WO2014185367A1 - Morpholinopurine-derivative production method - Google Patents

Morpholinopurine-derivative production method 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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compound
range
formula
compound represented
acceptable salt
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PCT/JP2014/062557
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French (fr)
Japanese (ja)
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倫明 川原
雄一郎 谷
文克 近藤
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第一三共株式会社
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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.

Abstract

The present invention provides a novel and industrially useful method for producing: a morpholinopurine derivative exhibiting excellent antitumor activity; and synthetic intermediates of said derivative. 2, 6-dichloropurine is used as a starting material, a reaction using 2-(N, N-di-tert-butoxycarbonylamino)pyrimidine-5-boronic acid is induced, and deprotection and a substitution reaction are performed to subsequently obtain a morpholinopurine derivative, i.e. a target compound. (In the formula, R1 and R2 each independently represent a substituent selected from the group consisting of hydrogen, C1-C6 alkoxycarbonyl groups, and benzyloxycarbonyl groups, with the caveat that R1 and R2 do not simultaneously represent hydrogen.)

Description

モルホリノプリン誘導体の製造方法Method for producing morpholinopurine derivative
　本発明は、ホスファチジルイノシトール３キナーゼ（Ｐｈｏｓｐｈａｔｉｄｙｌｉｎｏｓｉｔｏｌ　３－ｋｉｎａｓｅ：ＰＩ３Ｋ）および／またはＭａｍｍａｌｉａｎ　ｔａｒｇｅｔ　ｏｆ　ｒａｐａｍｙｃｉｎ（ｍＴＯＲ）阻害活性を有する化合物の製造方法、その合成中間体の製造方法、及び新規合成中間体に関する。 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.
　モルホリノプリン誘導体は、医薬あるいはその製造原料として有用であり、腫瘍の治療に有用であることが知られている（特許文献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 (Patent Document 1).
　当該特許文献の実施例５９において、５－｛８－［（３Ｒ）－４－アセチル－３－メチルピペラジン－１－イル］－６－モルホリン－４－イル－９－（２，２，２－トリフルオロエチル）－９Ｈ－プリン－２－イル｝ピリミジン－２－アミン（本明細書において式（ＶＩＩＩ）で示される化合物）、及びその製造方法が開示されている。 In 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.
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
特許文献１において、５－［６－モルホリン－４－イル－９－（２，２，２－トリフルオロエチル）－９Ｈ－プリン－２－イル］ピリミジン－２－アミン（本明細書において式（ＩＩＩ）で示される化合物）も開示されている。特許文献１中、式（ＩＩＩ）で示される化合物は、２－クロロ－６－モルホリン－４－イル－９－（２，２，２－トリフルオロエチル）－９Ｈ－プリン（本明細書において式（Ｉ）で示される化合物）を出発物質として、テトラキストリフェニルホスフィンパラジウム存在下、５－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）ピリミジン－２－アミンとカップリング反応を行った後に、ｔｅｒｔ－ブトキシカルボニル基を作用させて、２工程を経て合成されている。また、特許文献１中には、カラムクロマトグラフィー以外に、化合物の精製方法についての開示はされていない。 In 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. In 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.
ＷＯ２０１００４４４０１WO2010044401
本発明は、優れた抗腫瘍活性を有するモルホリノプリン誘導体、及びその合成中間体について、工業的に有用で新規な製造方法を提供するものである。 The present invention provides an industrially useful and novel production method for morpholinopurine derivatives having excellent antitumor activity and synthetic intermediates thereof.
本発明は、次の（１）～（１５）に関する。
（１）パラジウム触媒存在下、
式（Ｉ）で示される化合物： The present invention relates to the following (1) to (15).
(1) In the presence of a palladium catalyst,
Compound represented by formula (I):
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
を式（ＩＩ）で示される化合物：  A compound of formula (II):
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
と反応させ、
式（ＩＩＩ）で示される化合物またはその薬理上許容される塩：  React with
Compound represented by formula (III) or a pharmacologically acceptable salt thereof:
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
を製造する方法。
［式（ＩＩ）および式（ＩＩＩ）中、Ｒ１およびＲ２は、それぞれ独立に、水素原子、Ｃ１－Ｃ６アルコキシカルボニル基、およびベンジルオキシカルボニル基からなる群より選ばれる置換基を示す。ただし、Ｒ１およびＲ２は、同時に水素原子を示さない。］
（２）上記式（ＩＩ）および上記式（ＩＩＩ）において、Ｒ１およびＲ２のいずれもが、ｔｅｒｔ－ブトキシカルボニル基である（１）に記載の製造方法。
（３）パラジウム触媒が、酢酸パラジウム、及びトリフェニルホスフィンから調製される触媒である、（１）もしくは（２）に記載の製造方法。
（４）上記式（Ｉ）で示される化合物が、
式（ＩＶ）で示される化合物： How to manufacture.
[In Formula (II) and Formula (III), 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. ]
(2) The production method according to (1), wherein in the formula (II) and the formula (III), both R 1 and R 2 are a tert-butoxycarbonyl group.
(3) The production method according to (1) or (2), wherein the palladium catalyst is a catalyst prepared from palladium acetate and triphenylphosphine.
(4) The compound represented by the above formula (I) is
Compound represented by formula (IV):
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
に、モルホリンを添加し、次いでトリフルオロメタンスルホン酸２，２，２－トリフルオロエチルエステルを添加して製造されたものである、（１）乃至（３）のいずれか１つに記載の製造方法。
（５）（１）乃至（４）のいずれか１つに記載の製造方法を用いて製造された、上記式（ＩＩＩ）で示される化合物またはその薬理上許容される塩を、
塩素化剤と反応させ、式（Ｖ）で示される化合物またはその薬理上許容される塩： The production method according to any one of (1) to (3), which is produced by adding morpholine to trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester .
(5) A compound represented by the above formula (III) or a pharmacologically acceptable salt thereof produced using the production method according to any one of (1) to (4),
A compound represented by formula (V) or a pharmacologically acceptable salt thereof by reacting with a chlorinating agent:
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
を製造し、
脱保護を行い、
式（ＶＩ）で示される化合物またはその薬理上許容される塩： Manufacture and
Deprotect,
Compound represented by formula (VI) or a pharmacologically acceptable salt thereof:
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
を製造し、
（Ｒ）－２－メチルピペラジンと反応させ、式（ＶＩＩ）で示される化合物またはその薬理上許容される塩： Manufacture and
(R) -2-Methylpiperazine, a compound represented by the formula (VII) or a pharmacologically acceptable salt thereof:
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
を製造し、次いで、
アセチル化を行うことによる、式（ＶＩＩＩ）で示される化合物またはその薬理上許容される塩： And then
A compound represented by formula (VIII) or a pharmacologically acceptable salt thereof by carrying out acetylation:
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
の製造方法。
（６）（１）乃至（４）のいずれか１つに記載の製造方法を用いて製造された、上記式（ＩＩＩ）で示される化合物またはその薬理上許容される塩を、
塩素化剤と反応させ、上記式（Ｖ）で示される化合物またはその薬理上許容される塩を製造し、脱保護を行い、上記式（ＶＩ）で示される化合物またはその薬理上許容される塩を製造し、（２Ｒ）－１－アセチル－２－メチルピペラジンと反応させることによる、上記式（ＶＩＩＩ）で示される化合物またはその薬理上許容される塩の製造方法。
（７）上記式（ＶＩ）で示される化合物の薬理上許容される塩が、塩酸塩である、（５）もしくは（６）に記載の製造方法。
（８）塩素化剤が、Ｎ－クロロコハク酸イミド及び塩酸である、（５）乃至（７）のいずれか１つに記載の製造方法。
（９）（１）乃至（４）のいずれか１つに記載の製造方法を用いて製造された、上記式（ＩＩＩ）で示される化合物またはその薬理上許容される塩の精製方法であって、上記式（ＩＩＩ）で示される化合物またはその薬理上許容される塩の溶液に、チオ尿素誘導体を添加することを特徴とする精製方法。
（１０）チオ尿素誘導体が、１，３－ジエチルー２－チオ尿素である、（９）に記載の精製方法。
（１１）（９）もしくは（１０）に記載の精製方法であって、更に活性炭を添加することを特徴とする精製方法。
（１２）上記式（ＩＩ）において、Ｒ１およびＲ２のいずれもが、ｔｅｒｔ－ブトキシカルボニル基である化合物。
（１３）（１）乃至（４）のいずれか１つに記載の製造方法を用いて製造された、上記式（ＩＩＩ）で示される化合物またはその薬理上許容される塩の精製方法であって、上記式（ＩＩＩ）で示される化合物またはその薬理上許容される塩の溶液に、活性炭を添加して攪拌し、
ｉ）活性炭をろ過し、
ｉｉ）チオ尿素誘導体を添加して攪拌し、
ｉｉｉ）酸性水溶液にて洗浄する
ことを含む精製方法。
（１４）チオ尿素誘導体が、１，３－ジエチルー２－チオ尿素である、（１３）に記載の精製方法。
（１５）酸性水溶液が、クエン酸水溶液である、（１３）もしくは（１４）に記載の精製方法。 Manufacturing method.
(6) A compound represented by the above formula (III) or a pharmacologically acceptable salt thereof, produced using the production method according to any one of (1) to (4),
Reaction with a chlorinating agent to produce a compound represented by the above formula (V) or a pharmacologically acceptable salt thereof, deprotection, and a compound represented by the above formula (VI) or a pharmacologically acceptable salt thereof And reacting with (2R) -1-acetyl-2-methylpiperazine to produce a compound represented by the above formula (VIII) or a pharmacologically acceptable salt thereof.
(7) The production method according to (5) or (6), wherein the pharmacologically acceptable salt of the compound represented by the formula (VI) is a hydrochloride.
(8) The production method according to any one of (5) to (7), wherein the chlorinating agent is N-chlorosuccinimide and hydrochloric acid.
(9) A method for purifying a compound represented by the above formula (III) or a pharmacologically acceptable salt thereof, which is produced using the production method according to any one of (1) to (4). A purification method comprising adding a thiourea derivative to a solution of the compound represented by the formula (III) or a pharmacologically acceptable salt thereof.
(10) The purification method according to (9), wherein the thiourea derivative is 1,3-diethyl-2-thiourea.
(11) The purification method according to (9) or (10), further comprising adding activated carbon.
(12) A compound wherein in the above formula (II), both R 1 and R 2 are a tert-butoxycarbonyl group.
(13) A method for purifying a compound represented by the above formula (III) or a pharmacologically acceptable salt thereof, which is produced using the production method according to any one of (1) to (4). Activated carbon is added to the solution of the compound represented by the above formula (III) or a pharmacologically acceptable salt thereof and stirred,
i) Filter the activated carbon,
ii) Add thiourea derivative and stir,
iii) A purification method comprising washing with an acidic aqueous solution.
(14) The purification method according to (13), wherein the thiourea derivative is 1,3-diethyl-2-thiourea.
(15) The purification method according to (13) or (14), wherein the acidic aqueous solution is a citric acid aqueous solution.
本発明により、優れた抗腫瘍活性を有するモルホリノプリン誘導体、及びその合成中間体について、工業的に有用で新規な製造方法を提供することができる。
本発明によれば、第一に、式（ＩＩＩ）で示される化合物を、式（ＩＩ）で示される化合物を用いたカップリング反応を行うことにより、式（Ｉ）で示される化合物から１工程にて、得ることができる。第二に、チオ尿素誘導体を用いた精製方法により、式（ＩＩＩ）で示される化合物中の残留パラジウム量を減らすことができ、結果、高純度で式（ＶＩＩＩ）で示される化合物を得ることができる。第三に、式（ＩＶ）で示される化合物から、式（ＶＩＩＩ）で示される化合物までの各製造工程において、カラムクロマトグラフィーを使用せずに製造が可能である。 INDUSTRIAL APPLICABILITY According to the present invention, an industrially useful and novel production method can be provided for morpholinopurine derivatives having excellent antitumor activity and synthetic intermediates thereof.
According to the present invention, firstly, 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. Second, 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. Third, 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.
本発明において、「Ｃ１－Ｃ６アルキルオキシカルボニル基」は、例えば、メトキシカルボニル基、エトキシカルボニル基、ｎ－プロポキシカルボニル基、イソプロポキシカルボニル基、ｔｅｒｔ－ブトキシカルボニル基、ペンチルオキシカルボニル基、イソペンチルオキシカルボニル基、またはヘキシルオキシカルボニル基等が挙げられる。
本発明において、「塩素化剤」とは、化合物に塩素原子を導入することが可能な試薬のことを言う。例えば、塩化水素、塩酸、メタンスルホニルクロリド、塩化チオニル、塩化りん、塩化オキサリル、またはＮ－クロロコハク酸イミド等が挙げられる。
本発明において、「パラジウム触媒」とは、２価のパラジウム触媒、または０価のパラジウム触媒のことを言う。例えば、テトラキス（トリフェニルホスフィン）パラジウム（０）等が挙げられる。
本発明の「パラジウム触媒」には、例えば、塩化パラジウム、酢酸パラジウム等のパラジウム化合物に、例えば、トリフェニルホスフィン、トリｔ－ブチルホスフィン等の単座配位型ホスフィン配位子、或いは１，１－ビス（ジフェニルホスフィノ）メタン、１，２－ビス（ジフェニルホスフィノ）エタン等の二座配位型ホスフィン配位子等を作用させて反応系内で調製し、パラジウム触媒としたものも含む。
本発明において、「チオ尿素誘導体」とは、尿素の酸素原子を硫黄原子に置き換えた部分構造を有する化合物のことを言う。例えばチオ尿素、１，３－ジフェニル－２－チオ尿素、１，３－ジエチル－２－チオ尿素、または１－イソプロピル－２－チオ尿素等が挙げられる。
次に、式（ＩＩ）で示される化合物、式（ＩＩＩ）で示される化合物、および式（Ｖ）で示される化合物の好適な置換基について説明する。
Ｒ１およびＲ２は、好適には、Ｒ１およびＲ２のいずれもが、Ｃ１－Ｃ６アルコキシカルボニル基である。より好適には、Ｒ１およびＲ２のいずれもが、ｔｅｒｔ－ブトキシカルボニル基である。
本発明の式（ＩＩＩ）で示される化合物、式（Ｖ）で示される化合物、式（ＶＩ）で示される化合物、式（ＶＩＩ）で示される化合物、および式（ＶＩＩＩ）で示される化合物は、酸と反応させることで薬理上許容される塩とすることができる。 In the present invention, “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.
In the present invention, the “chlorinating agent” refers to a reagent capable of introducing a chlorine atom into a compound. Examples thereof include hydrogen chloride, hydrochloric acid, methanesulfonyl chloride, thionyl chloride, phosphorus chloride, oxalyl chloride, N-chlorosuccinimide, and the like.
In the present invention, “palladium catalyst” means a divalent palladium catalyst or a zero-valent palladium catalyst. For example, 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.
In the present invention, the “thiourea derivative” refers to a compound having a partial structure in which the oxygen atom of urea is replaced with a sulfur atom. Examples thereof include thiourea, 1,3-diphenyl-2-thiourea, 1,3-diethyl-2-thiourea, 1-isopropyl-2-thiourea, and the like.
Next, a preferred substituent of the compound represented by the formula (II), the compound represented by the formula (III), and the compound represented by the formula (V) will be described.
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.
　薬理上許容される塩とは、著しい毒性を有さず、医薬として使用され得る塩をいう。 Pharmacologically acceptable salt refers to a salt that has no significant toxicity and can be used as a medicine.
　例えば、フッ化水素酸塩、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩のようなハロゲン化水素酸塩、硝酸塩、過塩素酸塩、硫酸塩、燐酸塩等の無機酸塩；メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩のようなＣ１－Ｃ６アルキルスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩のようなアリ－ルスルホン酸塩、酢酸塩、りんご酸塩、フマ－ル酸塩、コハク酸塩、クエン酸塩、アスコルビン酸塩、酒石酸塩、蓚酸塩、マレイン酸塩等の有機酸塩；及び、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩を挙げることができる。 For example, 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.
　本発明の、式（ＩＩＩ）で示される化合物またはその薬理上許容される塩、式（Ｖ）で示される化合物またはその薬理上許容される塩、式（ＶＩ）で示される化合物またはその薬理上許容される塩、式（ＶＩＩ）で示される化合物またはその薬理上許容される塩、および式（ＶＩＩＩ）で示される化合物またはその薬理上許容される塩は、大気中に放置したり、又は、再結晶したりすることにより、水分子を取り込んで、水和物となる場合があり、そのような水和物も塩に包含される。 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.
　本発明の、式（ＩＩＩ）で示される化合物またはその薬理上許容される塩、式（Ｖ）で示される化合物またはその薬理上許容される塩、式（ＶＩ）で示される化合物またはその薬理上許容される塩、式（ＶＩＩ）で示される化合物またはその薬理上許容される塩、および式（ＶＩＩＩ）で示される化合物またはその薬理上許容される塩は、溶媒中に放置されたり、又は、再結晶したりすることにより、ある種の溶媒を吸収し、溶媒和物となる場合があり、そのような溶媒和物も塩に包含される。
［製造法］
次に本発明について説明する。本発明の反応条件はこれらに限定して解釈されるべきではない。本発明では、化合物の官能基を適当な保護基で保護する場合がある。このような官能基としては、例えば水酸基、カルボキシ基、アミノ基等を挙げることができ、保護基の種類、並びにそれらの保護基の導入と除去の条件は、例えばＰｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ（Ｔ．Ｗ．Ｇｒｅｅｎ　ａｎｄ　Ｐ．Ｇ．Ｍ．Ｗｕｔｓ，Ｊｏｈｎ　Ｗｉｌｅｙ　＆　Ｓｏｎｓ，Ｉｎｃ．，Ｎｅｗ　Ｙｏｒｋ，２００６）に記載のものを参考にすることができる。 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.
[Production method]
Next, the present invention will be described. The reaction conditions of the present invention should not be construed as being limited thereto. In the present invention, the functional group of the compound may be protected with an appropriate protecting group. Examples of such 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.
　１）化合物（Ｉ）の製造方法 1) Method for producing compound (I)
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
化合物（Ｉ）は、化合物（ＩＶ）とモルホリンを反応させ、次いでトリフルオロメタンスルホン酸２,２,２-トリフルオロエチルエステルと反応させることにより得られる。
１－１）モルホリンとの反応
化合物（ＩＶ）とモルホリンの反応は、溶媒中で塩基を作用させて行う。
モルホリン使用量は、化合物（ＩＶ）に対して１等量～１０等量の範囲であり、好ましくは、化合物（ＩＶ）に対して１等量～２等量の範囲であり、より好ましくは、化合物（ＩＶ）に対して１．００等量～１．０５等量の範囲である。
塩基は、例えば、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン等の３級アミン、ナトリウムエトキシド、ｔ－ブトキシカリウム等の有機塩基、水酸化ナトリウム、炭酸ナトリウム、炭酸水素ナトリウム、酢酸ナトリウム、水酸化カリウム、炭酸カリウム、炭酸水素カリウム、酢酸カリウム等の無機塩基等を用いることができ、好ましくは、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン等の３級アミンであり、より好ましくは、トリエチルアミンである。
塩基使用量は、化合物（ＩＶ）に対して１等量～１０等量の範囲であり、好ましくは、化合物（ＩＶ）に対して１等量～２等量の範囲であり、より好ましくは、化合物（ＩＶ）に対して１．１等量～１．３等量の範囲である。
溶媒は、例えば、メタノール、エタノール、２－プロパノール等のアルコール系溶媒、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン等のアミド系溶媒、ジエチルエーテル、テトラヒドロフラン等のエーテル系溶媒、アセトニトリル等のニトリル系溶媒、トルエン等の炭化水素系溶媒等のモルホリンに対して不活性なものを用いることができ、好ましくは、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン等のアミド系溶媒であり、より好ましくは、Ｎ，Ｎ－ジメチルアセトアミドである。
溶媒使用量は、化合物（ＩＶ）に対して１倍量～１００倍量の範囲であり、好ましくは、化合物（ＩＶ）に対して５倍量～２０倍量の範囲であり、より好ましくは、化合物（ＩＶ）に対して８倍量～１２倍量の範囲である。
反応温度は、０℃～使用溶媒の沸点の範囲であり、好ましくは、４０℃～使用溶媒の沸点の範囲であり、より好ましくは、４０℃～６０℃の範囲である。
反応時間は、３０分～２４時間の範囲であり、好ましくは、３０分～６時間の範囲であり、より好ましくは、３０分～３時間の範囲である。
１－２）トリフルオロメタンスルホン酸２,２,２-トリフルオロエチルエステルとの反応
トリフルオロメタンスルホン酸２,２,２-トリフルオロエチルエステルとの反応は、化合物(ＩＶ)とモルホリンの反応終了液に塩基、及びトリフルオロメタンスルホン酸２,２,２-トリフルオロエチルエステルを作用させて行う。
塩基は、例えば、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン等の３級アミン、ナトリウムエトキシド、ｔ－ブトキシカリウム等の有機塩基、水酸化ナトリウム、炭酸ナトリウム、炭酸水素ナトリウム、酢酸ナトリウム、水酸化カリウム、炭酸カリウム、炭酸水素カリウム、酢酸カリウム等の無機塩基等を用いることができ、好ましくは、水酸化ナトリウム、炭酸ナトリウム、炭酸水素ナトリウム、酢酸ナトリウム、水酸化カリウム、炭酸カリウム、炭酸水素カリウム、酢酸カリウム等の無機塩基であり、より好ましくは、炭酸カリウムである。
塩基使用量は、化合物（ＩＶ）に対して１等量～１０等量の範囲であり、好ましくは、化合物（ＩＶ）に対して１等量～５等量の範囲であり、より好ましくは、化合物（ＩＶ）に対して１．８等量～２．０等量の範囲である。
トリフルオロメタンスルホン酸２,２,２-トリフルオロエチルエステルの使用量は、化合物（ＩＶ）に対して１等量～１０等量の範囲であり、好ましくは、化合物（ＩＶ）に対して１等量～２等量の範囲であり、より好ましくは、化合物（ＩＶ）に対して１．０等量～１．２等量の範囲である。
反応温度は、０℃～使用溶媒の沸点の範囲であり、好ましくは、５０℃～使用溶媒の沸点の範囲であり、より好ましくは、５０℃～７０℃の範囲である。
反応時間は、３０分～２４時間の範囲であり、好ましくは、３０分～６時間の範囲であり、より好ましくは、３０分～４時間の範囲である。
化合物（Ｉ）は、通常の方法に従って単離することができる。例えば、反応溶媒がＮ，Ｎ－ジメチルアセトアミドである場合には、反応終了液に水を添加することで固体として析出させ、これを濾取することにより単離することができる。
水添加量は、含水率が１０％～９０％になる範囲であり、好ましくは、含水率が５０％～９０％になる範囲であり、より好ましくは、含水率が６５％～７５％になる範囲である。
２）化合物（ＩＩ）の製造方法 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. Preferred are 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).
Examples of 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. 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.
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 3 hours.
1-2) Reaction with trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester 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.
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. 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 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)
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
化合物（ＩＩ）は、５－ブロモピリミジン－２－アミンのアミノ基にＣ１－Ｃ６アルコキシカルボニル基、またはベンジルオキシカルボニル基を導入して化合物（ＩＩ’）とし、次いで化合物（ＩＩ’）のブロモ基をジヒドロキシボリル基に変換することで得られる。
２－１）保護基導入反応
５－ブロモピリミジン－２－アミンのアミノ基へのＣ１－Ｃ６アルコキシカルボニル基、またはベンジルオキシカルボニル基の導入反応は、溶媒中塩基存在下、Ｒ１およびＲ２に該当するＣ１－Ｃ６アルコキシカルボニル基導入試薬、またはベンジルオキシカルボニル基導入試薬を作用させて行う。
Ｃ１－Ｃ６アルコキシカルボニル基は、好ましくは、ｔ－ブトキシカルボニル基である。
Ｃ１－Ｃ６アルコキシカルボニル基導入試薬、及びベンジルオキシカルボニル基導入試薬は、例えば、二炭酸ジ－ｔ－ブチル等の二炭酸ジエステル、クロロギ酸ベンジル等のクロロギ酸エステル等を用いることができ、Ｒ１およびＲ２のいずれもがｔ－ブトキシカルボニル基の場合には、好ましくは、二炭酸ジ－ｔ－ブチルである。
Ｃ１－Ｃ６アルコキシカルボニル基導入試薬使用量、またはベンジルオキシカルボニル基導入試薬使用量は、５－ブロモピリミジン－２－アミンに対して２等量～２０等量の範囲であり、好ましくは、５－ブロモピリミジン－２－アミンに対して２等量～５等量の範囲であり、より好ましくは、５－ブロモピリミジン－２－アミンに対して２．５等量～３．５等量の範囲である。
塩基は、例えば、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン等の３級アミン、ナトリウムエトキシド、ｔ－ブトキシカリウム等の有機塩基、水酸化ナトリウム、炭酸ナトリウム、炭酸水素ナトリウム、酢酸ナトリウム、水酸化カリウム、炭酸カリウム、炭酸水素カリウム、酢酸カリウム等の無機塩基等を用いることができ、アルコキシカルボニル系保護基導入試薬として二炭酸ジエステルを用いる場合には、Ｎ，Ｎ－ジメチル－４－アミノピリジンを触媒として用いる方が好ましい。
塩基使用量は、５－ブロモピリミジン－２－アミンに対して２等量～２０等量の範囲であり、Ｎ，Ｎ－ジメチル－４－アミノピリジンを触媒として用いる場合は、５－ブロモピリミジン－２－アミンに対して０．０１ｍｏｌ％～５０ｍｏｌ％の範囲であり、好ましくは５－ブロモピリミジン－２－アミンに対して１ｍｏｌ％～２０ｍｏｌ％の範囲であり、より好ましくは、５－ブロモピリミジン－２－アミンに対して５ｍｏｌ％～１５ｍｏｌ％の範囲である。
溶媒は、例えば、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン等のアミド系溶媒、ジエチルエーテル、テトラヒドロフラン等のエーテル系溶媒、アセトニトリル等のニトリル系溶媒、トルエン等の炭化水素系溶媒、酢酸エチル等のエステル系溶媒、アセトン等のケトン系溶媒等のアルコキシカルボニル系保護基導入試薬に対して不活性なものを用いることができ、好ましくは、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン等のアミド系溶媒であり、より好ましくは、Ｎ，Ｎ－ジメチルアセトアミドである。
溶媒使用量は、５－ブロモピリミジン－２－アミンに対して１倍量～１００倍量の範囲であり、好ましくは、５－ブロモピリミジン－２－アミンに対して５倍量～２０倍量の範囲であり、より好ましくは、５－ブロモピリミジン－２－アミンに対して８倍量～１２倍量の範囲である。
反応温度は、０℃～使用溶媒の沸点の範囲であり、好ましくは、０℃～５０℃の範囲であり、より好ましくは、１０℃～３０℃の範囲である。
反応時間は、１時間～４８時間の範囲であり、好ましくは、１時間～２４時間の範囲であり、より好ましくは、１２時間～２４時間の範囲である。
化合物（ＩＩ’）は、通常の方法に従って単離することができる。例えば、Ｒ１及びＲ２のいずれもががｔ－ブトキシカルボニル基であり、反応溶媒がＮ，Ｎ－ジメチルアセトアミドである場合には、反応終了液に水を添加することで固体として析出させ、これを濾取することにより単離することができる。
水添加量は、含水率が１０％～９０％になる範囲であり、好ましくは、含水率が４０％～８０％になる範囲であり、より好ましくは、含水率が５５％～６５％になる範囲である。
２－２）ボロン酸導入反応
化合物（ＩＩ’）のブロモ基のジヒドロキシボリル基への変換反応は、窒素、アルゴン等の不活性ガス雰囲気下、溶媒中でビス（ピナコラト）ジボロン、パラジウム触媒、及び塩基を作用させてホウ酸エステルとし、次いで、水を作用させてホウ酸エステルを加水分解することで行う。
ビス（ピナコラト）ジボロン使用量は、化合物（ＩＩ’）に対して１等量～１０等量の範囲であり、好ましくは、化合物（ＩＩ’）に対して１等量～２等量の範囲であり、より好ましくは、化合物（ＩＩ’）に対して１．０等量～１．２等量の範囲である。
パラジウム触媒は、例えば、テトラキス（トリフェニルホスフィン）パラジウム等を用いても良く、また、例えば、塩化パラジウム、酢酸パラジウム等のパラジウム化合物に、例えば、トリフェニルホスフィン、トリｔ－ブチルホスフィン等の単座配位型ホスフィン配位子、或いは、１，１－ビス（ジフェニルホスフィノ）メタン、１，２－ビス（ジフェニルホスフィノ）エタン等の二座配位型ホスフィン配位子等を作用させて反応系内で調製しても良い。
パラジウム触媒使用量は、化合物（ＩＩ’）に対して０．０１ｍｏｌ％～５０ｍｏｌ％の範囲であり、好ましくは、化合物（ＩＩ’）に対して０．１ｍｏｌ％～１０ｍｏｌ％の範囲であり、より好ましくは、化合物（ＩＩ’）に対して０．５ｍｏｌ％～２ｍｏｌ％の範囲である。
パラジウム触媒を反応系内で調製する場合、パラジウム化合物は酢酸パラジウムが好ましく、ホスフィン配位子はトリフェニルホスフィンが好ましい。
パラジウム化合物の使用量は、化合物（ＩＩ’）に対して０．０１ｍｏｌ％～５０ｍｏｌ％の範囲であり、好ましくは化合物（ＩＩ’）に対して０．１ｍｏｌ％～１０ｍｏｌ％の範囲であり、より好ましくは、化合物（ＩＩ’）に対して０．５ｍｏｌ％～２ｍｏｌ％の範囲である。
ホスフィン配位子の使用量は、単座配位型ホスフィン配位子の場合は、パラジウム化合物に対して１等量～１０等量の範囲であり、好ましくは、パラジウム化合物に対して１等量～５等量の範囲であり、より好ましくは、パラジウム化合物に対して１等量～３等量の範囲である。二座配位型ホスフィン配位子の場合は、パラジウム化合物に対して０．５等量～５等量の範囲であり、好ましくは、パラジウム化合物に対して０．５等量～２．５等量の範囲であり、より好ましくは、パラジウム化合物に対して０．５等量～１．５等量の範囲である。
塩基は、例えば、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン等の３級アミン、ナトリウムエトキシド、ｔ－ブトキシカリウム等の有機塩基、水酸化ナトリウム、炭酸ナトリウム、炭酸水素ナトリウム、酢酸ナトリウム、水酸化カリウム、炭酸カリウム、炭酸水素カリウム、酢酸カリウム等の無機塩基等を用いることができ、好ましくは、水酸化ナトリウム、炭酸ナトリウム、炭酸水素ナトリウム、酢酸ナトリウム、水酸化カリウム、炭酸カリウム、炭酸水素カリウム、酢酸カリウム等の無機塩基であり、より好ましくは、酢酸カリウムである。
塩基使用量は、化合物（ＩＩ’）に対して１等量～１０等量の範囲であり、好ましくは、化合物（ＩＩ’）に対して２等量～５等量の範囲であり、より好ましくは、化合物（ＩＩ’）に対して２．５等量～３．５等量の範囲である。
溶媒は、例えば、メタノール、エタノール、２－プロパノール等のアルコール系溶媒、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン等のアミド系溶媒、ジエチルエーテル、テトラヒドロフラン等のエーテル系溶媒、アセトニトリル等のニトリル系溶媒、トルエン等の炭化水素系溶媒、酢酸エチル等のエステル系溶媒、アセトン等のケトン系溶媒等を用いることができ、好ましくは、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン等のアミド系溶媒であり、より好ましくは、Ｎ，Ｎ－ジメチルアセトアミドである。
溶媒使用量は、化合物（ＩＩ’）に対して１倍量～１００倍量の範囲であり、好ましくは、化合物（ＩＩ’）に対して３倍量～１０倍量の範囲であり、より好ましくは、化合物（ＩＩ’）に対して４倍量～６倍量の範囲である。
反応温度は、０℃～使用溶媒の沸点の範囲であり、好ましくは、５０℃～使用溶媒の沸点の範囲であり、より好ましくは、７０℃～９０℃の範囲である。
反応時間は、３０分～２４時間の範囲であり、好ましくは、１時間～１２時間の範囲であり、より好ましくは、２時間～６時間の範囲である。
化合物（ＩＩ）は、通常の方法に従って単離することができる。例えば、Ｒ１及びＲ２のいずれもがｔ－ブトキシカルボニル基であり、反応溶媒がＮ，Ｎ－ジメチルアセトアミドである場合には、反応終了液に水を添加することでホウ酸エステルを加水分解して固体として析出させ、これを濾取することで単離することができる。
水添加量は、含水率が１０％～９０％になる範囲であり、好ましくは、含水率が６０％～９０％になる範囲であり、より好ましくは、含水率が７０％～８０％になる範囲である。
２－３）化合物（ＩＩ）の精製
化合物（ＩＩ）は、５－ブロモピリミジン－２－アミンから化合物（ＩＩ）を製造する工程で得られる粗体の化合物（ＩＩ）を溶媒に溶解させ、活性炭を添加して撹拌し、活性炭を濾去した後に固体として析出させ、これを濾取することにより精製することができる。
活性炭は、例えば、アクティベーテッドカーボン,ダルコ（シグマアルドリッチ）、特製白鷺（日本エンバイロケミカルズ社製）、精製白鷺（日本エンバイロケミカルズ社製）、カルボラフィン（日本エンバイロケミカルズ社製）等を用いることができ、好ましくは、特製白鷺である。
活性炭使用量は、化合物（ＩＩ’）に対して０．１％～１００％の範囲であり、好ましくは、化合物（ＩＩ’）に対して１％～５０％の範囲であり、より好ましくは、化合物（ＩＩ’）に対して５％～２０％の範囲である。
溶媒は、例えば、メタノール、エタノール、２－プロパノール等のアルコール系溶媒、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン等のアミド系溶媒、ジエチルエーテル、テトラヒドロフラン等のエーテル系溶媒、アセトニトリル等のニトリル系溶媒、トルエン等の炭化水素系溶媒、酢酸エチル等のエステル系溶媒、アセトン等のケトン系溶媒等を用いることができ、好ましくは、メタノール、エタノール、２－プロパノール等のアルコール系溶媒であり、より好ましくは、２－プロパノールである。
溶媒使用量は、化合物（ＩＩ’）に対して１倍量～１００倍量の範囲であり、好ましくは、化合物（ＩＩ’）に対して５倍量～２０倍量の範囲であり、より好ましくは、化合物（ＩＩ’）に対して１０倍量～１５倍量の範囲である。
化合物（ＩＩ）は、通常の方法に従って単離することができる。例えば、Ｒ１、及びＲ２のいずれもがｔ－ブトキシカルボニル基であり、溶媒が２－プロパノールである場合には、水を添加することで固体として析出させ、これを濾取することで単離することができる。
水添加量は、含水率が１０％～９０％になる範囲であり、好ましくは、含水率が５０％～８０％になる範囲であり、より好ましくは、含水率が６０％～７０％になる範囲である。
３）化合物（ＩＩＩ）の製造方法 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.
2-1) Protecting group introduction reaction 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.
As the 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. When both 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. When dicarbonate diester is used as a reagent for introducing an alkoxycarbonyl protecting group, N, N-dimethyl-4-aminopyridine is used as a catalyst. It is preferable to use it.
The amount of base used is in the range of 2 to 20 equivalents relative to 5-bromopyrimidin-2-amine. When N, N-dimethyl-4-aminopyridine is used as a catalyst, 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.
Examples of the solvent 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. Preferably, 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.
2-2) Conversion reaction of boronic acid-introducing reaction compound (II ′) to bromo group to dihydroxyboryl group is carried out in the presence of nitrogen, argon, or other inert gas atmosphere in a solvent with bis (pinacolato) diboron, palladium catalyst, and The reaction is carried out by reacting a base to form a borate ester and then hydrolyzing the borate ester by acting water.
The amount of bis (pinacolato) diboron used is in the range of 1 equivalent to 10 equivalents relative to compound (II ′), preferably in the range of 1 equivalent to 2 equivalents relative to compound (II ′). More preferably, it is in the range of 1.0 equivalent to 1.2 equivalents relative to compound (II ′).
As the palladium catalyst, for example, tetrakis (triphenylphosphine) palladium or the like may be used. For example, 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 ′).
When 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 ′).
In the case of a monodentate coordination type phosphine ligand, 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. In the case of a bidentate phosphine ligand, 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 ′).
Examples of 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. to the boiling point of the solvent used, preferably from 50 ° C. to the boiling point of the solvent used, more preferably from 70 ° C. to 90 ° 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 (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.
As 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 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 ′).
Examples of 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, 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)
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
化合物（ＩＩＩ）は、化合物（Ｉ）と化合物（ＩＩ）を窒素、アルゴン等の不活性ガス雰囲気下、溶媒中でパラジウム触媒、及び塩基を作用させて反応させることにより得られる。
化合物（ＩＩ）の使用量は、化合物（Ｉ）に対して１等量～１０等量の範囲であり、好ましくは、化合物（Ｉ）に対して１等量～２等量の範囲であり、より好ましくは、化合物（Ｉ）に対して１．０等量～１．２等量である。
パラジウム触媒は、例えば、テトラキス（トリフェニルホスフィン）パラジウム等を用いても良く、また、例えば、塩化パラジウム、酢酸パラジウム等のパラジウム化合物に、例えば、トリフェニルホスフィン、トリｔ－ブチルホスフィン等の単座配位型ホスフィン配位子、或いは１，１－ビス（ジフェニルホスフィノ）メタン、１，２－ビス（ジフェニルホスフィノ）エタン等の二座配位型ホスフィン配位子等を作用させて反応系内で調製しても良い。
パラジウム触媒使用量は、化合物（Ｉ）に対して０．０１ｍｏｌ％～５０ｍｏｌ％の範囲であり、好ましくは化合物（Ｉ）に対して０．１ｍｏｌ％～１０ｍｏｌ％の範囲であり、より好ましくは、化合物（Ｉ）に対して０．５ｍｏｌ％～２ｍｏｌ％の範囲である。
パラジウム触媒を反応系内で調製する場合、パラジウム化合物は酢酸パラジウムが好ましく、ホスフィン配位子はトリフェニルホスフィンが好ましい。
パラジウム化合物の使用量は、化合物（Ｉ）に対して０．０１ｍｏｌ％～５０ｍｏｌ％の範囲であり、好ましくは、化合物（Ｉ）に対して０．１ｍｏｌ％～１０ｍｏｌ％の範囲であり、より好ましくは、（Ｉ）に対して０．５ｍｏｌ％～２ｍｏｌ％の範囲である。
ホスフィン配位子の使用量は、単座配位型ホスフィン配位子の場合は、パラジウム化合物に対して１等量～１０等量の範囲であり、好ましくは、パラジウム化合物に対して１等量～５等量の範囲であり、より好ましくは、パラジウム化合物に対して１等量～３等量の範囲である。二座配位型ホスフィン配位子の場合は、パラジウム化合物に対して０．５等量～５等量の範囲であり、好ましくは、パラジウム化合物に対して０．５等量～２．５等量の範囲であり、より好ましくは、パラジウム化合物に対して０．５等量～１．５等量の範囲である。
塩基は、例えば、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン等の３級アミン、ナトリウムエトキシド、ｔ－ブトキシカリウム等の有機塩基、水酸化ナトリウム、炭酸ナトリウム、炭酸水素ナトリウム、酢酸ナトリウム、水酸化カリウム、炭酸カリウム、炭酸水素カリウム、酢酸カリウム等の無機塩基等を用いることができ、好ましくは、水酸化ナトリウム、炭酸ナトリウム、炭酸水素ナトリウム、酢酸ナトリウム、水酸化カリウム、炭酸カリウム、炭酸水素カリウム、酢酸カリウム等の無機塩基であり、より好ましくは、炭酸水素カリウムである。
塩基使用量は、化合物（Ｉ）に対して１等量～１０等量の範囲であり、好ましくは、化合物（Ｉ）に対して１等量～５等量の範囲であり、より好ましくは、化合物（Ｉ）に対して１．９等量～２．１等量の範囲である。
溶媒は、プロトン性溶媒、或いはプロトン性溶媒と非プロトン性溶媒の混合溶媒を用いることができる。
プロトン性溶媒は、メタノール、エタノール、２－プロパノール等のアルコール系溶媒、及び水を用いることができ、好ましくは、メタノール、エタノール、２－プロパノール等のアルコール系溶媒であり、より好ましくは、エタノールである。
非プロトン性溶媒は、例えば、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン等のアミド系溶媒、ジエチルエーテル、テトラヒドロフラン等のエーテル系溶媒、アセトニトリル等のニトリル系溶媒、トルエン等の炭化水素系溶媒、酢酸エチル等のエステル系溶媒、アセトン等のケトン系溶媒等を用いることができ、好ましくは、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン等のアミド系溶媒であり、より好ましくは、Ｎ，Ｎ－ジメチルホルムアミドである。
プロトン性溶媒と非プロトン性溶媒の混合溶媒を用いる場合のプロトン性溶媒の比率は、１０％～９９％の範囲であり、好ましくは、５０％～９９％の範囲であり、より好ましくは、７０％～９０％の範囲である。
溶媒使用量は、化合物（Ｉ）に対して１倍量～１００倍量の範囲であり、好ましくは、化合物（Ｉ）に対して５倍量～２０倍量の範囲であり、より好ましくは、化合物（Ｉ）に対して８倍量～１２倍量の範囲である。
反応温度は、０℃～使用溶媒の沸点の範囲であり、好ましくは、５０℃～使用溶媒の沸点の範囲であり、より好ましくは、６０℃～８０℃の範囲である。
反応時間は、３０分～２４時間の範囲であり、好ましくは、１時間～１２時間の範囲であり、より好ましくは、２時間～６時間の範囲である。
化合物（ＩＩＩ）は、通常の方法に従って単離することができる。例えば、Ｒ１、及びＲ２のいずれもがｔ－ブトキシカルボニル基であり、反応溶媒がエタノールとＮ，Ｎ－ジメチルホルムアミドの混合溶媒である場合には、反応終了液に水を添加することで固体として析出させ、これを濾取することで単離することができる。
水添加量は、含水率が１０％～９０％になる範囲であり、好ましくは、含水率が２０％～５０％になる範囲であり、より好ましくは、含水率が３０％～４０％になる範囲である。
４）化合物（ＩＩＩ）の精製方法
化合物（ＩＩＩ）は、化合物（Ｉ）と化合物（ＩＩ）を作用させる工程で得られる粗体の化合物（ＩＩＩ）を溶媒に溶解させ、活性炭を添加して撹拌し、活性炭を濾去した後にチオ尿素誘導体を添加し、クエン酸水溶液で洗浄した後に固体として析出させ、これを濾取することにより精製することができる。
溶媒は、例えば、ジエチルエーテル、テトラヒドロフラン等のエーテル系溶媒、トルエン等の炭化水素系溶媒、酢酸エチル等のエステル系溶媒等の疎水性溶媒を用いることができ、好ましくは、酢酸エチル等のエステル系溶媒であり、より好ましくは、酢酸エチルである。
溶媒使用量は、化合物（Ｉ）に対して１倍量～１００倍量の範囲であり、好ましくは、化合物（Ｉ）に対して１０倍量～５０倍量の範囲であり、より好ましくは、化合物（Ｉ）に対して２０倍量～２５倍量の範囲である。
活性炭は、例えば、アクティベーテッドカーボン,ダルコ（シグマアルドリッチ）、特製白鷺（日本エンバイロケミカルズ社製）、精製白鷺（日本エンバイロケミカルズ社製）、カルボラフィン（日本エンバイロケミカルズ社製）等を用いることができ、好ましくは、特製白鷺である。
活性炭使用量は、化合物（Ｉ）に対して０．１％～５０％の範囲であり、好ましくは、化合物（Ｉ）に対して１％～２０％の範囲であり、より好ましくは、化合物（Ｉ）に対して５％～１０％の範囲である。
チオ尿素誘導体は、例えば、チオ尿素、１，３－ジメチルチオ尿素、１，３－ジエチル－２－チオ尿素等を用いることができ、好ましくは、１，３－ジエチル－２－チオ尿素である。
チオ尿素誘導体使用量は、化合物（Ｉ）に対して０．１％～５０％の範囲であり、好ましくは、化合物（Ｉ）に対して１％～２０％の範囲であり、より好ましくは、化合物（Ｉ）に対して５％～１０％の範囲である。
クエン酸水溶液濃度は、１％～飽和濃度の範囲であり、好ましくは、１％～２０％の範囲であり、より好ましくは、２％～１０％の範囲である。
クエン酸水溶液使用量は、化合物（Ｉ）に対して０．１倍量～１００倍量の範囲であり、好ましくは、化合物（Ｉ）に対して１倍量～１０倍量の範囲であり、より好ましくは、化合物（Ｉ）に対して４倍量～６倍量の範囲である。
なお、チオ尿素誘導体での処理とクエン酸水溶液での洗浄を繰り返すことで、残留パラジウムを更に削減させることができる。
化合物（ＩＩＩ）は、通常の方法に従って単離することができる。例えば、Ｒ１及びＲ２のいずれもがｔ－ブトキシカルボニル基である場合には、溶媒を親水性溶媒に置換した後に水を添加することで固体として析出させ、これを濾取することで単離することができる。
置換する際の親水性溶媒は、例えば、メタノール、エタノール、２－プロパノール等のアルコール系溶媒、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン等のアミド系溶媒、アセトニトリル等のニトリル系溶媒、アセトン等のケトン系溶媒等を用いることができ、好ましくは、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン等のアミド系溶媒であり、より好ましくは、Ｎ－メチル－２－ピロリドンである。
親水性溶媒に置換した後の溶媒量は、化合物（Ｉ）に対して１倍量～１００倍量の範囲であり、好ましくは、化合物（Ｉ）に対して３倍量～１０倍量の範囲であり、より好ましくは、化合物（Ｉ）に対して４倍量～６倍量の範囲である。
水添加量は、含水率が１０％～９０％になる範囲であり、好ましくは、含水率が３０％～７０％になる範囲であり、より好ましくは、含水率が４５％～５５％になる範囲である。
５）化合物（Ｖ）の製造方法 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).
As the palladium catalyst, for example, tetrakis (triphenylphosphine) palladium or the like may be used. For example, a monodentate such as triphenylphosphine or trit-butylphosphine may be combined with a palladium compound such as palladium chloride or palladium acetate. In the reaction system, 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). It is in the range of 0.5 mol% to 2 mol% with respect to compound (I).
When 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 (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).
In the case of a monodentate coordination type phosphine ligand, 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. In the case of a bidentate phosphine ligand, 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).
As the solvent, a protic solvent or a mixed solvent of a protic solvent and an aprotic solvent can be used.
As 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.
Examples of the aprotic solvent 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.
When a mixed solvent of a protic solvent and an aprotic solvent is used, 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. For example, when both R 1 and R 2 are t-butoxycarbonyl groups and 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.
4) Purification method of compound (III) 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).
As 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).
As the 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).
Note that residual palladium can be further reduced by repeating the treatment with the thiourea derivative and the washing with the aqueous citric acid solution.
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.
Examples of 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)
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
化合物（Ｖ）は、化合物（ＩＩＩ）に溶媒中で塩素化剤、及び濃塩酸を作用させて塩素化することにより得られる。また、後処理の際に、亜硫酸ナトリウム水溶液を用いても良い。
塩素化剤は、例えば、Ｎ－クロロコハク酸イミド、Ｎ－クロロフタル酸イミド、塩化チオニル等を用いることができ、好ましくは、Ｎ－クロロコハク酸イミドである。
塩素化剤使用量は、化合物（ＩＩＩ）に対して１等量～１０等量の範囲であり、好ましくは、化合物（ＩＩＩ）に対して１等量～５等量の範囲であり、より好ましくは、化合物（ＩＩＩ）に対して１．９等量～２．１等量の範囲である。
濃塩酸使用量は、化合物（ＩＩＩ）に対して０．０００１倍量～０．１倍量の範囲であり、好ましくは、化合物（ＩＩＩ）に対して０．００１倍量～０．０５倍量の範囲であり、より好ましくは、化合物（ＩＩＩ）に対して０．００５倍量～０．０１倍量の範囲である。
溶媒は、例えば、メタノール、エタノール、２－プロパノール等のアルコール系溶媒、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン等のアミド系溶媒、ジエチルエーテル、テトラヒドロフラン等のエーテル系溶媒、アセトニトリル等のニトリル系溶媒、トルエン等の炭化水素系溶媒、酢酸エチル等のエステル系溶媒、アセトン等のケトン系溶媒等を用いることができ、好ましくは、アセトニトリル等のニトリル系溶媒であり、より好ましくは、アセトニトリルである。
溶媒使用量は、化合物（ＩＩＩ）に対して１倍量～１００倍量の範囲であり、好ましくは、化合物（ＩＩＩ）に対して５倍量～２０倍量の範囲であり、より好ましくは、化合物（ＩＩＩ）に対して８倍量～１２倍量の範囲である。
反応温度は、０℃～使用溶媒の沸点の範囲であり、好ましくは、０℃～５０℃の範囲であり、より好ましくは、２５℃～３０℃の範囲である。
反応時間は、３０分～２４時間の範囲であり、好ましくは、１時間～１２時間の範囲であり、より好ましくは、２時間～６時間の範囲である。
亜硫酸ナトリウム水溶液濃度は、１％～飽和濃度の範囲、好ましくは１％～２０％の範囲であり、５％～１５％の範囲が特に好ましい。
亜硫酸ナトリウム水溶液使用量は、例えば化合物（ＩＩＩ）に対して０．１倍量～１００倍量の範囲であり、好ましくは、化合物（ＩＩＩ）に対して１倍量～１０倍量の範囲であり、より好ましくは、化合物（ＩＩＩ）に対して１倍量～３倍量の範囲である。
化合物（Ｖ）は、通常の方法に従って単離することができる。例えば、Ｒ１、及びＲ２のいずれもがｔ－ブトキシカルボニル基であり、反応溶媒がアセトニトリルである場合には、反応終了液に水を添加することで固体として析出させ、これを濾取することで単離することができる。
水添加量は、含水率が１０％～９０％になる範囲であり、好ましくは、含水率が３０％～７０％になる範囲であり、より好ましくは、含水率が４５％～５５％になる範囲である。
６）化合物（ＶＩ）の製造方法 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.
As the 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).
Examples of 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 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. to 50 ° C., and more preferably in the range of 25 ° C. to 30 ° 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)
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
化合物（ＶＩ）は、化合物（Ｖ）に溶媒中で、Ｒ１及びＲ２を除去するのに適切な試薬を作用させ、アミノ基の脱保護を行うことにより得られる。
Ｒ１及びＲ２を除去するのに適切な試薬は、例えばＰｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ（Ｔ．Ｗ．Ｇｒｅｅｎｅ　ａｎｄ　Ｐ．Ｇ．Ｍ．Ｗｕｔｓ，Ｊｏｈｎ　Ｗｉｌｅｙ　＆　ｓｏｎｓ，Ｉｎｃ．）等を参考にして選択することができる。Ｒ１及びＲ２のいずれもがｔ－ブトキシカルボニル基の場合には、例えば、塩化水素、硫酸等の無機酸、メタンスルホン酸、ｐ－トルエンスルホン酸等の有機酸等が挙げられ、塩化水素、好ましくは、硫酸等の無機酸が、より好ましくは、塩化水素である。
Ｒ１、及びＲ２を除去するのに適切な試薬の使用量は、化合物（Ｖ）に対して１等量～１００等量の範囲であり、好ましくは、化合物（Ｖ）に対して１等量～５０等量の範囲であり、より好ましくは、化合物（Ｖ）に対して５等量～１０等量の範囲である。Ｒ１、及びＲ２を除去する試薬として塩化水素を用いる場合は、塩化水素の有機溶媒溶液を用いても良く、その濃度は、０．１規定～飽和濃度の範囲であり、好ましくは、１規定～飽和濃度の範囲であり、より好ましくは、１規定～３規定の範囲である。
溶媒は、例えば、メタノール、エタノール、２－プロパノール等のアルコール系溶媒、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン等のアミド系溶媒、ジエチルエーテル、テトラヒドロフラン等のエーテル系溶媒、アセトニトリル等のニトリル系溶媒、トルエン等の炭化水素系溶媒、酢酸エチル等のエステル系溶媒、アセトン等のケトン系溶媒等を用いることができる。Ｒ１及びＲ２を除去する試薬として塩化水素を用いる場合は、好ましくは、メタノール、エタノール、２－プロパノール等のアルコール系溶媒であり、より好ましくは、メタノールである。
溶媒使用量は、化合物（Ｖ）に対して１倍量～１００倍量の範囲であり、好ましくは、化合物（Ｖ）に対して３倍量～１２倍量の範囲であり、より好ましくは、化合物（Ｖ）に対して５倍量～７倍量の範囲である。
反応温度は、０℃～使用溶媒の沸点の範囲であり、好ましくは、５０℃～使用溶媒の沸点の範囲であり、より好ましくは、５０℃～７０℃の範囲である。
反応時間は、３０分～２４時間の範囲であり、好ましくは、１時間～１２時間の範囲であり、より好ましくは、４時間～８時間の範囲である。
化合物（ＶＩ）は、通常の方法に従って単離することができる。例えば、反応溶媒がメタノールである場合には、Ｒ１及びＲ２を除去する試薬として塩化水素を用いることで反応終了後に塩酸塩の固体として析出させることができ、これを濾取することで塩酸塩として単離することができる。
７）化合物（ＶＩＩ）の製造方法 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. When both 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. Preferably, 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). When hydrogen chloride is used as a reagent for removing R 1 and R 2 , 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.
Examples of 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, and the like. When hydrogen chloride is used as a reagent for removing R 1 and R 2 , 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)
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
化合物（ＶＩＩ）は、化合物（ＶＩ）と（Ｒ）－２－メチルピペラジンを溶媒中で反応させることにより得られる。
（Ｒ）－２－メチルピペラジンの使用量は、化合物（ＶＩ）に対して２等量～２０等量の範囲であり、好ましくは、化合物（ＶＩ）に対して２等量～１０等量の範囲であり、より好ましくは、化合物（ＶＩ）に対して２等量～５等量の範囲である。
（Ｒ）－２－メチルピペラジンは固体状のものを用いても良く、各種溶媒に溶解させて調製した（Ｒ）－２－メチルピペラジン溶液を用いても良い。（Ｒ）－２－メチルピペラジン溶液を調製する場合の溶媒は、例えば、メタノール、エタノール、２－プロパノール等のアルコール系溶媒、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン等のアミド系溶媒、ジエチルエーテル、テトラヒドロフラン等のエーテル系溶媒、アセトニトリル等のニトリル系溶媒、トルエン等の炭化水素系溶媒、酢酸エチル等のエステル系溶媒、アセトン等のケトン系溶媒、及び水等を用いることができ、好ましくは、メタノール、エタノール、２－プロパノール等のアルコール系溶媒であり、より好ましくは、メタノールである。
調製する（Ｒ）－２－メチルピペラジン溶液の濃度は、１０％～９０％の範囲であり、好ましくは、３０％～７０％の範囲であり、より好ましくは、４０％～６０％の範囲である。
溶媒は、例えば、メタノール、エタノール、２－プロパノール等のアルコール系溶媒、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン等のアミド系溶媒、ジエチルエーテル、テトラヒドロフラン等のエーテル系溶媒、アセトニトリル等のニトリル系溶媒、トルエン等の炭化水素系溶媒、酢酸エチル等のエステル系溶媒、アセトン等のケトン系溶媒等を用いることができ、好ましくは、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン等のアミド系溶媒であり、より好ましくは、Ｎ－メチル－２－ピロリドンである。
溶媒使用量は、化合物（ＶＩ）に対して１倍量～１００倍量の範囲であり、好ましくは、化合物（ＶＩ）に対して２倍量～８倍量の範囲であり、より好ましくは、化合物（ＶＩ）に対して３倍量～５倍量の範囲である。
反応温度は、０℃～使用溶媒の沸点の範囲であり、好ましくは、５０℃～使用溶媒の沸点の範囲であり、より好ましくは、９０℃～１３０℃の範囲である。
反応時間は、３０分～２４時間の範囲であり、好ましくは、１時間～１２時間の範囲であり、より好ましくは、２時間～８時間の範囲である。
化合物（ＶＩＩ）は、通常の方法に従って単離することができる。例えば、反応溶媒がＮ－メチル－２－ピロリドンである場合には、反応終了液に水を添加することで固体として析出させ、これを濾取することで単離することができる。
水添加量は、含水率が１０％～９０％になる範囲であり、好ましくは、含水率が６０％～９０％になる範囲であり、より好ましくは、含水率が７５％～８５％になる範囲である。
８）化合物（ＶＩＩＩ）の製造方法１ 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.
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.
Examples of 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. 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.
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)
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
化合物（ＶＩＩＩ）は、化合物（ＶＩＩ）のアミノ基にアセチル基を導入することで得られる。
化合物（ＶＩＩ）のアミノ基へのアセチル基導入反応は、溶媒中でアセチル基導入試薬、及び塩基を作用させて行う。
アセチル基導入試薬は、例えば、塩化アセチル、無水酢酸等が挙げられ、好ましくは、無水酢酸である。
アセチル基導入試薬使用量は、化合物（ＶＩＩ）に対して１等量～１０等量の範囲であり、好ましくは、化合物（ＶＩＩ）に対して１等量～２等量の範囲であり、より好ましくは、化合物（ＶＩＩ）に対して１．２等量～１．４等量の範囲である。
塩基は、例えば、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン等の３級アミン、ナトリウムエトキシド、ｔ－ブトキシカリウム等の有機塩基、水酸化ナトリウム、炭酸ナトリウム、炭酸水素ナトリウム、酢酸ナトリウム、水酸化カリウム、炭酸カリウム、炭酸水素カリウム、酢酸カリウム等の無機塩基等を用いることができ、好ましくは、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン等の３級アミンであり、より好ましくは、トリエチルアミンである。
塩基使用量は、化合物（ＶＩＩ）に対して１等量～１０等量の範囲であり、好ましくは、化合物（ＶＩＩ）に対して１等量～２等量の範囲であり、より好ましくは、化合物（ＶＩＩ）に対して１．５等量～１．７等量の範囲である。
溶媒は、例えば、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン等のアミド系溶媒、ジエチルエーテル、テトラヒドロフラン等のエーテル系溶媒、アセトニトリル等のニトリル系溶媒、トルエン等の炭化水素系溶媒、酢酸エチル等のエステル系溶媒、アセトン等のケトン系溶媒等のアセチル基導入試薬に対して不活性なものを用いることができ、好ましくは、ジエチルエーテル、テトラヒドロフラン等のエーテル系溶媒等のエーテル系溶媒であり、より好ましくは、テトラヒドロフランである。
溶媒使用量は、化合物（ＶＩＩ）に対して１倍量～１００倍量の範囲であり、好ましくは、化合物（ＶＩＩ）に対して４倍量～１６倍量の範囲であり、より好ましくは、化合物（ＶＩＩ）に対して６倍量～１０倍量の範囲である。
反応温度は、０℃～使用溶媒の沸点の範囲であり、好ましくは、０℃～５０℃の範囲であり、より好ましくは、１０℃～３０℃の範囲である。
反応時間は、３０分～２４時間の範囲であり、好ましくは、３０分～６時間の範囲であり、より好ましくは、３０分～４時間の範囲である。
化合物（ＶＩＩＩ）は、例えば、反応溶媒がテトラヒドロフランである場合には、反応終了時に固体として析出しているが、水を添加して加熱することで溶解させることができ、この段階で不溶物を濾去することで精製を行うことができる。
水添加量は、含水率が１０％～９０％になる範囲であり、好ましくは、含水率が３０％～７０％になる範囲であり、より好ましくは、含水率が４５％～５５％になる範囲である。
溶解させる際の温度は、０℃～使用溶媒の沸点の範囲であり、好ましくは、４０℃～使用溶媒の沸点の範囲であり、より好ましくは、４０℃～６０℃の範囲である。
化合物（ＶＩＩＩ）は、通常の方法に従って単離することができる。例えば、含水テトラヒドロフランに溶解している場合には、水を更に添加することで結晶として析出させ、これを濾取することで単離することができる。
水添加量は、含水率が１０％～９０％になる範囲であり、好ましくは、含水率が５０％～９０％になる範囲であり、より好ましくは、含水率が６５％～７５％になる範囲である。
９）化合物（ＶＩＩＩ）の製造方法２ 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.
Examples of 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). Preferably, it is in the range of 1.2 equivalents to 1.4 equivalents with respect 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. Preferred are 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).
Examples of the solvent 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.
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.
For example, when 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. For example, when it is dissolved in hydrous tetrahydrofuran, it can be isolated by filtering it by adding water to precipitate as crystals.
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.
9) Production method 2 of compound (VIII)
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
化合物（ＶＩＩＩ）は、化合物（ＶＩ）と（２Ｒ）－１－アセチル－２－メチルピペラジンを溶媒中で反応させることにより得られる。
（２Ｒ）－１－アセチル－２－メチルピペラジンの使用量は、化合物（ＶＩ）に対して２等量～２０等量の範囲であり、好ましくは、化合物（ＶＩ）に対して２等量～１０等量の範囲であり、より好ましくは、化合物（ＶＩ）に対して２等量～５等量の範囲である。
（２Ｒ）－１－アセチル－２－メチルピペラジンは、例えば、ＡＫｏｓＣｏｎｓｕｌｔｉｎｇ　ａｎｄ　Ｓｏｌｕｔｉｏｎｓ　Ｄｅｕｔｓｃｈｌａｎｄ　ＧｍｂＨ等より購入することができる。
溶媒は、例えば、メタノール、エタノール、２－プロパノール等のアルコール系溶媒、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン等のアミド系溶媒、ジエチルエーテル、テトラヒドロフラン等のエーテル系溶媒、アセトニトリル等のニトリル系溶媒、トルエン等の炭化水素系溶媒、酢酸エチル等のエステル系溶媒、アセトン等のケトン系溶媒等を用いることができ、好ましくは、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン等のアミド系溶媒であり、より好ましくは、Ｎ－メチル－２－ピロリドンである。
溶媒使用量は、化合物（ＶＩ）に対して１倍量～１００倍量の範囲であり、好ましくは、化合物（ＶＩ）に対して２倍量～８倍量の範囲であり、より好ましくは、化合物（ＶＩ）に対して３倍量～５倍量の範囲である。
反応温度は、０℃～使用溶媒の沸点の範囲であり、好ましくは、５０℃～使用溶媒の沸点の範囲であり、より好ましくは、９０℃～１３０℃の範囲である。
反応時間は、３０分～２４時間の範囲であり、好ましくは、１時間～１２時間の範囲であり、より好ましくは、２時間～８時間の範囲である。
１０）化合物（ＶＩＩＩ）の結晶形の転換方法
化合物（ＶＩＩＩ）の結晶形の転換は、溶媒中で加熱することで行うことができる。
溶媒は、例えば、酢酸エチル、酢酸エチルとアセトニトリルの混合溶媒等を用いることができ、酢酸エチルとアセトニトリルの混合溶媒を用いる場合の酢酸エチルの比率は、１０％～９９％の範囲であり、好ましくは、５０％～９９％の範囲であり、より好ましくは、７０％～９０％の範囲である。
加熱温度は、０℃～使用溶媒の沸点の範囲であり、好ましくは、５０℃～使用溶媒の沸点の範囲であり、より好ましくは、５０℃～７０℃の範囲である。
加熱時間は、３０分～２４時間の範囲であり、好ましくは、１時間～１２時間の範囲であり、より好ましくは、５時間～９時間の範囲である。
化合物（ＶＩＩＩ）は、例えば、溶媒が酢酸エチル、酢酸エチルとアセトニトリルの混合溶媒である場合には、加熱終了後に結晶として析出しているため、これを濾取することで単離することができる。 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 Deutschland GmbH.
Examples of 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. 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.
10) Method for converting crystal form of compound (VIII) The crystal form of compound (VIII) can be converted by heating in a solvent.
As 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.
For example, when 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. .
　以下、実施例を挙げて、本発明をさらに詳細に説明するが、本発明の範囲はこれらに限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to examples, but the scope of the present invention is not limited thereto.
　原子吸光分光分析には、日立ハイテクノロジー社の日立偏光ゼーマン原子吸光光度計 Z-2710を用いた。尚、実施例で用いる略号は、次のような意義を有する。
mg : ミリグラム，g : グラム，ml: ミリリットル，L：リットル，MHz : メガヘルツ。 For the atomic absorption spectroscopic analysis, Hitachi Polarized Zeeman atomic absorption photometer Z-2710 of Hitachi High-Technology Corporation was used. The abbreviations used in the examples have the following significance.
mg: milligram, g: gram, ml: milliliter, L: liter, MHz: megahertz.
　以下の実施例において、核磁気共鳴（以下、1H NMR：４００ＭＨｚ)スペクトルは、テトラメチルシランを標準物質として、ケミカルシフト値をδ値(ppm)にて記載した。***パターンは一重線をs、二重線をd、三重線をt、四重線をq、多重線をm、ブロードをbrで示した。原子吸光分光分析結果は、濃度(ppm)にて記載した。
[実施例１]
ジ－ｔｅｒｔ－ブチル（５－ブロモピリミジン－２－イル）イミドジカーボネート In the following examples, nuclear magnetic resonance (hereinafter, 1 H NMR: 400 MHz) spectra are described with chemical shift values as δ values (ppm) using tetramethylsilane as a standard substance. The splitting pattern is indicated by s for single lines, d for double lines, t for triple lines, q for quadruple lines, m for multiple lines, and br for broad lines. The atomic absorption spectroscopic analysis results are shown in concentration (ppm).
[Example 1]
Di-tert-butyl (5-bromopyrimidin-2-yl) imide dicarbonate
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
Ｎ，Ｎ－ジメチルアセトアミド（１，５００ｍＬ）に５－ブロモピリミジン－２－アミン（１５０ｇ、８６２ｍｍｏｌ）、ジ－ｔｅｒｔ－ブチルジカーボネート（５６４ｇ、２，５８４ｍｍｏｌ）、及びＮ，Ｎ－ジメチル－４－アミノピリジン（１０．５ｇ、８５．９ｍｍｏｌ）を添加し、室温下で終夜撹拌した。水（２，２５０ｍＬ）を滴下し、２時間半撹拌した後に析出固体を濾取し、Ｎ，Ｎ－ジメチルアセトアミド／水＝２／３の混合液（７５０ｍＬ）、及び水（７５０ｍＬ）で洗浄した。取得固体を乾燥させ、標記化合物（３０３ｇ、９３．８％）を淡橙色固体として得た。
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ：１．４０（１８Ｈ，ｓ），９．０８（２Ｈ，ｓ）．
[実施例２]
２－（Ｎ，Ｎ－ジ－ｔｅｒｔ－ブトキシカルボニルアミノ）ピリミジン－５－ボロン酸 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). . The obtained solid was dried to give the title compound (303 g, 93.8%) as a pale orange solid.
1 H-NMR (DMSO-d 6 ) δ: 1.40 (18H, s), 9.08 (2H, s).
[Example 2]
2- (N, N-di-tert-butoxycarbonylamino) pyrimidine-5-boronic acid
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
Ｎ，Ｎ－ジメチルアセトアミド（９００ｍＬ）にジ－ｔｅｒｔ－ブチル（５－ブロモピリミジン－２－イル）イミドジカーボネート（１８０ｇ、４８１ｍｍｏｌ）、ビス（ピナコラト）ジボロン（１３４ｇ、５２８ｍｍｏｌ）、酢酸カリウム（１４２ｇ、１，４４７ｍｍｏｌ）、トリフェニルホスフィン（２．５２ｇ、９．６１ｍｍｏｌ）、及び酢酸パラジウム（１．０８ｇ、４．８１ｍｍｏｌ）を添加し、アルゴン雰囲気下８０℃で３時間半撹拌した。室温まで冷却して水（６３０ｍＬ）を滴下し、固体の析出を確認した後に更に水（２，０７０ｍＬ）を滴下した。１時間撹拌した後に析出固体を濾取し、Ｎ，Ｎ－ジメチルアセトアミド／水＝１／３の混合液（９００ｍＬ）、及び水（９００ｍＬ）で洗浄した。取得固体を乾燥させ、標記化合物の粗体（１８０ｇ）を淡褐色固体として得た。
２－プロパノール（５４６ｍＬ）に標記化合物の粗体（３９．７ｇ）、ＫＣ－フロック（８．４ｇ）、及び特製白鷺（４．２ｇ）を添加し、アルゴン雰囲気下室温で１時間撹拌した。不溶物を濾去して２－プロパノール（８４ｍＬ）で洗浄し、濾液と洗浄液を合わせて氷浴にて冷却した。水（１，１８０ｍＬ）を滴下し、２時間撹拌した後に析出固体を濾取し、２－プロパノール／水＝３／７の混合液（２１０ｍＬ）で洗浄した。取得固体を乾燥させ、標記化合物（３４．９ｇ、９１．６％）を乳白色固体として得た。
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６＋Ｈ２Ｏ）δ：１．４０（１８Ｈ，ｓ），８．８１（２Ｈ，ｂｒｓ），９．０２（２Ｈ，ｓ）．
 [実施例３]
２－クロロ－６－（モルホリン－４－イル）－９－（２，２，２－トリフルオロエチル）－９Ｈ－プリン N, N-dimethylacetamide (900 mL) to di-tert-butyl (5-bromopyrimidin-2-yl) imide dicarbonate (180 g, 481 mmol), bis (pinacolato) diboron (134 g, 528 mmol), potassium acetate (142 g, 1,447 mmol), triphenylphosphine (2.52 g, 9.61 mmol), and palladium acetate (1.08 g, 4.81 mmol) were added, and the mixture was stirred at 80 ° C. for 3 and a half hours under an argon atmosphere. After cooling to room temperature, water (630 mL) was added dropwise, and after confirming the precipitation of the solid, water (2,070 mL) was further added dropwise. After stirring for 1 hour, the precipitated solid was collected by filtration, and washed with a mixture of N, N-dimethylacetamide / water = 1/3 (900 mL) and water (900 mL). The obtained solid was dried to obtain a crude product of the title compound (180 g) as a light brown solid.
The crude product of the title compound (39.7 g), KC-Flock (8.4 g), and special white birch (4.2 g) were added to 2-propanol (546 mL), and the mixture was stirred at room temperature for 1 hour under an argon atmosphere. The insoluble material was removed by filtration and washed with 2-propanol (84 mL), and the filtrate and the washing solution were combined and cooled in an ice bath. Water (1,180 mL) was added dropwise, and after stirring for 2 hours, the precipitated solid was collected by filtration and washed with a mixed solution (210 mL) of 2-propanol / water = 3/7. The obtained solid was dried to give the title compound (34.9 g, 91.6%) as a milky white solid.
1 H-NMR (DMSO-d 6 + H 2 O) δ: 1.40 (18H, s), 8.81 (2H, brs), 9.02 (2H, s).
[Example 3]
2-Chloro-6- (morpholin-4-yl) -9- (2,2,2-trifluoroethyl) -9H-purine
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
Ｎ，Ｎ－ジメチルアセトアミド（９２０ｍＬ）に２，６－ジクロロプリン（１００ｇ、５２９ｍｍｏｌ）、及びトリエチルアミン（８８．５ｍＬ、６３５ｍｍｏｌ）を添加し、５０℃に加熱した。モルホリン（４７．７ｍＬ、５４５ｍｍｏｌ）を撹拌しながら滴下し、Ｎ，Ｎ－ジメチルアセトアミド（２０ｍＬ）で洗いこみ、５０℃で１時間撹拌した。粉末状炭酸カリウム（１３９ｇ、１，００６ｍｍｏｌ）を添加し、Ｎ，Ｎ－ジメチルアセトアミド（４０ｍＬ）で洗いこみ、６０℃に加熱した。トリフルオロメタンスルホン酸２，２，２－トリフルオロエチルエステル（８３．９ｍＬ、５８２ｍｍｏｌ）を撹拌しながら２時間かけて滴下し、Ｎ，Ｎ－ジメチルアセトアミド（２０ｍＬ）で洗いこみ、６０℃で２時間撹拌した。室温まで冷却して水（２，５００ｍＬ）を滴下し、室温で終夜撹拌した後に析出固体を濾取し、水（５００ｍＬ）で洗浄した。取得固体を乾燥させ、標記化合物（１５８ｇ、９２．９％）を白色固体として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ： ３．８０－３．８６（４Ｈ，ｍ），３．９５－４．６２（４Ｈ，ｍ），４．７７（２Ｈ，ｑ，Ｊ＝８．５Ｈｚ），７．７８（１Ｈ，ｓ）．
[実施例４]
ジ－ｔｅｒｔ－ブチル｛５－［６－（モルホリン－４－イル）－９－（２，２，２－トリフルオロエチル）－９Ｈ－プリン－２－イル］ピリミジン－２－イル｝イミドジカーボネート 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.
1 H-NMR (CDCl 3 ) δ: 3.80-3.86 (4H, m), 3.95-4.62 (4H, m), 4.77 (2H, q, J = 8.5 Hz) , 7.78 (1H, s).
[Example 4]
Di-tert-butyl {5- [6- (morpholin-4-yl) -9- (2,2,2-trifluoroethyl) -9H-purin-2-yl] pyrimidin-2-yl} imide dicarbonate
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
Ｎ，Ｎ－ジメチルアセトアミド（２００ｍＬ）とエタノール（８００ｍＬ）の混合液に２－クロロ－６－（モルホリン－４－イル）－９－（２，２，２－トリフルオロエチル）－９Ｈ－プリン（１００ｇ、３１１ｍｍｏｌ）、２－（Ｎ，Ｎ－ジ－ｔｅｒｔ－ブトキシカルボニルアミノ）ピリミジン－５－ボロン酸（１１６ｇ、３４２ｍｍｏｌ）、炭酸水素カリウム（６２．３ｇ、６２２ｍｍｏｌ）、トリフェニルホスフィン（１．６３ｇ、６．２１ｍｍｏｌ）、及び酢酸パラジウム（０．６９８ｇ、３．１１ｍｍｏｌ）を添加し、窒素気流下７０℃で３時間半撹拌した。室温まで冷却して固体の析出を確認した後に水（５００ｍＬ）を滴下し、終夜撹拌した。析出固体を濾取し、エタノール／水＝１／１の混合液（５００ｍＬ）で洗浄した後に取得固体を乾燥させ、標記化合物の粗体１９３ｇを灰色固体として得た。残留パラジウム量を原子吸光光度分析により測定した結果、１４８７ｐｐｍであった。
酢酸エチル（２２８０ｍＬ）に標記化合物の粗体（１８３ｇ）、及び特製白鷺（５．７ｇ）を添加し、室温で１時間撹拌した。不溶物を濾去して酢酸エチル（２８５ｍＬ）で洗浄し、濾液と洗浄液を合わせて１，３－ジエチル－２－チオ尿素（５．７ｇ）を添加し、室温で終夜撹拌した。５％クエン酸水溶液（４８５ｍＬ）で２回洗浄し、再度１，３－ジエチル－２－チオ尿素（５．７ｇ）を添加して１時間撹拌した後に５％クエン酸水溶液（４８５ｍＬ）で２回洗浄した（＊１）。Ｎ－メチル－２－ピロリドン（４４７ｍＬ）を添加して酢酸エチルを減圧留去し、Ｎ－メチル－２－ピロリドン／水＝１／１の混合液（２２８ｍＬ）を滴下した後に種晶（＊２）を添加し、室温で終夜撹拌した。水（４４７ｍＬ）を滴下し、２時間半撹拌した後に析出固体を濾取し、エタノール／水＝１／１の混合液（３８０ｍＬ）で洗浄した。取得固体を乾燥させ、標記化合物（１６５ｇ、９６．０％）を白色固体として得た。残留パラジウム量を原子吸光光度分析により測定した結果、１．０ｐｐｍ以下であった。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ： １．４６（１８Ｈ，ｓ），３．８５－３．９１（４Ｈ，ｍ），４．２６－４．５２（４Ｈ，ｍ），４．８８（２Ｈ，ｑ，Ｊ＝８．２Ｈｚ），７．８７（１Ｈ，ｓ），９．６５（２Ｈ，ｓ）．
＊１ 製造した酢酸エチル溶液を一部採取し、濃縮乾固することにより固体が得られた。
＊２ ＊１で得られた固体を種晶として使用した。
[実施例５]
ジ－ｔｅｒｔ－ブチル｛５－［８－クロロ－６－（モルホリン－４－イル）－９－（２，２，２－トリフルオロエチル）－９Ｈ－プリン－２－イル］ピリミジン－２－イル｝イミドジカーボネート To a mixture of N, N-dimethylacetamide (200 mL) and ethanol (800 mL), 2-chloro-6- (morpholin-4-yl) -9- (2,2,2-trifluoroethyl) -9H-purine ( 100 g, 311 mmol), 2- (N, N-di-tert-butoxycarbonylamino) pyrimidine-5-boronic acid (116 g, 342 mmol), potassium bicarbonate (62.3 g, 622 mmol), triphenylphosphine (1.63 g) 6.21 mmol) and palladium acetate (0.698 g, 3.11 mmol) were added, and the mixture was stirred at 70 ° C. for 3 hours and a half under a nitrogen stream. After cooling to room temperature and confirming the precipitation of solids, water (500 mL) was added dropwise and stirred overnight. The precipitated solid was collected by filtration and washed with a mixed solution of ethanol / water = 1/1 (500 mL), and then the obtained solid was dried to obtain 193 g of the title compound as a gray solid. The amount of residual palladium was measured by atomic absorption spectrophotometry and found to be 1487 ppm.
The crude product (183 g) of the title compound and special white birch (5.7 g) were added to ethyl acetate (2280 mL), and the mixture was stirred at room temperature for 1 hour. The insoluble material was removed by filtration, washed with ethyl acetate (285 mL), the filtrate and the washing solution were combined, 1,3-diethyl-2-thiourea (5.7 g) was added, and the mixture was stirred at room temperature overnight. Wash twice with 5% aqueous citric acid solution (485 mL), add 1,3-diethyl-2-thiourea (5.7 g) again, stir for 1 hour, and then twice with 5% aqueous citric acid solution (485 mL). Washed (* 1). N-methyl-2-pyrrolidone (447 mL) was added, ethyl acetate was distilled off under reduced pressure, and a mixture of N-methyl-2-pyrrolidone / water = 1/1 (228 mL) was added dropwise and seed crystals (* 2 ) And stirred at room temperature overnight. Water (447 mL) was added dropwise, and after stirring for 2.5 hours, the precipitated solid was collected by filtration and washed with a mixed solution (380 mL) of ethanol / water = 1/1. The obtained solid was dried to give the title compound (165 g, 96.0%) as a white solid. As a result of measuring the amount of residual palladium by atomic absorption spectrophotometry, it was 1.0 ppm or less.
1 H-NMR (CDCl 3 ) δ: 1.46 (18H, s), 3.85-3.91 (4H, m), 4.26-4.52 (4H, m), 4.88 (2H , Q, J = 8.2 Hz), 7.87 (1H, s), 9.65 (2H, s).
* 1 A portion of the produced ethyl acetate solution was collected and concentrated to dryness to obtain a solid.
* 2 The solid obtained in * 1 was used as a seed crystal.
[Example 5]
Di-tert-butyl {5- [8-chloro-6- (morpholin-4-yl) -9- (2,2,2-trifluoroethyl) -9H-purin-2-yl] pyrimidin-2-yl } Imidodicarbonate
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
アセトニトリル（７５０ｍＬ）にジ－ｔｅｒｔ－ブチル｛５－［６－（モルホリン－４－イル）－９－（２，２，２－トリフルオロエチル）－９Ｈ－プリン－２－イル］ピリミジン－２－イル｝イミドジカーボネート（７５．０ｇ、１２９ｍｍｏｌ）、及びＮ－クロロコハク酸イミド（３４．５ｇ、２５８ｍｍｏｌ）を添加し、２８℃に加熱した後に濃塩酸（０．５５ｍＬ）を添加し、２８℃で３時間半撹拌した。水（５２５ｍＬ）を滴下した後に１０％亜硫酸ナトリウム水溶液（１５０ｍＬ）を滴下し、室温で終夜撹拌した。析出固体を濾取し、アセトニトリル／水＝１／１の混合液（２２５ｍＬ）で洗浄した後に、取得固体を乾燥させ標記化合物（６９．１ｇ、８７．０％）を白色固体として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ： １．４８（１８Ｈ，ｓ），３．８４－３．９０（４Ｈ，ｍ），４．２０－４．４４（４Ｈ，ｍ），４．８６（２Ｈ，ｑ，Ｊ＝８．２Ｈｚ），９．６２（２Ｈ，ｓ）．
[実施例６]
５－［８－クロロ－６－（モルホリン－４－イル）－９－（２，２，２－トリフルオロエチル）－９Ｈ－プリン－２－イル］ピリミジン－２－アミン塩酸塩 Di-tert-butyl {5- [6- (morpholin-4-yl) -9- (2,2,2-trifluoroethyl) -9H-purin-2-yl] pyrimidin-2- in acetonitrile (750 mL) Yl} imide dicarbonate (75.0 g, 129 mmol) and N-chlorosuccinimide (34.5 g, 258 mmol) were added and heated to 28 ° C., followed by addition of concentrated hydrochloric acid (0.55 mL) at 28 ° C. Stir for 3 and a half hours. Water (525 mL) was added dropwise, then 10% aqueous sodium sulfite solution (150 mL) was added dropwise, and the mixture was stirred overnight at room temperature. The precipitated solid was collected by filtration and washed with a mixture of acetonitrile / water = 1/1 (225 mL), and then the obtained solid was dried to obtain the title compound (69.1 g, 87.0%) as a white solid.
1 H-NMR (CDCl 3 ) δ: 1.48 (18H, s), 3.84-3.90 (4H, m), 4.20-4.44 (4H, m), 4.86 (2H , Q, J = 8.2 Hz), 9.62 (2H, s).
[Example 6]
5- [8-Chloro-6- (morpholin-4-yl) -9- (2,2,2-trifluoroethyl) -9H-purin-2-yl] pyrimidin-2-amine hydrochloride
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
２ｍｏｌ／Ｌ塩化水素メタノール溶液（３６０ｍＬ）にジ－ｔｅｒｔ－ブチル｛５－［８－クロロ－６－（モルホリン－４－イル）－９－（２，２，２－トリフルオロエチル）－９Ｈ－プリン－２－イル］ピリミジン－２－イル｝イミドジカーボネート（６０．０ｇ、９７．６ｍｍｏｌ）を添加し、６０℃に加熱して５時間半撹拌した。氷浴にて冷却して１時間撹拌した後に析出固体を濾取し、冷却したメタノール（１８０ｍＬ）で洗浄した。取得固体を乾燥させ、標記化合物（４２．７ｇ、９７．０％）を黄色固体として得た。
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ：３．７０－３．８０（４Ｈ，ｍ），４．２１（４Ｈ，ｂｒｓ），５．２２（２Ｈ，ｑ，Ｊ＝８．９Ｈｚ），６．９５－８．６０（３Ｈ，ｂｒｍ），９．２９（２Ｈ，ｓ）．
 [実施例７]
５－｛８－［（３Ｒ）－３－メチルピペラジン－１－イル］－６－（モルホリン－４－イル）－９－（２，２，２－トリフルオロエチル）－９Ｈ－プリン－２－イル｝ピリミジン－２－アミン Di-tert-butyl {5- [8-chloro-6- (morpholin-4-yl) -9- (2,2,2-trifluoroethyl) -9H-] was added to a 2 mol / L hydrogen chloride methanol solution (360 mL). Purin-2-yl] pyrimidin-2-yl} imide dicarbonate (60.0 g, 97.6 mmol) was added, heated to 60 ° C. and stirred for 5 hours and a half. After cooling in an ice bath and stirring for 1 hour, the precipitated solid was collected by filtration and washed with cooled methanol (180 mL). The obtained solid was dried to give the title compound (42.7 g, 97.0%) as a yellow solid.
1 H-NMR (DMSO-d 6 ) δ: 3.70-3.80 (4H, m), 4.21 (4H, brs), 5.22 (2H, q, J = 8.9 Hz), 6 .95-8.60 (3H, brm), 9.29 (2H, s).
[Example 7]
5- {8-[(3R) -3-Methylpiperazin-1-yl] -6- (morpholin-4-yl) -9- (2,2,2-trifluoroethyl) -9H-purine-2- Il} pyrimidin-2-amine
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
Ｎ－メチル－２－ピロリドン（１６０ｍＬ）に５－［８－クロロ－６－（モルホリン－４－イル）－９－（２，２，２－トリフルオロエチル）－９Ｈ－プリン－２－イル］ピリミジン－２－アミン塩酸塩（４０．０ｇ、８８．６ｍｍｏｌ）、及び５０％（Ｒ）－２－メチルピペラジンメタノール溶液（７１．０ｇ、３５４ｍｍｏｌ）を添加し、メタノールを留去しながら１２０℃で４時間撹拌した。５０℃まで冷却して水（６００ｍＬ）を滴下した後に塩化ナトリウム（１６０ｇ）を添加して水（４０ｍＬ）で洗いこみ、室温まで冷却して終夜撹拌した。析出固体を濾取し、水（２００ｍＬ）で洗浄した後に、取得固体を乾燥させ標記化合物（３８．０ｇ、８９．７％）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ： １．１３（３Ｈ，ｄ，Ｊ＝６．３Ｈｚ），２．７１（１Ｈ，ｄｄ，Ｊ＝１１．７，１０．０Ｈｚ），３．００－３．１３（４Ｈ，ｍ），３．２０－３．２７（２Ｈ，ｍ），３．８２－３．８８（４Ｈ，ｍ），４．２１－４．３５（４Ｈ，ｂｒｍ），４．６４－４．７５（２Ｈ，ｍ）５．１８（２Ｈ，ｓ），９．２３（２Ｈ，ｓ）．
[実施例８]
１－｛（２Ｒ）－４－［２－（２－アミノピリミジン－５－イル）－６－（モルホリン－４－イル）－９－（２，２，２－トリフルオロエチル）－９Ｈ－プリン－８－イル］－２－メチルピペラジン－１－イル｝エタン－１－オン 5- [8-chloro-6- (morpholin-4-yl) -9- (2,2,2-trifluoroethyl) -9H-purin-2-yl] in N-methyl-2-pyrrolidone (160 mL) Pyrimidine-2-amine hydrochloride (40.0 g, 88.6 mmol) and 50% (R) -2-methylpiperazine methanol solution (71.0 g, 354 mmol) were added and the methanol was distilled off at 120 ° C. Stir for 4 hours. After cooling to 50 ° C. and adding water (600 mL) dropwise, sodium chloride (160 g) was added, rinsed with water (40 mL), cooled to room temperature and stirred overnight. The precipitated solid was collected by filtration and washed with water (200 mL), and then the obtained solid was dried to obtain the title compound (38.0 g, 89.7%) as a pale yellow solid.
1 H-NMR (CDCl 3 ) δ: 1.13 (3H, d, J = 6.3 Hz), 2.71 (1H, dd, J = 11.7, 10.0 Hz), 3.00-3. 13 (4H, m), 3.20-3.27 (2H, m), 3.82-3.88 (4H, m), 4.21-4.35 (4H, brm), 4.64- 4.75 (2H, m) 5.18 (2H, s), 9.23 (2H, s).
[Example 8]
1-{(2R) -4- [2- (2-aminopyrimidin-5-yl) -6- (morpholin-4-yl) -9- (2,2,2-trifluoroethyl) -9H-purine -8-yl] -2-methylpiperazin-1-yl} ethane-1-one
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
テトラヒドロフラン（８０ｍＬ）に５－｛８－［（３Ｒ）－３－メチルピペラジン－１－イル］－６－（モルホリン－４－イル）－９－（２，２，２－トリフルオロエチル）－９Ｈ－プリン－２－イル｝ピリミジン－２－アミン（１０．０ｇ、２０．９ｍｍｏｌ）、トリエチルアミン（３．３８ｇ、３３．４ｍｍｏｌ）、及び無水酢酸（２．７７ｇ、２７．１ｍｍｏｌ）を添加し、室温で２時間撹拌した。限外ろ過した水（７０ｍＬ）を添加して５０℃まで加熱し、不溶物を濾去してテトラヒドロフラン／限外ろ過した水＝１／１の混合液（２０ｍＬ）で洗浄した。濾液と洗浄液を合わせて４０℃まで加熱し、ＵＦ水（１２０ｍＬ）を滴下した後に室温まで徐冷しながら終夜撹拌した。再び４０℃まで加熱して１時間撹拌した後に、６℃まで冷却して３時間撹拌した。析出結晶を濾取し、冷却したテトラヒドロフラン／限外ろ過した水＝３／７の混合液（３０ｍＬ）で洗浄した後に取得結晶を乾燥させ、標記化合物の粗体（１０．９ｇ）を淡黄色結晶として得た。
酢酸エチル（３０ｍＬ）とアセトニトリル（１０ｍＬ）の混合液に標記化合物の粗体（３．４０ｇ）を添加し、６０℃に加熱して１時間撹拌した。標記化合物の粗体（３．３０ｇ）を添加して酢酸エチル（５ｍＬ）で洗いこみ、６０℃で１時間撹拌した。更に標記化合物の粗体（３．３０ｇ）を添加して酢酸エチル（５ｍＬ）で洗いこみ、６０℃で５時間撹拌　した。室温まで冷却して終夜撹拌した後に、氷浴にて冷却して３時間撹拌した。析出結晶を濾取し、冷却した酢酸エチル（３０ｍＬ）で洗浄した後に、取得結晶を乾燥させ標記化合物（８．６１ｇ、８５．９％）を白色結晶として得た。
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６，１４０℃）δ： １．２９（３Ｈ，ｄ，Ｊ＝６．９Ｈｚ），２．０３（３Ｈ，ｓ），２．９０－２．９７（１Ｈ，ｍ），３．１１－３．２０（１Ｈ，ｍ），３．２８－３．３５（２Ｈ，ｍ），３．４３－３．４６（１Ｈ，ｍ），３．７３－３．７６（４Ｈ，ｍ），３．９９－４．０４（１Ｈ，ｍ），４．１７－４．１９（４Ｈ，ｍ），４．４３－４．５１（１Ｈ，ｍ），４．９０－５．０１（２Ｈ，ｍ），６．４４（２Ｈ，ｂｒｓ），９．０６（２Ｈ，ｓ）． To tetrahydrofuran (80 mL) was added 5- {8-[(3R) -3-methylpiperazin-1-yl] -6- (morpholin-4-yl) -9- (2,2,2-trifluoroethyl) -9H. -Purin-2-yl} pyrimidin-2-amine (10.0 g, 20.9 mmol), triethylamine (3.38 g, 33.4 mmol), and acetic anhydride (2.77 g, 27.1 mmol) were added at room temperature. For 2 hours. Ultrafiltered water (70 mL) was added and heated to 50 ° C., insolubles were filtered off, and washed with a tetrahydrofuran / ultrafiltered water = 1/1 mixture (20 mL). The filtrate and the washing solution were combined and heated to 40 ° C., UF water (120 mL) was added dropwise, and the mixture was stirred overnight while gradually cooling to room temperature. The mixture was again heated to 40 ° C. and stirred for 1 hour, then cooled to 6 ° C. and stirred for 3 hours. Precipitated crystals were collected by filtration, washed with a cooled tetrahydrofuran / ultrafiltered water = 3/7 mixture (30 mL), and then the obtained crystals were dried to give crude title compound (10.9 g) as pale yellow crystals. Got as.
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. Further, a crude product of the title compound (3.30 g) was added, washed with ethyl acetate (5 mL), and stirred at 60 ° C. for 5 hours. After cooling to room temperature and stirring overnight, the mixture was cooled in an ice bath and stirred for 3 hours. The precipitated crystals were collected by filtration and washed with cooled ethyl acetate (30 mL), and then the obtained crystals were dried to obtain the title compound (8.61 g, 85.9%) as white crystals.
1 H-NMR (DMSO-d 6 , 140 ° C.) δ: 1.29 (3H, d, J = 6.9 Hz), 2.03 (3H, s), 2.90-2.97 (1H, m ), 3.11-3.20 (1H, m), 3.28-3.35 (2H, m), 3.43-3.46 (1H, m), 3.73-3.76 (4H) M), 3.99-4.04 (1H, m), 4.17-4.19 (4H, m), 4.43-4.51 (1H, m), 4.90-5.01. (2H, m), 6.44 (2H, brs), 9.06 (2H, s).

Claims (12)

  1. パラジウム触媒存在下、
    式（Ｉ）で示される化合物：
    Figure JPOXMLDOC01-appb-C000001
    を式（ＩＩ）で示される化合物： 
    Figure JPOXMLDOC01-appb-C000002
    と反応させ、
    式（ＩＩＩ）で示される化合物またはその薬理上許容される塩： 
    Figure JPOXMLDOC01-appb-C000003
    を製造する方法。
    ［式（ＩＩ）および式（ＩＩＩ）中、Ｒ１およびＲ２は、それぞれ独立に、水素原子、Ｃ１－Ｃ６アルコキシカルボニル基、およびベンジルオキシカルボニル基からなる群より選ばれる置換基を示す。ただし、Ｒ１およびＲ２は、同時に水素原子を示さない。］     In the presence of a palladium catalyst,
    Compound represented by formula (I):
    Figure JPOXMLDOC01-appb-C000001
    A compound of formula (II):
    Figure JPOXMLDOC01-appb-C000002
    React with
    Compound represented by formula (III) or a pharmacologically acceptable salt thereof:
    Figure JPOXMLDOC01-appb-C000003
    How to manufacture.
    [In Formula (II) and Formula (III), 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. ]
  2. 上記式（ＩＩ）および上記式（ＩＩＩ）において、Ｒ１およびＲ２のいずれもが、ｔｅｒｔ－ブトキシカルボニル基である請求項１に記載の製造方法。 The production method according to claim 1, wherein, in the formula (II) and the formula (III), both R 1 and R 2 are tert-butoxycarbonyl groups.
  3. パラジウム触媒が、酢酸パラジウム、及びトリフェニルホスフィンから調製される触媒である、請求項１もしくは２に記載の製造方法。 The production method according to claim 1 or 2, wherein the palladium catalyst is a catalyst prepared from palladium acetate and triphenylphosphine.
  4. 上記式（Ｉ）で示される化合物が、
    式（ＩＶ）で示される化合物：
    Figure JPOXMLDOC01-appb-C000004
    に、モルホリンを添加し、次いでトリフルオロメタンスルホン酸２，２，２－トリフルオロエチルエステルを添加して製造されたものである、請求項１乃至３のいずれか１項に記載の製造方法。     The compound represented by the formula (I) is
    Compound represented by formula (IV):
    Figure JPOXMLDOC01-appb-C000004
    The production method according to any one of claims 1 to 3, which is produced by adding morpholine to trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester.
  5. 請求項１乃至４のいずれか１項に記載の製造方法を用いて製造された、上記式（ＩＩＩ）で示される化合物またはその薬理上許容される塩を、
    塩素化剤と反応させ、式（Ｖ）で示される化合物またはその薬理上許容される塩：
    Figure JPOXMLDOC01-appb-C000005
    を製造し、
    脱保護を行い、
    式（ＶＩ）で示される化合物またはその薬理上許容される塩：
    Figure JPOXMLDOC01-appb-C000006
    を製造し、
    （Ｒ）－２－メチルピペラジンと反応させ、式（ＶＩＩ）で示される化合物またはその薬理上許容される塩：
    Figure JPOXMLDOC01-appb-C000007
    を製造し、次いで、
    アセチル化を行うことによる、式（ＶＩＩＩ）で示される化合物またはその薬理上許容される塩：
    Figure JPOXMLDOC01-appb-C000008
    の製造方法。     A compound represented by the above formula (III) or a pharmacologically acceptable salt thereof produced using the production method according to any one of claims 1 to 4.
    A compound represented by formula (V) or a pharmacologically acceptable salt thereof by reacting with a chlorinating agent:
    Figure JPOXMLDOC01-appb-C000005
    Manufacture and
    Deprotect,
    Compound represented by formula (VI) or a pharmacologically acceptable salt thereof:
    Figure JPOXMLDOC01-appb-C000006
    Manufacture and
    (R) -2-Methylpiperazine, a compound represented by the formula (VII) or a pharmacologically acceptable salt thereof:
    Figure JPOXMLDOC01-appb-C000007
    And then
    A compound represented by formula (VIII) or a pharmacologically acceptable salt thereof by carrying out acetylation:
    Figure JPOXMLDOC01-appb-C000008
    Manufacturing method.
  6. 請求項１乃至４のいずれか１項に記載の製造方法を用いて製造された、上記式（ＩＩＩ）で示される化合物またはその薬理上許容される塩を、
    塩素化剤と反応させ、上記式（Ｖ）で示される化合物またはその薬理上許容される塩を製造し、脱保護を行い、上記式（ＶＩ）で示される化合物またはその薬理上許容される塩を製造し、（２Ｒ）－１－アセチル－２－メチルピペラジンと反応させることによる、上記式（ＶＩＩＩ）で示される化合物またはその薬理上許容される塩の製造方法。     A compound represented by the above formula (III) or a pharmacologically acceptable salt thereof produced using the production method according to any one of claims 1 to 4.
    Reaction with a chlorinating agent to produce a compound represented by the above formula (V) or a pharmacologically acceptable salt thereof, deprotection, and a compound represented by the above formula (VI) or a pharmacologically acceptable salt thereof And reacting with (2R) -1-acetyl-2-methylpiperazine to produce a compound represented by the above formula (VIII) or a pharmacologically acceptable salt thereof.
  7. 上記式（ＶＩ）で示される化合物の薬理上許容される塩が、塩酸塩である、請求項５もしくは６に記載の製造方法。 The production method according to claim 5 or 6, wherein the pharmacologically acceptable salt of the compound represented by the formula (VI) is a hydrochloride.
  8. 塩素化剤が、Ｎ－クロロコハク酸イミド及び塩酸である、請求項５乃至７のいずれか１項に記載の製造方法。 The production method according to any one of claims 5 to 7, wherein the chlorinating agent is N-chlorosuccinimide and hydrochloric acid.
  9. 請求項１乃至４のいずれか１項に記載の製造方法を用いて製造された、上記式（ＩＩＩ）で示される化合物またはその薬理上許容される塩の精製方法であって、上記式（ＩＩＩ）で示される化合物またはその薬理上許容される塩の溶液に、チオ尿素誘導体を添加することを特徴とする精製方法。 A method for purifying a compound represented by the above formula (III) or a pharmacologically acceptable salt thereof, which is produced using the production method according to any one of claims 1 to 4, comprising the above formula (III) A purification method comprising adding a thiourea derivative to a solution of the compound represented by (1) or a pharmacologically acceptable salt thereof.
  10. チオ尿素誘導体が、１，３－ジエチルー２－チオ尿素である、請求項９に記載の精製方法。 The purification method according to claim 9, wherein the thiourea derivative is 1,3-diethyl-2-thiourea.
  11. 請求項９もしくは１０に記載の精製方法であって、更に活性炭を添加することを特徴とする精製方法。 The purification method according to claim 9 or 10, further comprising adding activated carbon.
  12. 上記式（ＩＩ）において、Ｒ１およびＲ２のいずれもが、ｔｅｒｔ－ブトキシカルボニル基である化合物。 In the above formula (II), compounds wherein both R 1 and R 2 are tert-butoxycarbonyl groups.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108187666A (en) * 2018-01-23 2018-06-22 杭州卢普生物科技有限公司 The preparation of biomass derived palladium catalyst and the application in the antitumor drug western synthesis for Buddhist nun difficult to understand

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010509429A (en) * 2006-11-07 2010-03-25 エルジー・ケム・リミテッド Method for removing residual catalyst in polymer solution and polymer purified thereby
WO2010044401A1 (en) * 2008-10-14 2010-04-22 第一三共株式会社 Morpholinopurine derivative
JP2011521968A (en) * 2008-05-30 2011-07-28 ジェネンテック， インコーポレイテッド Purine PI3K inhibitor compounds and methods of use
JP2011236198A (en) * 2010-04-13 2011-11-24 Daiichi Sankyo Co Ltd Morpholinopurine derivative
WO2012082997A1 (en) * 2010-12-16 2012-06-21 F. Hoffmann-La-Roche Ag Tricyclic pi3k inhibitor compounds and methods of use

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010509429A (en) * 2006-11-07 2010-03-25 エルジー・ケム・リミテッド Method for removing residual catalyst in polymer solution and polymer purified thereby
JP2011521968A (en) * 2008-05-30 2011-07-28 ジェネンテック， インコーポレイテッド Purine PI3K inhibitor compounds and methods of use
WO2010044401A1 (en) * 2008-10-14 2010-04-22 第一三共株式会社 Morpholinopurine derivative
JP2011236198A (en) * 2010-04-13 2011-11-24 Daiichi Sankyo Co Ltd Morpholinopurine derivative
WO2012082997A1 (en) * 2010-12-16 2012-06-21 F. Hoffmann-La-Roche Ag Tricyclic pi3k inhibitor compounds and methods of use

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108187666A (en) * 2018-01-23 2018-06-22 杭州卢普生物科技有限公司 The preparation of biomass derived palladium catalyst and the application in the antitumor drug western synthesis for Buddhist nun difficult to understand
CN108187666B (en) * 2018-01-23 2020-11-17 杭州卢普生物科技有限公司 Preparation of biomass derived palladium catalyst and application of biomass derived palladium catalyst in synthesis of antitumor drug ocitinib

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