Synthesis of boronic ester and acid compounds

• US 9,862,745 B2
• Filed: 01/08/2016
• Issued: 01/09/2018
• Est. Priority Date: 03/30/2004
• Status: Active Grant

• Current Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Original Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Inventors: Ammoscato, Vince, Bishop, John E., Chiu, Fang-Ting, Geiser, Achim, Gomez, Jean-Marc, Hett, Robert, Koellner, Christoph, Kulkarni, Vithalanand R., Lo, Young, Munk, Stephen, Pickersgill, I. Fraser
• Primary Examiner(s): Shiao, Rei Tsang
• Application Number:
  US14/991,363
• Publication Number:
  US 20160362449A1
• Time in Patent Office: 732 Days
• Field of Search: 544229
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07F 5/04 Esters of boric acids
• CPC Class Codes: C07K 5/06191 containing heteroatoms different from O, S, or N
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to the synthesis of boronic ester and acid compounds. More particularly, the invention provides improved synthetic processes for the large-scale production of boronic ester and acid compounds, including the peptide boronic acid proteasome inhibitor bortezomib.

Claims

1. A large-scale process for forming a compound of formula (XIV):

2. The process of claim 1, wherein step (dd)(iii) comprises the steps:

(1) separating the solvent layers;

(2) adjusting the aqueous layer to basic pH;

(3) washing the aqueous layer with an organic solvent; and

(4) adjusting the aqueous layer to a pH less than about 8.

3. The process of claim 2, wherein in step (dd)(iv), the compound of formula (XIV), or a boronic acid anhydride thereof, is extracted into dichloromethane, the solvent is exchanged to ethyl acetate, an the compound of formula (XIV), or a boronic acid anhydride thereof, is crystallized by addition of hexane or heptane.

4. The process of claim 3, wherein addition of hexane or heptane results in crystallization of a cyclic trimeric boronic acid anhydride of formula (XXIV):