Compounds and methods of making sterols using diols

Patent metadata

Field	Value
Publication number	US-10214557-B2
Application number	US-201715600375-A
Country	US
Kind code	B2
Filing date	May 19, 2017
Priority date	Dec 9, 2014
Publication date	Feb 26, 2019
Grant date	Feb 26, 2019

Abstract

Compounds and methods of synthesizing oxysterols are provided. The compounds and methods provided allow the oxysterol to be safely produced at a high yield. The compounds and methods provided can produce the oxysterol in a stereoselective manner. The oxysterols of the current application can be used in effective amounts to grow bone.

First claim

What is claimed is:

1. A method of making an oxysterol, the method comprising reacting a diol having the formula:

with a borane compound to form the oxysterol or a pharmaceutically acceptable salt or solvate thereof having the formula:

wherein R1 is a straight chain alkyl, and R2 is a straight chain alkyl, and the oxysterol is anhydrous.

2. The method of claim 1 , wherein the borane compound is BH 3 and is reacted with a peroxide.

3. The method of claim 2 , wherein the peroxide is hydrogen peroxide.

4. The method of claim 3 , wherein the BH 3 and the hydrogen peroxide are reacted in the presence of tetrahydrofuran to form the oxysterol.

5. The method of claim 4 , wherein (i) the borane is reacted with the diol at a temperature of less than 5° C., (ii) the hydrogen peroxide is reacted with the diol at a temperature of less than 15° C., or (iii) the oxysterol is solidified and separated by filtration.

6. The method of claim 1 , wherein the reaction is carried out in a single container to yield the oxysterol having the formula

or a pharmaceutically acceptable salt or solvate thereof.

7. The method of claim 1 , wherein the oxysterol is purified by dissolving the oxysterol in an organic solvent.

8. The method of claim 1 , wherein the borane compound is reacted with the diol at a temperature of less than 5° C.

9. The method of claim 4 , wherein the hydrogen peroxide is reacted with the diol after the borane is reacted and the hydrogen peroxide is reacted with the diol at a temperature of less than 15° C.

10. The method of claim 1 , wherein the reaction is carried out in a single container to yield the oxysterol.

11. A method of making an oxysterol, the method comprising reacting a diol having the formula:

with borane, hydrogen peroxide and tetrahydrofuran to form the oxysterol or a pharmaceutically acceptable salt or solvate thereof having the formula:

wherein R1 is a straight chain alkyl and R2 is a straight chain alkyl, and the oxysterol is anhydrous.

12. The method of claim 11 , wherein (i) the diol is (3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(S)-2-hydroxyoctan-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol or (ii) the oxysterol is 3S,5S,6S,8R,9S,10R,13S,14S,17S)-17-((S)-2-hydroxyoctan-2-yl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-3,6-diol.

13. The method of claim 11 wherein the reaction is carried out in a single container to yield the oxysterol having the formula:

or a pharmaceutically acceptable salt or solvate thereof.

Assignees

• Warsaw Orthopedic Inc

Inventors

• Harrington Roger E
• Jacobs Jerbrena C
• Gopal Damodaragounder
• Ling Ke-Qing
• Burello Marco

Classifications

• C07J9/00 Primary

  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 · CPC title

• C07J7/002

  not substituted in position 16 · CPC title

• C07J17/00

  Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton (cardanolide, bufanolide C07J19/00) · CPC title

• C07J51/00

  Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00 · CPC title