WO2016151438A1 - A process for the preparation of ibrutinib - Google Patents

A process for the preparation of ibrutinib Download PDF

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Publication number
WO2016151438A1
WO2016151438A1 PCT/IB2016/051489 IB2016051489W WO2016151438A1 WO 2016151438 A1 WO2016151438 A1 WO 2016151438A1 IB 2016051489 W IB2016051489 W IB 2016051489W WO 2016151438 A1 WO2016151438 A1 WO 2016151438A1
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formula
compound
process according
group
tert
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PCT/IB2016/051489
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French (fr)
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Kapil Sharma
Bhavin Prabhudas THANKI
Mahavir Singh Khanna
Mohan Prasad
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Sun Pharmaceutical Industries Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the present invention provides a process for the preparation of ibrutinib of Formula I.
  • Ibrutinib chemically is l-[(3i?)-3-[4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl]-l-piperidinyl]-2-propen-l-one, represented by Formula I.
  • Ibrutinib is an inhibitor of Bruton's tyrosine kinase (BTK).
  • the process involves the coupling of a compound of Formula X with a compound of Formula IV via a Mitsunobu reaction using costly chemicals, and forming a large number of byproducts.
  • the present invention provides a process for the preparation of ibrutinib of Formula I.
  • the process of the present invention makes use of inexpensive chemicals. Also, the process is environmentally as well as user friendly because the chemicals used are non-hazardous in nature. The simplification in work-up and product isolation procedures makes the process efficient for industrial utilization.
  • room temperature refers to a temperature in the range of about 25°C to 35°C.
  • halogen refers to chlorine, bromine, or iodine.
  • lower alkyl refers to both straight chain and branched chain alkyl groups having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, iso- propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, and iso- hexyl.
  • aryl refers to a substituted or unsubstituted aromatic carbocyclic monovalent or divalent radical of 6 to 12 carbon atoms having a single ring or multiple condensed rings.
  • aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, indanyl, anthracyl, and phenanthryl, as well as substituted derivatives thereof.
  • heterocyclic or “heterocycle,” as used herein, refer to a monovalent aromatic radical of 5, 6, or 7 membered rings, and include fused ring systems of 5-10 atoms, containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • heterocyclic moieties include, but are not limited to, 1,4- dioxanyl, 1,3-dioxanyl, pyrrolidinyl, pyrrolidin-2-onyl, piperidinyl, imidazolidine-2,4- dionepiperidinyl, piperazinyl, piperazine-2,5-dionyl, morpholinyl, dihydropyranyl, dihydrocinnolinyl, 2,3 -dihydrobenzo [ 1 ,4]dioxinyl, 3 ,4-dihydro-2H-benzo [b] [ 1 ,4] - dioxepinyl, tetrahydropyranyl, 2,3-dihydrofuranyl, 2,3-dihydrobenzofuranyl,
  • dihydroisoxazolyl tetrahydrobenzodiazepinyl, tetrahydroquinolinyl, tetrahydrofuranyl, tetrahydronaphthyridinyl, tetrahydropurinyl, tetrahydrothiopyranyl, tetrahydrothiophenyl, tetrahydroquinoxalinyl, tetrahydropyridinyl, tetrahydrocarbolinyl, 4H-benzo[l,3]-dioxinyl, benzo[l,3]dioxonyl, 2,2-difluorobenzo-[l,3]-dioxonyl, 2,3-dihydro-phthalazine-l,4- dionyl, and isoindole-l,3-dionyl.
  • salt refers to a salt prepared from an inorganic or an organic acid.
  • inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid.
  • organic acids include formic acid, acetic acid, propionic acid, hexanoic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,
  • An aspect of the present invention provides a process for the preparation of ibrutinib of Formula I,
  • Pr 1 is selected from the group consisting of tert-butyloxycarbonyl (Boc), benzyloxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, benzyl, benzoyl, carbamate, tosyl, and p-methoxybenzyl carbonyl;
  • Pr 2 is selected from the group consisting of mesyl, allyl, trityl, benzyl, p- methoxybenzyl, tetrahydropyranyl, and trimethylsilyl,
  • R 1 and R 2 are hydrogen or lower alkyl or R 1 and R 2 together with the oxygen atoms to which they are attached form a heterocyclic ring, which is optionally substituted with lower alkyl, aryl, or oxo,
  • R is hydroxy, halogen, tosyl, or mesyl
  • the compound of Formula II can be prepared by following the methods provided in the art such as PCT Publication Nos. WO 2011/094628, WO 2007/126841, WO 2010/006086, and WO 2012/003544; U.S. Publication No. 2007/0293516; U.S. Patent Nos. 6,921,763 and 8,673,925; or Helvetica Chimica Acta, 91(5), 958-963 (2008).
  • the halogenation of the compound of Formula II to obtain the compound of Formula III is carried out in the presence of a halogenating agent in a solvent.
  • the halogenating agent is selected from the group consisting of N- iodosuccinimide, N-bromosuccinimide, bromine, hydrobromic acid, hydroiodic acid, and N-bromophthalimide .
  • the solvent is selected from the group consisting of dimethylformamide, dimethylsulfoxide, dichloromethane, and mixtures thereof.
  • the halogenation of the compound of Formula II is carried out for about 3 hours to about 24 hours, for example, for about 4 hours to about 20 hours.
  • the halogenation of the compound of Formula II is carried out at a temperature of about 50°C to about 90°C, for example, of about 55°C to about 80°C.
  • the compound of Formula III may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • the compound of Formula III may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying.
  • reaction of the compound of Formula III with the compound of Formula IV to obtain the compound of Formula V is carried out in the presence of a base in a solvent, optionally in the presence of a catalyst.
  • the compound of Formula IV can be prepared by following the methods provided in the art, such as PCT Publication No. WO 2004/072086 or by following the method as exemplified herein.
  • the base is selected from the group consisting of cesium carbonate, potassium carbonate, sodium carbonate, sodium hydroxide, N,N-diisopropylethylamine, tert- butylamine, potassium hydroxide, potassium tert-butoxide, and sodium-tert-butoxide.
  • the solvent is selected from the group consisting of N-methylpyrrolidone, dimethylsulfoxide, dimethylformamide, dimethylacetamide, tetrahydrofuran, and mixtures thereof.
  • the catalyst is selected from the group consisting of dimethylaminopyridine, benzyltrimethylammonium chloride, hexadecyltributylphosphonium bromide, tetra-n- butylammonium bromide, and methyltrioctylammonium chloride.
  • reaction of the compound of Formula III with the compound of Formula IV is carried out for about 10 hours to about 30 hours, for example, for about 12 hours to about 25 hours.
  • the reaction of the compound of Formula III with the compound of Formula IV is carried out at a temperature of about 60°C to about 135°C, for example, of about 65°C to about 130°C.
  • the compound of Formula V may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • the compound of Formula V may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying.
  • the coupling of the compound of Formula V with the compound of Formula VI to obtain the compound of Formula VII is carried out in the presence of a base and a coupling agent in a solvent.
  • the base is selected from the group consisting of cesium carbonate, potassium carbonate, sodium carbonate, sodium hydroxide, N,N-diisopropylethylamine, tert- butylamine, potassium hydroxide, potassium tert-butoxide, and sodium-tert-butoxide.
  • the coupling agent is selected from the group consisting of palladium on carbon, [1,1 '-bis(diphenylphosphino)ferrocene] -dichloropalladium(II) complex with
  • the solvent is selected from the group consisting of toluene, water, dioxane, n- propanol, isopropanol, methanol, ethanol, acetone, toluene, acetonitrile,
  • the coupling of the compound of Formula V with the compound of Formula VI is carried out for about 1 hour to about 60 hours, for example, for about 2 hours to about 50 hours.
  • the coupling of the compound of Formula V with the compound of Formula VI is carried out at a temperature of about 70°C to about 120°C, for example, of about 85°C to about 110°C.
  • the compound of Formula VII may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • the compound of Formula VII may optionally be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying.
  • the deprotection of the compound of Formula VII to obtain the compound of Formula VIII or its salts is carried out with a deprotecting agent in a solvent.
  • the deprotecting agent is selected from the group consisting of hydrochloric acid, alcoholic hydrochloric acid, ethereal hydrochloric acid, trifluoroacetic acid, hydrobromic acid, and sulfuric acid.
  • the solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, tert-butanol, dioxane, methyl tert-butyl ether, and mixtures thereof.
  • alcoholic solvents for the preparation of alcoholic hydrochloric acid include methanol, ethanol, n-propanol, isopropanol, tert-butanol, and mixtures thereof.
  • Examples of ethereal solvents for the preparation of ethereal hydrochloric acid include dioxane, methyl tert-butyl ether, and mixtures thereof.
  • the deprotection of the compound of Formula VII is carried out for about 20 minutes to about 4 hours, for example, for about 30 minutes to about 2 hours.
  • the deprotection of the compound of Formula VII is carried out at a temperature of about 40°C to about 80°C, for example, of about 45°C to about 60°C.
  • the compound of Formula VIII or its salts may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • Formula VIII or its salts may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying.
  • reaction of the compound of Formula VIII or its salts with the compound of Formula IX to obtain ibrutinib of Formula I is carried out in the presence of a base in a solvent.
  • the base is selected from the group consisting of triethylamine, isopropylamine, pyridine, N,N-diisopropylethylamine, dimethylaminopyridine, and N-methylmorpholine.
  • the solvent is selected from the group consisting of dichloromethane, chloroform, dichloroethane, carbon tetrachloride, and mixtures thereof.
  • the reaction of the compound of Formula VIII or its salts with the compound of Formula IX is carried out for about 1 hour to about 6 hours, for example, for about 2 hours to about 4 hours.
  • reaction of the compound of Formula VIII or its salts with the compound of Formula IX is carried out at a temperature of about 10°C to about 25°C, for example, of about 15°C to about 20°C.
  • Ibrutinib of Formula I may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • Ibrutinib of Formula I may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying.
  • tert-Butyl (3S)-3-hydroxypiperidine-l-carboxylate (25 g) and triethylamine (30 g) were added to toluene (250 mL) at room temperature to obtain a reaction mixture.
  • the reaction mixture was cooled to 0°C to 5°C.
  • a solution of mesyl chloride (22.5 g) in toluene (100 mL) was added drop-wise over a period of 1 hour at 0°C to 5°C.
  • the reaction mixture was stirred for 2 hours at room temperature. Water (250 mL) was added to the reaction mixture, and then the mixture was stirred to separate the organic layer.
  • Pr 1 is Boc
  • tert-Butyl (3R)-3 -(4-amino-3 -iodo- lH-pyrazolo [3 ,4-d]pyrimidin- 1 -yl)piperidine- 1 - carboxylate (Formula V, when X is iodine and Pr 1 is Boc, Example 4, 12 g), cesium carbonate (21.9 g), and phenoxyphenylboronic acid (Formula VI, when R 1 and R 2 are hydrogen, 8.6 g) were added into a mixture of toluene (300 mL) and water (30 mL) under nitrogen.
  • Pr 1 is Boc
  • tert-Butyl (3R)-3 -(4-amino-3 -iodo- lH-pyrazolo [3 ,4-d]pyrimidin- 1 -yl)piperidine- 1 - carboxylate (Formula V, when X is iodine and Pr 1 is Boc, Example 4, 12 g), cesium carbonate (21.9 g), and phenoxyphenylboronic acid (Formula VI, when R 1 and R 2 are hydrogen, 8.6 g) were added into a mixture of dioxane (250 mL) and water (25 mL) under nitrogen.
  • Methyl tert-butyl ether 120 mL was added to the crude material at room temperature, and then the mixture was stirred for 3 hours to 4 hours. The material was filtered under nitrogen, and then washed with methyl tert-butyl ether (60 mL) at room temperature. The material was dried under vacuum at room temperature for 8 hours to 10 hours to obtain the title compound.
  • Oxalyl chloride (0.64 g) was added to a solution of acrylic acid (0.37 g) and dimethylformamide (0.05 mL) in dichloromethane (5 mL) at room temperature under nitrogen. The reaction mixture was stirred for 3 hours at room temperature, and was used as such for the next step.

Abstract

The present invention provides a process for the preparation of ibrutinib of Formula I.

Description

A PROCESS FOR THE PREPARATION OF IBRUTINIB
Field of the Invention
The present invention provides a process for the preparation of ibrutinib of Formula I.
Background of the Invention
Ibrutinib chemically is l-[(3i?)-3-[4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl]-l-piperidinyl]-2-propen-l-one, represented by Formula I.
Figure imgf000002_0001
Formula I
Ibrutinib is an inhibitor of Bruton's tyrosine kinase (BTK).
U.S. Patent No. 8, 158,786 and Chinese Publication No. CN 103121999 describe the following process for the preparation of an intermediate of Formula Vila, which is further used for the preparation of ibrutinib.
Figure imgf000003_0001
The process involves the coupling of a compound of Formula X with a compound of Formula IV via a Mitsunobu reaction using costly chemicals, and forming a large number of byproducts.
Therefore, there is a need in the art to develop an improved process for the preparation of ibrutinib.
Summary of the Invention
The present invention provides a process for the preparation of ibrutinib of Formula I. The process of the present invention makes use of inexpensive chemicals. Also, the process is environmentally as well as user friendly because the chemicals used are non-hazardous in nature. The simplification in work-up and product isolation procedures makes the process efficient for industrial utilization.
Detailed Description of the Invention
The term "about," as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value. The term "room temperature," as used herein, refers to a temperature in the range of about 25°C to 35°C.
The term "halogen," as used herein, refers to chlorine, bromine, or iodine.
The term "lower alkyl," as used herein, refers to both straight chain and branched chain alkyl groups having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, iso- propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, and iso- hexyl.
The term "aryl," as used herein, refers to a substituted or unsubstituted aromatic carbocyclic monovalent or divalent radical of 6 to 12 carbon atoms having a single ring or multiple condensed rings. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, indanyl, anthracyl, and phenanthryl, as well as substituted derivatives thereof.
The terms "heterocyclic" or "heterocycle," as used herein, refer to a monovalent aromatic radical of 5, 6, or 7 membered rings, and include fused ring systems of 5-10 atoms, containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of heterocyclic moieties include, but are not limited to, 1,4- dioxanyl, 1,3-dioxanyl, pyrrolidinyl, pyrrolidin-2-onyl, piperidinyl, imidazolidine-2,4- dionepiperidinyl, piperazinyl, piperazine-2,5-dionyl, morpholinyl, dihydropyranyl, dihydrocinnolinyl, 2,3 -dihydrobenzo [ 1 ,4]dioxinyl, 3 ,4-dihydro-2H-benzo [b] [ 1 ,4] - dioxepinyl, tetrahydropyranyl, 2,3-dihydrofuranyl, 2,3-dihydrobenzofuranyl,
dihydroisoxazolyl, tetrahydrobenzodiazepinyl, tetrahydroquinolinyl, tetrahydrofuranyl, tetrahydronaphthyridinyl, tetrahydropurinyl, tetrahydrothiopyranyl, tetrahydrothiophenyl, tetrahydroquinoxalinyl, tetrahydropyridinyl, tetrahydrocarbolinyl, 4H-benzo[l,3]-dioxinyl, benzo[l,3]dioxonyl, 2,2-difluorobenzo-[l,3]-dioxonyl, 2,3-dihydro-phthalazine-l,4- dionyl, and isoindole-l,3-dionyl.
The term "salt," as used herein, refers to a salt prepared from an inorganic or an organic acid. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids include formic acid, acetic acid, propionic acid, hexanoic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,
trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, benzenesulfonic acid, stearic acid, and muconic acid. The term "oxo," as used herein, refers to C=0.
An aspect of the present invention provides a process for the preparation of ibrutinib of Formula I,
Figure imgf000005_0001
Formula I
comprising:
a) halogenating a compound of Formula II
Figure imgf000005_0002
Formula II
in the presence of a halogenating agent to obtain a compound of Formula III,
Figure imgf000005_0003
Formula III
wherein X is halogen;
b) reacting the compound of Formula III with a compound of Formula IV,
Figure imgf000005_0004
Formula IV wherein Pr1 is selected from the group consisting of tert-butyloxycarbonyl (Boc), benzyloxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, benzyl, benzoyl, carbamate, tosyl, and p-methoxybenzyl carbonyl;
Pr2 is selected from the group consisting of mesyl, allyl, trityl, benzyl, p- methoxybenzyl, tetrahydropyranyl, and trimethylsilyl,
to obtain a compound of Formula V;
Figure imgf000006_0001
Formula V
coupling the compoun f Formula V with a compound of Formula VI,
Figure imgf000006_0002
Formula VI
wherein R1 and R2 are hydrogen or lower alkyl or R1 and R2 together with the oxygen atoms to which they are attached form a heterocyclic ring, which is optionally substituted with lower alkyl, aryl, or oxo,
to obtain a compound
Figure imgf000006_0003
Formula VII d) deprotecting the compound of Formula VII with a deprotecting agent to obtain a compound of Formula VIII or its salts; and
Figure imgf000007_0001
Formula VIII
e) reacting the compound of Formula VIII or its salts with a compound of
Formula IX,
Figure imgf000007_0002
Formula IX
wherein R is hydroxy, halogen, tosyl, or mesyl,
to obtain ibrutinib of Formula I.
The compound of Formula II can be prepared by following the methods provided in the art such as PCT Publication Nos. WO 2011/094628, WO 2007/126841, WO 2010/006086, and WO 2012/003544; U.S. Publication No. 2007/0293516; U.S. Patent Nos. 6,921,763 and 8,673,925; or Helvetica Chimica Acta, 91(5), 958-963 (2008).
The halogenation of the compound of Formula II to obtain the compound of Formula III is carried out in the presence of a halogenating agent in a solvent.
The halogenating agent is selected from the group consisting of N- iodosuccinimide, N-bromosuccinimide, bromine, hydrobromic acid, hydroiodic acid, and N-bromophthalimide .
The solvent is selected from the group consisting of dimethylformamide, dimethylsulfoxide, dichloromethane, and mixtures thereof. The halogenation of the compound of Formula II is carried out for about 3 hours to about 24 hours, for example, for about 4 hours to about 20 hours.
The halogenation of the compound of Formula II is carried out at a temperature of about 50°C to about 90°C, for example, of about 55°C to about 80°C.
The compound of Formula III may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of Formula III may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying.
The reaction of the compound of Formula III with the compound of Formula IV to obtain the compound of Formula V is carried out in the presence of a base in a solvent, optionally in the presence of a catalyst.
The compound of Formula IV can be prepared by following the methods provided in the art, such as PCT Publication No. WO 2004/072086 or by following the method as exemplified herein.
The base is selected from the group consisting of cesium carbonate, potassium carbonate, sodium carbonate, sodium hydroxide, N,N-diisopropylethylamine, tert- butylamine, potassium hydroxide, potassium tert-butoxide, and sodium-tert-butoxide.
The solvent is selected from the group consisting of N-methylpyrrolidone, dimethylsulfoxide, dimethylformamide, dimethylacetamide, tetrahydrofuran, and mixtures thereof.
The catalyst is selected from the group consisting of dimethylaminopyridine, benzyltrimethylammonium chloride, hexadecyltributylphosphonium bromide, tetra-n- butylammonium bromide, and methyltrioctylammonium chloride.
The reaction of the compound of Formula III with the compound of Formula IV is carried out for about 10 hours to about 30 hours, for example, for about 12 hours to about 25 hours.
The reaction of the compound of Formula III with the compound of Formula IV is carried out at a temperature of about 60°C to about 135°C, for example, of about 65°C to about 130°C. The compound of Formula V may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of Formula V may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying.
The coupling of the compound of Formula V with the compound of Formula VI to obtain the compound of Formula VII is carried out in the presence of a base and a coupling agent in a solvent.
The base is selected from the group consisting of cesium carbonate, potassium carbonate, sodium carbonate, sodium hydroxide, N,N-diisopropylethylamine, tert- butylamine, potassium hydroxide, potassium tert-butoxide, and sodium-tert-butoxide.
The coupling agent is selected from the group consisting of palladium on carbon, [1,1 '-bis(diphenylphosphino)ferrocene] -dichloropalladium(II) complex with
dichloromethane, bis(triphenylphosphine)palladium(II) dichloride,
dichlorobistriphenylphosphine palladium (II), tetrakistriphenylphosphine palladium (0), and palladium(II) acetate.
The solvent is selected from the group consisting of toluene, water, dioxane, n- propanol, isopropanol, methanol, ethanol, acetone, toluene, acetonitrile,
dimethylformamide, tetrahydrofuran, and mixtures thereof.
The coupling of the compound of Formula V with the compound of Formula VI is carried out for about 1 hour to about 60 hours, for example, for about 2 hours to about 50 hours.
The coupling of the compound of Formula V with the compound of Formula VI is carried out at a temperature of about 70°C to about 120°C, for example, of about 85°C to about 110°C.
The compound of Formula VII may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of Formula VII may optionally be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying. The deprotection of the compound of Formula VII to obtain the compound of Formula VIII or its salts is carried out with a deprotecting agent in a solvent.
The deprotecting agent is selected from the group consisting of hydrochloric acid, alcoholic hydrochloric acid, ethereal hydrochloric acid, trifluoroacetic acid, hydrobromic acid, and sulfuric acid.
The solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, tert-butanol, dioxane, methyl tert-butyl ether, and mixtures thereof.
When alcoholic hydrochloric acid or ethereal hydrochloric acid are used as deprotecting agents, these serve as the solvents also.
Examples of alcoholic solvents for the preparation of alcoholic hydrochloric acid include methanol, ethanol, n-propanol, isopropanol, tert-butanol, and mixtures thereof.
Examples of ethereal solvents for the preparation of ethereal hydrochloric acid include dioxane, methyl tert-butyl ether, and mixtures thereof.
The deprotection of the compound of Formula VII is carried out for about 20 minutes to about 4 hours, for example, for about 30 minutes to about 2 hours.
The deprotection of the compound of Formula VII is carried out at a temperature of about 40°C to about 80°C, for example, of about 45°C to about 60°C.
The compound of Formula VIII or its salts may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of
Formula VIII or its salts may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying.
The reaction of the compound of Formula VIII or its salts with the compound of Formula IX to obtain ibrutinib of Formula I is carried out in the presence of a base in a solvent.
The base is selected from the group consisting of triethylamine, isopropylamine, pyridine, N,N-diisopropylethylamine, dimethylaminopyridine, and N-methylmorpholine.
The solvent is selected from the group consisting of dichloromethane, chloroform, dichloroethane, carbon tetrachloride, and mixtures thereof. The reaction of the compound of Formula VIII or its salts with the compound of Formula IX is carried out for about 1 hour to about 6 hours, for example, for about 2 hours to about 4 hours.
The reaction of the compound of Formula VIII or its salts with the compound of Formula IX is carried out at a temperature of about 10°C to about 25°C, for example, of about 15°C to about 20°C.
Ibrutinib of Formula I may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. Ibrutinib of Formula I may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying.
The following examples are set forth to demonstrate general synthetic procedures for the preparation of representative compounds. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention.
Examples
Example 1 : Preparation of 3-iodo-lH-pyrazolor3.4-dlpyrimidin-4-amine (Formula III, when X is iodine)
A mixture of lH-pyrazolo[3,4-d]pyrimidin-4-amine (Formula II, 20 g), N- iodosuccinimide (41.6 g), and dimethylformamide (300 mL) was stirred at 75°C to 80°C for 16 hours. Water (1 L) was added to the reaction mixture, and then the mixture was stirred at 15°C for 4 hours. The solid obtained was filtered, then washed with water (100 mL), and then washed with cold ethanol (60 mL). The resulting solid was dried at 45°C under vacuum for 16 hours to obtain the title compound.
Yield: 26.8 g
Example 2: Preparation of 3-bromo-lH-pyrazolor3.4-dlpyrimidin-4-amine (Formula III, when X is bromine)
A mixture of lH-pyrazolo[3,4-d]pyrimidin-4-amine (Formula II, 25 g), N- bromosuccinimide (36.2 g), and dimethylformamide (150 mL) was stirred at 60°C for 4 hours. The reaction mixture was gradually cooled to room temperature, and then filtered. The filtrate was poured into deionized water (750 mL), and then the mixture was stirred at room temperature for 30 minutes. The solid obtained was filtered, then washed with water (50 mL). The resulting solid was dried at 60°C under vacuum for 10 hours to 12 hours to obtain the title compound.
Yield: 27.9 g
Example 3: Preparation oftert-butyl (3S)-3-r(methylsulfonyl)oxylpiperidine-l-carboxylate (Formula IV. when Pr1 is tert-butoxycarbonyl (Boc) and Pr2 is mesyl)
tert-Butyl (3S)-3-hydroxypiperidine-l-carboxylate (25 g) and triethylamine (30 g) were added to toluene (250 mL) at room temperature to obtain a reaction mixture. The reaction mixture was cooled to 0°C to 5°C. A solution of mesyl chloride (22.5 g) in toluene (100 mL) was added drop-wise over a period of 1 hour at 0°C to 5°C. The reaction mixture was stirred for 2 hours at room temperature. Water (250 mL) was added to the reaction mixture, and then the mixture was stirred to separate the organic layer. The organic layer was washed with water (100 mL), and then evaporated under vacuum to obtain a pale yellow viscous crude material (52 g). Toluene (30 mL) was added at 45°C, and a solid was obtained by the slow addition of hexane (150 mL) over a period of 15 minutes. The mixture was stirred for 1 hour at room temperature. The solid was filtered, and then kept in a vacuum oven at 45°C for 3 hours to obtain the title compound.
Yield: 31 g
Example 4: Preparation oftert-butyl (3R)-3-(4-amino-3-iodo-lH-pyrazolor3.4- dlpyrimidin-l-vDpiperidine-l-carboxylate (Formula V. when X is iodine and Pr1 is Boc)
A mixture of 3-iodo-lH-pyrazolo[3,4-d]pyrimidin-4-amine (Formula III, when X is iodine, Example 1, 18 g), cesium carbonate (51.8 g), and dimethylaminopyridine (0.88 g) was added to N-methylpyrrolidone (400 mL) under nitrogen at room temperature. The temperature of the reaction mixture was raised to 70°C. A solution of tert-butyl (3S)-3- [(methylsulfonyl)oxy]piperidine-l-carboxylate (Formula IV, when Pr1 is Boc and Pr2 is mesyl, Example 3, 29 g) in N-methylpyrrolidone (150 mL) was added drop-wise over a period of 1 hour at 70°C. The reaction mixture was stirred overnight at 70°C. Water (1.7 L) was added to the reaction mixture, then the mixture was stirred at 5°C for 3 hours, and then stirred overnight at room temperature. The yellowish solid product was filtered, then washed with water (100 mL). The resulting solid was dried at 45 °C under vacuum for 9 hours to obtain the title compound.
Yield: 13.8 g
Example 5: Preparation of tert-butyl (3R)-3-(4-amino-3-bromo-lH-pyrazolo[3.4- dlpyrimidin-l-vDpiperidine-l-carboxylate (Formula V. when X is bromine and Pr1 is Boc)
A mixture of 3-bromo-lH-pyrazolo[3,4-d]pyrimidin-4-amine (Formula III, when X is bromine, Example 2, 10 g), potassium carbonate (12.9 g), and tert-butyl (3S)-3- [(methylsulfonyl)oxy]piperidine-l-carboxylate (Formula IV, when Pr1 is Boc and Pr2 is mesyl, Example 3, 13.7 g) in dimethylsulfoxide (110 mL) was stirred at 120°C for 12 hours. tert-Butyl (3S)-3-[(methylsulfonyl)oxy]piperidine-l-carboxylate (Formula IV, when Pr1 is Boc and Pr2 is mesyl, Example 3, 3 g) was added to the reaction mixture, and the reaction mixture was heated with stirring overnight at 120°C. The reaction mixture was cooled to room temperature, and then water (1 L) was added to it. The product was extracted with ethyl acetate (2 χ 500 mL) at room temperature. The solvent was recovered under vacuum at a temperature not more than 50°C. Hexane (250 mL) was added to the crude product, and then the mixture was stirred overnight at room temperature. The mixture was filtered off, and then dried under vacuum at 50°C for 8 hours to obtain the title compound.
Yield: 7.52 g
Example 6: Preparation of tert-butyl (3R)-3-r4-amino-3-(4-phenoxyphenyl)-lH- pyrazolor3.4-dlpyrimidin-l-vHpiperidine-l-carboxylate (Formula VII. wherein Pr1 is Boc) tert-Butyl (3R)-3 -(4-amino-3 -iodo- lH-pyrazolo [3 ,4-d]pyrimidin- 1 -yl)piperidine- 1 - carboxylate (Formula V, when X is iodine and Pr1 is Boc, Example 4, 12 g), cesium carbonate (21.9 g), and phenoxyphenylboronic acid (Formula VI, when R1 and R2 are hydrogen, 8.6 g) were added into a mixture of toluene (300 mL) and water (30 mL) under nitrogen. Palladium on carbon (2 g, 10% palladium, 50% wet) was added to the reaction mixture, and then the reaction mixture was stirred at 95 °C for 24 hours. Palladium on carbon (2 g, 10% palladium, 50% wet) and phenoxyphenylboronic acid (2 g) were added to the reaction mixture, and then the reaction mixture was stirred for another 24 hours. The reaction mixture was then diluted with water (50 mL) and ethyl acetate (100 mL), and the organic layer was separated off and passed through a Hyflo®. The organic layer was evaporated to obtain a dark brown viscous crude solid (22 g), which was used as such for the next step.
Example 7: Preparation of tert-butyl (3R)-3-[4-amino-3-(4-phenoxyphenyl)-lH- pyrazolo[3.4-d]pyrimidin-l-yl]piperidine-l-carboxylate (Formula VII. wherein Pr1 is Boc) tert-Butyl (3R)-3 -(4-amino-3 -iodo- lH-pyrazolo [3 ,4-d]pyrimidin- 1 -yl)piperidine- 1 - carboxylate (Formula V, when X is iodine and Pr1 is Boc, Example 4, 12 g), cesium carbonate (21.9 g), and phenoxyphenylboronic acid (Formula VI, when R1 and R2 are hydrogen, 8.6 g) were added into a mixture of dioxane (250 mL) and water (25 mL) under nitrogen. [l,l'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (1.14 g) was added to the reaction mixture, then the temperature of the reaction mixture was raised to 95°C, and then the mixture was stirred for 2 hours. The reaction mixture was diluted with a mixture of water (200 mL) and ethyl acetate (300 mL), and then the organic layer was separated off and passed through a Hyflo®. After washing with ethyl acetate (150 mL), the organic layer was evaporated to obtain a dark viscous crude material. Ethyl acetate (50 mL) was added to the crude material at 45 °C, followed by the addition of hexane (150 mL). The reaction mixture was stirred at room temperature for 30 minutes, and then stirred at 5°C for 2 hours, and thereafter stirred at room temperature overnight. The light yellow colored supernatant was decanted, and then evaporated under vacuum to complete dryness. The crude bright yellowish solid (8 g) obtained was used as such for the next step.
Example 8: Preparation of tert-butyl (3R)-3-r4-amino-3-(4-phenoxyphenyl)-lH- pyrazolor3.4-dlpyrimidin-l-vHpiperidine-l -carboxylate (Formula VII. wherein Pr1 is Boc)
A mixture of tert-butyl (3R)-3-(4-amino-3-bromo-lH-pyrazolo[3,4-d]pyrimidin-l- yl)piperidine-l -carboxylate (Formula V, when X is bromine and Pr1 is Boc, Example 5, 5 g), potassium carbonate (8.7 g), and phenoxyphenylboronic acid (Formula VI, when R1 and R2 are hydrogen, 4 g) were added to a mixture of dioxane (45 mL) and water (25 mL) under nitrogen. [l, l'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (0.45 g) was added to the reaction mixture, and then the reaction mixture was stirred at 100°C to 105°C for 4 hours. The reaction mixture was then diluted with water (150 mL) and ethyl acetate (100 mL), and was then stirred for 10 minutes to 15 minutes at room temperature. The organic layer was separated out. The aqueous layer was again extracted with ethyl acetate (100 mL) at room temperature. The organic layers were combined, and then washed with a brine solution (50 mL). The excess of ethyl acetate was recovered under vacuum at a temperature not more than 50°C. Hexane (100 mL) was added to the crude material, and then the mixture was stirred overnight at room temperature to obtain a sticky mass. The excess solvent was dried completely under vacuum at a temperature not more than 50°C to obtain the title compound (1.2 g), which was used as such for next step.
Example 9: Preparation of 3-(4-phenoxyphenyl)-l-r(3R)-piperidin-3-yll-lH-pyrazolor3.4- dlpyrimidin-4-amine hydrochloride salt (hydrochloride salt of Formula VIII)
Methanolic hydrochloric acid (50 mL) was added to the dark brown viscous crude solid as obtained from Example 6 (22 g). The reaction mixture was stirred at 45 °C for 1 hour and then evaporated to complete dryness at 45 °C and degassed using methanol (50 χ 3 mL). The crude material obtained was washed further with ethyl acetate (100 mL) at room temperature. The light brown solid was filtered off and dried under vacuum. The filtrate was evaporated under vacuum at 40°C to 45°C to complete dryness, then ethyl acetate (50 mL) was added to the mixture, and then the mixture was stirred vigorously for 1 hour at room temperature. The mixture was filtered off to obtain the title compound as light brown solid.
Yield: 9.1 g
Example 10: Preparation of 3-(4-phenoxyphenyl)-l-r(3R)-piperidin-3-vH-lH- pyrazolo[3.4-d]pyrimidin-4-amine hydrochloride salt (hydrochloride salt of Formula VIII)
Methanolic hydrochloric acid (50 mL) was added to tert-butyl (3R)-3-[4-amino-3- (4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carboxylate (Formula VII, wherein Pr1 is Boc, as obtained from Example 7, 8 g) and the reaction mixture was stirred at 50°C for 1 hour. The reaction mixture was evaporated to dryness, and then degassed using methanol (2 χ 50 mL). Chloroform (50 mL) was added to the reaction mixture, and then the mixture was stirred at 45°C for 10 minutes, followed by the subsequent addition of chloroform (50 mL). The reaction mixture was cooled to room temperature, and then the bright white solid was filtered off, then kept in an oven at 45°C for 2 hours to obtain the title compound.
Yield: 6 g
Example 11 : Preparation of 3-(4-phenoxyphenyl)-l-r(3R)-piperidin-3-vH-lH- pyrazolor3.4-dlpyrimidin-4-amine hydrochloride salt (hydrochloride salt of Formula VIII)
Methanolic hydrochloric acid (120 mL) was added to tert-butyl (3R)-3-[4-amino-3- (4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carboxylate (Formula VII as obtained from Example 8, wherein Pr1 is Boc, 6 g) and the reaction mixture was stirred at 45°C for 2 hours. The reaction mixture was evaporated to dryness. Ethyl acetate (80 mL) was added to the crude material obtained, and then the mixture was stirred overnight at room temperature. The excess of ethyl acetate was recovered under vacuum at a temperature not more than 45 °C to obtain a crude material. Methyl tert-butyl ether (120 mL) was added to the crude material at room temperature, and then the mixture was stirred for 3 hours to 4 hours. The material was filtered under nitrogen, and then washed with methyl tert-butyl ether (60 mL) at room temperature. The material was dried under vacuum at room temperature for 8 hours to 10 hours to obtain the title compound.
Yield: 3 g
Example 12: Preparation of prop-2-enoyl chloride (Formula IX. when R is CI)
Oxalyl chloride (0.64 g) was added to a solution of acrylic acid (0.37 g) and dimethylformamide (0.05 mL) in dichloromethane (5 mL) at room temperature under nitrogen. The reaction mixture was stirred for 3 hours at room temperature, and was used as such for the next step.
Example 13: Preparation of ibrutinib (Formula I)
3 -(4-Phenoxyphenyl)- 1 -[(3R)-piperidin-3 -yl] - lH-pyrazolo [3 ,4-d]pyrimidin-4- amine hydrochloride salt (hydrochloride salt of Formula VIII, 2 g) was suspended in dichloromethane (30 mL), and then triethylamine (1.42 g) was added to this mixture at room temperature under nitrogen atmosphere. The clear solution obtained was maintained at 5°C, and then prop-2-enoyl chloride solution (as obtained in Example 12) was added drop-wise over a period of 1 hour. The reaction mixture was stirred at 15°C for 3 hours. Water (30 mL) was added to the reaction mixture, and then the separated organic layer was evaporated to dryness to obtain a crude light brown crystalline solid. The solid obtained was purified by column chromatography using a gradient elusion with dichloromethane to 10% methanol-dichloromethane (2.75 L) to obtain a white solid, which was dried under vacuum at a temperature not more than 40°C to obtain the title compound.
Yield: 1.1 g

Claims

We claim:
1. A process for the preparation of ibrutinib of Formula I,
Figure imgf000018_0001
Formula I
comprising:
a) halogenating a compound of Formula II
Figure imgf000018_0002
Formula II
in the presence of a halogenating agent to obtain a compound of Formula III,
Figure imgf000018_0003
Formula III
wherein X is halogen;
b) reacting the compound of Formula III with a compound of Formula IV,
Figure imgf000018_0004
Formula IV wherein Pr1 is selected from the group consisting of tert-butyloxycarbonyl (Boc), benzyloxycarbonyl,
2-(trimethylsilyl)ethoxycarbonyl, benzyl, benzoyl, carbamate, tosyl, and p-methoxybenzyl carbonyl;
Pr2 is selected from the group consisting of mesyl, allyl, trityl, benzyl, p- methoxybenzyl, tetrahydropyranyl, and trimethylsilyl,
to obtain a compound of Formula V;
Figure imgf000019_0001
Formula V
coupling the compound of Formula V with a compound of Formula VI,
Figure imgf000019_0002
Formula VI
wherein R1 and R2 are hydrogen or lower alkyl or R1 and R2 together with the oxygen atoms to which they are attached form a heterocyclic ring, which is optionally substituted with lower alkyl, aryl, or oxo,
to obtain a compound of Formula VII;
Figure imgf000020_0001
Formula VII
d) deprotecting the compound of Formula VII with a deprotecting agent to obtain a compound of Formula VIII or its salts; and
Figure imgf000020_0002
Formula VIII
e) reacting the compound of Formula VIII or its salts with a compound of
Formula IX,
Figure imgf000020_0003
Formula IX
wherein R is hydroxy, halogen, tosyl, or mesyl,
to obtain ibrutinib of Formula I.
The process according to claim 1, wherein the halogenation of the compound of Formula II is carried out in the presence of a halogenating agent in a solvent.
3. The process according to claim 2, wherein the halogenating agent is selected from the group consisting of N-iodosuccinimide, N-bromosuccinimide, bromine, hydrobromic acid, hydroiodic acid, and N-bromophthalimide.
4. The process according to claim 2, wherein the solvent is selected from the group
consisting of dimethylformamide, dimethylsulfoxide, dichloromethane, and mixtures thereof.
5. The process according to claim 1 , wherein the reaction of the compound of Formula III with the compound of Formula IV is carried out in the presence of a base in a solvent, optionally in the presence of a catalyst.
6. The process according to claim 5, wherein the base is selected from the group
consisting of cesium carbonate, potassium carbonate, sodium carbonate, sodium hydroxide, N,N-diisopropylethylamine, tert-butylamine, potassium hydroxide, potassium tert-butoxide, and sodium-tert-butoxide.
7. The process according to claim 5, wherein the solvent is selected from the group
consisting of N-methylpyrrolidone, dimethylsulfoxide, dimethylformamide, dimethylacetamide, tetrahydrofuran, and mixtures thereof.
8. The process according to claim 5, wherein the catalyst is selected from the group
consisting of dimethylaminopyridine, benzyltrimethylammonium chloride, hexadecyltributylphosphonium bromide, tetra-n-butylammonium bromide, and methyltrioctylammonium chloride.
9. The process according to claim 1, wherein the coupling of the compound of Formula V with the compound of Formula VI is carried out in the presence of a base and a coupling agent in a solvent.
10. The process according to claim 9, wherein the base is selected from the group
consisting of cesium carbonate, potassium carbonate, sodium carbonate, sodium hydroxide, N,N-diisopropylethylamine, tert-butylamine, potassium hydroxide, potassium tert-butoxide, and sodium-tert-butoxide.
1 1. The process according to claim 9, wherein the coupling agent is selected from the group consisting of palladium on carbon, [l, l'-bis(diphenylphosphino)ferrocene]- dichloropalladium(II) complex with dichloromethane, bis(triphenylphosphine)palladium(II) dichloride, dichlorobistriphenylphosphine palladium (II), tetrakistriphenylphosphine palladium (0), and palladium(II) acetate.
12. The process according to claim 9, wherein the solvent is selected from the group
consisting of toluene, water, dioxane, n-propanol, isopropanol, methanol, ethanol, acetone, toluene, acetonitrile, dimethylformamide, tetrahydrofuran, and mixtures thereof.
13. The process according to claim 1, wherein the deprotection of the compound of
Formula VII is carried out with a deprotecting agent in a solvent.
14. The process according to claim 13, wherein the deprotecting agent is selected from the group consisting of hydrochloric acid, alcoholic hydrochloric acid, ethereal hydrochloric acid, trifluoroacetic acid, hydrobromic acid, and sulfuric acid.
15. The process according to claim 13, wherein the solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, tert-butanol, dioxane, methyl tert-butyl ether, and mixtures thereof.
16. The process according to claim 13, wherein the alcoholic solvents for the preparation of alcoholic hydrochloric acid include methanol, ethanol, n-propanol, isopropanol, tert- butanol, and mixtures thereof.
17. The process according to claim 13, wherein the ethereal solvents for the preparation of ethereal hydrochloric acid include dioxane, methyl tert-butyl ether, and mixtures thereof.
18. The process according to claim 1 , wherein the reaction of the compound of Formula VIII or its salts with the compound of Formula IX is carried out in the presence of a base in a solvent.
19. The process according to claim 18, wherein the base is selected from the group
consisting of triethylamine, isopropylamine, pyridine, N,N-diisopropylethylamine, dimethylaminopyridine, and N-methylmorpholine.
20. The process according to claim 18, wherein the solvent is selected from the group consisting of dichloromethane, chloroform, dichloroethane, carbon tetrachloride, and mixtures thereof.
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107501270A (en) * 2017-09-01 2017-12-22 南京宏腾建设工程有限公司 A kind of compound containing sulphonyl ethylene imine structure, pharmaceutical composition and its application
US10266535B2 (en) * 2015-01-21 2019-04-23 Hefei Institutes Of Physical Science, Chinese Academy Of Sciences Inhibitor of FLT3 kinase and use thereof
CN110256438A (en) * 2018-03-12 2019-09-20 新发药业有限公司 A kind of Ah can replace the preparation method of Buddhist nun
WO2019213184A1 (en) 2018-05-03 2019-11-07 Juno Therapeutics, Inc. Combination therapy of a chimeric antigen receptor (car) t cell therapy and a kinase inhibitor
CN111196813A (en) * 2018-11-20 2020-05-26 山东大学 1,3, 4-trisubstituted pyrazolopyrimidine compound as well as preparation method and application thereof
WO2023220655A1 (en) 2022-05-11 2023-11-16 Celgene Corporation Methods to overcome drug resistance by re-sensitizing cancer cells to treatment with a prior therapy via treatment with a t cell therapy

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2561875A2 (en) * 2007-03-28 2013-02-27 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase
WO2014022390A1 (en) * 2012-07-30 2014-02-06 Concert Pharmaceuticals, Inc. Deuterated ibrutinib

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2561875A2 (en) * 2007-03-28 2013-02-27 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase
WO2014022390A1 (en) * 2012-07-30 2014-02-06 Concert Pharmaceuticals, Inc. Deuterated ibrutinib

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10266535B2 (en) * 2015-01-21 2019-04-23 Hefei Institutes Of Physical Science, Chinese Academy Of Sciences Inhibitor of FLT3 kinase and use thereof
CN107501270A (en) * 2017-09-01 2017-12-22 南京宏腾建设工程有限公司 A kind of compound containing sulphonyl ethylene imine structure, pharmaceutical composition and its application
CN110256438A (en) * 2018-03-12 2019-09-20 新发药业有限公司 A kind of Ah can replace the preparation method of Buddhist nun
CN110256438B (en) * 2018-03-12 2020-07-17 新发药业有限公司 Preparation method of Acotinib
WO2019213184A1 (en) 2018-05-03 2019-11-07 Juno Therapeutics, Inc. Combination therapy of a chimeric antigen receptor (car) t cell therapy and a kinase inhibitor
CN111196813A (en) * 2018-11-20 2020-05-26 山东大学 1,3, 4-trisubstituted pyrazolopyrimidine compound as well as preparation method and application thereof
CN111196813B (en) * 2018-11-20 2021-10-26 山东大学 1,3, 4-trisubstituted pyrazolopyrimidine compound as well as preparation method and application thereof
WO2023220655A1 (en) 2022-05-11 2023-11-16 Celgene Corporation Methods to overcome drug resistance by re-sensitizing cancer cells to treatment with a prior therapy via treatment with a t cell therapy

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