Process for preparing vitamin D.sub.2 compounds and the corresponding 1 .alpha.-hydroxylated derivatives

• US 5,030,772 A
• Filed: 02/14/1990
• Issued: 07/09/1991
• Est. Priority Date: 02/14/1990
• Status: Expired due to Term

• Current Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Original Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Inventors: Okada, Shigeya, DeLuca, Hector F., Schnoes, Heinrich K.
• Primary Examiner(s): Lone, Werren B.
• Application Number:
  US07/481,990
• Time in Patent Office: 510 Days
• Field of Search: 568/715, 568/822, 568/823, 568/835, 568/838, 568/817, 568/
• US Class Current: 568/817
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/12 for decreasing, blocking or antagonising the activity of the posterior pituitary hormones
• 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: C07J 71/0042 Nitrogen only

Abstract

This invention relates to hydroxylated derivatives of vitamin D₂ and a process for preparing such compounds. In particular, a process for preparing the 24-epimer of vitamin D₂ and the corresponding 1α-hydroxylated derivative thereof is disclosed. The vitamin D₂ derivatives would find application in the treatment of or prophylaxsis for various disease states characterized by calcium and phosphorous imbalances.

Claims

1. A method for preparing vitamin D compounds having the formula

where R₃ can have either the R or S configuration and wherein n is an integer having a value of from 1 to 5, X₁ is selected from hydrogen or a hydroxy protecting group, R₃ is selected from an alkyl of 1 to 6 carbon atoms, hydroxy, protected hydroxy, hydrogen or fluorine, and where R₁ and R₂, which may be the same or different, are each selected from an alkyl of 1 to 6 carbon atoms or an aryl, said aryl selected from the group consisting of a phenyl or a substituted phenyl, which comprises condensing in the presence of a strong base in an organic solvent at a temperature below 0°

C. a steroidal aldehyde of the formula ##STR6## wherein X₁ is as defined above, with an arylsulfone of the formula

space="preserve" listing-type="equation">ArSO.sub.2 CH.sub.2 R

wherein Ar is selected from the group consisting of a phenyl and a tolyl, and R is selected from the group consisting of an alkyl of from 1 to 25 carbon atoms, hydroxylated alkyl, hydroxy-protected hydroxylated alkyl, fluoro-substituted alkyl, fluoro-substituted hydroxylated alkyl and fluoro-substituted hydroxy-protected alkyl, whereby a hydroxy-sulfonyl adduct of the formula ##STR7## is obtained, wherein Ar, R and X₁ are as defined above, reducing said adduct with a metal amalgum reagent in an organic solvent at a temperature of from about 0°

C. to about ambient to obtain an intermediate of the formula ##STR8## wherein R and X₁ are as defined above, and converting said intermediate to obtain the desired vitamin D compound.

2. The method of claim 1 wherein X₁ is hydrogen.

3. The method of claim 1 wherein R₁ and R₂ are both an alkyl group of 1 to 6 carbon atoms.

4. The method of claim 1 wherein R is a hydroxylated alkyl group or a hydroxy-protected hydroxylated alkyl group of from 1 to 25 carbon atoms.

5. The method of claim 1 wherein R is a fluoro-substituted alkyl group of from 1 to 25 carbon atoms.

6. The method of claim 1 wherein R is a fluoro-substituted hydroxylated alkyl group of from 1 to 25 carbon atoms, or a fluoro-substituted hydroxy-protected alkyl group of from 1 to 25 carbon atoms.

7. The method of claim 1 wherein the vitamin D compound is 24-epi-vitamin D₂.

8. The method of claim 1 wherein the vitamin D compound is vitamin D₂.

13. The method of claim 1 wherein the vitamin D compound is further subjected to a 1α

hydroxylation process so as to obtain the corresponding 1α

hydroxylated vitamin D compound.

9. A method for preparing 24-epi-vitamin D₂ having the formula ##STR9## which comprises condensing in the presence of a strong base in an organic solvent at a temperature below 0°

C. a steroidal aldehyde of the formula ##STR10## with a phenylsulfone of the formula ##STR11## whereby a hydroxy-sulfonyl adduct of the formula ##STR12## is obtained, reducing said adduct with a metal amalgum reagent in an organic solvent at a temperature of from about 0°

C. to about ambient to obtain an intermediate of the formula ##STR13## and converting said intermediate to obtain 24-epi-vitamin D₂.

10. The method of claim 9 wherein the 24-epi-vitamin D₂ compound is further subjected to a 1α

hydroxylation process so as to obtain the corresponding 1α

hydroxylated-24-epi-vitamin D₂ compound.

11. A method for preparing vitamin D₂ having the formula ##STR14## which comprises condensing in the presence of a strong base in an organic solvent at a temperature below 0°

C. a steroidal aldehyde of the formula ##STR15## with a phenyl sulfone of the formula ##STR16## whereby a hydroxy-sulfonyl adduct of the formula ##STR17## is obtained, reducing said adduct with a metal amalgum reagent in an organic solvent at a temperature of from about 0°

C. to about ambient to obtain an intermediate of the formula ##STR18## and converting said intermediate to obtain vitamin D₂.

12. The method of claim 11 wherein the vitamin D₂ compound is further subjected to a 1α

hydroxylation process so as to obtain the corresponding 1α

hydroxylated vitamin D₂ compound.