CN109134474A - The preparation of Buddhist nun's intermediate is replaced according to Shandong - Google Patents
The preparation of Buddhist nun's intermediate is replaced according to Shandong Download PDFInfo
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- CN109134474A CN109134474A CN201811206741.XA CN201811206741A CN109134474A CN 109134474 A CN109134474 A CN 109134474A CN 201811206741 A CN201811206741 A CN 201811206741A CN 109134474 A CN109134474 A CN 109134474A
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- shandong
- buddhist nun
- mentioned
- amino
- pyrimidine
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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 a kind of preparations that Buddhist nun's intermediate is replaced according to Shandong, and the preparation of specially 3- (4- Phenoxyphenyl) -4- amino -1H- pyrazolo [3,4-d] pyrimidine, not only reaction step is few for this method, but also avoid using expensive reagent.
Description
Technical field
The present invention relates to anticancer drug according to Shandong for Buddhist nun's intermediate 3- (4- Phenoxyphenyl) -4- amino -1H- pyrazolo [3,
4-d] pyrimidine synthesis.Reaction step can be reduced by this method, is avoided using expensive reagent.
Background technique
The signal path of B cell antigen receptor (BCR) is the key that numerous tumour growths and sends out driver.BTK
(Bruton ' s tyrosine kinase) participant indispensable as BCR signal peptide, formation, differentiation, information to bone-marrow-derived lymphocyte
It transmits and survives and is most important.BTK is the identifiable signal peptide molecule in the channel BCR, when the signal peptide molecule passes through bone-marrow-derived lymphocyte
When surface receptor, bone-marrow-derived lymphocyte realizes that the required channel of transhipment, chemotaxis and adhesion is activated, this is pernicious swollen for B cell
The formation of tumor is provided convenience.
Replacing Buddhist nun (ibrutinib) according to Shandong is a kind of BTK inhibitor of small molecule, it can be with half Guang on BTK active site
Histidine residue (Cys-481) selectively covalent bond irreversibly inhibits the activity of BTK, and then inhibits BCR signal path
Activation effectively prevents tumour from migrating from B cell to the lymphoid tissue of suitable tumour growth, reduces B cell malignant proliferation and induces
The apoptosis of cell, to play the work for the treatment of chronic lymphocytic leukemia (CLL) and tissue basophile granulocytic leukemia (MCL)
With.Non-clinical study shows to be able to suppress the proliferation and survival of malignant B in vivo according to Shandong for Buddhist nun.The change of Buddhist nun is replaced according to Shandong
It is as follows to learn structural formula:
Although replacing Buddhist nun according to Shandong is a kind of active drug for the treatment of that can be used for lymphoma mantle cell, but since its technique is closed
At route complexity, therefore price is costly.Technique is improved, cost is reduced and is of great significance for treating such disease.
According to Shandong for Buddhist nun synthesis substantially will by intermediate 3- (4- Phenoxyphenyl) -4- amino -1H- pyrazolo [3,
4-d] pyrimidine (V) realizes.Currently, the intermediate (V) synthesis has 3 routes substantially:
First route, such as the patent (WO2016/66673) that the Sang Duosi limited liability company of Switzerland reports, synthesis
Route is as follows:
The synthetic route totally 4 step, step is more, and wherein to use chloride compounds (II) as intermediate and be Fu-
Gram reaction.Acyl chlorides has biggish harmfulness to human body and natural environment, therefore this method lacks environmental protection and economy.
Article 2 route, such as the patent (CN106608877) that Xinfa Pharmaceutical Co., Ltd. reports, synthetic route is as follows:
Such method, synthesis step totally 3 step, but need to use malononitrile (VII) in synthesis process, toxicity is like cyanide.Cause
This, this method lacks safety and environmental protection.
Third class method is mostly synthesized using palladium chtalyst coupling method, such as external Concert
The patent (WO2014/22390,2014, A1) of Pharmaceuticals company, there are also domestic Chinese Academy of Sciences's Shanghai drugs
The patent (CN107759602) of research institute, the synthesis of its report of the patent (CN105859728) of Jiangsu Zhong Bang pharmaceutcal corporation, Ltd
Under route:
Such synthetic method totally 3 step, but needs expensive palladium catalyst and corresponding boron or silica reagent (XIII).It purified
Journey is harmful to the human body since palladium is heavy metal, and the catalyst is homogeneous catalyst, and therefore, completely removing will spend largely
Manpower and material resources.
The shortcomings that based on the patent reported before and deficiency, this research carry out following process modification.Buddhist nun is replaced according to Shandong to reduce
The synthesis technology cost of intermediate, this research are reduced to two steps from three steps, and without using expensive palladium catalyst and accordingly
Boron or silica reagent and severe toxicity and harmful raw material.This research intermediate X I synthesis is identical with third class synthetic method.Intermediate X I
It is instead given birth to compound XIV and reacts in the presence of a base, obtains product V.Eliminate the intermediate X II of third class synthetic method
Synthesis, specific synthetic route is as follows:
Summary of the invention
The present invention relates to anticancer drugs to replace Buddhist nun's intermediate -- 3- (4- Phenoxyphenyl) -4- amino -1H- pyrazolo according to Shandong
The synthesis of [3,4-d] pyrimidine.Reaction step can be reduced by this method, is avoided using palladium catalyst, reaction equation is as follows:
The solvent described above that use that reacts is DMSO, DMF, DMA.
Reaction temperature described above is 100-150 DEG C.
The dosage described above for reacting the 4- amino-pyrazol that uses simultaneously [3,4-d] pyrimidine is 0.1-1.0 equivalent.
The dosage described above for reacting the 4- iodine diphenyl ether used is 1.0-40.0 equivalent.
Reaction time described above is 12-36 hours.
Specific embodiment
The present invention can be more specifically understood by the following examples, but it illustrates rather than the limitation present invention
Range.
Embodiment
1. preparing 3- (4- Phenoxyphenyl) -4- amino -1H- pyrazolo [3,4-d] pyrimidine
By 270.1g (2.0mol) 4- amino-pyrazol, simultaneously [3,4-d] pyrimidine and 295.9g (1.0mol) 4- iodine diphenyl ether add
Enter into 1L DMSO, 448.8g (4.0mol) potassium tert-butoxide is added later.After adding, nitrogen displacement is carried out, is heated to 120 DEG C,
Reaction 24 hours.By controlling in HPLC, when 4- iodine diphenyl ether runs out of, reaction terminates.It is down to room temperature, 5L methyl- tert fourth is added
Base ether carries out 3 washings with 5L water later.Organic phase is concentrated under reduced pressure after being dried using anhydrous sodium sulfate, residue routine column layer
Gained crude product carries out being recrystallized to give 3- (4- Phenoxyphenyl) -4- amino -1H- pyrazolo [3,4-d] using DMF solvent after analysis
Pyrimidine (248.5g, 82%, HPLC purity 99.7%).
2. preparing 3- (4- Phenoxyphenyl) -4- amino -1H- pyrazolo [3,4-d] pyrimidine
By 270.1mg (2.0mmol) 4- amino-pyrazol simultaneously [3,4-d] pyrimidine and 295.9mg (1.0mmol) 4- iodine diphenyl
Ether is added in 1mL DMSO, and 448.8mg (4.0mmol) potassium tert-butoxide is added later.After adding, nitrogen displacement, heating are carried out
To 120 DEG C, react 24 hours.By controlling in HPLC, when 4- iodine diphenyl ether runs out of, reaction terminates.It is down to room temperature, is added
5mL methyl tertiary butyl ether(MTBE) carries out 3 washings with 5mL water later.Organic phase is concentrated under reduced pressure after being dried using anhydrous sodium sulfate, residual
Gained crude product carries out being recrystallized to give 3- (4- Phenoxyphenyl) -4- amino -1H- using DMF solvent after excess routine column chromatography
Pyrazolo [3,4-d] pyrimidine (249.0mg, 82%, HPLC purity 99.8%).
Claims (6)
- Buddhist nun's intermediate 3- (4- Phenoxyphenyl) -4- amino -1H- pyrazolo [3,4- is replaced according to Shandong 1. the present invention relates to anticancer drugs D] pyrimidine synthesis.Reaction step can be reduced by this method, is avoided using expensive reagent, reaction equation is as follows:
- 2. the method as mentioned by claim 1, reacting used solvent is DMSO, DMF, DMA.
- 3. the method as mentioned by claim 1, reaction temperature is 100-150 DEG C.
- 4. the method as mentioned by claim 1, the dosage for reacting the 4- amino-pyrazol used simultaneously [3,4-d] pyrimidine is 0.1- 1.0 equivalent.
- 5. the method as mentioned by claim 1, the dosage for reacting the 4- iodine diphenyl ether used is 1.0-40.0 equivalent.
- 6. the method as mentioned by claim 1, the reaction time is 12-36 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811206741.XA CN109134474A (en) | 2018-10-17 | 2018-10-17 | The preparation of Buddhist nun's intermediate is replaced according to Shandong |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201811206741.XA CN109134474A (en) | 2018-10-17 | 2018-10-17 | The preparation of Buddhist nun's intermediate is replaced according to Shandong |
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| CN201811206741.XA Pending CN109134474A (en) | 2018-10-17 | 2018-10-17 | The preparation of Buddhist nun's intermediate is replaced according to Shandong |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016079693A1 (en) * | 2014-11-19 | 2016-05-26 | Sun Pharmaceutical Industries Limited | A process for the preparation of ibrutinib |
| CN105859728A (en) * | 2016-05-26 | 2016-08-17 | 江苏中邦制药有限公司 | Preparation method for ibrutinib |
| CN107383017A (en) * | 2017-07-20 | 2017-11-24 | 河南师范大学 | Buddhist nun's high efficiency preparation method is replaced according to Shandong |
-
2018
- 2018-10-17 CN CN201811206741.XA patent/CN109134474A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016079693A1 (en) * | 2014-11-19 | 2016-05-26 | Sun Pharmaceutical Industries Limited | A process for the preparation of ibrutinib |
| CN105859728A (en) * | 2016-05-26 | 2016-08-17 | 江苏中邦制药有限公司 | Preparation method for ibrutinib |
| CN107383017A (en) * | 2017-07-20 | 2017-11-24 | 河南师范大学 | Buddhist nun's high efficiency preparation method is replaced according to Shandong |
Non-Patent Citations (1)
| Title |
|---|
| I. Z. RAKHMATULLIN ET AL.: "Stereodynamics of some pyridoxine derivatives", 《MAGN. RESON. CHEM.》 * |
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| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information | ||
| CB02 | Change of applicant information |
Address after: 226123 No. 18 Qinghua Road, three Factory Street, Haimen City, Nantong, Jiangsu Applicant after: Jiangsu Huiju Pharmaceutical Co.,Ltd. Address before: 226123 No. 18 Qinghua Road, three Factory Street, Haimen City, Nantong, Jiangsu Applicant before: WISDOM PHARMACEUTICAL Co.,Ltd. |
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| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190104 |