# US 8,772,544 B2 · Process for the production of bimatoprost

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- Number: US 8,772,544 B2
- Document ID: US8772544B2
- Status: Granted
- Kind: B2
- Application number: 12/999,112
- Filed: 2009-06-10
- Published: 2011-07-21
- Granted: 2014-07-08
- Earliest claimed: 2008-06-20
- Assignees: Sandoz Ltd.
- Applicants: Dominic De Souza; Martin Albert; Hubert Sturm
- Inventors: Dominic De Souza; Martin Albert; Hubert Sturm
- Web page: https://patentgrep.com/patent/US8772544B2

## CPC

- C07C 231/24: Separation; Purification
- C07C 231/12: by reactions not involving the formation of carboxamide groups
- C07C 235/34: having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C 2601/08: the ring being saturated
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The present invention relates to a process for the purification of crude bimatoprost to obtain pure bimatoprost comprising a chromatography, preferably a chromatography using an achiral stationary phase and an eluent comprising an alcohol and an apolar solvent; and crystallization of the product obtained the chromatography to obtain pure bimatoprost.

## Claims

### Claim 1

A method for the purification of crude bimatoprost according to formula (I)
comprising at least the steps of:
(a) subjecting crude bimatoprost according to formula (I) to chromatography to form a product, wherein the chromatography is carried out using an achiral stationary phase comprising silica and an eluent comprising an alcohol and an apolar solvent, and wherein the alcohol is selected from methanol and ethanol and the apolar solvent is selected from heptane, hexane and cylcohexane; and
(b) crystallizing the product obtained in step (a) from a solvent selected from ethers, acetonnitrile, alcohols, esters, or mixtures of any of these solvents to form pure bimatoprost containing less than 0.2% in total of any combination of 15R-bimatoprost and 5, 6-trans-bimatoprost.

### Claim 2 (depends on 1)

The method according to claim 1, further comprising preparing the crude bimatoprost by
(i) reacting a compound of formula (6)
with a compound of general formula (IV)
wherein A- represents a group selected from
X represents a halide; and
R represents a C6 to C10 aryl or C1 or C10 alkyl residue, to provide the crude bimatoprost.

### Claim 3

A method for the preparation of crude bimatoprost comprising at least step (i):
(i) reacting a compound of formula (6)
with a compound of general formula (IV)
wherein A- represents a group selected from
X represents a halide; and
R represents a C6 to C10 aryl or C1 or C10 alkyl residue, to provide crude bimatoprost.

### Claim 4 (depends on 3)

The method according to claim 3, wherein the reaction according to step (i) is performed in the presence of a base selected from alkali or alkaline earth metal alkoxides, alkali or alkaline earth metal hydroxides, carbonates, or oxides, sodium, potassium, or lithium hexamethylsilazide, tetramethylguanidine, or 1,8-diazabicyclo[5.4.0]undec-7-en (DBU), organolithium reagents, metal amides, or metal hydrides.

### Claim 5

A method for the preparation of crude bimatoprost comprising at least step (x) and (y):
(x) reacting a compound of formula (6)
with a compound of general formula (V)
wherein A- represents a group selected from
X represents a halide; and
R represents a C6 to C10 aryl or C1 or C10 alkyl residue, to provide a compound of formula (7)
and
(y) converting the compound of formula (7) obtained in step (x) to provide crude bimatoprost by activation of the carboxylic group of compound (7) as a mixed anhydride to form an activated intermediate, and reacting the activated intermediate with ethylamine.

### Claim 6 (depends on 5)

The method according to claim 5, wherein the reaction according to step (x) is performed in the presence of a base selected from alkali or alkaline earth metal alkoxides, alkali or alkaline earth metal hydroxides, carbonates, or oxides, sodium, potassium, or lithium hexamethylsilazide, tetramethylguanidine, or 1,8-diazabicyclo[5.4.0]undec-7-en (DBU), organolithium reagents, metal amides, or metal hydrides.

### Claim 7 (depends on 6)

A method according to claim 6, wherein in step (y), activation of the carboxylic group is achieved by reaction with pivalic acid chloride or chloroalkylformate in the presence of a base.