Synthesis of carbamoylpyridone HIV integrase inhibitors and intermediates

• US 8,624,023 B2
• Filed: 12/08/2009
• Issued: 01/07/2014
• Est. Priority Date: 12/11/2008
• Status: Active Grant

• Current Assignee: VIIV Healthcare Company (GlaxoSmithKline PLC), Shionogi & Co., Ltd.
• Original Assignee: VIIV Healthcare Company (GlaxoSmithKline PLC), Shionogi & Co., Ltd.
• Inventors: Yoshida, Hiroshi, Taoda, Yoshiyuki, Johns, Brian, Kawasuji, Takashi, Nagamatsu, Daiki
• Primary Examiner(s): Habte, Kahsay
• Application Number:
  US13/128,992
• Publication Number:
  US 20110282055A1
• Time in Patent Office: 1,491 Days
• Field of Search: 544/95, 544/343
• US Class Current: 544/95
• CPC Class Codes: A61K 31/351 not condensed with another ring
• CPC Class Codes: A61K 31/4412 having oxo groups directly attached to the heterocyclic ring
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 213/803 Processes of preparation
• CPC Class Codes: C07D 213/81 Amides; Imides
• CPC Class Codes: C07D 471/22 in which the condensed systems contains four or more hetero rings
• CPC Class Codes: C07D 487/22 in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07D 498/14 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 synthesis approach providing an early ring attachment via a bromination to compound I-I yielding compound II-II:

whereby a final product such as AA:

can be synthesized. In particular, the 2,4-difluorophenyl-containing sidechain is attached before creation of the additional ring Q.

Claims

1. A process of for the preparation of a pyridone compound of formula (AA), (BB) or (CC):

3. The process according to claim 1, wherein said step P-2) is carried out before creation of the Q ring.

4. The process according to claim 1, wherein said pyridone compound is of the formula AA.

5. The process according to claim 1, wherein said pyridone compound is of the formula BB.

6. The process according to claim 1, wherein said pyridone compound is of the formula CC.

7. The process according to claim 1, wherein said step P-2) is carried out after creation of the Q ring.

8. The process according to claim 7, wherein said pyridone compound is of the formula AA.

9. The process of claim 7, wherein said pyridone compound is of the formula BB.

10. The process of claim 7, wherein said pyridone compound is of the formula CC.

11. A process according to claim 1 wherein P¹ is benzyl;

P³ is methyl; and

R is —

CHO, —

CH(OH)(OR⁴), —

CH(OR⁵)(OR⁵) wherein R⁴ and R⁵ are lower alkyl.

2. A process is provided for the preparation of a pyridone compound of the following formula (AA), (BB) or (CC):