CN104447761A - Method for preparing pyrazole derivative - Google Patents
Method for preparing pyrazole derivative Download PDFInfo
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- CN104447761A CN104447761A CN201410714363.1A CN201410714363A CN104447761A CN 104447761 A CN104447761 A CN 104447761A CN 201410714363 A CN201410714363 A CN 201410714363A CN 104447761 A CN104447761 A CN 104447761A
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- compound
- organic solvent
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- propyl carbinol
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- HNIMEQCLCNSCGH-UHFFFAOYSA-N Nc([nH]nc1-c(cc2)ccc2Oc2ccccc2)c1C#N Chemical compound Nc([nH]nc1-c(cc2)ccc2Oc2ccccc2)c1C#N HNIMEQCLCNSCGH-UHFFFAOYSA-N 0.000 description 1
- YYVUOZULIDAKRN-UHFFFAOYSA-N Nc1c(c(-c(cc2)ccc2Oc2ccccc2)n[nH]2)c2ncn1 Chemical compound Nc1c(c(-c(cc2)ccc2Oc2ccccc2)n[nH]2)c2ncn1 YYVUOZULIDAKRN-UHFFFAOYSA-N 0.000 description 1
Classifications
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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 relates to a method for preparing a pyrazole derivative for preparing ibrutinib, and belongs to the technical field of pharmacy. The method comprises the following steps: reacting raw materials with formamidine acetate in an organic solvent at 80-130 DEG C, cooling after the reaction is completed, and collecting solids to obtain a product, wherein the organic solvent is one or more of N,N-dimethyl formamide, N,N-dimethylacetamide, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, glycol dimethyl ether, n-butyl alcohol, isobutanol, n-amyl alcohol and isoamyl alcohol. The method can be used for solving the problem of long-time high temperature reaction in the prior art, is simple and convenient, is low in cost, and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of pyrazole derivatives, belong to pharmaceutical technology sectors.
Background technology
According to Shandong for Buddhist nun (Ibrutinib), chemistry 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base]-piperidino]-2-propylene-1-ketone by name; A kind of irreversible bruton's tyrosine kinase (BTK, Bruton's tyrosine kinase) inhibitor, the propagation of malignant B cell, existence can be suppressed, can be used for the diseases such as treatment chronic lymphocytic leukemia (CLL) and lymphoma mantle cell (MCL).
Replace in the process of Buddhist nun according to Shandong in preparation, need first to prepare midbody compound 3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine, its structure is such as formula shown in (02):
In prior art, be typically employed in high temperature 180 DEG C and react to prepare compound (02) for a long time; This method temperature of reaction is high, long reaction time, causes reaction cost high, and because long-time pyroreaction, easily produces more impurity, and make the difficult purity of the product purification of acquisition low, yield is low; And bring larger potential safety hazard, be unsuitable for suitability for industrialized production.
Summary of the invention
Summary of the invention
The invention provides the preparation method of a kind of compound (02), which solve the problem that high temperature of the prior art reacts for a long time, and product purity is high, yield is high, method is easy and simple to handle, and cost is low, is suitable for suitability for industrialized production.
Detailed Description Of The Invention
The invention provides the method that one prepares compound (02), it comprises: the salt of compound (01) and carbonamidine in organic solvent, reacts in certain temperature, after completion of the reaction, cooling, collects the solid of separating out, obtain compound (02), be shown below:
Contriver finds, compound (01) reacts in organic solvent with the salt of carbonamidine, is conducive to reducing temperature of reaction, reduces impurity and produces.
The salt of described carbonamidine comprises FORMAMIDINE ACETATE, formamidine hydrochloride.In some embodiments, compound (01) and FORMAMIDINE ACETATE are reacted, and obtained compound (02).
The molar ratio of the salt of described carbonamidine and compound (01) is 1.2:1-4.5:1.In some embodiments, the molar ratio of described FORMAMIDINE ACETATE and compound (01) is 2.5:1-4.5:1.In some embodiments, the molar ratio of described FORMAMIDINE ACETATE and compound (01) is 3:1-4:1.In some embodiments, the molar ratio of described FORMAMIDINE ACETATE and compound (01) is 3:1-3.5:1.
Described organic solvent is N, one or more in dinethylformamide (DMF), N,N-dimethylacetamide (DMA), ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, glycol dimethyl ether (DME), propyl carbinol, isopropylcarbinol, Pentyl alcohol and primary isoamyl alcohol.In some embodiments, described organic solvent is one or more in ethylene glycol monomethyl ether, ethylene glycol monoethyl ether and propyl carbinol.In some embodiments, described organic solvent is ethylene glycol monomethyl ether, propyl carbinol or its combination.In some embodiments, described organic solvent is propyl carbinol.In some embodiments, described organic solvent is ethylene glycol monomethyl ether.
Described consumption of organic solvent, according to the Mass Calculation of compound (01), each g of compound (01), consumption of organic solvent is 3 milliliters-20 milliliters.In some embodiments, each g of compound (01), consumption of organic solvent is 5 milliliters-15 milliliters.In some embodiments, each g of compound (01), consumption of organic solvent is 7 milliliters-13 milliliters.
Described compound (01) is 60 DEG C-130 DEG C with the temperature of reaction of the reactant salt of carbonamidine.In some embodiments, described compound (01) is 80 DEG C-130 DEG C with the temperature of reaction of the salt of carbonamidine.In some embodiments, described compound (01) is 100 DEG C-120 DEG C with the temperature of reaction of the salt of carbonamidine.
Described compound (01) is 8 hours-24 hours with the reaction times of the reactant salt of carbonamidine.In some embodiments, described compound (01) is 10 hours-20 hours with the reaction times of the reactant salt of carbonamidine.In some embodiments, described compound (01) is 12 hours-16 hours with the reaction times of the reactant salt of carbonamidine.
Compound (01) and the reactant salt of carbonamidine, after completion of the reaction, be cooled to-5 DEG C-35 DEG C, then through solid-liquid separation, obtain product by reaction mixture.In some embodiments, after completion of the reaction, reaction mixture is cooled to 0 DEG C-35 DEG C.In some embodiments, after completion of the reaction, reaction mixture is cooled to 10 DEG C-30 DEG C.In some embodiments, after completion of the reaction, reaction mixture is cooled to 15 DEG C-30 DEG C.In some embodiments, after completion of the reaction, reaction mixture is cooled to 15 DEG C-25 DEG C.In some embodiments, after completion of the reaction, reaction mixture is cooled to 0 DEG C-5 DEG C.
After solid-liquid separation, gained solid crude product can be passed through the operations such as washing, making beating, purifying, crystallization to improve its purity Coriolis mass further.
Gained solid product can be passed through dry to remove desolventizing, and the drying means that can adopt has vacuum-drying, the conventional drying methods such as forced air drying.In some embodiments, gained solid is 40 DEG C of-100 DEG C of vacuum-dryings.In some embodiments, gained solid is 50 DEG C of-80 DEG C of vacuum-dryings.
In some embodiments, the method that one prepares compound (02) comprises: compound (01) and FORMAMIDINE ACETATE are in propyl carbinol, 80 DEG C-120 DEG C reactions 12 hours-16 hours, then reaction mixture is cooled to-5 DEG C-35 DEG C, stir, filter, gained solid, with dry after propyl carbinol washing, obtains compound (02).
In some embodiments, the method that one prepares compound (02) comprises: compound (01) and FORMAMIDINE ACETATE are in propyl carbinol, 100 DEG C-120 DEG C reactions 12 hours-16 hours, then reaction mixture is cooled to-5 DEG C-5 DEG C, stir, filter, gained solid, with dry after propyl carbinol washing, obtains compound (02).
In some embodiments, the method that one prepares compound (02) comprises: compound (01) and FORMAMIDINE ACETATE are in propyl carbinol, 80 DEG C-120 DEG C reactions 12 hours-16 hours, then reaction mixture is cooled to 15 DEG C-30 DEG C, stir, filter, gained solid, with extremely dry 40 DEG C of-80 DEG C of vacuum-dryings after propyl carbinol washing, obtains compound (02).
In some embodiments, the method that one prepares compound (02) comprises: compound (01) and FORMAMIDINE ACETATE are in propyl carbinol, 100 DEG C-120 DEG C reactions 12 hours-16 hours, then reaction mixture is cooled to 15 DEG C-30 DEG C, stir, filter, gained solid, with extremely dry 40 DEG C of-80 DEG C of vacuum-dryings after propyl carbinol washing, obtains compound (02); Wherein, the molar ratio of FORMAMIDINE ACETATE and compound (01) is 3:1-3.5:1, each g of compound (01), and the consumption of propyl carbinol is 3 milliliters-20 milliliters.
In some embodiments, the method that one prepares compound (02) comprises: compound (01) and FORMAMIDINE ACETATE are in propyl carbinol, 100 DEG C-120 DEG C reactions 12 hours-16 hours, then reaction mixture is cooled to-5 DEG C-5 DEG C, stir, filter, gained solid, with extremely dry 40 DEG C of-80 DEG C of vacuum-dryings after propyl carbinol washing, obtains compound (02); Wherein, the molar ratio of FORMAMIDINE ACETATE and compound (01) is 3:1-3.5:1, each g of compound (01), and the consumption of propyl carbinol is 5 milliliters-15 milliliters.
Method of the present invention, by with an organic solvent, particularly propyl carbinol, be that temperature of reaction reduces, impurity is less, and method is easy, can be used for suitability for industrialized production.
Embodiment
In order to make those skilled in the art understand technical scheme of the present invention better, below disclose further some non-limiting embodiments the present invention is described in further detail.
Reagent used in the present invention all can be buied from the market or can be obtained by method described in the invention preparation.
In the present invention, g represents gram, and mL represents milliliter.
Embodiment 1
In reactor, add 3-amino-5-(4-Phenoxyphenyl)-4-cyano group-1H-pyrazoles 10.00g, FORMAMIDINE ACETATE 7.61g and propyl carbinol 100mL, stirred at ambient temperature is even.Be heated to 110 DEG C, 110 DEG C of reactions 15 hours.Then reaction mixture is cooled to 20 DEG C-30 DEG C, filter, filter cake propyl carbinol 20mL drip washing, gained solid is extremely dry 60 DEG C of vacuum-dryings, obtain solid 10.21g, confirming through mass spectrum and nucleus magnetic hydrogen spectrum, is 3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine, purity: 99.43%.
Mass spectrum MS:304.90;
Nuclear-magnetism
1h NMR (600MHz, DMSO) δ 13.55 (s, 1H), 8.22 (s, 1H), 7.67 (d, J=8.5Hz, 2H), 7.44 (t, J=7.8Hz, 2H), 7.16 (ddd, J=21.5,13.8,7.7Hz, 5H).
Embodiment 2
In reactor, add 3-amino-5-(4-Phenoxyphenyl)-4-cyano group-1H-pyrazoles 10.00g, FORMAMIDINE ACETATE 6.74g and propyl carbinol 80mL, stirred at ambient temperature is even.Be heated to 100 DEG C-110 DEG C, 100 DEG C-110 DEG C reactions 16 hours.Then reaction mixture is cooled to 10 DEG C-20 DEG C, filter, filter cake 20mL propyl carbinol drip washing, gained solid is extremely dry 70 DEG C of vacuum-dryings, obtain solid 10.28g, purity: 99.21%, confirms as 3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine through mass spectrum.
Embodiment 3
In reactor, add 3-amino-5-(4-Phenoxyphenyl)-4-cyano group-1H-pyrazoles 10.00g, FORMAMIDINE ACETATE 8.70g and propyl carbinol 120mL, stirred at ambient temperature is even.Be heated to 120 DEG C, 120 DEG C of reactions 13 hours.Then reaction mixture is cooled to 25 DEG C-35 DEG C, filter, filter cake propyl carbinol 20mL drip washing, gained solid is extremely dry 60 DEG C of vacuum-dryings, obtain solid 10.24g, purity: 99.65%, confirms as 3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine through mass spectrum.
Embodiment 4
In reactor, add 3-amino-5-(4-Phenoxyphenyl)-4-cyano group-1H-pyrazoles 10.00g, FORMAMIDINE ACETATE 8.70g and propyl carbinol 130mL, stirred at ambient temperature is even.Be heated to 120 DEG C, 110 DEG C-120 DEG C reactions 14 hours.Then reaction mixture is cooled to 0 DEG C-5 DEG C, filter, filter cake propyl carbinol 20mL drip washing, gained solid is extremely dry 60 DEG C of vacuum-dryings, obtain solid 10.24g, purity: 99.65%, confirms as 3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine through mass spectrum.
Embodiment 5
In reactor, add 3-amino-5-(4-Phenoxyphenyl)-4-cyano group-1H-pyrazoles 10.00g, FORMAMIDINE ACETATE 8.70g and ethylene glycol monomethyl ether 130mL, stirred at ambient temperature is even.Be heated to 130 DEG C, 120 DEG C-130 DEG C reactions 14 hours.Then reaction mixture is cooled to 10 DEG C-20 DEG C, filter, filter cake spent glycol monomethyl ether 20mL drip washing, gained solid is extremely dry 70 DEG C of vacuum-dryings, obtain solid 10.30g, purity: 99.69%, confirms as 3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine through mass spectrum.
Embodiment 6
In reactor, add 3-amino-5-(4-Phenoxyphenyl)-4-cyano group-1H-pyrazoles 10.00g, FORMAMIDINE ACETATE 10.10g and ethylene glycol monoethyl ether 130mL, stirred at ambient temperature is even.Be heated to 130 DEG C, 120 DEG C-130 DEG C reactions 14 hours.Then reaction mixture is cooled to 10 DEG C-20 DEG C, filter, filter cake spent glycol list ether 30mL drip washing, gained solid is extremely dry 75 DEG C of vacuum-dryings, obtain solid 10.27g, purity: 99.63%, confirms as 3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine through mass spectrum.
Method of the present invention is described by preferred embodiment, and related personnel obviously can change methods and applications as herein described or suitably change and combination in content of the present invention, spirit and scope, realizes and applies the technology of the present invention.Those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.
Claims (7)
1. prepare a method for compound (02),
Comprise: in organic solvent, 80 DEG C-130 DEG C reactions, after completion of the reaction, cooling, collects solid, obtain compound (02) for compound (01) and FORMAMIDINE ACETATE,
Wherein, described organic solvent is one or more in DMF, N,N-dimethylacetamide, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, glycol dimethyl ether, propyl carbinol, isopropylcarbinol, Pentyl alcohol and primary isoamyl alcohol.
2. method according to claim 1, the molar ratio of described FORMAMIDINE ACETATE and compound (01) is 3:1-3.5:1.
3. method according to claim 1, each g of compound (01), consumption of organic solvent is 5 liters-15 liters.
4. method according to claim 1, compound (01) and FORMAMIDINE ACETATE in organic solvent, are reacted 10 hours-20 hours at 80 DEG C-130 DEG C.
5. method according to claim 1, after completion of the reaction, is cooled to-5 DEG C-35 DEG C by reaction mixture.
6., according to the arbitrary described method of claim 1-5, described organic solvent is ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, propyl carbinol or its combination.
7. according to the arbitrary described method of claim 1-5, reaction mixture, in propyl carbinol, 100 DEG C-120 DEG C reactions 12 hours-16 hours, is then cooled to 15 DEG C-30 DEG C by compound (01) and FORMAMIDINE ACETATE, collect solid, obtain compound (02).
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| CN201410714363.1A CN104447761A (en) | 2014-11-27 | 2014-11-27 | Method for preparing pyrazole derivative |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017029586A1 (en) * | 2015-08-19 | 2017-02-23 | Sun Pharmaceutical Industries Limited | Crystalline forms of ibrutinib |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008054827A2 (en) * | 2006-11-03 | 2008-05-08 | Pharmacyclics, Inc. | Bruton's tyrosine kinase activity probe and method of using |
| CN101610676A (en) * | 2006-09-22 | 2009-12-23 | 药品循环公司 | The inhibitor of bruton's tyrosine kinase |
| CN103319488A (en) * | 2007-03-28 | 2013-09-25 | 环状药物公司 | Inhibitors of bruton's tyrosine kinase |
| WO2014139970A1 (en) * | 2013-03-15 | 2014-09-18 | Janssen Pharmaceutica Nv | Processes and intermediates for preparing a medicament |
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2014
- 2014-11-27 CN CN201410714363.1A patent/CN104447761A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101610676A (en) * | 2006-09-22 | 2009-12-23 | 药品循环公司 | The inhibitor of bruton's tyrosine kinase |
| WO2008054827A2 (en) * | 2006-11-03 | 2008-05-08 | Pharmacyclics, Inc. | Bruton's tyrosine kinase activity probe and method of using |
| CN103319488A (en) * | 2007-03-28 | 2013-09-25 | 环状药物公司 | Inhibitors of bruton's tyrosine kinase |
| WO2014139970A1 (en) * | 2013-03-15 | 2014-09-18 | Janssen Pharmaceutica Nv | Processes and intermediates for preparing a medicament |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017029586A1 (en) * | 2015-08-19 | 2017-02-23 | Sun Pharmaceutical Industries Limited | Crystalline forms of ibrutinib |
| US11001585B2 (en) | 2015-08-19 | 2021-05-11 | Sun Pharmaceutical Industries Limited | Crystalline forms of ibrutinib |
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