Process for making bortezomib and intermediates for the process

• US 8,884,009 B2
• Filed: 10/14/2010
• Issued: 11/11/2014
• Est. Priority Date: 10/14/2010
• Status: Active Grant

• Current Assignee: Synthon BV (Synthon International Holding BV)
• Original Assignee: Synthon BV (Synthon International Holding BV)
• Inventors: Castulik, Jakub, Zabadal, Miroslav
• Primary Examiner(s): MCDOWELL, BRIAN E
• Application Number:
  US13/879,515
• Publication Number:
  US 20130203988A1
• Time in Patent Office: 1,489 Days
• Field of Search: 544/229, 544/406
• US Class Current: 544/229
• CPC Class Codes: C07D 241/24 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07F 5/04 Esters of boric acids
• CPC Class Codes: C07F 9/3895 Pyrophosphonic acids; phosphonic acid anhydrides
• CPC Class Codes: C07F 9/657163 the ring phosphorus atom being bound to at least one carbon atom
• CPC Class Codes: C07F 9/657181 the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative

Abstract

The invention relates to processes of making bortezomib of formula (1) enantiomers thereof and/or intermediates thereof, comprising at least one step of coupling a carboxylic acid with an amine, wherein the coupling step is performed in a presence of the compound of formula (8), wherein A is C1-C6 alkyl group, preferably wherein A is n-propyl group.

Claims

1. In a process for making bortezomib of formula (1),

2. The process according to claim 1, wherein said coupling reaction produces a protected bortezomib of formula (4A),

3. The process according to claim 2, wherein said coupling reaction comprises coupling protected (R)-1-amino-3-methylbutylboronic acid of formula (2A),

4. The process according to claim 3, wherein PR is an (S)-pinanediol protective group.

5. The process according to claim 2, wherein said coupling reaction comprises coupling a compound of formula (3A)

6. The process according to claim 1, wherein said coupling reaction comprises coupling a compound of formula (5) and/or an acid addition salt thereof

7. The process according to claim 1, wherein said coupling reaction comprises coupling a compound of formula (2A),

8. The process according to claim 7, wherein PR is an (S)-pinanediol protective group.

9. The process according to claim 1, wherein A in formula (8) is n-propyl.

10. The process according to claim 1, wherein said process for making bortezomib comprises two coupling reactions, each between a carboxylic acid and an amine in the presence of a coupling reagent, to form the two peptide bonds in the bortezomib structure, and wherein said coupling reagent in both of said coupling reactions is a compound of formula (8).

11. The process according to claim 4, wherein A in formula (8) is n-propyl.

12. The process according to claim 8, wherein A in formula (8) is n-propyl.

13. The process according to claim 10, wherein A in formula (8) is n-propyl.