Method for producing a substituted 6,7,8,9-tetrahydropyrimido[5,4-b]indolizine, substituted 7,8,9,10-tetrahydro-6H-pyrimido[5′,4′:4,5]pyrrolo[1,2-a]azepine and substituted 6,7,8,9,10,11-hexahydropyrimido[5′,4′:4,5]pyrrolo[1,2-a]azocine

A method for producing a compound represented by Formula (1)

• or a salt thereof,
• wherein
• R1 is hydrogen or a functional group selected from the group consisting of halogen;
• hydroxy;
• cyano;
• nitro;
• alkyl which may be substituted by C1-6 alkoxy, acyl, C2-7 alkoxycarbonyl, C1-6 alkylamino, 4- to 10-membered saturated heterocycle or 4- to 10-membered unsaturated heterocycle;
• haloalkyl;
• cycloalkyl which may be substituted by halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, acyl, C2-7 alkoxycarbonyl, C1-6 alkylamino, C3-10 cycloalkyl, C6-14 aromatic hydrocarbon, 4- to 10-membered saturated heterocycle, or 4- to 10-membered unsaturated heterocycle;
• cycloalkyl-alkyl;
• aralkyl;
• alkenyl;
• alkynyl;
• alkoxy;
• haloalkoxy;
• cycloalkoxy;
• cycloalkyl-alkoxy;
• aralkyloxy;
• alkylthio;
• cycloalkyl-alkylthio;
• amino;
• alkylamino;
• cycloalkyl-alkylamino;
• acyl;
• acyloxy;
• carboxy;
• alkoxycarbonyl;
• aralkyloxycarbonyl;
• carbamoyl;
• saturated or unsaturated heterocycle which may be substituted by halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, acyl, C2-7 alkoxycarbonyl, C1-6 alkylamino, C3-10 cycloalkyl, C6-14 aromatic hydrocarbon, 4- to 10-membered saturated heterocycle, or 4- to 10-membered unsaturated heterocycle;
• aromatic hydrocarbon which may be substituted by halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, acyl, C2-7 alkoxycarbonyl, C1-6 alkylamino, C3-10 cycloalkyl, C6-14 aromatic hydrocarbon, 4- to 10-membered saturated heterocycle, or 4- to 10-membered unsaturated heterocycle;
• and saturated heterocyclic oxy;
• one of R2 and R2′ is
• hydroxy protected by a protecting group selected from the group consisting of lower alkylsilyl, lower alkyldiphenylsilyl, lower alkyl lower alkoxyphenylsilyl, and lower alkoxydiphenylsilyl,
• amino protected by alkoxycarbonyl or C1-6 alkylamino protected by alkoxycarbonyl, each of which may be substituted, or
• thiol protected by a protecting group selected from the group consisting of aralkyl, benzyloxymethyl, benzylthiomethyl, lower alkoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 9-fluorenylmethoxycarbonyl, tert-butylsulfanyl, and 3-nitro-2-pyridinesulfenyl;
• wherein said alkyloxycarbonyl is unsubstituted or substituted with a substituent selected from the group consisting of halogen, adamantyl, trimethylsilyl, phenyl, methoxyphenyl, nitrophenyl, anthryl, and fluorenyl;
• the other of R2 and R2′ is hydrogen;
• R3 is amino which is unsubstituted or substituted with a substituent selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, acyl, C2-7 alkoxycarbonyl, C1-6 alkylamino, C3-10 cycloalkyl and 4- to 10-membered saturated heterocycle;
• m is 0 or 1;
• and
• n or 1 or 2,
• the method comprising the steps of:
• (I) reacting an organoborane with a compound represented by Formula (2)
• or a salt thereof,
• wherein said organoborane is selected from the group consisting of 9-borabicyclo[3.3.1]nonane, 9-borabicyclo[3.3.1]nonane dimer, bis(1,2-dimethylpropyl)borane and (1,1,2-trimethylpropyl)borane,
• wherein X is halogen, and R1, R2, R2′, R3, m, and n are as defined above;
• and
• (II) intramolecularly cyclizing the product obtained in step (I) in the presence of a zerovalent palladium catalyst and an alkali metal hydroxide.