Methods of preparing inhibitors of influenza viruses replication

• US 10,640,501 B2
• Filed: 06/06/2018
• Issued: 05/05/2020
• Est. Priority Date: 11/13/2013
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Tanoury, Gerald J., Nugent, William Aloysius, Dvornikovs, Vadims, Rose, Peter Jamison
• Primary Examiner(s): Pagano, Alexander R
• Assistant Examiner(s): Sackey, Ebenezer O
• Application Number:
  US16/000,939
• Publication Number:
  US 20180282330A1
• Time in Patent Office: 699 Days
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: B01J 2231/44 Allylic alkylation, amination, alkoxylation or analogues
• CPC Class Codes: B01J 2531/824 Palladium
• CPC Class Codes: B01J 31/04 containing carboxylic acids or their salts B01J31/0277 - B01J31/0298 take precedence; multi-metal carboxylate complexes like Pd (II) acetate, i.e. Pd3 (OAc) 6 or Cr(II)acetate, i.e. Cr2(OAc)4 B01J31/2226
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

A method of preparing Compound (1) or a pharmaceutically acceptable salt thereof:

comprises: (a) reacting Compound (X):

or a pharmaceutically acceptable salt thereof with Compound (Y):

in the presence of a palladium catalyst and a carbonate or phosphate base to form compound (Z):

or a pharmaceutically acceptable salt thereof; and (b) deprotecting the Ts group of Compound (Z) to form Compound (1) or a pharmaceutically acceptable salt thereof.

Claims

1. A method of preparing Compound (1) or a pharmaceutically acceptable salt thereof, wherein Compound (1) is represented by the following structural formula:

2. The method of claim 1, wherein the palladium catalyst of step (a) comprises a palladium-XPhos complex and a phosphate or carbonate base, wherein XPhos is 2-dicyclohexylphosphino-2′

,4′

,6′

-triisopropylbiphenyl.

3. The method of claim 2, wherein the carbonate base comprises Na₂CO₃, K₂CO₃, or a combination thereof, and the phosphate base comprises K₃PO₄, Na₃PO₄, or a combination thereof.

4. The method of claim 3, wherein carbonate base comprises K₂CO₃, and the phosphate base comprises K₃PO₄.

5. The method of claim 2, wherein the base comprises K₂CO₃.

6. The method of claim 1, wherein deprotection step (b) comprises treating Compound (Z) or a pharmaceutically acceptable salt thereof with an inorganic hydroxide comprising LiOH, NaOH, KOH, or any combination thereof.

7. The method of claim 1, wherein each of X¹ and X² are —

F.

8. The method of claim 1, wherein X¹ is —

Cl and X² is —

F.

9. The method of claim 1, wherein the epimerization of step (i) comprises treating Compound (C-1) with a C_1-6 alkoxide.

10. The method of claim 9, wherein the C_1-6 alkoxide comprises tert-butoxide, tert-amylate, or any combination thereof.