Process for producing pyripyropene derivatives
View Patent ↗Disclosed is a process for efficiently producing pyripyropene derivatives having acyloxy at the 1-position and 11-position and hydroxyl at the 7-position. The process comprises selectively acylating hydroxyl at the 1-position and 11-position of a compound represented by formula B1 through one to three steps with an acylating agent in the presence or absence of a base.
1. A process for producing a compound C represented by formula C:
wherein R represents a straight chain, branched chain, or cyclic C 2-6 alkylcarbonyl, provided that, when the alkyl moiety in the alkylcarbonyl group is of a branched chain or cyclic type, then R represents C 3-6 alkylcarbonyl, the process comprising:
selectively acylating hydroxyl groups at the 1-position and 11-position of a compound B1 represented by formula B1:
with an acylating agent in an amount of 2.0 to 5.0 equivalents based on the amount of the compound B1, through one to three steps in the presence or absence of a base, in an aprotic polar organic solvent selected from the group consisting of N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, acetonitrile, N-methyl-2-pyrrolidinone, N-methyl-2-piperazinone and N,N-dimethyl-2-imidazolidinone,
to obtain the compound C.
2. The process according to claim 1 , wherein the compound C is produced by acylating the hydroxyl groups at the 1-position and 11-position of the compound B1 through one step.
3. The process according to claim 1 , which comprises producing the compound C by acylation through two steps consisting of the steps of:
acylating a hydroxyl group at the 11-position of the compound B1 with an acylating agent to give a compound B2 represented by formula B2:
wherein R is as defined in formula C in claim 1 ; and
further acylating a hydroxyl group at the 1-position of the compound B2.
4. The process according to claim 1 , which comprises producing the compound C by acylation through three steps consisting of the steps of:
acylating a hydroxyl group at the 11-position of the compound B1 to give a compound B2 represented by formula B2:
wherein R is as defined in formula C in claim 1 ;
transferring acyl at the 11-position of the compound B2 to a hydroxyl at the 1-position to give a compound B3 represented by formula B3:
wherein R is as defined in formula C in claim 1 ; and
acylating a hydroxyl group at the 11-position of the compound B3.
5. The process according to claim 1 , which further comprises, as a step of producing the compound B1, hydrolyzing acyl groups at the 1-position, 7-position, and 11-position of a compound A1 represented by formula A1:
wherein A 1 , A 7 , and A 11 , which may be the same or different, represent acetyl or propionyl,
in the presence of a base.
6. The process according to claim 1 , wherein the acylation is carried out in the absence of a base.
7. The process according to claim 1 , wherein the base used in acylating the hydroxyl at the 1-position and/or 11-position of the compound B1 is 2,4,6-collidine or 2,6-lutidine.
8. The process according to claim 3 , wherein the base is used in the step of producing the compound B2 and in the step of further acylating the hydroxyl at the 1-position of the compound B2, and wherein the amount of the base used in the step of producing the compound B2 is 1.0 to 3.0 equivalents based on the compound B1, and the total amount of the base used in the step of producing the compound B2 and the base used in the step of further acylating the hydroxyl at the 1-position of the compound B2 is 2.0 to 4.5 equivalents.
9. The process according to claim 3 , wherein the acylating agent is used in the step of producing the compound B2 and in the step of further acylating the hydroxyl at the 1-position of the compound B2, and wherein the amount of the acylating agent used in the step of producing the compound B2 is 1.0 to 3.5 equivalents based on the compound B1, and the total amount of the acylating agent used in the step of producing the compound B2 and the acylating agent used in the step of further acylating the hydroxyl at the 1-position of the compound B2 is 2.0 to 4.5 equivalents.
10. The process according to claim 1 , wherein R represents cyclopropanecarbonyl.
11. The process according to claim 4 , wherein the step of producing the compound B3 from the compound B2 is carried out in the presence of a base.
12. The process according to claim 1 , which further comprises a step of isolating and purifying the compound C from a reaction solution comprising the compound C by crystallization.