Synthesis of boronic ester and acid compounds

• US 8,283,467 B2
• Filed: 02/16/2010
• Issued: 10/09/2012
• 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:
  US12/706,063
• Publication Number:
  US 20100174072A1
• Time in Patent Office: 966 Days
• Field of Search: 544/229
• US Class Current: 544/229
• 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, characterized by at least one of the following features (1)-(5):

(1) in the boron “

ate”

complex of formula (XV), R³ and Y both are chloro;

(2) the coupling step (e) comprises the steps;

(i) coupling the compound of formula (XVIII) with a compound of formula (XIX) wherein X is OH in the presence of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) and a tertiary amine in dichloromethane;

(ii) performing a solvent exchange to replace dichloromethane with ethyl acetate; and

(iii) performing an aqueous wash of the ethyl acetate solution. (3) the protecting group removing step (f) comprises the steps;

(i) treating the compound of formula (XX) with HCl in ethyl acetate;

(ii) adding heptane to the reaction mixture; and

(iii) isolating by crystallization the compound of formula (XXI) as its HCl addition salt;

(4) the coupling step (g) comprises the steps;

(i) coupling the compound of formula (XXI) with 2-pyrazine-carboxylic acid in the presence of TBTU and a tertiary amine in dichloromethane;

(ii) performing a solvent exchange to replace dichloromethane with ethyl acetate; and

(iii) performing an aqueous wash of the ethyl acetate solution; and

(5) the boronic acid deprotecting step (h) comprises the steps;

(i) providing a biphasic mixture comprising the compound of formula (XXIII), an organic boronic acid acceptor, a lower alkanol , a C_5-8hydrocarbon solvent, and aqueous mineral acid;

(ii) stirring the biphasic mixture to afford the compound of formula (XIV);

(iii) separating the solvent layers; and

(iv) extracting the compound of formula (XIV), or a boronic acid anhydride thereof, into an organic solvent.

3. The process of claim 2, characterized by all five features (1)-(5).

4. The process of claim 1, wherein step (h)(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.

5. The process of claim 4, wherein in step (h)(iii)(3), the aqueous layer is washed with dichloromethane.

6. The process of claim 2, wherein in step (h)(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.

7. The process of claim 6, wherein addition of hexane or heptane results in crystallization of a cyclic trimeric boronic acid anhydride of formula (XXIV):