1-Hydroxylation process

• US 4,338,250 A
• Filed: 04/27/1981
• Issued: 07/06/1982
• Est. Priority Date: 04/27/1981
• 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: DeLuca, Hector F., Paaren, Herbert E., Schnoes, Heinrich K., Hamer, David E.
• Primary Examiner(s): Roberts, Elbert L.
• Application Number:
  US06/258,125
• Time in Patent Office: 435 Days
• Field of Search: 260/397.2, 424/236
• US Class Current: 552/653
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2602/24 the ring system containing nine carbon atoms, e.g. perhydroindane
• 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

Abstract

A process for preparing biologically active 1α-hydroxyvitamin D compounds from vitamin D compounds by hydroxylation at carbon 1 and subsequent photochemical isomerization, and novel intermediates and products resulting from this process are provided.

Claims

1. A process for preparing 1α

-hydroxy-5,6-trans-vitamin D compounds which comprises, treating a 5,6-cis-vitamin D compound having the formula ##STR3## wherein X is selected from the group consisting of hydrogen, hydroxy and protected-hydroxy, and R is any sidechain substituent desired in the 1α

-hydroxy-5,6-trans-vitamin D product,

with iodine and a mixture of SeO₂ and a hydroperoxide in the presence of organic nitrogenous base, and recovering the desired 1α

-hydroxy-5,6-trans-vitamin D product.

2. The process of claim 1 wherein the hydroperoxide is an alkylhydroperoxide.

3. The process of claim 1 wherein the nitrogenous base is selected from the group consisting of pyridine, collidine, picoline, quinoline, and octahydroacridine.

4. The process of claim 3 where the nitrogenous base is pyridine.

5. The process of claim 1 wherein SeO₂ is used in stoichometric amounts relative to vitamin D starting material.

6. The process of claim 1, wherein SeO₂ is used in catalytic amounts relative to vitamin D starting material.

7. The process of claim 1 wherein the 1α

-hydroxy-5,6-trans-vitamin D compound is isomerized to the corresponding 1α

-hydroxy vitamin D compound by irradiation in the presence of a photosensitizer, and the 1α

-hydroxyvitamin D compound is recovered.

8. The process of claim 7 wherein the photosensitizer used is selected from the group consisting of anthracene, phenazine, and acridine.

9. The process of claims 1 or 7 where R is selected from ##STR4## wherein each of R₁ and R₂ is selected from the group consisting of hydrogen, hydroxy, protected-hydroxy, and fluoro, or where R₁ and R₂ when taken together form a double bond or an epoxide grouping, where each of R₃, R₄, and R₅ is selected from the group consisting of hydrogen, hydroxy, protected-hydroxy and fluoro, or where R₃ and R₄, or R₄ and R₅, when taken together form an epoxide grouping or a double bond, where R₆ is selected from the group consisting of hydrogen, alkyl, and fluoro, where R₇ is selected from the group consisting of hydroxy, alkyl and O-alkyl, and n is an integer from about 1 to about 4.

14. The process of claim 1 wherein the vitamin D starting material is vitamin D₃.

15. The process of claim 1 wherein the Vitamin D starting material is 25-hydroxy-vitamin D₃.

16. The process of claim 1 wherein the vitamin D starting material is 24,25-dihydroxyvitamin D₃.

17. The process of claim 1 wherein the vitamin D starting material is 25,26-dihydroxyvitamin D₃.

18. The process of claim 1 wherein the vitamin D starting material is vitamin D₂.

19. The process of claim 1 wherein the vitamin D starting material is 25-hydroxyvitamin D₂.

20. The process of claim 1 wherein the vitamin D starting material is 24,25-dihydroxyvitamin D₂.

21. The process of claim 1 wherein the vitamin D starting material is 24-hydroxyvitamin D₂.

10. A process for separating a vitamin D compound having a 1,3-trans-diol configuration, or a 5,6-trans vitamin D compound having a 1,3-trans-diol configuration, from an epimeric mixture containing said vitamin D compound and the corresponding 1,3-cis-diol epimer, or containing said 5,6-trans vitamin D compound and the corresponding 1,3-cis-diol epimer, which comprises,

treating said epimeric mixture with an alkyl or aryl-boronic acid whereby a cyclic 1,3-boronate ester of the vitamin D compound or the 5,6-trans vitamin D compound having the 1,3-cis-diol configuration is obtained,

separating said vitamin D or 5,6-trans-vitamin D boronate ester from the reaction mixture, and

recovering the desired vitamin D compound or 5,6-trans-vitamin D compound having a 1,3-trans-diol configuration.

11. A process according to claim 10 wherein the boronic acid used is phenylboronic acid.

12. A process according to claim 10 or 11 wherein the recovered vitamin D compound having a 1,3-trans-diol configuration is a 1α

-hydroxyvitamin D compound.

13. A process according to claim 10 or 11 wherein the recovered 5,6-trans-vitamin D compound having a 1,3-trans-diol configuration is a 1α

-hydroxy-5,6-trans-vitamin D compound.