Granted Patent B2

US 12,365,691 · App. 18/298,226 · Granted Jul 22, 2025

Inventors: Arun K. Ghosh (West Lafayette, IN); Shivaji Markad (West Lafayette, IN)

Assignee: Purdue Research Foundation

C07D493/04

Abstract

Claims (68)

1. A method of making a compound of the formula (I):

or a salt thereof, with an enantiomeric excess (ee) of at least 90%;

wherein:

X 1 is alkylene, —O—, —CH 2 NR 1 — or —NHR 1 —, wherein R 1 is alkyl, aryl or heteroaryl, and

R 2 is hydroxy, alkoxy or amido;

the method comprising

(i) converting a compound of the formula (II):

or a salt thereof,

to a compound of the formula (III):

or a salt thereof;

(ii) converting the compound of formula (III), or a salt thereof, to a compound of the formula (IV):

or a salt thereof; and

(iii) converting the compound of formula (IV), or a salt thereof, to the compound of the formula (I).

2. The method of claim 1 , wherein the converting in step (i) comprises ring opening of the compound of the formula (II).

3. The method of claim 1 , wherein the converting in step (ii) comprise reducing the compound of formula (III) to a compound of the formula (IV), or a salt thereof.

4. The method of claim 1 , wherein the converting in step (iii) comprises ozonolysis of the compound of formula (IV), or a salt thereof, to give an ozonolysis product, or a salt thereof.

5. The method of claim 4 , further comprising reducing the ozonolysis product, or a salt thereof, to obtain the compound of the formula (I).

6. The method of claim 4 , wherein the ozonolysis product is of the formula (V):

or a salt thereof.

7. The method of claim 1 , wherein X 1 is alkylene.

8. The method of claim 7 , wherein alkylene is a C 1 -C 3 (alkylene) group.

9. The method of claim 8 , wherein the alkylene is —CH 2 —.

10. The method of claim 1 , wherein X 1 is alkylene and R 2 is hydroxy.

11. A method of making a compound of the formula (VI):

or a salt thereof, with an enantiomeric excess (ee) of at least 90%;

wherein:

X 1 is alkylene, —O—, —CH 2 NR 1 — or —NHR 1 —, wherein R 1 is alkyl, aryl or heteroaryl;

the method comprising:

(i) converting a compound of the formula (I):

or a salt thereof,

wherein:

X 1 is alkylene, —O—, —CH 2 NR 1 — or —NHR 1 —, wherein R 1 is alkyl, aryl or heteroaryl, and

R 2 is hydroxy, alkoxy or amido,

to a compound of the formula (VII):

or a salt thereof, wherein X 2 is O or CH 2 ; and

(ii) converting the compound of formula (VII), or a salt thereof, to a compound of the formula (VI), or a salt thereof.

12. The method of claim 11 , further comprising (iii) converting the compound of the formula (I) to a compound of the formula (VIII):

or a salt thereof,

wherein:

X 1 is alkylene —O—, —CH 2 NR 1 — or —NHR 1 —, wherein R 1 is alkyl, aryl or heteroaryl, and

R 3 is hydroxyalkyl or COR 2 , wherein R 2 is hydroxy, alkoxy or amido; and

(iv) converting the compound of the formula (VIII) to the compound of the formula (VII), wherein X 2 is CH 2 .

13. The method of claim 12 , wherein R 3 is —CH 2 OH.

14. The method of claim 12 , further comprising (v) converting the compound of the formula (VII), or a salt thereof, wherein X 2 is CH 2 to the compound of the formula (VII), or a salt thereof, wherein X 2 is O.

15. The method of claim 11 , wherein X 1 is alkylene.

16. The method of claim 14 , wherein alkylene is a C 1 -C 3 (alkylene) group.

17. The method of claim 15 , wherein the alkylene is —CH 2 —.

18. The method of claim 11 , further comprising (vi) converting the compound of formula (VI), or a salt thereof, to a compound of the formula (IX):

or a salt thereof, wherein R 4 is optionally substituted aryl.

19. The method of claim 18 , further comprising conjugating the compound of the formula (IX), or a salt thereof, with a compound of the formula (X):

or a salt thereof, wherein:

n is an integer from 1 to 3;

R 5 is alkoxy, hydroxyalkyl, halo or heterocyclylalkyloxy;

R 6 is alkyl, haloalkyl, arylalkyl, cycloalkylalkyl, heterocyclylcarbonyl or heterocyclylalkyl; and

R 7 is aryl or heteroaryl, to give a compound of the formula (XI):

or a salt thereof.

20. A method of making a compound of the formula (VIII):

or a salt thereof, with an enantiomeric excess (ee) of at least 90%;

wherein:

X 1 is alkylene —O—, —CH 2 NR 1 — or —NHR 1 —, wherein R 1 is alkyl, aryl or heteroaryl, and

R 3 is hydroxyalkyl or COR 2 , wherein R 2 is hydroxy, alkoxy or amido;

the method comprising:

(i) converting a compound of the formula (I):

or a salt thereof,

wherein:

X 1 is alkylene —O—, —CH 2 NR 1 — or —NHR 1 —, wherein R 1 is alkyl, aryl or heteroaryl; and

R 2 is hydroxy, alkoxy or amido,

to a compound of the formula (VIII).

Assignments (2)

Continuity (2)

References Cited (11)