CN103965201A - Method for synthesizing intermediate 4-amino-3-(4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine of Ibrutinib - Google Patents

Method for synthesizing intermediate 4-amino-3-(4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine of Ibrutinib Download PDF

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CN103965201A
CN103965201A CN201410194883.4A CN201410194883A CN103965201A CN 103965201 A CN103965201 A CN 103965201A CN 201410194883 A CN201410194883 A CN 201410194883A CN 103965201 A CN103965201 A CN 103965201A
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amino
pyrimidine
pyrazolo
formula
compound
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程青芳
周菲菲
林敏�
王启发
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Huaihai Institute of Techology
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Huaihai Institute of Techology
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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 method for synthesizing an important intermediate 4-amino-3-(4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine of Ibrutinib. The method comprises the following steps: step one, condensing malononitrile and triethyl orthoformate and then carrying out a one-pot reaction with hydrazine hydrate to obtain 5-amino-4-cyano-pyrazole; step two, condensing the 5-amino-4-cyano-pyrazole with formamide to prepare a compound of formula (II) 4-amino-1H-pyrazolo[3,4-d]pyrimidine; step three, carrying out a bromination reaction of the compound of formula (II) and brominating agent to obtain a compound of formula (III) 4-amino-3-bromine-1H-pyrazolo[3,4-d]pyrimidine; step four, carrying out a Stille reaction on the compound of formula (III) and trimethyl p-phenoxy phenyltin under the catalyst effect of metal palladium to prepare a compound of formula (I) 4-amino-3-(4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine. According to the method for synthesizing the important intermediate 4-amino-3-(4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine of Ibrutinib provided by the invention, raw materials are low in price and easily obtained, the reaction conditions are moderate, the operation is simple and convenient, the method is suitable for industrial production, and a new way is provided for preparing Ibrutinib and intermediate.

Description

A kind of synthetic method of replacing Buddhist nun's intermediate 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine according to Shandong
Technical field
The invention belongs to organic preparing technical field, be specifically related to a kind of synthetic method of replacing Buddhist nun's intermediate 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine according to Shandong.
Background technology
According to Shandong, replace Buddhist nun (formula A), chemistry 1-[(3R by name)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-yl]-piperidino]-2-propylene-1-ketone, be Pharmacyclics company and Johson & Johnson's joint research and development exploitation, accelerate approval Initial Public Offering through FDA (Food and Drug Adminstration) in November, 2013, and commodity are called Imbruvica.According to Shandong, for Buddhist nun, be a kind of pioneering new drug of oral bruton's tyrosine kinase by name (BTK) inhibitor, be mainly used in treating a kind of rare aggressive leukemia---lymphoma mantle cell (MCL).This medicine is by optionally suppressing to covalent attachment non-reversibility BTK with target protein Btk avtive spot cysteine residues, thereby effectively stops tumour from B cell migration to the Lymphoid tissue that is adapted to tumor growth environment.
Formula (I) compound 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine be synthetic according to Shandong the key intermediate for Buddhist nun, for synthetic significant for Buddhist nun according to Shandong.Patent US7514444 has reported the synthetic of formula (I) compound 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine.This technique is that take to phenoxy benzoic acid is raw material, with after propane dinitrile condensation, by (TMS) diazomethane, methylate again, then be condensed into pyrazole ring with hydrazine hydrate, make formula (I) compound 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine with methane amide condensation again.
Synthetic route is:
In this technique, except need are used more expensive starting raw material, also need to use expensive (TMS) diazomethane that is difficult for having bought, this reagent is more responsive to empty G&W, and therefore, methylation reaction need carry out under anhydrous, oxygen free condition.Therefore, complex operation, production cost is high, is unfavorable for industrial production.
Summary of the invention
Technical problem to be solved by this invention is to overcome existing preparation formula (I) compound 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] the technology Raw of pyrimidine report is not easy to obtain, production cost is high, complicated operation, be unfavorable for the defect that large-scale industrialization is produced, a kind of effective preparation 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3 is provided, 4-d] method of pyrimidine, the method raw material is cheap and easy to get, reaction conditions is gentle, production cost is lower, is applicable to suitability for industrialized production.
Technical scheme of the present invention is summarized as follows:
Step (1), to after propane dinitrile and triethyl orthoformate condensation, make 5-amino-4-cyano pyrazole with hydrazine hydrate one pot reaction, step (2), 5-amino-4-cyano pyrazole and methane amide condensation obtain formula (II) compound 4-amino-1H-pyrazolo [3,4-d] pyrimidine; Step (3), formula (II) compound and bromizating agent generation bromo-reaction obtain formula (III) the compound 4-bromo-1H-pyrazolo of amino-3-[3,4-d] pyrimidine; Step (4), under metal palladium catalyst effect, to Phenoxyphenyl tin, there is Stille with formula (IV) compound trimethylammonium and react the formula that makes (I) compound 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine in formula (III) compound.
Synthetic route is:
Reaction in step (1) be take propane dinitrile as starting raw material, after reacting with triethyl orthoformate and aceticanhydride without separation and purification, directly and one pot of cyclization of hydrazine hydrate make 5-amino-4-cyano pyrazole, operate very simply, yield is high.
Bromizating agent in step (3) is the brominated reagent such as bromine, N-bromo-succinimide, wherein preferred valency bromine.
Catalyzer in step (4) is palladium metal compound, can be Pd (PPh 3) 4, (PPh 3) 2pdCl 2, Pd (dba) 2, (MeCN) 4pdCl 2, Pd[P (o-To1)] 2deng, preferred Pd (PPh wherein 3) 4.
Metal palladium catalyst catalytic efficiency is very high, and its consumption is only 2～5% of formula (III) compound molar mass.
Formula (IV) compound trimethylammonium in described step (4) is easy to preparation to Phenoxyphenyl tin, by 4-dibromodiphenyl ether, is reacted and can make with hexamethyl tin.
Reaction in described step (4) is all less sensitive to empty G&W, and reaction conditions is gentle, simple to operate.
Most suitable temperature of reaction in described step (4) is 60 ℃～80 ℃.
Solvent in described step (4) is weak polar solvent, and 2-methyltetrahydrofuran, toluene, ethylene dichloride, DMF etc. are relatively suitable as the solvent of this reaction, wherein preferential ethylene dichloride.
The advantage of this technique: reagent used is inexpensive, be easy to get, simple to operate, total recovery is higher.
Embodiment
Below in conjunction with implementing specific embodiment, further illustrate the present invention.Should be understood that these embodiment are only not used in and limit the scope of the invention for the present invention is described.
In embodiment, raw material used or reagent is except special instruction, all commercially available obtaining.
The preparation of embodiment 15-amino-4-cyano pyrazole
100mmol propane dinitrile and 200mmol aceticanhydride are added in there-necked flask, 100mmol triethyl orthoformate is added stir 1h at 100 ℃～105 ℃ after, maintain 100 ℃～105 ℃ and continue to stir 0.5h.Steam except lower boiling raw material, obtain oily residue.The hydrazine hydrate of 15mL85% is added, system temperature is risen to 90～95 ℃, and the 2h that refluxes at this temperature.Stop heating, in reaction flask, add 20mL water, stir, separate out solid.Suction filtration, with frozen water washing 2～3 times, dry, obtain solid, yield 90%.
The preparation of embodiment 2 formulas (II) compound 4-amino-1H-pyrazolos [3,4-d] pyrimidine
50mmol5-amino-4-cyano pyrazole, 50mmol methane amide, 2mL anhydrous stannic chloride and 100mL toluene are added in reaction flask, and reflux 4h, is cooled to room temperature, adds 50mL saturated aqueous sodium carbonate, is stirred to and no longer includes bubble effusion.Separate organic layer, by toluene (100mL * 3) aqueous phase extracted, merge organic layer, by pressure reducing and steaming solvent after anhydrous sodium sulfate drying, resistates re-crystallizing in ethyl acetate, obtain formula (II) compound, yield 83%.
The preparation of embodiment 3 formulas (III) the compound 4-bromo-1H-pyrazolos of amino-3-[3,4-d] pyrimidine
50mmol1H-pyrazolo [3,4-d] pyrimidine-4-amine, 3 DMF and 50mL thionyl chloride are added in reaction flask, after stirring at room reaction 1h, 65mmol bromine are splashed into, after dripping off, system temperature is risen to 60～70 ℃, and at this temperature stirring reaction 3h.Stop heating, in reaction flask, add 150mL toluene, pressure reducing and steaming toluene and unreacted thionyl chloride and bromine after stirring, after adding again 100mL toluene to stir, add 150mL distilled water, separate organic layer, and with distilled water wash 3 times, with pressure reducing and steaming solvent after anhydrous sodium sulfate drying, obtain formula (III) compound, yield 80%.
The preparation of embodiment 4 formulas (I) compound 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine
By 50mmol formula (III) compound, 55mmol formula (IV) compound, 1.5mmol Pd (PPh 3) 4add in three-necked bottle with 30mL ethylene dichloride.System temperature is risen to 70～80 ℃, and at this temperature stirring reaction 24h.Pressure reducing and steaming solvent, to the methyl alcohol saturated solution that adds 30mLKF in residue, stirring at room 4h.Filter, in filtrate, add 30mL distilled water, stir 30min, separate organic phase, water (10mL * 2) washing, anhydrous sodium sulfate drying.Be evaporated to dryly, obtain thick solid, by thick solid Virahol recrystallization, drying under reduced pressure obtains formula (I) compound, yield 88%.

Claims (6)

  1. One kind suc as formula shown in (I) according to Shandong for Buddhist nun's intermediate 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] synthetic method of pyrimidine, it is characterized in that: step 1, will make 5-amino-4-cyano pyrazole with hydrazine hydrate one pot reaction after propane dinitrile and triethyl orthoformate condensation; Step 2, makes amino 1H-pyrazolo [3, the 4-d] pyrimidine of formula (II) compound 4-by 5-amino-4-cyano pyrazole and methane amide condensation; Step 3, obtains formula (III) the compound 4-bromo-1H-pyrazolo of amino-3-[3,4-d] pyrimidine by formula (II) compound and bromizating agent generation bromo-reaction; Step 4, to Phenoxyphenyl tin, under metal palladium catalyst effect, be there is to Stille in formula (III) compound and formula (IV) compound trimethylammonium and react the formula that makes (I) compound 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine.Described reaction formula is:
  2. 2. a kind of synthesizing according to Shandong according to claim 1 replaced Buddhist nun's intermediate 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] method of pyrimidine, it is characterized in that: the reaction in described step (1) be take more cheap propane dinitrile as starting raw material, by one pot reaction, synthesized 5-amino-4-cyano pyrazole, operate very simply, yield is high.
  3. 3. a kind of synthesizing according to Shandong according to claim 1 replaced Buddhist nun's intermediate 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] method of pyrimidine, it is characterized in that: the bromizating agent in step (3) is the brominated reagent such as bromine, N-bromo-succinimide, wherein preferred cheap bromine.
  4. 4. a kind of synthetic method of replacing Buddhist nun's intermediate 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine according to Shandong according to claim 1, is characterized in that: the catalyzer in step (4) is palladium metal compound, as Pd (PPh 3) 4, (PPh 3) 2pdCl 2, Pd (dba) 2, (MeCN) 4pdCl 2, Pd[P (o-Tol)] 2deng, preferred Pd (PPh wherein 3) 4.
  5. 5. a kind of synthesizing according to Shandong according to claim 1 replaced Buddhist nun's intermediate 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] method of pyrimidine, it is characterized in that: the palladium catalyst catalytic efficiency in step (4) is very high, its consumption is only 2～5% of formula (III) compound molar mass.
  6. 6. a kind of synthesizing according to Shandong according to claim 1 replaced Buddhist nun's intermediate 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] method of pyrimidine, it is characterized in that: the reaction conditions of described step (4) is gentle, simple to operate, most suitable temperature of reaction is 60 ℃～80 ℃.
CN201410194883.4A 2014-04-30 2014-04-30 Method for synthesizing intermediate 4-amino-3-(4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine of Ibrutinib Pending CN103965201A (en)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105198887A (en) * 2015-09-23 2015-12-30 上海泰坦科技股份有限公司 Synthetic process of novel pyrazol [3,4-d] miazines reagent with biological activity
CN105859728A (en) * 2016-05-26 2016-08-17 江苏中邦制药有限公司 Preparation method for ibrutinib
CN106153797A (en) * 2015-04-20 2016-11-23 北京睿创康泰医药研究院有限公司 One replaces Buddhist nun and according to Shandong for Buddhist nun's preparation Related substance method according to Shandong
CN106608877A (en) * 2015-10-21 2017-05-03 新发药业有限公司 Preparation method of Ibrutinib intermediate 4-amino-3-(4-phenoxy) phenyl-1H-pyrazol [3,4-d] pyrimidine
CN108349980A (en) * 2015-10-28 2018-07-31 台湾神隆股份有限公司 It is used to prepare according to Shandong for Buddhist nun and its method of intermediate
CN110511225A (en) * 2019-08-19 2019-11-29 杭州中美华东制药有限公司 Her a kind of cloth replaces the synthetic method of Buddhist nun's intermediate
CN111606907A (en) * 2019-02-25 2020-09-01 兰州大学 Preparation of ibrutinib key intermediate
WO2021038540A1 (en) 2019-08-31 2021-03-04 Sun Pharma Advanced Research Company Limited Cycloalkylidene carboxylic acids and derivatives as btk inhibitors
CN113200987A (en) * 2021-04-29 2021-08-03 湖南华腾制药有限公司 Preparation method of ibrutinib

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WO2013010136A2 (en) * 2011-07-13 2013-01-17 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase
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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106153797A (en) * 2015-04-20 2016-11-23 北京睿创康泰医药研究院有限公司 One replaces Buddhist nun and according to Shandong for Buddhist nun's preparation Related substance method according to Shandong
CN106153797B (en) * 2015-04-20 2017-08-29 北京睿创康泰医药研究院有限公司 It is a kind of to replace Buddhist nun's preparation Related substance method according to Shandong for Buddhist nun and according to Shandong
CN105198887A (en) * 2015-09-23 2015-12-30 上海泰坦科技股份有限公司 Synthetic process of novel pyrazol [3,4-d] miazines reagent with biological activity
CN106608877B (en) * 2015-10-21 2018-11-13 新发药业有限公司 One kind replacing Buddhist nun's intermediate 4- amino -3- according to Shandong（4- phenoxy groups）The preparation method of phenyl -1H- pyrazolos [3,4-d] pyrimidine
CN106608877A (en) * 2015-10-21 2017-05-03 新发药业有限公司 Preparation method of Ibrutinib intermediate 4-amino-3-(4-phenoxy) phenyl-1H-pyrazol [3,4-d] pyrimidine
CN108349980A (en) * 2015-10-28 2018-07-31 台湾神隆股份有限公司 It is used to prepare according to Shandong for Buddhist nun and its method of intermediate
CN105859728B (en) * 2016-05-26 2018-06-08 江苏中邦制药有限公司 A kind of preparation method that Buddhist nun is replaced according to Shandong
CN105859728A (en) * 2016-05-26 2016-08-17 江苏中邦制药有限公司 Preparation method for ibrutinib
CN111606907A (en) * 2019-02-25 2020-09-01 兰州大学 Preparation of ibrutinib key intermediate
CN111606907B (en) * 2019-02-25 2023-03-03 兰州大学 Preparation of ibrutinib key intermediate
CN110511225A (en) * 2019-08-19 2019-11-29 杭州中美华东制药有限公司 Her a kind of cloth replaces the synthetic method of Buddhist nun's intermediate
CN110511225B (en) * 2019-08-19 2023-07-18 杭州中美华东制药有限公司 Synthesis method of ibutinib intermediate
WO2021038540A1 (en) 2019-08-31 2021-03-04 Sun Pharma Advanced Research Company Limited Cycloalkylidene carboxylic acids and derivatives as btk inhibitors
CN113200987A (en) * 2021-04-29 2021-08-03 湖南华腾制药有限公司 Preparation method of ibrutinib

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