# US 8,541,590 B2 · Proteasome inhibitors and processes for their preparation, purification and use

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- Number: US 8,541,590 B2
- Document ID: US8541590B2
- Status: Granted
- Kind: B2
- Application number: 13/528,147
- Filed: 2012-06-20
- Published: 2012-10-25
- Granted: 2013-09-24
- Earliest claimed: 2009-12-22
- Assignees: Cephalon, Inc.
- Applicants: Renee Caroline Roemmele
- Inventors: Renee Caroline Roemmele
- Web page: https://patentgrep.com/patent/US8541590B2

## CPC

- C07F 5/025: {Boronic and borinic acid compounds}
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07F 5/02: Boron compounds
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention provides boronic esters of Formula I wherein R1, R2, R3, and R4 are as described herein, and methods for the preparation and purification thereof.

## Claims

### Claim 1

A boronic ester of Formula I
wherein
R1 is 2-(6-phenyl)pyridinyl, R2 is (1R)-1-hydroxyethyl, and R3 and R4 are H;
R1 is 2-(6-phenyl)pyridinyl, R2 is (1R)-1-hydroxyethyl, and R3 and R4 are methyl; or
R1 is 2-pyrazinyl, R2 is benzyl, and R3 and R4 are H.

### Claim 2 (depends on 1)

The boronic ester of claim 1, wherein the boronic ester is Formula IX

### Claim 3 (depends on 1)

The boronic ester of claim 1, wherein the boronic ester is Formula X

### Claim 4 (depends on 1)

The boronic ester of claim 1, wherein the boronic ester is Formula XI

### Claim 5 (depends on 1, 2, 3, 4)

A process for preparing a pharmaceutical composition, comprising the step of combining the boronic ester of any of claims 1-4 with a pharmaceutically acceptable carrier, diluent, or excipient.

### Claim 6 (depends on 1, 2, 3, 4)

A process for preparing a pharmaceutical composition of a boronic acid of Formula IA
wherein R1 is 2-(6-phenyl)pyridinyl and R2 is (1R)-1-hydroxyethyl, or R1 is 2-pyrazinyl and R2 is benzyl;
comprising the steps of:
(a) converting a boronic ester of any of claims 1-4 into a boronic acid of Formula IA; and
(b) combining the boronic acid of Formula IA with a pharmaceutically acceptable carrier, diluent, or excipient.

### Claim 7 (depends on 6)

The process of claim 6, wherein R1 is 2-(6-phenyl)pyridinyl and R2 is (1R)-1-hydroxyethyl.

### Claim 8 (depends on 6)

The process of claim 6, wherein R1 is 2-pyrazinyl and R2 is benzyl.

### Claim 9

A process for purifying a boronic acid of Formula IA
wherein
R1 is 2-(6-phenyl)pyridinyl and R2 is (1R)-1-hydroxyethyl, or R1 is 2-pyrazinyl and R2 is benzyl;
comprising the steps of:
(a) converting the boronic acid of Formula IA into a boronic ester of Formula VII
(b) crystallizing the boronic ester of Formula VII from solution;
(c) isolating the crystallized boronic ester of Formula VII from the solution; and
(d) converting the isolated boronic ester of Formula VII back into the boronic acid of Formula IA.

### Claim 10 (depends on 9)

The process of claim 9, wherein R1 is 2-(6-phenyl)pyridinyl and R2 is (1R)-1-hydroxyethyl.

### Claim 11 (depends on 9)

The process of claim 9, wherein R1 is 2-pyrazinyl and R2 is benzyl.

### Claim 12

A process for preparing a boronic acid of Formula IA
wherein
R1 is 2-(6-phenyl)pyridinyl and R2 is (1R)-1-hydroxyethyl, or R1 is 2-pyrazinyl and R2 is benzyl;
comprising the steps of:
(a) preparing a boronic ester of Formula V
wherein
R1 is 2-(6-phenyl)pyridinyl, R2 is (1R)-1-hydroxyethyl, and R3 and R4 are H;
R1 is 2-(6-phenyl)pyridinyl, R2 is (1R)-1-hydroxyethyl, and R3 and R4 are methyl;
or
R1 is 2-pyrazinyl, R2 is benzyl, and R3 and R4 are H;
(b) crystallizing a boronic ester of Formula I from a solution of the boronic ester of Formula V
(c) converting the boronic ester of Formula I into the boronic acid of Formula IA.

### Claim 13 (depends on 12)

The process of claim 12, wherein R1 is 2-(6-phenyl)pyridinyl, R2 is (1R)-1-hydroxyethyl, and R3 and R4 are H.

### Claim 14 (depends on 12)

The process of claim 12, wherein R1 is 2-(6-phenyl)pyridinyl, R2 is (1R)-1-hydroxyethyl, and R3 and R4 are methyl.

### Claim 15 (depends on 12)

The process of claim 12, wherein R1 is 2-pyrazinyl, R2 is benzyl, and R3 and R4 are H.