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

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 enantioselectivity inducer is

or a solvate thereof.

11. The method of claim 7 , wherein the compound is synthesized and worked-up by a process comprising:

(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.

12. 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 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 compound of claim 7 is prepared.

13. The method of claim 9 , wherein the ZnI 2 is formed by reacting Et 2 Zn with I 2 .

14. The method of claim 1 , further comprising purification of the compound of Formula (XI), wherein said purification comprises recrystallization.

15. The method of claim 4 , further comprising purification of the compound of Formula (XI), wherein said purification consists of solvent stripping, filtration, extraction, distillation, evaporation, recrystallization, or combinations thereof.

16. The method of claim 7 , wherein said working-up comprises purification of the compound of Formula (XI), wherein said purification comprises recrystallization.

17. The method of claim 11 , wherein said working-up comprises purification of the compound of Formula (XI), wherein said purification consists of solvent stripping, filtration, extraction, distillation, evaporation, recrystallization, or combinations thereof.