Process for producing purinone derivative

A method for producing a compound represented by the formula (D):

• wherein R1 represents (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C1-4 haloalkyl group or (5) a C1-4 haloalkoxy group;
• R2 represents (1) a halogen atom;
• (2) a C1-4 alkyl group;
• (3) a C1-4 alkoxy group;
• (4) a nitrile;
• (5) a C1-4 haloalkyl group or (6) a C1-4 haloalkoxy group;
• m represents an integer of 0 to 4;
• and n represents an integer of 0 to 5;
• or a salt thereof,
• the method comprising the following steps (i) to (iii):
• step (i):
• subjecting a compound represented by the formula (A):
• wherein all symbols represent the same meanings as above;
• or a salt thereof to a reaction with a halomalonic diester compound in the presence of a bromide salt, a phase-transfer catalyst and a base to produce a compound represented by the formula (B):
• wherein R3 and R4 respectively and independently represent a C1-3 alkoxy group;
• and
• all other symbols represent the same meanings as above;
• or a salt thereof;
• step (ii):
• subjecting the compound represented by the formula (B) obtained in the step (i) or a salt thereof to a reaction with a formamidine salt in the presence of a base to produce a compound represented by the formula (C):
• wherein all symbols represent the same meanings as above;
• or a salt thereof;
• and
• step (iii):
• subjecting the compound represented by the formula (C) obtained in the step (ii) or a salt thereof to a reaction with phosphorus oxychloride in the presence of N,N-dimethylformamide to produce the compound represented by the formula (D) or a salt thereof.

A method for producing a compound represented by the formula (I):

• wherein R1 represents (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C1-4 haloalkyl group or (5) a C1-4 haloalkoxy group;
• R2 represents (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a nitrile, (5) a C1-4 haloalkyl group or (6) a C1-4 haloalkoxy group;
• R5 represents a C2-4 alkenyl group or C2-4 alkynyl group which may be substituted by 1 to 5 substituents selected from the group consisting of (1) NR6R7, (2) a halogen atom, (3) CONR8R9, (4) CO2R10 and (5) OR11;
• R6 and R7 respectively and independently represent (1) a hydrogen atom or (2) a C1-4 alkyl group which may be substituted by OR12 or CONR13R14;
• R6 and R7 may form together with a nitrogen atom to which R6 and R7 are attached a 4- to 7-membered nitrogen-containing saturated heterocycle which may be substituted by an oxo group or a hydroxy group;
• R8 and R9 respectively and independently represent (1) a hydrogen atom, (2) a C1-4 alkyl group or (3) a phenyl group;
• R10 represents (1) a hydrogen atom or (2) a C1-4 alkyl group;
• R11 represents (1) a hydrogen atom, (2) a C1-4 alkyl group, (3) a phenyl group or (4) a benzotriazolyl group;
• R12 represents (1) a hydrogen atom or (2) a C1-4 alkyl group;
• and R13 and R14 respectively and independently represent (1) a hydrogen atom or (2) a C1-4 alkyl group;
• ring1 represents an azetidine, pyrrolidine or piperidine ring;
• m represents an integer of 0 to 4;
• and n represents an integer of 0 to 5;
• or a salt thereof,
• the method comprising:
• step (i):
• subjecting a compound represented by the formula (A):
• wherein all symbols represent the same meanings as above;
• or a salt thereof to a reaction with a halomalonic diester compound in the presence of a bromide salt, a phase-transfer catalyst and a base to produce a compound represented by the formula (B):
• wherein R3 and R4 respectively and independently represent a C1-3 alkoxy group;
• and
• all other symbols represent the same meanings as above;
• or a salt thereof;
• step (ii):
• subjecting the compound represented by the formula (B) obtained in the step (i) or a salt thereof to a reaction with a formamidine salt in the presence of a base to produce a compound represented by the formula (C):
• wherein all symbols represent the same meanings as above;
• or a salt thereof;
• step (iii):
• subjecting the compound represented by the formula (C) obtained in the step (ii) or a salt thereof to a reaction with phosphorus oxychloride in the presence of N,N-dimethylformamide to produce a compound represented by the formula (D):
• wherein all symbols represent the same meanings as above;
• or a salt thereof;
• step (iv):
• subjecting the compound represented by the formula (D) obtained in the step (iii) or a salt thereof to a reaction with a compound represented by the formula (a):
• wherein Boc represents a tert-butoxycarbonyl group and ring1 represents the same meaning as above;
• or a salt thereof in the presence of a base followed by alkaline hydrolysis to produce a compound represented by the formula (E):
• wherein all symbols represent the same meanings as above;
• or a salt thereof;
• step (v):
• subjecting the compound represented by the formula (E) obtained in the step (iv) or a salt thereof to a reaction with 1,1′-carbonyldiimidazole in the presence of a base to produce a compound represented by the formula (F):
• wherein all symbols represent the same meanings as above;
• or a salt thereof;
• step (vi):
• subjecting the compound represented by the formula (F) obtained in the step (v) or a salt thereof to a reaction with a protected amine or a salt thereof to produce a compound represented by the formula (G):
• wherein R15 and R16 respectively and independently represent a hydrogen atom, a benzyloxycarbonyl group, a t-butoxycarbonyl group, an allyloxycarbonyl group, a 1-methyl-1-(4-biphenyl)ethoxycarbonyl group, a trifluoroacetyl group, a 9-fluorenylmethoxycarbonyl group, a benzyl group, a p-methoxybenzyl group, a benzyloxymethyl group or a 2-(trimethylsilyl)ethoxymethyl group, provided that R15 and R16 do not simultaneously represent hydrogen atoms;
• and all other symbols represent the same meanings as above;
• or a salt thereof;
• step (vii):
• subjecting the compound represented by the formula (G) obtained in the step (vi) or a salt thereof to a deprotection reaction to produce the compound represented by a formula (H):
• wherein all symbols represent the same meanings as above;
• or a salt thereof;
• and
• step (viii):
• subjecting the compound represented by the formula (H) obtained in the step (vii) or a salt thereof to an amidation reaction with a compound represented by the formula (b):
• wherein all symbols represent the same meanings as above;
• or a salt thereof in the presence of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinan-2,4,6-trioxide to produce the compound represented by the formula (I) or a salt thereof.

A method for producing 6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-one or a salt thereof, the method comprising:

• step (i):
• subjecting 4-phenoxyaniline or a salt thereof to a reaction with diethyl chloromalonate in the presence of a bromide salt, a phase-transfer catalyst and a base to produce diethyl [(4-phenoxyphenyl)amino]propanediate or a salt thereof;
• step (ii):
• subjecting diethyl [(4-phenoxyphenyl)amino]propanediate obtained in the step (i) or a salt thereof to a reaction with a formamidine salt in the presence of a base to produce 5-[(4-phenoxyphenyl)amino]pyrimidine-4,6-diol or a salt thereof;
• step (iii):
• subjecting 5-[(4-phenoxyphenyl)amino]pyrimidine-4,6-diol obtained in the step (ii) or a salt thereof to a reaction with phosphorus oxychloride in the presence of N,N-dimethylformamide to produce N-(4,6-dichloropyrimidin-5-yl)-N-(4-phenoxyphenyl)formamide or a salt thereof;
• step (iv):
• subjecting N-(4,6-dichloropyrimidin-5-yl)-N-(4-phenoxyphenyl)formamide obtained in the step (iii) or a salt thereof to a reaction with tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate or a salt thereof in the presence of a base followed by alkaline hydrolysis to produce tert-butyl (3R)-3-({6-chloro-5-[(4-phenoxyphenyl)amino]pyrimidin-4-yl}amino)pyrrolidine-1-carboxylate or a salt thereof;
• step (v):
• subjecting tert-butyl (3R)-3-({6-chloro-5-[(4-phenoxyphenyl)amino]pyrimidin-4-yl}amino)pyrrolidine-1-carboxylate obtained in the step (iv) or a salt thereof to a reaction with 1,1′-carbonyldiimidazole in the presence of a base to produce tert-butyl (3R)-3-[6-chloro-8-oxo-7-(4-phenoxyphenyl)-7,8-dihydro-9H-purin-9-yl]pyrrolidine-1-carboxylate or a salt thereof;
• step (vi):
• subjecting tert-butyl (3R)-3-[6-chloro-8-oxo-7-(4-phenoxyphenyl)-7,8-dihydro-9H-purin-9-yl]pyrrolidine-1-carboxylate obtained in the step (v) or a salt thereof to a reaction with benzylamine or a salt thereof to produce tert-butyl (3R)-3-[6-(benzylamino)-8-oxo-7-(4-phenoxyphenyl)-7,8-dihydro-9H-purin-9-yl]pyrrolidine-1-carboxylate or a salt thereof;
• step (vii):
• subjecting tert-butyl (3R)-3-[6-(benzylamino)-8-oxo-7-(4-phenoxyphenyl)-7,8-dihydro-9H-purin-9-yl]pyrrolidine-1-carboxylate obtained in the step (vi) or a salt thereof to a deprotection reaction to produce 6-amino-7-(4-phenoxyphenyl)-9-[(3R)-pyrrolidin-3-yl]-7,9-dihydro-8H-purin-8-one or a salt thereof;
• and
• step (viii):
• subjecting 6-amino-7-(4-phenoxyphenyl)-9-[(3R)-pyrrolidin-3-yl]-7,9-dihydro-8H-purin-8-one obtained in the step (vii) or a salt thereof to an amidation reaction with 2-butynoic acid or a salt thereof in the presence of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinan-2,4,6-trioxide to produce 6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-one or a salt thereof.