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WO2017163257A1 - Procédé de préparation d'un dérivé lh-pyrazolo[3,4-d] pyrimidine pur - Google Patents

Procédé de préparation d'un dérivé lh-pyrazolo[3,4-d] pyrimidine pur Download PDF

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Publication number
WO2017163257A1
WO2017163257A1 PCT/IN2017/000061 IN2017000061W WO2017163257A1 WO 2017163257 A1 WO2017163257 A1 WO 2017163257A1 IN 2017000061 W IN2017000061 W IN 2017000061W WO 2017163257 A1 WO2017163257 A1 WO 2017163257A1
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Prior art keywords
formula
compound
amino
phenoxyphenyl
reacting
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Ramakrishnan Arul
Gurdeep Singh Sarin
Sandeep WAS
Vishal Kumar
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IND-SWIFT LABORATORIES Ltd
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IND-SWIFT LABORATORIES Ltd
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms

Definitions

  • the present invention relates to an efficient and industrially advantageous process for the preparation of pure lH-pyrazolo[3,4-d] pyrimidine derivative.
  • the present invention provides a process for the preparation of pure 4-amino-3-(4- phenoxyphenyl)-lH-pyrazolo[3,4-d] pyrimidine, a key intermediate of ibrutinib, wherein none of the intermediates have been isolated to prepare 3-amino-4-cyano-5- (4-phenoxy phenyl)pyrazole, an important precursor.
  • Ibrutinib (IMBRUVICA), chemically known as l-[(3R)-3-[4-amino-3-(4- phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin- 1 -yl]piperidin- 1 -yl] prop-2-en- 1 -one is an orally administered drug that targets Bruton's tyrosine kinase (BTK).
  • BTK Bruton's tyrosine kinase
  • Ibrutinib may be used for treating both B cell-related hematological cancers/ B cell chronic lymphocytic leukemia, and autoimmune diseases such as rheumatoid arthritis, Sjogrens syndrome, lupus and asthma and is represented by following chemical formula:
  • the process comprises the conversion of 4-phenoxybenzoic acid to the corresponding acid chloride, which is then taken up in mixture of toluene and tetrahydrofuran and further reacted with malononitrile in the presence of diisopropylethylethylamine in toluene.
  • the reaction mixture is stirred overnight and after completion of reaction, followed by work up 1 , 1 -dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene is isolated as a residue and which is further purified.
  • the resulting l, l-dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene is reacted with trimethylsilyldiazomethane in a mixture of acetonitrile and methanol in the presence of diisopropylethylamine as a base.
  • the resulting reaction mixture is stirred for 2 days to give l, l-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene (O-methylated product) as an oil, which is purified by flash chromatography.
  • the O-methylated product is treated with hydrazine hydrate to give 3-amino-4-cyano- 5-(4-phenoxyphenyl)pyrazole, which is further reacted with formamide at a temperature of 180°C to give 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4- d]pyrimidine as pale brown-grey solid.
  • the cyclization reaction has been carried out at 180°C and it is observed that the cyclization reaction at high temperature of 180°C, results in grey brown solid colour of 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine, may be due to presence of inorganic impurities.
  • the said process also requires the use of expensive (trimethylsilyl)diazomethane to obtain O-methylated product, which is sensitive to air and water, and hence, the methylation reaction has to be carried out in the absence of water, under anaerobic conditions; silica and flash chromatography are also used for purifying O-methylated product. Since the above process involves complicated operation processes, which leads to high production cost and therefore is not an attractive option at industrially scale.
  • PCT publication WO2014/173289A1 discloses a process for preparation of 3-amino- 4-cyano-5-(4-phenoxyphenyl)pyrazole as shown below and its conversion into 4- amino-3-(4-phenoxy phenyl)- lH-pyrazolo[3,4-d]pyrimidine has not been disclosed.
  • the process involves conversion of 4-phenoxybenzoic acid to the corresponding acid chloride, followed by reaction with malononitrile in the presence of diisopropylethylethylamine in tetrahydrofuran.
  • the reaction mixture has been stirred for 16 hours and thereafter l, l -dicyano-2-hydroxy-2-(4-phenoxyphenyl) ethene is isolated from reaction mixture.
  • the process involves conversion of 4-phenoxybenzoic acid to the corresponding acyl chloride by using sulfurous dichloride, followed by reaction with malononitrile in the presence of sodium hydride to obtain l, l-dicyano-2-hydroxy-2-(4-phenoxy phenyl)ethene, which is recrystallized from 1,4-dioxane.
  • the hydroxy moiety is then methylated using dimethyl sulphate to give l, l-dicyano-2-methoxy-2-(4-phenoxy phenyl)ethene (O-methylated product) which is recrystallized from a mixture of hexane and ethylactetate.
  • a Chinese patent application CN103121999A discloses a process of preparation of 4- amino-3 -(4-phenoxy phenyl)- 1 H-pyrazolo[3 ,4-d] pyrimidine, as below :
  • the process involves reaction of 3-bromo-lH-pyrazolo[3,4-d]pyrimidin-4-amine with (4-phenoxyphenyl)boronic acid in the presence of alkali agents and aprotic solvents to give 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine.
  • the said Chinese application is also silent about the purity of target compound and even starts with the advance intermediates, which are expensive and make the process unattractive from industrial point of view.
  • Another Chinese patent application CN 103965201 A discloses a process for the preparation of 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine, wherein 3-bromo-lH-pyrazolo[3,4-d]pyrimidin-4-amine was reacted with trimethyl tin (4- phenoxy phenyl) to give 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidine and followed by its recrystallization in isopropanol, as shown below:
  • the said Chinese application is also silent about the purity of 4-amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine and is not cost-effective because it starts with advance intermediates, which are expensive. Therefore, said route of synthesis is not industrially applicable.
  • Purity of an API as well as intermediates is of great importance in the field of pharmaceutical chemistry. It is well documented in the art that direct product of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards.
  • the impurities that can be present in pharmaceutical compounds are starting materials, by-products of the reaction, products of side reactions, or degradation products.
  • process impurities should be maintained below set limits by specifying the quality of raw materials, their stoichiometric ratios, controlling process parameters, such as temperature, pressure, time and including purification steps, such as crystallization, distillation and liquid-liquid extraction etc., in the manufacturing process.
  • these limits should less than about 0.15 % by weight of each identified impurity.
  • Limits for unidentified and/or uncharacterized impurities are obviously lower, typically less than 0.10 % by weight.
  • the limits for genotoxic impurities could be much lower depending upon the daily dose of the drug and duration of the treatment. Therefore, in the manufacture of a drug substance, the purity of the starting materials is also important, as impurities may carry forward to the active pharmaceutical ingredient such as ibrutinib.
  • the present invention fulfills the need in the art and provides an improved, industrially advantageous process for the synthesis of pure 4-amino-3-(4- phenoxyphenyl)-lH-pyrazolo[3,4-d] pyrimidine, a key intermediate in the preparation of ibrutinib, through preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole from 4-phenoxy benzoic acid using same organic solvent and none of the intermediates have been isolated.
  • the main object of the present invention is to provide an improved and industrially advantageous process for the preparation of pure 4-amino-3-(4-phenoxyphenyl)-lH- pyrazolo[3,4-d]pyrimidine, a key intermediate in the preparation of ibrutinib or pharmaceutically acceptable salt thereof by minimizing the use of mixture of solvents during the preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole.
  • Yet another object of the present invention is to provide process for the preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole wherein none of the intermediates have been isolated.
  • Yet another object of the present invention is to provide a process for the purification of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole.
  • Yet another object of the present invention is to provide process for the conversion of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole into pure 4-amino-3-(4- phenoxyphenyl)-lH-pyrazolo[3,4-d] pyrimidine.
  • the present invention provides a convenient, industrially advantageous, efficient process for preparation of pure 4-amino-3-(4-phenoxyphenyl)-lH- pyrazolo[3,4-d]pyrimidine compound of formula I, a key intermediate in the preparation of ibrutinib or pharmaceutically acceptable salt thereof,
  • Another object of present invention provides a process for preparation of pure 4- amino-3- -phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine compound of formula I Formula I
  • Another object of present invention is to provide a processes for the preparation of 3- amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V
  • Another object of present invention is to provide a processes for the preparation of 3- amino- -cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V
  • Another object of present invention is to provide a process for the purification of 3- amino-4-cyano-5-(4-phenoxyphenyl)pyrazole of formula V
  • the present invention provides an improved and industrially advantageous process for preparation of preparation of pure 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d] pyrimidine compound of formula I, a key intermediate in the preparation of ibrutinib or pharmaceutically acceptable salt thereof.
  • Pure 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d] pyrimidine compound of formula I refers to have purity greater than 95% by HPLC, preferably greater than 99% by HPLC and assay more than 97%, preferably greater than 98%.
  • the term 'assay' represents a quantitative measurement of the major component in the desired chemical substance/drug substance. It refers to content or potency to provide an exact result which allows an accurate statement on the content or potency of the analyte in a sample.
  • Pure 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V refers to have purity greater than 93% by HPLC, preferably greater than 97% by HPLC.
  • the process involves the conversion of 4-phenoxybenzoic acid to the corresponding acid chloride by reacting with a suitable reagent such as thionyl chloride, oxalyl chloride or sulfuryl chloride.
  • a suitable reagent such as thionyl chloride, oxalyl chloride or sulfuryl chloride.
  • the reaction can be carried out at a temperature of 20°C to 70 °C and it take about 1 to 5 hours for completion of reaction.
  • the reaction is carried out using thionyl chloride.
  • thionyl chloride may be distilled off and a suitable organic solvent can be added.
  • the suitable organic solvent can be selected from non-polar aprotic solvents such as toluene, xylene, hexane, tetrahydrofuran, 1 ,4-dioxane, and the like, preferably toluene and preferably toluene.
  • toluene is added to the resulting acid chloride and followed by distillation of solvent to give 4- phenoxybenzoyl chloride compound of formula II, which is used as such in the next step.
  • the reaction can be performed at a temperature of 20°C to 55°C for few minutes to 5 hours.
  • the suitable organic solvent can be selected from non-polar aprotic solvents such as toluene, xylene, hexane, tetrahydrofuran, 1,4-dioxane, and the like, and is the same organic solvent which is used during first step to remove traces of chlorinating reagent used during acid chloride formation.
  • the base can be selected from diisopropylethylamine, triethylamine, l ,8-Diazabicyclo[5.4.0]undec-7- ene (DBU) and tertiary amines; sodium bicarbonate, sodium carbonate, sodium hydride and the like,
  • the reaction mass can be cooled to a temperature of 15 °C to 40°C and treated with a suitable acid such as sulfuric acid.
  • the reaction mixture can be then stirred at a temperature of 15°C to 40°C for few minutes to about 2 hours, preferably for 30 minutes. Thereafter, the layers can be separated and organic layer can be washed with 10 % sodium chloride solution. The resulting organic layer can be sed directly in next reaction.
  • the resulting compound of formula III then can be reacted in-situ with a suitable methylating agent in the presence of a base at a suitable temperature to give O- methylated product, l, l-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene compound of formula IV.
  • the suitable methylating agent can be selected from dimethyl sulphate, methyl iodide, dimethyl carbonate, tetramethylammonium chloride, methyl triflate preferable dimethyl sulphate is used.
  • the base can be selected from inorganic base such as sodium hydroxide, sodium carbonate, sodium bicarbonate, calcium hydroxide, and calcium carbonate.
  • the reaction may take place at a temperature of 20°C to 90 °C for 20 minutes to 5 hours. After completion of the reaction, the resulting reaction mass may be cooled to 15°C to 60°C and water is added to the reaction mass. The reaction mass can be stirred to form layers and the layers are separated. The aqueous layer is extracted with a suitable solvent.
  • the suitable organic solvent can be selected from non-polar aprotic solvents such as toluene, xylene, hexane, tetrahydrofuran, 1,4-dioxane, and the like, and is the same organic solvent which is used during earlier steps. Both the organic layers can be combined, washed with sodium chloride solution and the resulting organic layer can be used directly in next reaction.
  • non-polar aprotic solvents such as toluene, xylene, hexane, tetrahydrofuran, 1,4-dioxane, and the like
  • the resulting l, l-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene compound of formula IV in-situ is reacted with hydrazine hydrate at a suitable temperature for sufficient time to complete the reaction.
  • hydrazine hydrate can be added slowly, since the reaction may be exothermic during addition of hydrazine hydrate and temperature may rise up to 50°C. Thereafter the reaction mixture can stirred at ambient temperature over a period of 20 minutes to 5 hours.
  • the resulting solid can be collected by any means known the art such as filtration, centrifugation, distillation, and the like and preferably filtration.
  • the resulting 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V can optionally be purified by combining any suitable means such as processing by extraction, treatment with activated carbon, acid-base treatment, slurry wash and recrystalliztion and solvent/ antisolvent like addition of second solvent to facilitate the crystallization.
  • the said purification methods can optionally be combined and repeated to achieve the desired purity.
  • the purification process involves the preparation of a solution of 3- amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V in a suitable solvent.
  • Solution can be prepared by heating up to reflux temperature in a suitable solvent.
  • a suitable second solvent can be added as antisolvent to facilitate the complete crystallization.
  • the reaction mixture can be cooled and resulting solid can be collected to obtain pure 3- amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V.
  • the reaction solution can be cooled to a temperature of less than 15°C to facilitate crystallization.
  • 3-amino-4-cyano-5-(4-phenoxy phenyl)pyrazole compound of formula V can be slurry washed using a suitable solvent.
  • the suitable solvent used for the purification of 3-amino-4-cyano-5-(4-phenoxy phenyl)pyrazole compound of formula V can be selected from alcoholic solvent such as methanol, ethanol, n-propanol, isopropanol, butanol, n-butanol; a chlorinated solvent such as chloroform, dichloromethane and the like.
  • the suitable second solvent used to facilitate the crystallization can be selected from but not limited to water, ethers such as dipropyl ether, diisopropyl ether, diethyl ether, isopropyl ether methyl tert-butyl ether, 1,2-dimethoxy ether, 1,2-diethoxy ether and the like.
  • ethers such as dipropyl ether, diisopropyl ether, diethyl ether, isopropyl ether methyl tert-butyl ether, 1,2-dimethoxy ether, 1,2-diethoxy ether and the like.
  • the resulting 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V prepared by using process of present invention is pure and have purity of grater than 93% by HPLC, preferably more than more than 97% by HPLC.
  • the preparation of 3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V from 4-phenoxybenzoic acid in four steps, without isolating any intermediate and using a same single organic solvent during all reactions forms an inventive part of the invention.
  • 3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V can be then converted to pure 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d] pyrimidine compound of formula I using any method reported in literature.
  • 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V can be reacted with a suitable reagent such as formamide at a suitable temperature to give pure 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d] pyrimidine compound of formula I.
  • the reaction may take place at a temperature of not higher than 140°C for few hours till the completion of reaction.
  • the reaction can be carried out at a temperature between 120°C to 140°C for 20 hours to 30 hours.
  • the resulting reaction mass may be cooled to 25°C to 60°C and treated with a suitable solvent such as water and resulting reaction mixture is stirred for 10 to 30 minutes.
  • the resulting solid can be collected by suitable means known the art.
  • the resulting compound can be washed with water or suitable organic solvent.
  • the suitable organic solvent can be selected from hydrocarbon solvent selected from toluene, hexane, cyclohexane, heptane; alcohol solvent such as methanol, ethanol, propanol, isopropanol; ketone solvent such acetone, tetrahydrofuran, methyl isobutyl ketone, methyl ethyl ketone and a like, preferably organic solvent selected from methanol, isopropanol, acetone and toluene.
  • the pure 4- amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine compound of formula I have purity of greater than 95% by weight as determined using HPLC, preferably greater than 99% by HPLC and assay more than 97%, preferably greater than 98%.
  • the present invention provides a process for the conversion of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula
  • the present invention provides a process for the preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula
  • the present invention provides a process for the purification of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V.
  • the purification process involves suspension of 3-amino-4-cyano-5-(4- phenoxyphenyl)pyrazole compound of formula V in a suitable solvent. Then, the resulting reaction mixture is then heated at reflux temperature to obtain a solution; optionally, suitable second solvent is added to the resulting solution to facilitate the crystallization, the reaction mixture is cooled and the product is filtered to obtain pure 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V.
  • the suitable solvent used for the purification of 3-amino-4-cyano-5-(4- phenoxyphenyl)pyrazole compound of formula V is selected from alcoholic solvents such as methanol, ethanol, isopropanol, n-propanol, butanol, n-butanol; a chlorinated solvent such as chloroform, dichloromethane and the like.
  • the suitable second solvent are those solvent which facilitate crystallization; preferably selected from water, ethers such as diethyl ether, dipropyl ether, diisopropyl ether, isopropyl ether methyl tert-butyl ether, 1,2-dimethoxy ether, 1,2-diethoxy ether and the like.
  • the above purification is advantageous because with recrystallization in alcoholic solvent or with alcoholic solvent followed by addition of second solvent results in enhanced purity such as removal of inorganic impurities/unknown colored impurities and traces of heavy metal if present.
  • the resulting 3-amino-4-cyano-5-(4- phenoxyphenyl)pyrazole compound of formula V qualify heavy metal test i.e. less than 20ppm and residue on ignition test i.e. not more than 0.05%.
  • the present invention provides conversion of 3- amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V, prepared by using process of present invention into 4-amino-3-(4-phenoxyphenyl)-lH- pyrazolo[3,4-d] pyrimidine compound of formula I.
  • 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d] pyrimidine compound of formula I, prepared by using process of present invention can be converted to ibrutinib.
  • the resulting compound of formula VI can be purified by any means such as crystallization, by using chromatographic techniques such as column chromatography or flash chromatography to remove triphenylphosphine oxide. Thereafter, tert- butyloxycarbonyl protected ( 1 S)- 1 -[(3R)-3-piperidyl]-3-(p-phenoxyphenyl)- 1 ,2,5,7- tetraza-lH-inden-4-ylamine of formula VI is deprotected using a suitable reagent to prepare ( 1 S)- l-[(3R)-3-piperidyl]-3-(p-phenoxyphenyl)- 1 ,2,5,7-tetraza- lH-inden-4- ylamine of f
  • Boc-deprotection can be accomplished with strong acids such as trifluoroacetic acid neat or in a suitable solvent or with HCl in a suitable solvent.
  • the suitable solvent can be selected from dichloromethane, chloroform, diethyl ether, 1,4-dioxane, toluene, alcohols , preferably trifluoroacetic acid is used in dichloromethane.
  • the indenylamine compound of formula VII is then acylated using acryloyl chloride in the presence of a base in a suitable solvent to obtain ibrutinib.
  • the base can be selected from triethylamine, tri-n-butylamine, diisopropylethylamine,N- methylmorpholine, DBU and the like.
  • the suitable solvent can be selected from dichloromethane, chloroform, dichloroethane, ether such as tetrahydrofuran, 2-methyl tetrahydrofuran, 2-dimethoxy ether, 2- diethoxy ether, isopropyl ether and methyl tert butyl ether; toluene, xylene, acetonitrile and the like.
  • the acylation reaction can be accomplished at a temperature of 0°C- 50°C and it takes 30 minutes to sevral hours to complete the reaction and preferably reaction is carried out at ambient temperature.
  • the resulting ibrutinib can be purified by any means such as crystallization, by using chromatographic techniques such as column chromatography or flash chromatography .
  • reaction at any stage can be monitored by any one of the chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), ultra-high pressure liquid chromatography (UPLC), IR, NMR and the like.
  • TLC thin layer chromatography
  • HPLC high pressure liquid chromatography
  • UPLC ultra-high pressure liquid chromatography
  • IR IR
  • NMR nuclear magnetic resonance
  • 4-Phenoxybenzoic acid 200g was slowly added to thionyl chloride (400ml) at a temperature of 25-30°C and resulting reaction mixture was heated under stirring to a temperature of 60-65°C for 5 hours.
  • Thionyl chloride was distilled off under vacuum at temperature below 60°C.
  • Toluene (2x400ml) was added to the resulting oily residue and thereafter distilled out completely under vacuum below 60°C to remove traces of thionyl chloride to obtain 4-phenoxybenzoyl chloride as a viscous oil.
  • the resulting viscous oil of 4-phenoxybenzoyl chloride was dissolved in toluene (2000ml).
  • Dimethyl sulfate (200ml) and sodium bicarbonate (200g) were added to the resulting organic layer at a temperature of 25-30°C. Thereafter, temperature of reaction mass was raised to 80-90°C and reaction mass was stirred for 1-2 hours. After completion of reaction, the reaction mass was cooled to a temperature of 25-30°C, demineralized water (2000ml) was added and stirred for 10-15 minutes. The layers were separated and the aqueous layer was extracted with toluene (1000ml). All the organic layers were combined and washed with sodium chloride solution ( 10%). Activated carbon (20g) was added and reaction mixture was stirred for 30 minutes.
  • 4-Phenoxybenzoic acid (lOOg) was slowly added to thionyl chloride (200ml) at a temperature of 25-30°C and resulting reaction mixture was heated under stirring to a temperature of 50-55°C for 5 hours.
  • Thionyl chloride was distilled off under vacuum at temperature below 50°C.
  • Toluene 250ml was added to the resulting oily residue and thereafter distilled out completely under vacuum below 50°C to remove traces of thionyl chloride to obtain 4-phenoxybenzoyl chloride as a viscous oil.
  • the resulting viscous oil of 4-phenoxybenzoyl chloride was dissolved in toluene (500ml).
  • 3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (36g) was suspended in isopropanol (350ml) and temperature of the reaction mixture was raised and allowed to reflux to dissolve the solid completely to provide a clear solution. Then, solvent was distilled off under vacuum to obtain a residue and isopropanol (50ml) was added and after stirring for hours the solid was filtered and dried to afford 3-amino-4-cyano-5-(4- phenoxyphenyl)pyrazole compound of formula V (26g) and having purity of 97.54 % by HPLC .
  • 3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (36g) was suspended in isopropanol (350ml) and temperature of the reaction mixture was raised upto reflux to dissolve the solid completely upto clear solution. Water (1050ml) was added to the solution and the reaction mixture was gradually cooled to crystallize the product. The resulting solid was filtered, washed with two volumes of isopropanol, dried in vacuum oven at a temperature of 40-45 °C to afford 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V (20g) and having a HPLC purity of 97.23% .
  • 3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (20g) was suspended in formamide (100 ml) and heated at a temperature of 130°C, after completion of reaction, the reaction mixture was cooled to a temperature of 30-35°C and demineralized water (500ml) was added and the reaction mixture was stirred at a temperature of 25-30°C for 45 minutes. The resulting solid was filtered and acetone (200ml) was added stirred the reaction mixture for 30-45 minutes.
  • 3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (lOOg) was suspended in formamide (500ml) and heated at a temperature of 135-140°C, after completion of reaction, the reaction mixture was cooled to a temperature of 30-35°C and demineralized water (1000ml) was added and the reaction mixture was stirred at a temperature of 20-25°C for 1 hour.
  • Diisopropyl diazodicarboxylate (DAID, 1.2 ml,) was added to a solution of 1-tert- butyloxycarbonyl-3-(S)-hydroxypiperidine ( l .Og,) and triphenylphosphine (2.59g) in tetrahydrofuran (50.0ml).
  • tetrahydrofuran 50.0ml
  • 3-(p-phenoxyphenyl)- l ,2,5,7-tetraza- lH-inden-4-ylamine (l .Og). was added and warmed till dissolution, and stirred overnight at room temperature.
  • reaction mixture was filtered and the solvent was distilled under vacuum to get an oily residue, which was further purified by flash chromatography (30-50 % ethyl acetate/ hexane) on silicagel to give 0.3 g (0.3 w/w) of tert-butyloxycarbonyl-( l S)- l-[(3R)-3-piperidyl]-3-(p- phenoxyphenyl)- l,2,5,7-tetraza- lH-inden-4-ylamine as a light brown solid.
  • the resulting solid was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (0.6 ml) was added to it.

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Abstract

La présente invention concerne un procédé efficace et industriellement avantageux destiné à la préparation d'un dérivé 1H-pyrazolo[3,4-d] pyrimidine pur. En particulier la présente invention décrit un procédé de préparation de 4-amino-3-(4-phénoxyphényl)-1H-pyrazolo[3,4-d] pyrimidine pure, un intermédiaire clé de l'ibrutinib. En particulier, la présente invention décrit un procédé de préparation de 3-amino-4-cyano-5-(4-phénoxy phényl)pyrazole, où aucun des intermédiaires n'a été isolé, un précurseur important pour la préparation de 4-amino-3-(4-phénoxyphényl)-1H-pyrazolo[3,4-d] pyrimidine.
PCT/IN2017/000061 2016-03-21 2017-03-20 Procédé de préparation d'un dérivé lh-pyrazolo[3,4-d] pyrimidine pur Ceased WO2017163257A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107652294A (zh) * 2017-11-14 2018-02-02 安徽诺全药业有限公司 一种伊鲁替尼的制备方法
CN108623606A (zh) * 2018-08-02 2018-10-09 杭州中美华东制药有限公司 一种依鲁替尼的合成方法
CN113200987A (zh) * 2021-04-29 2021-08-03 湖南华腾制药有限公司 一种伊布替尼的制备方法
CN113929685A (zh) * 2020-06-29 2022-01-14 鲁南制药集团股份有限公司 一种伊布替尼中间体的制备方法
CN113968842A (zh) * 2020-07-24 2022-01-25 鲁南制药集团股份有限公司 一种伊布替尼中间体化合物

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080108636A1 (en) * 2006-09-22 2008-05-08 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase
WO2014082598A1 (fr) * 2012-11-30 2014-06-05 Centaurus Biopharma Co., Ltd. Inhibiteurs de la tyrosine kinase de bruton
WO2015074464A1 (fr) * 2013-11-20 2015-05-28 苏州明锐医药科技有限公司 Procédé de préparation d'ibrutinib

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080108636A1 (en) * 2006-09-22 2008-05-08 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase
WO2014082598A1 (fr) * 2012-11-30 2014-06-05 Centaurus Biopharma Co., Ltd. Inhibiteurs de la tyrosine kinase de bruton
WO2015074464A1 (fr) * 2013-11-20 2015-05-28 苏州明锐医药科技有限公司 Procédé de préparation d'ibrutinib

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107652294A (zh) * 2017-11-14 2018-02-02 安徽诺全药业有限公司 一种伊鲁替尼的制备方法
CN108623606A (zh) * 2018-08-02 2018-10-09 杭州中美华东制药有限公司 一种依鲁替尼的合成方法
CN108623606B (zh) * 2018-08-02 2019-11-12 杭州中美华东制药有限公司 一种依鲁替尼的合成方法
CN113929685A (zh) * 2020-06-29 2022-01-14 鲁南制药集团股份有限公司 一种伊布替尼中间体的制备方法
CN113929685B (zh) * 2020-06-29 2024-05-17 鲁南制药集团股份有限公司 一种伊布替尼中间体的制备方法
CN113968842A (zh) * 2020-07-24 2022-01-25 鲁南制药集团股份有限公司 一种伊布替尼中间体化合物
CN113968842B (zh) * 2020-07-24 2024-05-03 鲁南制药集团股份有限公司 一种伊布替尼中间体化合物
CN113200987A (zh) * 2021-04-29 2021-08-03 湖南华腾制药有限公司 一种伊布替尼的制备方法

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