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

Patent metadata

Field	Value
Publication number	US-10590059-B2
Application number	US-201816194141-A
Country	US
Kind code	B2
Filing date	Nov 16, 2018
Priority date	Nov 17, 2017
Publication date	Mar 17, 2020
Grant date	Mar 17, 2020

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,
wherein:
Compound 38 has an enantiomeric excess of Compound A,

of least about 98.0%;

comprising a synthetic process of preparing an intermediate compound, wherein the intermediate compound is Formula (XIa),

or a hydrate or a solvate thereof,

wherein the intermediate compound has an enantiomeric excess of a compound of Formula (XI),

or a hydrate or a solvate thereof,

of at least about 80.0%; wherein the process of preparing the intermediate compound, comprises contacting a compound of Formula (XII),

or a solvate thereof, with:

a) CH 2 I 2 , Et 2 Zn, ZnI 2 , and an enantioselectivity inducer of Formula (XV) or its enantiomer,

or a solvate thereof,
such that the intermediate compound is prepared; or

b) (i) an enantioselectivity inducer of Formula (XIII),

or a solvate thereof,
in a solution in the presence of CH 2 I 2 and Et 2 Zn to form a reaction product of the compound of Formula (XII), or a solvate thereof; and

 (ii) subsequently, contacting the solution of step (i) with H 2 O 2 , such that the compound of Formula (XI) or a solvate thereof is prepared; or
c) an enantioselectivity inducer of Formula (XIV) or its enantiomer,

or a solvate thereof,
in the presence of CH 2 I 2 and dialkylzinc such that the intermediate compound is prepared,
wherein the entire method of making Compound 38 comprises only a single synthetic step to produce the compound of Formula (XI).

2. The method of claim 1 , wherein the process of preparing the intermediate compound, comprises:
contacting a compound of Formula (XII),

or a solvate thereof,
with CH 2 I 2 , Et 2 Zn, ZnI 2 , and the enantioselectivity inducer of Formula (XV) or its enantiomer,

or a solvate thereof,

such that the intermediate compound is prepared.

3. The method of claim 2 , wherein the enantioselectivity inducer or a solvate thereof, is

or a solvate thereof.

4. The method of claim 1 , wherein the process of preparing the intermediate compound, comprises:
(i) contacting a compound of Formula (XII),

or a solvate thereof,

with the enantioselectivity inducer of Formula (XIII),

or a solvate thereof,
in a solution in the presence of CH 2 I 2 and Et 2 Zn to form a reaction product of the compound of Formula (XII), or a solvate thereof; and

(ii) subsequently, contacting the solution of step (i) with H 2 O 2 , such that the compound of Formula (XI) or a solvate thereof is prepared.

5. The method of claim 1 , wherein the process of preparing the intermediate compound, comprises:
contacting a compound of Formula (XII),

or a solvate thereof,

with the enantioselectivity inducer of Formula (XIV) or its enantiomer,

or a solvate thereof,

in the presence of CH 2 I 2 and dialkylzinc such that the intermediate compound is prepared.

6. The method of claim 2 , wherein the ZnI 2 is formed by reacting Et 2 Zn with I 2 .

7. A method of synthesizing and working-up a compound of, Formula (XI),

or a hydrate or a solvate thereof,
having an enantiomeric excess of at least about 85% over its enantiomer wherein the of Formula (XI) compound is prepared by a process comprising:
contacting a compound of Formula (XII),

or a solvate thereof,

a) CH 2 I 2 , Et 2 Zn, ZnI 2 , and an enantioselectivity inducer of Formula (XV) or its enantiomer,

or a solvate thereof,
such that the compound of Formula (XI) is prepared; or

b) (i) an enantioselectivity inducer of Formula (XIII),

or a solvate thereof,
in a solution in the presence of CH 2 I 2 and Et 2 Zn to form a reaction product of the compound of Formula (XII), or a solvate thereof; and

 (ii) subsequently, contacting the solution of step (i) with H 2 O 2 , such that the compound of Formula (XI) or a solvate thereof is prepared; or
c) an enantioselectivity inducer of Formula (XIV) or its enantiomer,

or a solvate thereof,
in the presence of CH 2 I 2 and dialkylzinc such that the compound of Formula (XI) is prepared,
wherein the synthesis and work-up comprise a single synthetic step.

8. The method of claim 7 , wherein the compound is present in an enantiomeric excess is at least about 98.0% over its enantiomer.

9. The method of claim 7 , wherein the compound is synthesized and worked-up by a process comprising:
contacting a compound of Formula (XII),

or a solvate thereof,
with CH 2 I 2 , Et 2 Zn, ZnI 2 , and the enantioselectivity inducer of Formula (XV) or its enantiomer,

or a solvate thereof,

such that the compound is prepared.

10. The method of claim 9 , wherein the enantioselec

Assignees

• Io Therapeutics Inc

Inventors

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

Classifications

• C07C33/36

  Polyhydroxylic alcohols containing six-membered aromatic rings and other rings · CPC title

• C07C57/50 Primary

  containing condensed ring systems · CPC title

• A61K31/198

  Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00) · CPC title

• C07C51/255

  of compounds containing six-membered aromatic rings without ring-splitting · CPC title

• C07B2200/07

  Optical isomers · CPC title