Process for preparing 1-.alpha.-hydroxy cholesterol derivatives

• US 4,046,760 A
• Filed: 07/01/1976
• Issued: 09/06/1977
• Est. Priority Date: 07/01/1976
• Status: Expired due to Term

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Jones, Howard, Frankshun, Robert A.
• Primary Examiner(s): Roberts, Elbert L.
• Application Number:
  US05/701,917
• Time in Patent Office: 432 Days
• Field of Search: 260/397.2, 260/239.55
• US Class Current: 540/78
• CPC Class Codes: C07J 71/001 Oxiranes
• CPC Class Codes: C07J 9/00 Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

Abstract

Improved processes are described for introducing a 1-α-hydroxy group into the cholesterol ring system. Novel intermediates and their preparation are disclosed.

Claims

1. A process for the preparation of a 1α

-hydroxycholes-5-enol of the formula;

##STR3## wherein R₂₄ is a member selected from the group consisting of hydrogen and methyl and R₂₅ is a member selected from the group consisting of hydrogen and hydroxy and wherein the dashed line at C-22-23 represents the optional presence of a double bond, which comprises;

p1 a. treating R₂₄, R₂₅ -Δ

⁴ -cholestene-3-one of formula I with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in the presence of a hydrocarbon solvent having a boiling point of about 70°

to about 120°

C. to produce R₂₄, R₂₅ -Δ

¹,4 -cholestediene-3-one of formula II;

b. rearranging the product of Step (a) with a proton abstracting base to produce R₂₄, R₂₅ -Δ

¹,5 -cholestediene-3-one of formula III;

c. treating the product of Step (b) with a reducing agent capable of reducing a keto group to a hydroxy group to produce R₂₄, R₂₅ -Δ

¹,5 -cholestediene-3β

-ol of formula IV;

d. treating the product of Step (c) with an oxidizing agent capable of epoxidizing the 3-hydroxy-Δ

'"'"'-system to produce R₂₄,R₂₅,1α

,2α

-epoxy-Δ

⁵ -cholestene-3β

-ol of formula V; and

e. treating the product of Step (d) with a reducing agent capable of reducing the epoxide group to a hydroxy group to produce R₂₄,R₂₅,1α

-hydroxycholest-5-enol of formula VI.

2. A process for the preparation of a 1α

-hydroxycholest-5-enol of the formula;

##STR4## wherein R₂₄ is a member selected from the group consisting of hydrogen and methyl and R₂₅ is a member selected from the group consisting of hydrogen and hydroxy, and wherein the dashed line at C-22-23 represents the optional presence of a double bond, which comprises;

a. acetylating R₂₄,R₂₅ -Δ

¹,5 -cholestediene-3β

-ol of formula IV with acetic anhydride to produce R₂₄,R₂₅ -Δ

¹,5 -cholestediene-3-β

-acetate of formula VII;

b. treating the product of Step (a) with an oxidizing agent capable of epoxidizing the 3-hydroxy-Δ

'"'"'-system to produce R₂₄,R₂₅,1α

,2α

-epoxy-Δ

⁵ -cholestene-3β

-acetate of formula VIII; and

c. treating the product of Step (b) with a reducing agent capable of reducing the epoxide group to a hydroxy group to produce R₂₄,R₂₅,1α

-hydroxycholest-5-enol of formula VI.

3. A 1α

,2α

-epoxy-Δ

⁵ -cholestene-3β

-ol of the formula;

##STR5## wherein R₂₄ is a member selected from the group consisting of hydrogen and methyl, R₂₅ is a member selected from the group consisting of hydrogen and hydroxy and R is a member selected from the group consisting of hydrogen and acetyl and wherein the dashed line at C-22-23 represents the optional presence of a double bond.

4. The compound of claim 3 wherein R₂₄ and R₂₅ are hydrogen.

5. The compound of claim 4 which is 1α

-2α

-epoxy-Δ

⁵ -cholestene-3β

-ol.

6. The compound of claim 4 which is 1α

,2α

-epoxy-Δ

⁵ -cholestene-3β

-acetate.