Method for producing prostaglandin derivative
AssigneeAGC Inc.
InventorsYasushi Matsumura, Yusuke Nagai, Yu Yamaguchi, Lanfang Wang
Life of this patent
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Abstract
The present invention relates to a novel production method of a novel prostaglandin derivative or a pharmaceutically acceptable salt thereof useful as a medicament, and an intermediate therefor. According to the present invention, a production method of a novel prostaglandin derivative or a pharmaceutically acceptable salt thereof including a conversion step from a compound represented by the following formula 3 to a compound represented by the formula 1 can be provided: wherein each symbol is as defined in the DESCRIPTION.
Claims13
A compound represented by the formula 3:
- wherein, in the formula 3, R is an alkyl group having 2 to 3 carbon atoms, a substituted alkyl group having 2 to 3 carbon atoms, a cycloalkyl group having 3 to 5 carbon atoms, or a substituted cycloalkyl group having 3 to 5 carbon atoms;
- R3 is a hydroxy-protecting group;
- a methyl group bonded by a wavy line is a methyl group having α-configuration, β-configuration or a mixed configuration of α-configuration and β-configuration;
- and
- Z is an alkyl group having 1 to 4 carbon atoms or a substituted alkyl group having 1 to 4 carbon atoms.
A method for producing a compound represented by the formula 1 or a pharmaceutically acceptable salt thereof, comprising protecting a hydroxy group of a compound represented by the formula 3, and converting same to a compound represented by the formula 1 by subsequently removing R3 and hydrolyzing a CO2Z group:
- wherein, in the formula 1, R is an alkyl group having 2 to 3 carbon atoms, a substituted alkyl group having 2 to 3 carbon atoms, a cycloalkyl group having 3 to 5 carbon atoms or a substituted cycloalkyl group having 3 to 5 carbon atoms;
- R1 and R2 are each independently a hydroxy-protecting group;
- and
- a methyl group bonded by a wavy line is a methyl group having α-configuration, β-configuration or a mixed configuration of α-configuration and β-configuration,
- wherein, in the formula 3, R3 is a hydroxy-protecting group different from R1 and R2;
- Z is an alkyl group having 1 to 4 carbon atoms or a substituted alkyl group having 1 to 4 carbon atoms;
- and R and a methyl group bonded by a wavy line are as defined above.
A compound represented by the formula 4,
- wherein, in the formula 4, R is an alkyl group having 2 to 3 carbon atoms, a substituted alkyl group having 2 to 3 carbon atoms, a cycloalkyl group having 3 to 5 carbon atoms, or a substituted cycloalkyl group having 3 to 5 carbon atoms;
- R3 is a hydroxy-protecting group;
- R4 is a hydroxy-protecting group different from R3;
- a methyl group bonded by a wavy line is a methyl group having α-configuration, β-configuration or a mixed configuration of α-configuration and α-configuration;
- and
- Z is an alkyl group having 1 to 4 carbon atoms or a substituted alkyl group having 1 to 4 carbon atoms.
A method for producing a compound represented by the formula 3, comprising reducing a carbonyl group of the compound represented by the formula 4, and removing R4:
- wherein, in the formula 3, R is an alkyl group having 2 to 3 carbon atoms, a substituted alkyl group having 2 to 3 carbon atoms, a cycloalkyl group having 3 to 5 carbon atoms, or a substituted cycloalkyl group having 3 to 5 carbon atoms;
- R3 is a hydroxy-protecting group;
- a methyl group bonded by a wavy line is a methyl group having α-configuration, β-configuration or a mixed configuration of α-configuration and β-configuration;
- and
- Z is an alkyl group having 1 to 4 carbon atoms or a substituted alkyl group having 1 to 4 carbon atoms,
- wherein, in the formula 4, R3, R, a methyl group bonded by a wavy line, and Z are as defined above;
- and
- R4 is a hydroxy-protecting group different from R3.
A method for producing a compound represented by the formula 4, comprising oxidizing a hydroxy group of a compound represented by the formula 5 to convert the compound to the corresponding aldehyde, and reacting same with a compound represented by the formula 6
- wherein, in the formula 5, R3 is a hydroxy-protecting group;
- R4 is a hydroxy-protecting group different from R3;
- and
- Z is an alkyl group having 1 to 4 carbon atoms or a substituted alkyl group having 1 to 4 carbon atoms,
- wherein, in the formula 6, R′ is an alkyl group having 1 to 4 carbon atoms, R is an alkyl group having 2 to 3 carbon atoms, a substituted alkyl group having 2 to 3 carbon atoms, a cycloalkyl group having 3 to 5 carbon atoms, or a substituted cycloalkyl group having 3 to 5 carbon atoms, and a methyl group bonded by a wavy line is a methyl group having α-configuration, β-configuration or a mixed configuration of α-configuration and β-configuration,
- wherein, in the formula 4, R3, R4, R, a methyl group bonded by a wavy line, and Z are as defined above.
A method for producing a compound represented by the formula 2 or a pharmaceutically acceptable salt thereof, comprising
- arylselenylating a compound represented by the formula 7 to convert same to a compound represented by the formula 8, protecting a hydroxy group of the compound represented by the formula 8, removing R5 to convert the compound to a compound represented by the formula 9,
- oxidatively eliminating an arylselenyl group of the compound represented by the formula 9 to introduce a double bond and convert the compound to a compound represented by the formula 5,
- oxidizing a hydroxy group of the compound represented by the formula 5 to convert same to the corresponding aldehyde,
- reacting same with a compound represented by the formula 6 to convert the compound to a compound represented by the formula 4,
- reducing a carbonyl group of the compound represented by the formula 4, removing R4 to convert the compound to a compound represented by the formula 3,
- protecting a hydroxy group of the compound represented by the formula 3, subsequently removing R3 and hydrolyzing a CO2Z group to convert the compound to a compound represented by the formula 1 or a pharmaceutically acceptable salt thereof, and
- oxidizing a hydroxy group of the compound represented by the formula 1 or a pharmaceutically acceptable salt thereof, and removing R1 and R2 to convert the compound to a compound represented by the formula 2 or a pharmaceutically acceptable salt thereof,
- wherein, in the formula 2, R is an alkyl group having 2 to 3 carbon atoms, a substituted alkyl group having 2 to 3 carbon atoms, a cycloalkyl group having 3 to 5 carbon atoms or a substituted cycloalkyl group having 3 to 5 carbon atoms;
- and a methyl group bonded by a wavy line is a methyl group having α-configuration, β-configuration or a mixed configuration of α-configuration and β-configuration,
- wherein, in the formula 7, Z is an alkyl group having 1 to 4 carbon atoms or a substituted alkyl group having 1 to 4 carbon atoms;
- R4 is a hydroxy-protecting group;
- and
- R5 is a hydroxy-protecting group different from R3 and R4,
- wherein, in the formula 8, R4, R5 and Z are as defined above;
- and
- Ar is an aryl group or a substituted aryl group,
- wherein, in the formula 9, R4, Ar and Z are as defined above;
- and
- R3 is a hydroxy-protecting group different from R4,
- wherein, in the formula 5, R3, R4 and Z are as defined above,
- wherein, in the formula 6, R′ is an alkyl group having 1 to 4 carbon atoms, and R and a methyl group bonded by a wavy line are as defined above,
- wherein, in the formula 4, R, R3, R4, a methyl group bonded by a wavy line and Z are as defined above,
- wherein, in the formula 3, R, R3, a methyl group bonded by a wavy line and Z are as defined above,
- wherein, in the formula 1, R1 and R2 are each independently a hydroxy-protecting group;
- and
- R and a methyl group bonded by a wavy line, are as defined above.
Dependencies are inferred from the claim text.