Intermediate compound for synthesizing pharmaceutical agent and production method thereof

An optically active compound represented by the formula 11:

• wherein R is an aryl optionally having substituent(s) or a heteroaryl optionally having substituent(s), R1 is a C1-C6 alkyl, an aralkyl optionally having substituent(s) or a C2-C6 alkenyl, and R10 is a hydrogen atom or a group represented by the formula:
• —CO—CH2—X2 (wherein X2 is a halogen), or a salt thereof.

An optically active morpholine compound represented by the formula 12:

• wherein R is an aryl optionally having substituent(s) or a heteroaryl optionally having substituent(s), R1a is a hydrogen atom, a C1-C6 alkyl, an aralkyl optionally having substituent(s), a C2-C6 alkenyl or a group represented by the formula:
• —COOR2 (wherein R2 is a C1-C6 alkyl, a C1-C6 haloalkyl, an aryl optionally having substituent(s) or a benzyl optionally having substituent(s)), and Z is O or H2,
• provided that when R1a is a hydrogen atom and Z is H2, then R should not be a 4-fluorophenyl, or a salt thereof.

A production method of an optically active morpholine compound represented by the formula 10, which comprises reacting a compound of the formula 13 with hydrogen in the presence of a transition metal catalyst:

• wherein R is an aryl optionally having substituent(s) or a heteroaryl optionally having substituent(s), and R3 is a benzyl optionally having substituent(s), a 1-phenylethyl optionally having substituent(s) or a benzyloxycarbonyl optionally having substituent(s).

An optically active compound represented by the formula 31:

• wherein R is an aryl optionally having substituent(s) or a heteroaryl optionally having substituent(s), R1 is a C1-C6 alkyl, an aralkyl optionally having substituent(s) or a C2-C6 alkenyl, and R10 is a hydrogen atom or a group represented by the formula:
• —CO—CH2—X2 (wherein X2 is a halogen), or a salt thereof.

An optically active morpholine compound represented by the formula 32:

• wherein R is an aryl optionally having substituent(s) or a heteroaryl optionally having substituent(s), R1a is a hydrogen atom, a C1-C6 alkyl, an aralkyl optionally having substituent(s), a C2-C6 alkenyl or a group represented by the formula:
• —COOR2 (wherein R2 is a C1-C6 alkyl, a C1-C6 haloalkyl, an aryl optionally having substituent(s) or a benzyl optionally having substituent(s)), and Z is O or H2,
• provided that when R1a is a hydrogen atom and Z is H2, then R should not be a 4-fluorophenyl, or a salt thereof.

A production method of an optically active morpholine compound represented by the formula 30, which comprises reacting a compound of the formula 33 with hydrogen in the presence of a transition metal catalyst:

• wherein R is an aryl optionally having substituent(s) or a heteroaryl optionally having substituent(s), and R3 is a benzyl optionally having substituent(s), a 1-phenylethyl optionally having substituent(s) or a benzyloxycarbonyl optionally having substituent(s).

A production method of an optically active compound represented by the formula 35, which comprises reacting a compound of the formula 34 with isopropanol or formic acid in the presence of a ruthenium catalyst and an optically active amino alcohol or amine ligand:

• wherein R is an aryl optionally having substituent(s) or a heteroaryl optionally having substituent(s), R1 is a hydrogen atom, a C1-C6 alkyl, an aralkyl optionally having substituent(s) or a C2-C6 alkenyl, and R1′ is a hydrogen atom or a tert-butoxycarbonyl group.

A compound represented by the formula 34:

• wherein R is an aryl optionally having substituent(s) or a heteroaryl optionally having substituent(s), R1′ is a hydrogen atom, a C1-C6 alkyl, an aralkyl optionally having substituent(s) or a C2-C6 alkenyl, and R11 is a hydrogen atom or a tert-butoxycarbonyl group, or a salt thereof.

A production method of an optically active compound represented by the formula 36, which comprises reacting a compound of the formula 34 with isopropanol or formic acid in the presence of a ruthenium catalyst and an optically active amino alcohol or amine ligand:

• wherein R is an aryl optionally having substituent(s) or a heteroaryl optionally having substituent(s), R1′ is a hydrogen atom, a C1-C6 alkyl, an aralkyl optionally having substituent(s) or a C2-C6 alkenyl, and R11 is a hydrogen atom or a tert-butoxycarbonyl group.

A production method of a compound represented by the formula 52, which comprises reacting orotic acid of the formula 51 with an alkylating agent in a solvent in the presence of a base:

• wherein Ra is a C1-6 alkyl.

A production method of a compound represented by the formula 53, which comprises heating a compound of the formula 52 under reflux with a chlorinating agent:

• wherein Ra is a C1-6 alkyl.

A production method of a compound represented by the formula 54, which comprises dechlorinating a compound of the formula 53 in the presence of a base:

• wherein Ra is a C1-6 alkyl.