Methods of preparing inhibitors of influenza viruses replication

• US 10,023,569 B2
• Filed: 05/10/2016
• Issued: 07/17/2018
• 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:
  US15/150,476
• Publication Number:
  US 20160251354A1
• Time in Patent Office: 798 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-XPhos complex is prepared in situ by mixing a Pd(0) or a Pd(II) source with XPhos.

3. The method of claim 2, wherein the Pd(0) or the Pd(II) source comprises Pd₂(dba)₃, Pd(OAc)₂, PdCl₂, or any combination thereof, wherein dba is dibenzyllideneacetone and OAc is acetate.

4. The method of claim 3, wherein the palladium-XPhos complex is prepared in situ by mixing Pd(OAc)₂ and XPhos.

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

F.

6. The method of claim 1, wherein the base is a phosphate base or a carbonate base selected from Na₂CO₃, K₂CO₃, K₃PO₄, or Na₃PO₄.

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

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

Cl and X² is —

F.

9. The method of claim 1, wherein step (a) is performed in a solvent system comprising water and an organic solvent selected from 2-methyl THF or THF, or any combination thereof.

10. The method of claim 7, wherein step (b) comprises treating Compound (Z) or a pharmaceutically acceptable salt thereof with LiOH in a solvent system that comprises THF.

11. The method of claim 1, further comprising:

(c) reacting Compound (F)

12. The method of claim 11, further comprising:

(e) reacting Compound (C)

13. The method of claim 11, further comprising hydrogenating Compound (S)

14. The method of claim 13, further comprising reacting Compound (R)

15. The method of claim 14, further comprising:

(j) reacting 1,3-cyclohexadiene with CH≡

CHC(O)OR¹ in the presence of an aluminum catalyst to form Compound (Q)

16. The method of claim 15, wherein the aluminum catalyst comprises EtAlCl₂, Et₂AlCl, a mixture of AlCl₃ and trioctylaluminum, or any combination thereof.

17. The method of claim 15, wherein the hydrogenation of Compound (Q) comprises reacting Compound (Q) with H₂ in the presence of a Rh(I) catalyst or a poisoned Pd(0) catalyst.

18. The method of claim 17, wherein the Rh(I) catalyst comprises (PPh₃)₃RhCl or a mixture of (PPh₃)₃RhCl and ethyl propiolate, wherein Ph is phenyl.

19. The method of claim 17, wherein the poisoned Pd(0) catalyst comprises a lead-poisoned Pd(0) catalyst on CaCO₃ (Pd(Pb)/CaCO₃).