# US 2014/0155608 A1 · Method for the manufacturing of naltrexone

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- Number: US 2014/0155608 A1
- Document ID: US20140155608A1
- Status: Published application
- Kind: A1
- Application number: 13/875,351
- Filed: 2013-05-02
- Published: 2014-06-05
- Earliest claimed: 2012-05-03
- Assignees: H. Lundbeck A/S
- Applicants: H.Lundbeck A/S
- Inventors: Carla De Faveri; Mariano Stivanello; Florian Anton Martin Huber
- Web page: https://patentgrep.com/patent/US20140155608A1

## CPC

- C07D 489/08: Oxygen atom
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to a new process for producing naltrexone [17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxy-morphinan-6-one] from noroxymorphone [4,5-α-epoxy-3,14-dihydroxy-morphinan-6-one] by alkylation with a cyclopropylmethyl halide.

## Claims

### Claim 1

A process for the manufacturing of naltrexone, comprising reacting noroxymorphone with cyclopropylmethyl halide in the presence of N-methyl-2-pyrrolidone and water, wherein the total amount of water compared to noroxymorphone is from 0.4 to 4.0 equivalents.

### Claim 2 (depends on 1)

The process according to claim 1, wherein the total amount of water compared to noroxymorphone is from 0.7 to 3.5 equivalents.

### Claim 3 (depends on 1)

The process according to claim 1, wherein the reaction takes place in the presence of an acid scavenger.

### Claim 4 (depends on 3)

The process according to claim 3, wherein the acid scavenger is an inorganic or organic base or a mixture thereof.

### Claim 5 (depends on 1)

The process according to claim 1, wherein the cyclopropylmethyl halide is cyclopropylmethyl bromide.

### Claim 6 (depends on 1)

The process according to claim 1, wherein N-methyl-2-pyrrolidone is used in a weight by weight ratio of 0.5:1 to 10:1 with respect to noroxymorphone.

### Claim 7 (depends on 3)

The process according to claim 3, wherein the molar relationship between noroxymorphone and the acid scavenger is from 1:0.5 to 1:2.

### Claim 8 (depends on 1)

The process according to claim 1, wherein the molar relationship between noroxymorphone and cyclopropylmethyl halide is from 1:1 to 1:2.

### Claim 9 (depends on 1)

The process according to claim 1, wherein the reaction temperature is in the range of 30-100° C.

### Claim 10 (depends on 9)

The process according to claim 9, wherein the reaction temperature is in the range of 55-60° C.

### Claim 11 (depends on 1)

The process according to claim 1, wherein the reaction is running for at least 8 hours.

### Claim 12 (depends on 1)

The process according to claim 1, wherein the formed naltrexone is isolated by a method comprising the following steps
(a) concentrating the reaction mixture under vacuum;
(b) mixing the reaction mixture of step (a) with an acid;
(c) mixing the resulting mixture of step (b) with water;
(d) mixing the resulting mixture of step (c) with a base;
(e) isolating the resulting solid of step (d); and
(f) drying the solid.

### Claim 13 (depends on 1)

The process according to claim 1, wherein the formation of 3-cyclopropylmethylnaltrexone is less than about 0.5% (by area).

### Claim 14 (depends on 1)

The process according to claim 1, wherein the naltrexone obtained from the process is further processed to give nalmefene.

### Claim 15 (depends on 1)

A process for the manufacturing of nalmefene comprising the following steps
(i) manufacturing naltrexone by the process according to claim 1; and
(ii) further processing the naltrexone obtained from step (i) to yield nalmefene.

### Claim 16 (depends on 15)

The process according to claim 15, wherein the further processing of step (ii) comprises the Wittig reaction.

### Claim 17 (depends on 16)

The process according to claim 16, further comprising precipitating nalmefene as a pharmaceutically acceptable salt.

### Claim 18 (depends on 17)

The process according to claim 17, further comprising purifying the pharmaceutically acceptable salt of nalmefene.

### Claim 19 (depends on 11)

The process according to claim 11, wherein the reaction is running in the range of 8-48 hours.

### Claim 20 (depends on 19)

The process according to claim 19, wherein the reaction is running in the range of 16-20 hours.

### Claim 21 (depends on 1)

The process according to claim 1, wherein the total amount of water compared to noroxymorphone is from 1.0 to 3.0 equivalents.