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WO2014185367A1 - Procédé de production de dérivé de morpholinopurine - Google Patents

Procédé de production de dérivé de morpholinopurine Download PDF

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Publication number
WO2014185367A1
WO2014185367A1 PCT/JP2014/062557 JP2014062557W WO2014185367A1 WO 2014185367 A1 WO2014185367 A1 WO 2014185367A1 JP 2014062557 W JP2014062557 W JP 2014062557W WO 2014185367 A1 WO2014185367 A1 WO 2014185367A1
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Prior art keywords
compound
range
formula
compound represented
acceptable salt
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Japanese (ja)
Inventor
倫明 川原
雄一郎 谷
文克 近藤
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Daiichi Sankyo Co Ltd
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Daiichi Sankyo Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a method for producing a compound having phosphatidylinositol 3-kinase (PI3K) and / or Mammalian target of rapamycin (mTOR) inhibitory activity, a method for producing the synthetic intermediate, and a novel synthetic intermediate.
  • PI3K phosphatidylinositol 3-kinase
  • mTOR Mammalian target of rapamycin
  • Patent Document 1 It is known that a morpholinopurine derivative is useful as a medicine or a raw material for producing the same, and is useful for treating tumors.
  • Example 59 of the patent document 5- ⁇ 8-[(3R) -4-acetyl-3-methylpiperazin-1-yl] -6-morpholin-4-yl-9- (2,2,2- (Trifluoroethyl) -9H-purin-2-yl ⁇ pyrimidin-2-amine (a compound represented by the formula (VIII) in the present specification) and a method for producing the same are disclosed.
  • Patent Document 1 5- [6-morpholin-4-yl-9- (2,2,2-trifluoroethyl) -9H-purin-2-yl] pyrimidin-2-amine (herein represented by the formula ( A compound represented by III) is also disclosed.
  • Patent Document 1 the compound represented by the formula (III) is 2-chloro-6-morpholin-4-yl-9- (2,2,2-trifluoroethyl) -9H-purine (in the present specification, Compound (I)) as a starting material in the presence of tetrakistriphenylphosphine palladium in the presence of 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidine-2 -After a coupling reaction with an amine, tert-butoxycarbonyl group is allowed to act, and then synthesized through two steps. Further, Patent Document 1 does not disclose a method for purifying a compound other than column chromatography.
  • the present invention provides an industrially useful and novel production method for morpholinopurine derivatives having excellent antitumor activity and synthetic intermediates thereof.
  • the present invention relates to the following (1) to (15).
  • R 1 and R 2 each independently represent a substituent selected from the group consisting of a hydrogen atom, a C 1 -C 6 alkoxycarbonyl group, and a benzyloxycarbonyl group. . However, R 1 and R 2 do not represent a hydrogen atom at the same time.
  • R 1 and R 2 do not represent a hydrogen atom at the same time.
  • the palladium catalyst is a catalyst prepared from palladium acetate and triphenylphosphine.
  • the compound represented by the above formula (I) is Compound represented by formula (IV):
  • an industrially useful and novel production method can be provided for morpholinopurine derivatives having excellent antitumor activity and synthetic intermediates thereof.
  • the compound represented by the formula (III) is subjected to a coupling reaction using the compound represented by the formula (II) to thereby perform one step from the compound represented by the formula (I). Can be obtained.
  • the amount of residual palladium in the compound represented by the formula (III) can be reduced by the purification method using the thiourea derivative, and as a result, the compound represented by the formula (VIII) can be obtained with high purity. it can.
  • the production in each production process from the compound represented by the formula (IV) to the compound represented by the formula (VIII), the production can be performed without using column chromatography.
  • C 1 -C 6 alkyloxycarbonyl group means, for example, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, A pentyloxycarbonyl group, a hexyloxycarbonyl group, etc. are mentioned.
  • the “chlorinating agent” refers to a reagent capable of introducing a chlorine atom into a compound.
  • palladium catalyst means a divalent palladium catalyst or a zero-valent palladium catalyst.
  • tetrakis (triphenylphosphine) palladium (0) and the like can be mentioned.
  • the “palladium catalyst” of the present invention includes, for example, palladium compounds such as palladium chloride and palladium acetate, monodentate phosphine ligands such as triphenylphosphine and trit-butylphosphine, or 1,1- Also included are palladium catalysts prepared by reacting with bidentate phosphine ligands such as bis (diphenylphosphino) methane and 1,2-bis (diphenylphosphino) ethane.
  • the “thiourea derivative” refers to a compound having a partial structure in which the oxygen atom of urea is replaced with a sulfur atom.
  • R 1 and R 2 are preferably both of R 1 and R 2 is C 1 -C 6 alkoxycarbonyl group. More preferably, both R 1 and R 2 are tert-butoxycarbonyl groups.
  • the compound represented by the formula (III), the compound represented by the formula (V), the compound represented by the formula (VI), the compound represented by the formula (VII), and the compound represented by the formula (VIII) of the present invention are: It can be made into a pharmacologically acceptable salt by reacting with an acid.
  • Pharmacologically acceptable salt refers to a salt that has no significant toxicity and can be used as a medicine.
  • hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, inorganic acid salts such as nitrate, perchlorate, sulfate, phosphate; methane C 1 -C 6 alkyl sulfonates such as sulfonate, trifluoromethane sulfonate, ethane sulfonate, aryl sulfonate such as benzene sulfonate, p-toluene sulfonate, acetate, Organic acid salts such as malate, fumarate, succinate, citrate, ascorbate, tartrate, succinate, maleate; and glycine, lysine, arginine, ornithine And amino acid salts such as glutamate and aspartate.
  • inorganic acid salts such as nitrate, perchlorate, sulfate, phosphate
  • the compound of formula (III) or a pharmacologically acceptable salt thereof, the compound of formula (V) or a pharmaceutically acceptable salt thereof, the compound of formula (VI) or a pharmacological thereof An acceptable salt, a compound represented by formula (VII) or a pharmacologically acceptable salt thereof, and a compound represented by formula (VIII) or a pharmacologically acceptable salt thereof are left in the atmosphere, or By recrystallizing, water molecules may be taken in to form hydrates, and such hydrates are also included in the salt.
  • the compound of formula (III) or a pharmacologically acceptable salt thereof, the compound of formula (V) or a pharmaceutically acceptable salt thereof, the compound of formula (VI) or a pharmacological thereof An acceptable salt, a compound represented by formula (VII) or a pharmacologically acceptable salt thereof, and a compound represented by formula (VIII) or a pharmacologically acceptable salt thereof are left in a solvent, or By recrystallizing, a certain solvent may be absorbed to be a solvate, and such a solvate is also included in the salt.
  • the functional group of the compound may be protected with an appropriate protecting group.
  • a functional group include a hydroxyl group, a carboxy group, an amino group, and the like.
  • the types of protecting groups and the conditions for introducing and removing these protecting groups are, for example, Protective Groups in Organic Synthesis (T. W. Green and PMGM Wuts, John Wiley & Sons, Inc., New York, 2006) can be referred to.
  • Compound (I) is obtained by reacting compound (IV) with morpholine and then reacting with trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester.
  • 1-1) Reaction with morpholine
  • the reaction between compound (IV) and morpholine is carried out by reacting a base in a solvent.
  • the amount of morpholine used is in the range of 1 equivalent to 10 equivalents relative to compound (IV), preferably in the range of 1 equivalent to 2 equivalents relative to compound (IV), more preferably It is in the range of 1.00 equivalent to 1.05 equivalent relative to compound (IV).
  • Bases include, for example, tertiary amines such as triethylamine, N, N-diisopropylethylamine, organic bases such as sodium ethoxide, t-butoxypotassium, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium acetate, potassium hydroxide, Inorganic bases such as potassium carbonate, potassium hydrogen carbonate, and potassium acetate can be used.
  • tertiary amines such as triethylamine and N, N-diisopropylethylamine, and more preferred is triethylamine.
  • the amount of base used is in the range of 1 equivalent to 10 equivalents relative to compound (IV), preferably in the range of 1 equivalent to 2 equivalents relative to compound (IV), more preferably It is in the range of 1.1 equivalents to 1.3 equivalents with respect to compound (IV).
  • the solvent include alcohol solvents such as methanol, ethanol and 2-propanol, amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone, diethyl ether, tetrahydrofuran and the like.
  • Inert solvents such as ether solvents, nitrile solvents such as acetonitrile, hydrocarbon solvents such as toluene, and the like, which are inert to morpholine, preferably N, N-dimethylformamide, N, N-dimethyl Amide solvents such as acetamide and N-methyl-2-pyrrolidone, more preferably N, N-dimethylacetamide.
  • the amount of solvent used is in the range of 1 to 100 times the amount of compound (IV), preferably in the range of 5 to 20 times the amount of compound (IV), more preferably The amount is in the range of 8 times to 12 times the amount of compound (IV).
  • the reaction temperature ranges from 0 ° C.
  • reaction time is in the range of 30 minutes to 24 hours, preferably in the range of 30 minutes to 6 hours, and more preferably in the range of 30 minutes to 3 hours.
  • Reaction with trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester is a reaction completed solution of compound (IV) and morpholine. The reaction is carried out by reacting a base with trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester.
  • Bases include, for example, tertiary amines such as triethylamine, N, N-diisopropylethylamine, organic bases such as sodium ethoxide, t-butoxypotassium, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium acetate, potassium hydroxide, Inorganic bases such as potassium carbonate, potassium hydrogen carbonate and potassium acetate can be used, preferably sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium acetate, potassium hydroxide, potassium carbonate, potassium hydrogen carbonate, potassium acetate An inorganic base such as potassium carbonate, more preferably potassium carbonate.
  • tertiary amines such as triethylamine, N, N-diisopropylethylamine
  • organic bases such as sodium ethoxide, t-butoxypotassium
  • sodium hydroxide sodium carbonate, sodium carbonate, sodium bicarbonate, sodium acetate, potassium hydroxide
  • Inorganic bases such
  • the amount of base used is in the range of 1 to 10 equivalents relative to compound (IV), preferably in the range of 1 to 5 equivalents relative to compound (IV), more preferably It is in the range of 1.8 equivalents to 2.0 equivalents with respect to compound (IV).
  • the amount of trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester used ranges from 1 equivalent to 10 equivalents relative to compound (IV), preferably 1 equivalent relative to compound (IV).
  • the amount is in the range of 2 to 2 equivalents, and more preferably in the range of 1.0 to 1.2 equivalents with respect to compound (IV).
  • the reaction temperature ranges from 0 ° C. to the boiling point of the solvent used, preferably from 50 ° C.
  • reaction time is in the range of 30 minutes to 24 hours, preferably in the range of 30 minutes to 6 hours, and more preferably in the range of 30 minutes to 4 hours.
  • Compound (I) can be isolated according to a usual method. For example, when the reaction solvent is N, N-dimethylacetamide, it can be isolated as a solid by adding water to the reaction completion solution and collected by filtration. The amount of water added is in the range where the moisture content is 10% to 90%, preferably in the range where the moisture content is 50% to 90%, and more preferably, the moisture content is 65% to 75%. It is a range. 2) Method for producing compound (II)
  • Compound (II) is compound (II ′) obtained by introducing a C 1 -C 6 alkoxycarbonyl group or benzyloxycarbonyl group into the amino group of 5-bromopyrimidin-2-amine, and then compound (II ′) It can be obtained by converting a bromo group into a dihydroxyboryl group.
  • the introduction reaction of C 1 -C 6 alkoxycarbonyl group or benzyloxycarbonyl group into the amino group of 5-bromopyrimidin-2-amine is carried out in the presence of a base in a solvent in the presence of a base R 1 and R C 1 -C 6 alkoxycarbonyl group introduction reagent corresponding to 2 or benzyloxycarbonyl group introduction reagent is allowed to act.
  • the C 1 -C 6 alkoxycarbonyl group is preferably a t-butoxycarbonyl group.
  • C 1 -C 6 alkoxycarbonyl group introduction reagent and the benzyloxycarbonyl group introduction reagent for example, dicarbonate diesters such as di-t-butyl dicarbonate, chloroformates such as benzyl chloroformate, etc. can be used.
  • dicarbonate diesters such as di-t-butyl dicarbonate
  • chloroformates such as benzyl chloroformate, etc.
  • R 1 and R 2 are t-butoxycarbonyl groups
  • di-t-butyl dicarbonate is preferred.
  • the amount of C 1 -C 6 alkoxycarbonyl group introduction reagent used or the amount of benzyloxycarbonyl group introduction reagent used is in the range of 2 to 20 equivalents relative to 5-bromopyrimidin-2-amine, preferably It is in the range of 2 to 5 equivalents relative to 5-bromopyrimidin-2-amine, more preferably 2.5 to 3.5 equivalents relative to 5-bromopyrimidin-2-amine. It is a range.
  • Bases include, for example, tertiary amines such as triethylamine, N, N-diisopropylethylamine, organic bases such as sodium ethoxide, t-butoxypotassium, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium acetate, potassium hydroxide, Inorganic bases such as potassium carbonate, potassium hydrogen carbonate, and potassium acetate can be used.
  • tertiary amines such as triethylamine, N, N-diisopropylethylamine
  • organic bases such as sodium ethoxide, t-butoxypotassium, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium acetate, potassium hydroxide
  • Inorganic bases such as potassium carbonate, potassium hydrogen carbonate, and potassium acetate can be used.
  • dicarbonate diester is used as a reagent for introducing an alkoxycarbonyl protecting group
  • N N-dimethyl-4-aminopyridine
  • 5-bromopyrimidine- It is in the range of 0.01 mol% to 50 mol% with respect to 2-amine, preferably in the range of 1 mol% to 20 mol% with respect to 5-bromopyrimidin-2-amine, more preferably 5-bromopyrimidine- The range is from 5 mol% to 15 mol% with respect to 2-amine.
  • the solvent examples include amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, ether solvents such as diethyl ether and tetrahydrofuran, nitrile solvents such as acetonitrile, toluene Inert solvents such as hydrocarbon solvents such as ethyl acetate, ester solvents such as ethyl acetate, and ketone-based solvents such as acetone can be used.
  • amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone
  • ether solvents such as diethyl ether and tetrahydrofuran
  • nitrile solvents such as acetonitrile
  • Inert solvents such as hydrocarbon solvents such as ethyl acetate, ester solvents such as e
  • N, N— Amide solvents such as dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, and more preferably N, N-dimethylacetamide.
  • the amount of the solvent used is in the range of 1 to 100 times the amount of 5-bromopyrimidin-2-amine, preferably 5 to 20 times the amount of 5-bromopyrimidin-2-amine.
  • the range is more preferably 8 to 12 times the amount of 5-bromopyrimidin-2-amine.
  • the reaction temperature is in the range of 0 ° C. to the boiling point of the solvent used, preferably in the range of 0 ° C. to 50 ° C., more preferably in the range of 10 ° C. to 30 ° C.
  • the reaction time is in the range of 1 hour to 48 hours, preferably in the range of 1 hour to 24 hours, and more preferably in the range of 12 hours to 24 hours.
  • Compound (II ′) can be isolated according to a usual method. For example, when both R 1 and R 2 are a t-butoxycarbonyl group and the reaction solvent is N, N-dimethylacetamide, it is precipitated as a solid by adding water to the reaction end solution, This can be isolated by filtration.
  • the amount of water added is in the range where the moisture content is 10% to 90%, preferably in the range where the moisture content is 40% to 80%, and more preferably, the moisture content is 55% to 65%. It is a range.
  • the palladium catalyst for example, tetrakis (triphenylphosphine) palladium or the like may be used.
  • a monodentate such as triphenylphosphine or trit-butylphosphine may be combined with a palladium compound such as palladium chloride or palladium acetate.
  • Reaction system by reacting a coordination phosphine ligand or a bidentate phosphine ligand such as 1,1-bis (diphenylphosphino) methane or 1,2-bis (diphenylphosphino) ethane It may be prepared in-house.
  • the amount of palladium catalyst used is in the range of 0.01 mol% to 50 mol% with respect to the compound (II ′), preferably in the range of 0.1 mol% to 10 mol% with respect to the compound (II ′). Preferably, it is in the range of 0.5 mol% to 2 mol% with respect to compound (II ′).
  • the palladium catalyst is prepared in the reaction system, the palladium compound is preferably palladium acetate, and the phosphine ligand is preferably triphenylphosphine.
  • the amount of the palladium compound used is in the range of 0.01 mol% to 50 mol% with respect to the compound (II ′), preferably in the range of 0.1 mol% to 10 mol% with respect to the compound (II ′). Preferably, it is in the range of 0.5 mol% to 2 mol% with respect to compound (II ′).
  • the amount of the phosphine ligand used is in the range of 1 equivalent to 10 equivalents with respect to the palladium compound, preferably 1 equivalent to the palladium compound. It is in the range of 5 equivalents, and more preferably in the range of 1 equivalent to 3 equivalents with respect to the palladium compound.
  • the amount is in the range of 0.5 to 5 equivalents with respect to the palladium compound, preferably 0.5 to 2.5 equivalents with respect to the palladium compound.
  • the amount is more preferably in the range of 0.5 to 1.5 equivalents with respect to the palladium compound.
  • Bases include, for example, tertiary amines such as triethylamine, N, N-diisopropylethylamine, organic bases such as sodium ethoxide, t-butoxypotassium, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium acetate, potassium hydroxide, Inorganic bases such as potassium carbonate, potassium hydrogen carbonate and potassium acetate can be used, preferably sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium acetate, potassium hydroxide, potassium carbonate, potassium hydrogen carbonate, potassium acetate An inorganic base such as potassium acetate, more preferably potassium acetate.
  • the amount of base used is in the range of 1 equivalent to 10 equivalents relative to compound (II ′), preferably in the range of 2 equivalents to 5 equivalents relative to compound (II ′), more preferably. Is in the range of 2.5 to 3.5 equivalents with respect to compound (II ′).
  • the solvent include alcohol solvents such as methanol, ethanol and 2-propanol, amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone, diethyl ether, tetrahydrofuran and the like.
  • Ether solvents nitrile solvents such as acetonitrile, hydrocarbon solvents such as toluene, ester solvents such as ethyl acetate, ketone solvents such as acetone, etc., preferably N, N-dimethylformamide N, N-dimethylacetamide, N-methyl-2-pyrrolidone and the like, more preferably N, N-dimethylacetamide.
  • the amount of solvent used is in the range of 1 to 100 times the amount of compound (II ′), preferably in the range of 3 to 10 times the amount of compound (II ′), more preferably. Is in the range of 4 to 6 times the amount of compound (II ′).
  • the reaction temperature ranges from 0 ° C.
  • reaction time is in the range of 30 minutes to 24 hours, preferably in the range of 1 hour to 12 hours, and more preferably in the range of 2 hours to 6 hours.
  • Compound (II) can be isolated according to a usual method. For example, when both R 1 and R 2 are t-butoxycarbonyl groups and the reaction solvent is N, N-dimethylacetamide, the boric acid ester is hydrolyzed by adding water to the reaction end solution. Then, it is precipitated as a solid, which can be isolated by filtration.
  • the amount of water added is in the range where the moisture content is 10% to 90%, preferably in the range where the moisture content is 60% to 90%, and more preferably, the moisture content is 70% to 80%. It is a range. 2-3) Purification of Compound (II) Compound (II) is obtained by dissolving crude compound (II) obtained in the step of producing compound (II) from 5-bromopyrimidin-2-amine in a solvent, Is added and stirred, and the activated carbon is filtered off and then precipitated as a solid, which can be purified by filtration.
  • activated carbon for example, activated carbon, Darco (Sigma Aldrich), special white birch (manufactured by Nihon Enviro Chemicals), purified white birch (manufactured by Nihon Enviro Chemicals), carborafin (manufactured by Nihon Enviro Chemicals), etc.
  • a special white birch is preferable.
  • the amount of activated carbon used is in the range of 0.1% to 100% with respect to the compound (II ′), preferably in the range of 1% to 50% with respect to the compound (II ′), and more preferably, It is in the range of 5% to 20% with respect to compound (II ′).
  • the solvent examples include alcohol solvents such as methanol, ethanol and 2-propanol, amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone, diethyl ether, tetrahydrofuran and the like.
  • Ether solvents such as acetonitrile, nitrile solvents such as acetonitrile, hydrocarbon solvents such as toluene, ester solvents such as ethyl acetate, ketone solvents such as acetone, etc., preferably methanol, ethanol, 2- Alcohol solvents such as propanol, more preferably 2-propanol.
  • the amount of solvent used is in the range of 1 to 100 times the amount of compound (II ′), preferably in the range of 5 to 20 times the amount of compound (II ′), more preferably. Is in the range of 10 to 15 times the amount of compound (II ′).
  • Compound (II) can be isolated according to a usual method. For example, when both R 1 and R 2 are t-butoxycarbonyl groups and the solvent is 2-propanol, it is precipitated as a solid by adding water, and is simply filtered off. Can be separated. The amount of water added is in a range where the moisture content is 10% to 90%, preferably in a range where the moisture content is 50% to 80%, and more preferably, the moisture content is 60% to 70%. It is a range. 3) Method for producing compound (III)
  • Compound (III) can be obtained by reacting compound (I) and compound (II) by reacting a palladium catalyst and a base in a solvent in an inert gas atmosphere such as nitrogen or argon.
  • the amount of compound (II) used is in the range of 1 equivalent to 10 equivalents relative to compound (I), preferably in the range of 1 equivalent to 2 equivalents relative to compound (I). More preferably, it is 1.0 equivalent to 1.2 equivalents relative to compound (I).
  • the palladium catalyst for example, tetrakis (triphenylphosphine) palladium or the like may be used.
  • a monodentate such as triphenylphosphine or trit-butylphosphine may be combined with a palladium compound such as palladium chloride or palladium acetate.
  • a coordinated phosphine ligand or a bidentate phosphine ligand such as 1,1-bis (diphenylphosphino) methane or 1,2-bis (diphenylphosphino) ethane is allowed to act. May be prepared.
  • the amount of palladium catalyst used is in the range of 0.01 mol% to 50 mol% with respect to compound (I), preferably in the range of 0.1 mol% to 10 mol%, more preferably, relative to compound (I).
  • the palladium compound is preferably palladium acetate, and the phosphine ligand is preferably triphenylphosphine.
  • the amount of the palladium compound used is in the range of 0.01 mol% to 50 mol% with respect to the compound (I), preferably in the range of 0.1 mol% to 10 mol% with respect to the compound (I), and more preferably. Is in the range of 0.5 mol% to 2 mol% with respect to (I).
  • the amount of the phosphine ligand used is in the range of 1 equivalent to 10 equivalents with respect to the palladium compound, preferably 1 equivalent to the palladium compound. It is in the range of 5 equivalents, and more preferably in the range of 1 equivalent to 3 equivalents with respect to the palladium compound.
  • the amount is in the range of 0.5 to 5 equivalents with respect to the palladium compound, preferably 0.5 to 2.5 equivalents with respect to the palladium compound. The amount is more preferably in the range of 0.5 to 1.5 equivalents with respect to the palladium compound.
  • Bases include, for example, tertiary amines such as triethylamine, N, N-diisopropylethylamine, organic bases such as sodium ethoxide, t-butoxypotassium, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium acetate, potassium hydroxide, Inorganic bases such as potassium carbonate, potassium hydrogen carbonate and potassium acetate can be used, preferably sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium acetate, potassium hydroxide, potassium carbonate, potassium hydrogen carbonate, potassium acetate An inorganic base such as potassium hydrogen carbonate is more preferable.
  • the amount of base used is in the range of 1 equivalent to 10 equivalents relative to compound (I), preferably in the range of 1 equivalent to 5 equivalents relative to compound (I), more preferably It is in the range of 1.9 equivalents to 2.1 equivalents with respect to compound (I).
  • a protic solvent or a mixed solvent of a protic solvent and an aprotic solvent can be used.
  • the protic solvent alcohol solvents such as methanol, ethanol and 2-propanol, and water can be used, and alcohol solvents such as methanol, ethanol and 2-propanol are preferable, and ethanol is more preferable. is there.
  • aprotic solvent examples include amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone, ether solvents such as diethyl ether and tetrahydrofuran, and nitrile solvents such as acetonitrile.
  • Solvents, hydrocarbon solvents such as toluene, ester solvents such as ethyl acetate, ketone solvents such as acetone, etc. can be used, preferably N, N-dimethylformamide, N, N-dimethylacetamide, N—
  • An amide solvent such as methyl-2-pyrrolidone, and more preferably N, N-dimethylformamide.
  • the ratio of the protic solvent is in the range of 10% to 99%, preferably in the range of 50% to 99%, more preferably 70%. % To 90%.
  • the amount of solvent used is in the range of 1 to 100 times the amount of compound (I), preferably in the range of 5 to 20 times the amount of compound (I), more preferably The amount is in the range of 8 to 12 times the amount of compound (I).
  • the reaction temperature ranges from 0 ° C. to the boiling point of the solvent used, preferably from 50 ° C. to the boiling point of the solvent used, more preferably from 60 ° C. to 80 ° C.
  • the reaction time is in the range of 30 minutes to 24 hours, preferably in the range of 1 hour to 12 hours, and more preferably in the range of 2 hours to 6 hours.
  • Compound (III) can be isolated according to a usual method.
  • the reaction solvent is a mixed solvent of ethanol and N, N-dimethylformamide
  • water can be added to the reaction end solution. It precipitates as a solid and can be isolated by filtration.
  • the amount of water added is in the range where the moisture content is 10% to 90%, preferably in the range where the moisture content is 20% to 50%, and more preferably, the moisture content is 30% to 40%. It is a range.
  • Compound (III) is prepared by dissolving crude compound (III) obtained in the step of reacting compound (I) and compound (II) in a solvent, adding activated carbon and stirring. After the activated carbon is filtered off, a thiourea derivative is added, washed with an aqueous citric acid solution, precipitated as a solid, and can be purified by filtration.
  • the solvent may be, for example, an ether solvent such as diethyl ether or tetrahydrofuran, a hydrocarbon solvent such as toluene, or an ester solvent such as ethyl acetate, preferably an ester solvent such as ethyl acetate.
  • a solvent and more preferably ethyl acetate.
  • the amount of the solvent used is in the range of 1 to 100 times the amount of compound (I), preferably in the range of 10 to 50 times the amount of compound (I), more preferably The amount is in the range of 20 to 25 times the amount of compound (I).
  • the activated carbon for example, activated carbon, Darco (Sigma Aldrich), special white birch (manufactured by Nihon Enviro Chemicals), purified white birch (manufactured by Nihon Enviro Chemicals), carborafin (manufactured by Nihon Enviro Chemicals), etc. can be used.
  • a special white birch is preferable.
  • the amount of the activated carbon used is in the range of 0.1% to 50% with respect to the compound (I), preferably in the range of 1% to 20% with respect to the compound (I), more preferably the compound (I). It is in the range of 5% to 10% with respect to I).
  • thiourea derivative for example, thiourea, 1,3-dimethylthiourea, 1,3-diethyl-2-thiourea and the like can be used, and 1,3-diethyl-2-thiourea is preferable.
  • the amount of thiourea derivative used is in the range of 0.1% to 50% with respect to compound (I), preferably in the range of 1% to 20% with respect to compound (I), and more preferably, It is in the range of 5% to 10% with respect to compound (I).
  • the concentration of the citric acid aqueous solution is in the range of 1% to saturated concentration, preferably in the range of 1% to 20%, and more preferably in the range of 2% to 10%.
  • the amount of citric acid aqueous solution used is in the range of 0.1 to 100 times the amount of Compound (I), preferably in the range of 1 to 10 times the amount of Compound (I). More preferably, it is in the range of 4 to 6 times the amount of compound (I).
  • Compound (III) can be isolated according to a usual method. For example, when both R 1 and R 2 are t-butoxycarbonyl groups, water is added after replacing the solvent with a hydrophilic solvent, and then precipitated as a solid. Can be separated.
  • the hydrophilic solvent for substitution include alcohol solvents such as methanol, ethanol and 2-propanol, and amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone.
  • Nitrile solvents such as acetonitrile, ketone solvents such as acetone, and the like, preferably amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, etc. More preferably, N-methyl-2-pyrrolidone is used.
  • the amount of the solvent after substitution with the hydrophilic solvent is in the range of 1 to 100 times the amount of the compound (I), preferably in the range of 3 to 10 times the amount of the compound (I). More preferably, it is in the range of 4 to 6 times the amount of compound (I).
  • the amount of water added is in the range where the moisture content is 10% to 90%, preferably in the range where the moisture content is 30% to 70%, and more preferably, the moisture content is 45% to 55%. It is a range. 5) Method for producing compound (V)
  • Compound (V) can be obtained by chlorinating compound (III) with a chlorinating agent and concentrated hydrochloric acid in a solvent. Further, an aqueous sodium sulfite solution may be used in the post-treatment.
  • a chlorinating agent for example, N-chlorosuccinimide, N-chlorophthalimide, thionyl chloride and the like can be used, and N-chlorosuccinimide is preferable.
  • the amount of chlorinating agent used is in the range of 1 to 10 equivalents relative to compound (III), preferably in the range of 1 to 5 equivalents relative to compound (III), and more preferably Is in the range of 1.9 to 2.1 equivalents relative to compound (III).
  • the amount of concentrated hydrochloric acid used is in the range of 0.0001 to 0.1 times the amount of compound (III), preferably 0.001 to 0.05 times the amount of compound (III). More preferably, it is in the range of 0.005 to 0.01 times the amount of compound (III).
  • the solvent include alcohol solvents such as methanol, ethanol and 2-propanol, amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone, diethyl ether, tetrahydrofuran and the like.
  • Ether solvents such as acetonitrile, hydrocarbon solvents such as toluene, ester solvents such as ethyl acetate, ketone solvents such as acetone, etc., preferably nitrile solvents such as acetonitrile More preferably, it is acetonitrile.
  • the amount of solvent used is in the range of 1 to 100 times the amount of compound (III), preferably in the range of 5 to 20 times the amount of compound (III), more preferably The amount is in the range of 8 times to 12 times the amount of compound (III).
  • the reaction temperature is in the range of 0 ° C. to the boiling point of the solvent used, preferably in the range of 0 ° C.
  • the reaction time is in the range of 30 minutes to 24 hours, preferably in the range of 1 hour to 12 hours, and more preferably in the range of 2 hours to 6 hours.
  • the concentration of the sodium sulfite aqueous solution is in the range of 1% to saturated concentration, preferably in the range of 1% to 20%, and particularly preferably in the range of 5% to 15%.
  • the amount of sodium sulfite aqueous solution used is, for example, in the range of 0.1 to 100 times the amount of compound (III), preferably in the range of 1 to 10 times the amount of compound (III). More preferably, it is in the range of 1 to 3 times the amount of compound (III).
  • Compound (V) can be isolated according to a usual method. For example, when both R 1 and R 2 are t-butoxycarbonyl groups and the reaction solvent is acetonitrile, it is precipitated as a solid by adding water to the reaction end solution, and this is collected by filtration. Can be isolated. The amount of water added is in the range where the moisture content is 10% to 90%, preferably in the range where the moisture content is 30% to 70%, and more preferably, the moisture content is 45% to 55%. It is a range. 6) Method for producing compound (VI)
  • Compound (VI) can be obtained by reacting compound (V) with an appropriate reagent for removing R 1 and R 2 in a solvent to deprotect the amino group.
  • Suitable reagents for removing R 1 and R 2 are selected with reference to, for example, Protective Groups in Organic Synthesis (TW Greene and PMGM Wuts, John Wiley & Sons, Inc.). can do.
  • R 1 and R 2 are t-butoxycarbonyl groups, examples thereof include inorganic acids such as hydrogen chloride and sulfuric acid, organic acids such as methanesulfonic acid and p-toluenesulfonic acid, and the like.
  • an inorganic acid such as sulfuric acid is more preferable, and hydrogen chloride is more preferable.
  • the amount of the reagent used for removing R 1 and R 2 is in the range of 1 equivalent to 100 equivalents relative to compound (V), preferably 1 equivalent relative to compound (V).
  • the amount is in the range of 50 to 50 equivalents, and more preferably in the range of 5 to 10 equivalents with respect to compound (V).
  • an organic solvent solution of hydrogen chloride may be used, and its concentration ranges from 0.1 N to a saturated concentration, preferably 1 The range is from normal to saturated concentration, and more preferably from 1 normal to 3 normal.
  • the solvent examples include alcohol solvents such as methanol, ethanol and 2-propanol, amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone, diethyl ether, tetrahydrofuran and the like.
  • Ether solvents nitrile solvents such as acetonitrile, hydrocarbon solvents such as toluene, ester solvents such as ethyl acetate, ketone solvents such as acetone, and the like.
  • alcohol solvents such as methanol, ethanol and 2-propanol are preferable, and methanol is more preferable.
  • the amount of solvent used is in the range of 1 to 100 times the amount of compound (V), preferably in the range of 3 to 12 times the amount of compound (V), more preferably The amount is in the range of 5 to 7 times the amount of compound (V).
  • the reaction temperature ranges from 0 ° C. to the boiling point of the solvent used, preferably from 50 ° C. to the boiling point of the solvent used, more preferably from 50 ° C. to 70 ° C.
  • the reaction time is in the range of 30 minutes to 24 hours, preferably in the range of 1 hour to 12 hours, and more preferably in the range of 4 hours to 8 hours.
  • Compound (VI) can be isolated according to a usual method. For example, when the reaction solvent is methanol, hydrogen chloride can be used as a reagent for removing R 1 and R 2 , so that it can be precipitated as a hydrochloride solid after completion of the reaction. It can be isolated as a salt. 7) Method for producing compound (VII)
  • Compound (VII) can be obtained by reacting compound (VI) with (R) -2-methylpiperazine in a solvent.
  • the amount of (R) -2-methylpiperazine used is in the range of 2 to 20 equivalents relative to compound (VI), preferably 2 to 10 equivalents relative to compound (VI). More preferably, it is in the range of 2 to 5 equivalents with respect to compound (VI).
  • (R) -2-methylpiperazine may be used in the form of a solid, or (R) -2-methylpiperazine solution prepared by dissolving in various solvents may be used.
  • Solvents for preparing the (R) -2-methylpiperazine solution include, for example, alcohol solvents such as methanol, ethanol, 2-propanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl- Amide solvents such as 2-pyrrolidone, ether solvents such as diethyl ether and tetrahydrofuran, nitrile solvents such as acetonitrile, hydrocarbon solvents such as toluene, ester solvents such as ethyl acetate, ketone solvents such as acetone, and Water or the like can be used, and alcohol solvents such as methanol, ethanol and 2-propanol are preferable, and methanol is more preferable.
  • alcohol solvents such as methanol, ethanol and 2-propanol
  • N-methyl- Amide solvents such as 2-pyrrolidone
  • the concentration of the (R) -2-methylpiperazine solution to be prepared is in the range of 10% to 90%, preferably in the range of 30% to 70%, more preferably in the range of 40% to 60%. is there.
  • the solvent include alcohol solvents such as methanol, ethanol and 2-propanol, amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone, diethyl ether, tetrahydrofuran and the like.
  • Ether solvents nitrile solvents such as acetonitrile, hydrocarbon solvents such as toluene, ester solvents such as ethyl acetate, ketone solvents such as acetone, etc., preferably N, N-dimethylformamide N, N-dimethylacetamide, N-methyl-2-pyrrolidone and the like, more preferably N-methyl-2-pyrrolidone.
  • the amount of solvent used is in the range of 1 to 100 times the amount of compound (VI), preferably in the range of 2 to 8 times the amount of compound (VI), more preferably The amount is in the range of 3 to 5 times the amount of compound (VI).
  • the reaction temperature ranges from 0 ° C.
  • reaction time is in the range of 30 minutes to 24 hours, preferably in the range of 1 hour to 12 hours, and more preferably in the range of 2 hours to 8 hours.
  • Compound (VII) can be isolated according to a usual method. For example, when the reaction solvent is N-methyl-2-pyrrolidone, it can be isolated as a solid by adding water to the reaction-terminated liquid, and isolated by filtration. The amount of water added is in the range where the moisture content is 10% to 90%, preferably in the range where the moisture content is 60% to 90%, and more preferably, the moisture content is 75% to 85%. It is a range. 8) Production method 1 of compound (VIII)
  • Compound (VIII) can be obtained by introducing an acetyl group into the amino group of compound (VII).
  • the acetyl group introduction reaction to the amino group of compound (VII) is carried out by allowing an acetyl group introduction reagent and a base to act in a solvent.
  • the acetyl group introduction reagent include acetyl chloride and acetic anhydride, and acetic anhydride is preferable.
  • the amount of the acetyl group introduction reagent used is in the range of 1 equivalent to 10 equivalents relative to compound (VII), preferably in the range of 1 equivalent to 2 equivalents relative to compound (VII).
  • Bases include, for example, tertiary amines such as triethylamine, N, N-diisopropylethylamine, organic bases such as sodium ethoxide, t-butoxypotassium, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium acetate, potassium hydroxide, Inorganic bases such as potassium carbonate, potassium hydrogen carbonate, and potassium acetate can be used.
  • tertiary amines such as triethylamine and N, N-diisopropylethylamine, and more preferred is triethylamine.
  • the amount of the base used is in the range of 1 equivalent to 10 equivalents relative to compound (VII), preferably in the range of 1 equivalent to 2 equivalents relative to compound (VII), more preferably It is in the range of 1.5 equivalents to 1.7 equivalents relative to compound (VII).
  • the solvent examples include amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, ether solvents such as diethyl ether and tetrahydrofuran, nitrile solvents such as acetonitrile, toluene Inert solvents such as hydrocarbon solvents such as ethyl acetate, ester solvents such as ethyl acetate, ketone solvents such as acetone, and the like, preferably ethers such as diethyl ether and tetrahydrofuran An ether solvent such as a solvent, and more preferably tetrahydrofuran.
  • amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone
  • ether solvents such as diethyl ether and tetrahydrofuran
  • nitrile solvents such as
  • the amount of solvent used is in the range of 1 to 100 times the amount of compound (VII), preferably in the range of 4 to 16 times the amount of compound (VII), more preferably The amount is in the range of 6 to 10 times the amount of compound (VII).
  • the reaction temperature is in the range of 0 ° C. to the boiling point of the solvent used, preferably in the range of 0 ° C. to 50 ° C., more preferably in the range of 10 ° C. to 30 ° C.
  • the reaction time is in the range of 30 minutes to 24 hours, preferably in the range of 30 minutes to 6 hours, and more preferably in the range of 30 minutes to 4 hours.
  • the reaction solvent is tetrahydrofuran
  • the compound (VIII) is precipitated as a solid at the end of the reaction, but can be dissolved by adding water and heating. Purification can be performed by filtration.
  • the amount of water added is in the range where the moisture content is 10% to 90%, preferably in the range where the moisture content is 30% to 70%, and more preferably, the moisture content is 45% to 55%. It is a range.
  • the temperature at the time of dissolution is from 0 ° C. to the boiling point of the solvent used, preferably from 40 ° C. to the boiling point of the solvent used, more preferably from 40 ° C. to 60 ° C.
  • Compound (VIII) can be isolated according to a usual method.
  • Compound (VIII) can be obtained by reacting compound (VI) with (2R) -1-acetyl-2-methylpiperazine in a solvent.
  • the amount of (2R) -1-acetyl-2-methylpiperazine used is in the range of 2 to 20 equivalents relative to compound (VI), preferably 2 equivalents to compound (VI). It is in the range of 10 equivalents, and more preferably in the range of 2 equivalents to 5 equivalents with respect to compound (VI).
  • (2R) -1-acetyl-2-methylpiperazine can be purchased from, for example, AKos Consulting and Solutions GmbH.
  • the solvent examples include alcohol solvents such as methanol, ethanol and 2-propanol, amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone, diethyl ether, tetrahydrofuran and the like.
  • Ether solvents nitrile solvents such as acetonitrile, hydrocarbon solvents such as toluene, ester solvents such as ethyl acetate, ketone solvents such as acetone, etc., preferably N, N-dimethylformamide N, N-dimethylacetamide, N-methyl-2-pyrrolidone and the like, more preferably N-methyl-2-pyrrolidone.
  • the amount of solvent used is in the range of 1 to 100 times the amount of compound (VI), preferably in the range of 2 to 8 times the amount of compound (VI), more preferably The amount is in the range of 3 to 5 times the amount of compound (VI).
  • the reaction temperature ranges from 0 ° C. to the boiling point of the solvent used, preferably from 50 ° C. to the boiling point of the solvent used, and more preferably from 90 ° C. to 130 ° C.
  • the reaction time is in the range of 30 minutes to 24 hours, preferably in the range of 1 hour to 12 hours, and more preferably in the range of 2 hours to 8 hours.
  • Method for converting crystal form of compound (VIII) The crystal form of compound (VIII) can be converted by heating in a solvent.
  • the solvent for example, ethyl acetate, a mixed solvent of ethyl acetate and acetonitrile, and the like can be used, and the ratio of ethyl acetate in the case of using a mixed solvent of ethyl acetate and acetonitrile is in the range of 10% to 99%, preferably Is in the range of 50% to 99%, more preferably in the range of 70% to 90%.
  • the heating temperature is in the range of 0 ° C. to the boiling point of the solvent used, preferably 50 ° C. to the boiling point of the solvent used, more preferably in the range of 50 ° C. to 70 ° C.
  • the heating time is in the range of 30 minutes to 24 hours, preferably in the range of 1 hour to 12 hours, and more preferably in the range of 5 hours to 9 hours.
  • the solvent is ethyl acetate or a mixed solvent of ethyl acetate and acetonitrile
  • the compound (VIII) is precipitated as crystals after heating, and can be isolated by filtration. .
  • N, N-dimethylacetamide (1,500 mL) to 5-bromopyrimidin-2-amine (150 g, 862 mmol), di-tert-butyl dicarbonate (564 g, 2,584 mmol), and N, N-dimethyl-4- Aminopyridine (10.5 g, 85.9 mmol) was added and stirred at room temperature overnight. Water (2,250 mL) was added dropwise, and after stirring for 2.5 hours, the precipitated solid was collected by filtration and washed with a mixture of N, N-dimethylacetamide / water 2/3 (750 mL) and water (750 mL). .
  • 2,6-Dichloropurine (100 g, 529 mmol) and triethylamine (88.5 mL, 635 mmol) were added to N, N-dimethylacetamide (920 mL) and heated to 50 ° C.
  • Morpholine (47.7 mL, 545 mmol) was added dropwise with stirring, washed with N, N-dimethylacetamide (20 mL), and stirred at 50 ° C. for 1 hour.
  • Powdered potassium carbonate (139 g, 1,006 mmol) was added, washed with N, N-dimethylacetamide (40 mL) and heated to 60 ° C.
  • Trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester (83.9 mL, 582 mmol) was added dropwise with stirring over 2 hours, washed with N, N-dimethylacetamide (20 mL), and at 60 ° C. for 2 hours. Stir. After cooling to room temperature, water (2,500 mL) was added dropwise, and after stirring overnight at room temperature, the precipitated solid was collected by filtration and washed with water (500 mL). The obtained solid was dried to give the title compound (158 g, 92.9%) as a white solid.
  • the crude title compound (3.40 g) was added to a mixture of ethyl acetate (30 mL) and acetonitrile (10 mL), heated to 60 ° C. and stirred for 1 hour.
  • the crude title compound (3.30 g) was added, washed with ethyl acetate (5 mL), and stirred at 60 ° C. for 1 hour.

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Abstract

L'invention concerne un procédé novateur et présentant une utilité industrielle qui permet de produire un dérivé de morpholinopurine doté d'une excellente activité antitumorale et des intermédiaires synthétiques dudit dérivé. Selon l'invention, on utilise une 2, 6-dichloropurine comme produit de départ, on provoque une réaction au moyen d'un acide 2-(N, N-di-tert-butoxycarbonylamino)pyrimidine-5-boronique, on procède à une déprotection et on provoque une réaction de substitution pour obtenir ensuite un dérivé de morpholinopurine, c'est-à-dire un composé cible. (Dans la formule, R1 et R2 représentent chacun indépendamment un substituant choisi dans le groupe composé de l'hydrogène, de groupes C1-C6 alcoxycarbonyle, et de groupes benzyloxycarbonyle, avec la réserve que R1 et R2 ne représentent pas simultanément l'hydrogène.)
PCT/JP2014/062557 2013-05-13 2014-05-12 Procédé de production de dérivé de morpholinopurine Ceased WO2014185367A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108187666A (zh) * 2018-01-23 2018-06-22 杭州卢普生物科技有限公司 生物质衍生钯催化剂的制备及在抗肿瘤药物奥西替尼合成中的应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010509429A (ja) * 2006-11-07 2010-03-25 エルジー・ケム・リミテッド 高分子溶液内の残留触媒の除去方法およびこれによって精製された高分子
WO2010044401A1 (fr) * 2008-10-14 2010-04-22 第一三共株式会社 Dérivé de morpholinopurine
JP2011521968A (ja) * 2008-05-30 2011-07-28 ジェネンテック， インコーポレイテッド プリンｐｉ３ｋ阻害剤化合物および使用方法
JP2011236198A (ja) * 2010-04-13 2011-11-24 Daiichi Sankyo Co Ltd モルホリノプリン誘導体
WO2012082997A1 (fr) * 2010-12-16 2012-06-21 F. Hoffmann-La-Roche Ag Composés tricycliques inhibiteurs de pi3k et procédés d'utilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010509429A (ja) * 2006-11-07 2010-03-25 エルジー・ケム・リミテッド 高分子溶液内の残留触媒の除去方法およびこれによって精製された高分子
JP2011521968A (ja) * 2008-05-30 2011-07-28 ジェネンテック， インコーポレイテッド プリンｐｉ３ｋ阻害剤化合物および使用方法
WO2010044401A1 (fr) * 2008-10-14 2010-04-22 第一三共株式会社 Dérivé de morpholinopurine
JP2011236198A (ja) * 2010-04-13 2011-11-24 Daiichi Sankyo Co Ltd モルホリノプリン誘導体
WO2012082997A1 (fr) * 2010-12-16 2012-06-21 F. Hoffmann-La-Roche Ag Composés tricycliques inhibiteurs de pi3k et procédés d'utilisation

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108187666A (zh) * 2018-01-23 2018-06-22 杭州卢普生物科技有限公司 生物质衍生钯催化剂的制备及在抗肿瘤药物奥西替尼合成中的应用
CN108187666B (zh) * 2018-01-23 2020-11-17 杭州卢普生物科技有限公司 生物质衍生钯催化剂的制备及在抗肿瘤药物奥西替尼合成中的应用

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