Compounds and synthetic methods for the preparation of retinoid X receptor-specific retinoids

Patent metadata

Field	Value
Publication number	US-10919835-B2
Application number	US-202016799176-A
Country	US
Kind code	B2
Filing date	Feb 24, 2020
Priority date	Nov 17, 2017
Publication date	Feb 16, 2021
Grant date	Feb 16, 2021

Abstract

Provided herein are compounds useful for the preparation of compounds that have retinoid-like biological activity. Also provided herein are processes for the preparation of compounds that have retinoid-like biological activity.

First claim

What is claimed is:

1. A method of making Compound 38,

or a pharmaceutically acceptable salt thereof,

comprising a synthetic process of preparing intermediate compound 8, (Z)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)but-2-en-1-ol, of Formula (XII),

or a solvate thereof,

by reacting compound 4, sodium (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)boronate of Formula (XVI),

or a solvate thereof,

with compound 7, (Z)-3-iodobut-2-en-1-ol, of Formula (XVII),

or a solvate thereof,

in the presence of Pd/C and a base, such that the compound of Formula (XII) or a solvate thereof is prepared.

2. The method of claim 1 , wherein Compound 38 has an enantiomeric excess of Compound A,

of at east about 98.0%.

3. The method of claim 1 , wherein the base is K 2 CO 3 .

4. The method of claim 1 , wherein the reaction comprises a solvent comprising EtOH.

5. A method of synthesizing compound 8, (Z)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)but-2-en-1-ol, of Formula (XII),

or a solvate thereof,

by reacting compound 4, sodium (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)boronate of Formula (XVI),

or a solvate thereof,

with compound 7, (Z)-3-iodobut-2-en-1-ol, of Formula (XVII),

or a solvate thereof,

in the presence of Pd/C and a base, such that the compound of Formula (XII) or a solvate thereof is prepared.

6. The method of claim 5 , wherein the base is K 2 CO 3 .

7. The method of claim 5 , wherein the reaction comprises a solvent comprising EtOH.

8. The method of claim 1 , wherein the synthetic process of preparing intermediate compound 8 is carried out at kilogram scale.

9. The method of claim 1 , wherein the synthetic process of preparing intermediate compound 8 is carried out utilizing at least 1 kilogram of each of compound 4 and compound 7.

10. The method of claim 1 , wherein the synthetic process of preparing intermediate compound 8 produces at least 1 kilogram of compound 8.

11. The method of claim 1 , wherein the synthetic process of preparing intermediate compound 8 has a yield of about 84%.

12. The method of claim 1 , wherein the synthetic process of preparing intermediate compound 8 has a yield of at least 84%.

13. The method of claim 5 , wherein synthesizing compound 8 is carried out at kilogram scale.

14. The method of claim 5 , wherein synthesizing compound 8 is carried out utilizing at least 1 kilogram of each of compound 4 and compound 7.

15. The method of claim 5 , wherein synthesizing compound 8 produces at least 1 kilogram of compound 8.

16. The method of claim 5 , wherein synthesizing compound 8 has a yield of about 84%.

17. The method of claim 5 , wherein synthesizing compound 8 has a yield of at least 84%.

Assignees

• Io Therapeutics Inc

Inventors

• Chandraratna Roshantha A
• Vuligonda Vidyasagar Pradeep
• Jacks Thomas
• Wade Peter
• Thompson Andrew

Classifications

• C07C2602/10

  the other ring being six-membered, e.g. tetraline · CPC title

• C07C51/09

  from carboxylic acid esters or lactones · CPC title

• C07C45/29

  of hydroxy groups · CPC title

• C07C29/44

  increasing the number of carbon atoms by addition reactions, i.e. reactions involving at least one carbon-to-carbon double or triple bond (C07C29/16 takes precedence) · CPC title

• C07C29/32 Primary

  increasing the number of carbon atoms by reactions without formation of -OH groups · CPC title