# US 9,428,442 B2 · Process for the preparation of Clomiphene

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- Number: US 9,428,442 B2
- Document ID: US9428442B2
- Status: Granted
- Kind: B2
- Application number: 14/869,065
- Filed: 2015-09-29
- Published: 2016-06-02
- Granted: 2016-08-30
- Earliest claimed: 2014-10-28
- Assignees: F.I.S. Fabbrica Italiana Sintetici S.p.A.
- Applicants: F.I.S.—Fabbrica Italiana Sintetici S.P.A.
- Inventors: Siro Serafini; Pierluigi Padovan
- Web page: https://patentgrep.com/patent/US9428442B2

## CPC

- C07C 213/08: by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
- C07F 9/65744: {condensed with carbocyclic or heterocyclic rings or ring systems}
- C07B 2200/09: Geometrical isomers
- C07C: ACYCLIC OR CARBOCYCLIC 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)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

An improved process for the preparation of the active pharmaceutical ingredient Clomiphene and, in particular, trans-Clomiphene, using acetic acid or trifluoroacetic acid is disclosed.

## Claims

### Claim 1

A process for the preparation of Clomiphene and salts thereof, comprising reacting a mixture of geometric isomers of formula (V-E) and (V-Z) or salts thereof:
in an organic solvent with a chlorinating agent, wherein the reacting is performed in presence of acetic acid or trifluoroacetic acid.

### Claim 2 (depends on 1)

The process according to the claim 1, wherein the amount of acetic acid or trifluoroacetic acid is between 1 and 3 volumes.

### Claim 3 (depends on 1)

The process according to claim 1, wherein the organic solvent is methylene chloride.

### Claim 4 (depends on 2)

The process according to claim 2, wherein the amount of methylene chloride is between 5 and 11 volumes.

### Claim 5 (depends on 1)

The process according to claim 1, wherein the amount of acetic acid or trifluoroacetic acid is between 1 and 3 volumes and the amount of methylene chloride is between 5 and 11 volumes.

### Claim 6 (depends on 5)

The process according to the claim 5, wherein the amount of acetic acid or trifluoroacetic acid is about 2 volumes and the amount of methylene chloride is about 8 volumes.

### Claim 7 (depends on 1)

The process according to claim 1, wherein the reacting is performed at a temperature between 20° C. and 40° C.

### Claim 8 (depends on 1)

The process according to claim 1, wherein the amount of chlorinating agent is in the range of from 0.45 to 0.60 molecular equivalents.

### Claim 9 (depends on 1)

The process according to claim 1, wherein the chlorinating agent is dichlorodimethylhydantoin.

### Claim 10 (depends on 1)

The process according to claim 1, wherein the reacting is carried out under anhydrous conditions.

### Claim 11

A process for the preparation of trans-Clomiphene and salts thereof, comprising reacting a mixture of geometric isomers of formula (V-E) and (V-Z) or salts thereof:
in an organic solvent with a chlorinating agent, wherein the organic solvent is methylene chloride and the reacting is performed in presence of acetic acid or trifluoroacetic acid.

### Claim 12 (depends on 1)

The process according to claim 1, wherein the Clomiphene prepared by said process is a mixture of trans-Clomiphene and cis-Clomiphene in ratio from 75:25 to 99:1.