83%.
Embodiment 5
Macroporous adsorbent resin column chromatography
To adding dichloromethane to dissolve in concentrate, loading large pore resin absorption column, resin model is HP20, resin column footpath
Height compares 1:8~10, flow velocity is 35ml/min, and it is 1 with petroleum ether ratio that ethyl acetate is used after end of the sample:300 solution rinse resin
Post, is detected by TLC, collects purer eluent, is concentrated under reduced pressure, and thickening temperature is 50 DEG C, collection solid, sabot,
Temperature is 12~14h of vacuum drying under the conditions of 50 DEG C, obtains solid, HPLC：99.81%, yield 76%.
Embodiment 6
Macroporous adsorbent resin column chromatography
To adding dichloromethane to dissolve in concentrate, loading large pore resin absorption column, resin model is HP20, resin column footpath
Height compares 1:8~10, flow velocity is 15ml/min, and it is 1 with petroleum ether ratio that ethyl acetate is used after end of the sample:300 solution rinse resin
Post, is detected by TLC, collects purer eluent, is concentrated under reduced pressure, and thickening temperature is 50 DEG C, collection solid, sabot,
Temperature is 12~14h of vacuum drying under the conditions of 50 DEG C, obtains solid, HPLC：99.80%, yield 78%.
Embodiment 7
Macroporous adsorbent resin column chromatography
To purity about 98%, loading macroporous absorption tree after adding dichloromethane dissolving, the concentrate to dry in concentrate
Fat post, resin model is HP20, resin column blade diameter length ratio 1:10, flow velocity is 20ml/min, and ethyl acetate and stone are used after end of the sample
Oily ether ratio is 1:230 solution rinse resin column, are detected by TLC, collect purer eluent, are concentrated under reduced pressure, concentration temperature
It is 40~45 DEG C to spend, and collects solid, and sabot is vacuum dried 12~14h, obtains solid, HPLC under the conditions of being 40 DEG C in temperature：
99.99%, yield 85%.
Claims (9)
1. her cloth a kind of replaces Buddhist nun's process for purification, it is characterised in that add after being first well mixed macroporous absorbent resin and organic solvent
Enter in large pore resin absorption column, be compacted with compression pump, then her cloth is dissolved loading for Buddhist nun's crude product with a small amount of above-mentioned organic solvent,
Eluted with eluant ethyl acetate and petroleum ether, detect and collect eluent, concentrated under reduced pressure be dried to obtain her pure cloth and replace
Buddhist nun.
2. her cloth according to claim 1 replaces Buddhist nun's process for purification, it is characterised in that by quality ratio, the macroporous absorption
Resin：Yi Bu replaces Buddhist nun crude product=20~30：1.
3. her cloth according to claim 1 replaces Buddhist nun's process for purification, it is characterised in that the organic solvent is dichloromethane.
4. her cloth according to claim 1 replaces Buddhist nun's process for purification, it is characterised in that the eluant ethyl acetate and oil
The volume ratio of ether is 1:100~230；Preferably 1:200.
5. her cloth according to claim 1 replaces Buddhist nun's process for purification, it is characterised in that the eluant, eluent can also be acetic acid second
Ester and n-hexane, ethyl acetate and pentane, methyl alcohol and petroleum ether, ethyl acetate and dichloromethane, ethyl acetate and three chloromethanes
Alkane, methyl alcohol and chloroform, absolute ethyl alcohol and petroleum ether, absolute ethyl alcohol and dichloromethane, absolute ethyl alcohol and chloroform, methyl alcohol
With n-hexane, methyl alcohol and normal heptane.
6. her cloth according to claim 1 replaces Buddhist nun's process for purification, it is characterised in that the footpath of pillar in the column chromatography for separation
Height is than being 1:8~10.
7. her cloth according to claim 1 replaces Buddhist nun's process for purification, it is characterised in that the stream eluted in the column chromatography for separation
Speed is 20~30ml/min.
8. her cloth according to claim 1 replaces Buddhist nun's process for purification, it is characterised in that it is described it is concentrated under reduced pressure in temperature be 40~
45℃。
9. her cloth according to claim 1 replaces Buddhist nun's process for purification, it is characterised in that in the drying steps temperature be 40~
45 DEG C, drying mode is vacuum drying.
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| CN201710054191.3A CN106831788B (en) | 2017-01-22 | 2017-01-22 | Ibutotinib refining method |
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| CN201710054191.3A CN106831788B (en) | 2017-01-22 | 2017-01-22 | Ibutotinib refining method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107353291A (en) * | 2017-07-17 | 2017-11-17 | 郑州大学 | Her a kind of cloth replaces the refined preparation method of Buddhist nun |
| CN110804058A (en) * | 2018-08-06 | 2020-02-18 | 鲁南制药集团股份有限公司 | Novel ibrutinib crystal form and preparation method thereof |
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| CN103121999A (en) * | 2012-08-29 | 2013-05-29 | 苏州迪飞医药科技有限公司 | Method for synthesizing tyrosine kinase inhibitor PCI-32765 |
| CN105017256A (en) * | 2014-04-29 | 2015-11-04 | 浙江导明医药科技有限公司 | Polyfluorinated compound Bruton tyrosine kinase inhibitor |
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| WO2016079216A1 (en) * | 2014-11-20 | 2016-05-26 | Sandoz Ag | Physical forms of ibrutinib, a bruton's kinase inhibitor |
| CN105669679A (en) * | 2015-03-20 | 2016-06-15 | 苏州晶云药物科技有限公司 | Preparation method of PCI-32765 crystal form A |
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| CN103121999A (en) * | 2012-08-29 | 2013-05-29 | 苏州迪飞医药科技有限公司 | Method for synthesizing tyrosine kinase inhibitor PCI-32765 |
| CN105017256A (en) * | 2014-04-29 | 2015-11-04 | 浙江导明医药科技有限公司 | Polyfluorinated compound Bruton tyrosine kinase inhibitor |
| WO2016079216A1 (en) * | 2014-11-20 | 2016-05-26 | Sandoz Ag | Physical forms of ibrutinib, a bruton's kinase inhibitor |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107353291A (en) * | 2017-07-17 | 2017-11-17 | 郑州大学 | Her a kind of cloth replaces the refined preparation method of Buddhist nun |
| CN110804058A (en) * | 2018-08-06 | 2020-02-18 | 鲁南制药集团股份有限公司 | Novel ibrutinib crystal form and preparation method thereof |
| CN110804058B (en) * | 2018-08-06 | 2022-11-11 | 鲁南制药集团股份有限公司 | Novel ibrutinib crystal form and preparation method thereof |
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| CN106831788B (en) | 2020-10-30 |
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Effective date of registration: 20221116 Address after: 276006 No. 209 Hongqi Road, Shandong, Linyi Patentee after: LUNNAN BETTER PHARMACEUTICAL Co.,Ltd. Address before: 276005 No. 209 Hongqi Road, Shandong, Linyi Patentee before: LUNAN PHARMACEUTICAL Group Corp. |
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Denomination of invention: Ibutini refining method Effective date of registration: 20230117 Granted publication date: 20201030 Pledgee: Industrial and Commercial Bank of China Limited Linyi Shizhong Sub-branch Pledgor: LUNNAN BETTER PHARMACEUTICAL Co.,Ltd. Registration number: Y2023980031096 |