Vitamin D.sub.3 derivatives and production process thereof

• US 5,719,297 A
• Filed: 02/06/1996
• Issued: 02/17/1998
• Est. Priority Date: 06/07/1994
• Status: Expired due to Term

• Current Assignee: Teijin Limited
• Original Assignee: Teijin Limited
• Inventors: Tanaka, Hiroko, Gao, Qingzhi, Manabe, Kenji, Hazato, Atsuo, Tabe, Masayasu
• Primary Examiner(s): OWENS, AMELIA A
• Application Number:
  US08/591,547
• Time in Patent Office: 742 Days
• Field of Search: 549/323, 552/653
• US Class Current: 549/323
• CPC Class Codes: C07C 401/00 Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
• CPC Class Codes: C07C 69/675 of saturated hydroxy-carboxylic acids
• CPC Class Codes: C07C 69/716 Esters of keto-carboxylic acids or aldehydo-carboxylic acids
• CPC Class Codes: C07C 69/732 of unsaturated hydroxy carboxylic acids
• CPC Class Codes: C07D 307/33 in position 2, the oxygen atom being in its keto or unsubstituted enol form
• CPC Class Codes: C07D 307/58 One oxygen atom, e.g. butenolide
• CPC Class Codes: C07D 317/34 Oxygen atoms
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896

Abstract

A vitamin D₃ derivative represented by the following formula: ##STR1## wherein, R is, independently, a hydrogen atom, tri(C₁ to C₇ hydrocarbon)silyl group, C₂ to C₈ acyl group, or group forming an acetal bond together with an oxygen atom of a hydroxyl group, A is ##STR2## where, R¹ is a methyl group or methylene group, and when R¹ is a methylene group, the bond between the R¹ and the 3-position of the lactone ring is a double bond, R² is a hydrogen atom or C₁ to C₃ alkyl group, R³ is a hydrogen atom, or R² and R³ together indicate a substitutable single methylene group.

Claims

1. A vitamin D₃ derivative represented by the following formula (I):

##STR95## wherein, R is, independently, a hydrogen atom, triC₁ to C₇ hydrocarbon silyl group, a C₂ to C₈ acyl group, or a group forming an acetal bond together with an oxygen atom of a hydroxyl group, A is ##STR96## where, R¹ is a methyl group or a methylene group and when R¹ is a methylene group, the bond between the R¹ and the 3-position of the lactone ring is a double bond, R² is a hydrogen atom or a C₁ to C₃ alkyl group, R³ is a hydrogen atom, or R² and R³ together indicate a substitutable single methylene group.

2. A vitamin D₃ derivative as claimed in claim 1 represented by the following formula (1-1):

##STR97##

3. A vitamin D₃ derivative as claimed in claim 2, wherein the asymmetric center of the C-1 position of the cyclopentene ring of the formula (1-1) is an (R) configuration and the asymmetric center of the C-4 position is a (S) configuration.

4. A vitamin D₃ derivative as claimed in claim 2, wherein the asymmetric center of the C-1 position of the cyclopentene ring of the formula (1-1) is a (S) configuration and the asymmetric center of the C-4 position is a (S) configuration.

5. A process for producing a vitamin D₃ derivative according to claim 2 of the following formula (1-1):

##STR98## comprising reacting a cyclopentene derivative represented by the following formula (1-2);

##STR99## wherein, R₁ ¹ is a hydrogen atom, a triC₁ to C₇ hydrocarbon silyl group, a C₂ to C₇ acyl group or a group forming an acetal bond together with an oxygen atom of a hydroxyl group and X₁ is a bromine atom or an iodine atom and an enyne derivative represented by the following formula (1-3);

##STR100## wherein, R₁², and R₁³ are a hydrogen atom, a tri C₁ to C₇ hydrocarbon silyl group, a C₂ to C₇ acyl group, or a group forming an acetal bond together with an oxygen atom of a hydroxyl group

in the presence of a palladium catalyst to produce a vitamin D₃ derivative represented by the following formula (1-4);

##STR101## wherein, R₁¹, R₁², and R₁³ are the same as defined above and, optionally, effecting a deblocking reaction.

6. A vitamin D₃ derivative as claimed in claim 1 represented by the following formula (2-1):

##STR102## wherein, R₂¹ is a methyl group or methylene group provided that when R₂¹ is a methylene group, the bond between R₂¹ and the 3-position of the lactone ring is a double bond, R₂² and R₂³ are the same or different and represent a hydrogen atom, triC₁ to C₇ hydrocarbon silyl group, or a C₂ to C₈ acyl group.

7. A vitamin D₃ derivative as claimed in claim 6, wherein the R¹ of the above formula (2-1) is a methyl group, the asymmetric center of the 3-position of the lactone ring is an (S) configuration, and the asymmetric center of the 5-position is an (S) configuration.

8. A vitamin D₃ derivative as claimed in claim 6, wherein the R₂¹ of the above formula (2-1) is a methyl group, the asymmetric center of the 3-position of the lactone ring is an (S) configuration, and the asymmetric center of the 5-position is an (R) configuration.

9. A vitamin D₃ derivative as claimed in claim 6, wherein the R₂¹ of the above formula (2-1) is a methylene group, and the asymmetric center of the 5-position of the lactone ring is an (S) configuration.

10. A vitamin D₃ derivative as claimed in claim 6, wherein the R₂¹ of the above formula (2-1) is the methylene group, and the asymmetric center of the 5-position of the lactone ring is the (R) configuration.

11. A process for producing a vitamin D₃ derivative according to claim 12 represented by the following formula (2-1):

##STR103## wherein, R₂¹, R₂², and R₂³ are the same as defined, in claim 6 comprising reacting a lactone compound represented by the following formula (2-2);

##STR104## wherein, R₂¹ is the same as defined in claim 12 and X₂ is a bromine atom or an iodine atom, R₂¹ is a methyl group or a methylene group with an enyne compound represented by the following formula (2-10);

##STR105## wherein, R₂² and R₂³ are the same as defined in claim 12, in the presence of a palladium catalyst.

12. A vitamin D₃ derivative as claimed in claim 1 represented by the following formula (3-1):

##STR106## wherein, R₃¹ is a hydrogen atom or a C₁ to C₃ alkyl group and R₃² is a hydrogen atom or R₃¹ and R₃² together are a single substitutable group, R₃³ is a hydrogen atom, triC₁ to C₇ hydrocarbon silyl group, a C₂ to C₈ acyl group, or group forming an acetal bond together with an oxygen atom of a hydroxyl group.

13. A vitamin D₃ derivative as claimed in claim 6, wherein the asymmetric center of the 25-position of the above formula (3-1) is a (R) configuration.

14. A vitamin D₃ derivative as claimed in claim 6, wherein the asymmetric center of the 25-position of the above formula (3-1) is a (S) configuration.

15. A process for producing a vitamin D₃ derivative according to claim 21, of the following formula (3-1):

##STR107## wherein, R₃¹, R₃², and R₃³ are the same as defined in claim 12 comprising reacting a heptanoic acid derivative represented by the following formula (3-2);

##STR108## wherein R₃¹ and R₃² are the same as defined in claim 12, with an enyne compound represented by the following formula (3-5);

##STR109## wherein, R₃¹ is the same as defined in claim 12 in the presence of a palladium catalyst.