Methods of preparing regioselective N-alkyl triazoles

• US 10,494,349 B2
• Filed: 04/22/2019
• Issued: 12/03/2019
• Est. Priority Date: 04/23/2018
• Status: Active Grant

• Current Assignee: Corcept Therapeutics Inc.
• Original Assignee: Corcept Therapeutics Inc.
• Inventors: Hunt, Hazel, Breman, Arjen Christiaan, Gruijters, Bas Wilhelmus Theodorus
• Primary Examiner(s): Yoo, Sun Jae
• Application Number:
  US16/390,169
• Publication Number:
  US 20190322629A1
• Time in Patent Office: 225 Days
• CPC Class Codes: C07D 249/04 1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
• CPC Class Codes: C07D 249/06 with aryl radicals directly attached to ring atoms

Abstract

Methods of preparing N-2 alkylated triazoles substantially free from N-1 and N-3 alkylated triazoles are disclosed.

The methods include one-step alkylation methods and two-step alkylation methods for the preparation of N-alkylated triazoles.

Claims

1. A method of making a compound of Formula I:

2. The method of claim 1, wherein the compounds of Formula IIIa and IIIb are different, such that the method comprises

a) forming the first reaction mixture comprising a compound of Formula II:

3. The method of claim 1, wherein

R^1a is ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or cyclopropylmethyl;

and

R^1b is methyl.

4. The method of claim 1, wherein the compounds of Formula IIIa and IIIb are the same, such that the method comprises:

a) forming the first reaction mixture comprising the compound of Formula II, the non-nucleophilic base, the first solvent, and the compounds of Formula IIIa and IIIb, wherein the molar ratio of the compounds of Formula IIIa and IIIb to the compound of Formula II is greater than 2, and wherein the reaction mixture is mixed for at least two hours at or above room temperature under conditions suitable to form the compound of Formula I and at least one compound of Formula IVa or Formula IVb;

5. The method of claim 1, wherein the compounds of Formula IIIa and IIIb are the same, such that the method comprises:

a) forming the first reaction mixture comprising the compound of Formula II, the non-nucleophilic base, the first solvent, and the compounds of Formula IIIa and IIIb, wherein the molar ratio of the compounds of Formula IIIa and IIIb to the compound of Formula II is greater than 2, and wherein the reaction mixture is mixed for at least two hours at or above room temperature under conditions suitable to form the compound of Formula I and at least one compound of Formula IVa or Formula IVb;

6. The method of claim 1, wherein the non-nucleophilic base is selected from the group consisting of potassium carbonate, sodium carbonate, potassium tert-butoxide, and sodium tert-butoxide.

7. The method of claim 1, wherein the non-nucleophilic base is potassium carbonate.

8. The method of claim 1, wherein the first solvent is selected from the group consisting of acetone, acetonitrile, dimethylacetamide, tetrahydrofuran, dimethylsulfoxide, toluene, methyl tert-butyl ether, ethanol, and dimethylformamide, or combinations thereof.

9. The method of claim 1, wherein the first solvent is selected from the group consisting of dimethylacetamide, methyl tert-butyl ether, and ethanol, or combinations thereof.

10. The method of claim 1, wherein the first solvent is dimethylacetamide.

11. The method of claim 1, wherein the first reaction mixture is maintained at a temperature of from about room temperature to about 40°

C.

12. The method of claim 1, wherein the first reaction mixture is mixed for at least eight hours.

13. The method of claim 1, wherein the organic solvent in the partition mixture is dichloromethane.

14. The method of claim 4, wherein R^1a and R^1b are methyl.

15. The method of claim 1, wherein R² is SCH₂Ar, wherein Ar is phenyl.

16. The method of claim 1, wherein R² is halogen.

17. The method of claim 1, wherein

LG^1b is OSO₂R³;

and

R³ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₆-C₁₂ aryl, wherein the aryl group is substituted with 1-3 R^1a groups each independently hydrogen, C₁-C₆ alkyl, halogen, or NO₂.

18. The method of claim 1, wherein

LG^1b is OSO₂R³;

and

R³ is C₆-C₁₂ aryl substituted with 1-3 R^1a groups each independently hydrogen, C₁-C₆ alkyl, halogen, or NO₂.

19. The method of claim 1, wherein

LG^1b is OSO₂R³;

and

R³ is C₆-C₁₂ aryl substituted with 1-3 R^1a groups each independently C₁-C₆ alkyl.

20. The method of claim 1, wherein

LG^1b is OSO₂R³;

and

R³ is p-tolyl.

21. The method of claim 1, wherein LG^1b is I.

22. The method of claim 1, wherein the compound of Formula I has the structure:

23. The method of claim 1, wherein the compound of Formula I has the structure: