# US 9,518,017 B2 · Purification of intermediates used in the preparation of heterobifunctional linkers

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- Number: US 9,518,017 B2
- Document ID: US9518017B2
- Status: Granted
- Kind: B2
- Application number: 14/897,675
- Filed: 2014-06-26
- Published: 2016-05-19
- Granted: 2016-12-13
- Earliest claimed: 2013-06-28
- Assignees: ImmunoGen, Inc.
- Applicants: ImmunoGen, Inc.
- Inventors: Wayne C. Widdison
- Web page: https://patentgrep.com/patent/US9518017B2

## CPC

- C07D 213/71: to which a second hetero atom is attached
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention is directed to a method of separating a monocarboxylic represented by the following structural formula: (I) from a dicarboxylic acid represented by the following structural formula: (II) using silica chromatography.

## Claims

### Claim 1

A method of separating a monocarboxylic acid represented by the following structural formula:
from a dicarboxylic acid represented by the following structural formula:
in a mixture comprising the mono and dicarboxylic acids, wherein R1 and R2 are each independently H or a C1-C4 alkyl group, said method comprising the steps of:
1) applying the mixture to a silica gel column; and
2) separating the monocarboxylic acid and the dicarboxylic acid by eluting them from the silica gel column using an elution solvent system and collecting an eluent comprising the monocarboxylic acid, wherein the elution solvent system comprises an organic solvent in the absence of an acid.

### Claim 2 (depends on 1)

The method of claim 1, wherein the elution solvent system comprises a non-polar organic solvent and a polar organic solvent in the absence of an organic acid.

### Claim 3 (depends on 2)

The method of claim 2, wherein the mixture is the isolated reaction product between a first starting material represented by
and a second starting material represented by

### Claim 4 (depends on 2)

The method of claim 2, wherein the polar organic solvent is an organic solvent having a dielectric point of greater than 15.

### Claim 5 (depends on 2)

The method of claim 2, wherein the polar organic solvent is an ester solvent.

### Claim 6 (depends on 2)

The method of claim 2, wherein the polar organic solvent is an alcohol solvent or an ether solvent.

### Claim 7 (depends on 2)

The method of claim 2, wherein the polar organic solvent is methyl acetate, ethyl acetate, ethyl formate, methyl propionate, ethyl propionate, propyl propionate, tetrahydrafuran, 2-methyl tetrahydrofuran, methanol, ethanol, propanol, dimethoxyethane or a mixture of any of the foregoing.

### Claim 8 (depends on 7)

The method of claim 7, wherein the non-polar organic solvent is a hydrocarbon solvent.

### Claim 9 (depends on 8)

The method of claim 8, wherein the hydrocarbon solvent is pentane, hexane, heptane, octane, petroleum ether or a mixture of any of the forgoing.

### Claim 10 (depends on 2)

The method of claim 2 wherein the elution solvent system is a mixture of heptane and ethyl acetate.

### Claim 11 (depends on 2)

The method of claim 2, wherein the volume ratio of the non-polar organic solvent to the polar organic solvent is between 1:1 and 10:1.

### Claim 12 (depends on 11)

The method of claim 11, the volume ratio of the non-polar organic solvent to the polar organic solvent is 4:1.

### Claim 13 (depends on 1)

The method of claim 1, wherein R1 and R2 are both hydrogen.

### Claim 14 (depends on 1)

The method of claim 1, wherein R1 is hydrogen and R2 is methyl.