# US 10,370,382 B2 · Process for preparing hydromorphone and derivatives thereof

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- Number: US 10,370,382 B2
- Document ID: US10370382B2
- Status: Granted
- Kind: B2
- Application number: 15/747,980
- Filed: 2016-07-26
- Published: 2018-12-13
- Granted: 2019-08-06
- Earliest claimed: 2015-07-27
- Assignees: Cambrex Charles City, Inc.
- Applicants: Cambrex Charles City, Inc.
- Inventors: Pär Holmberg; Michael Robert Tracey; Zhiming Eric Dong
- Web page: https://patentgrep.com/patent/US10370382B2

## CPC

- C07D 489/04: Salts; Organic complexes
- C07D 489/02: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

There is provided a novel process for the preparation of a compound of formula (I), wherein R1 is as described in the description, by demethylation of a corresponding O-methyl derivative.

## Claims

### Claim 1

A process for the preparation of a compound of formula I,
or a pharmaceutically acceptable salt thereof;
wherein:
R1 represents hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl or C3-12 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl (which latter four groups are optionally substituted by one or more halogen atoms or phenyl groups;
the process comprises contacting a compound of formula II,
or a salt thereof, wherein R1a is defined according to R1,
with a mixture comprising water, a carboxylic acid, a sulfonic acid, and a sulfide compound;
wherein the water is present in the mixture at from about 0.1% to about 70% by weight relative to combined weight of the water and the compound of formula II, and the sulfide compound is selected from the group consisting of cyclic sulfur-containing compounds and sulfides of formula III,
X1—S—X2 III
wherein X1 and X2 each independently represent hydrogen, phenyl, —C(O)R3 or a C1-12 alkyl group, wherein the phenyl, R3 and alkyl are each independently optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —NH2, phenyl, —O—C1-4 alkyl, —C(O)R4 and —S(O)m—C1-4 alkyl;
R3 and R4 independently represent —OH, —C1-4 alkyl or —O—C1-4 alkyl; and
m represents from 0 to 2.

### Claim 2 (depends on 1)

The process as claimed in claim 1, wherein R1 represents methyl, ethyl, propyl, butyl, benzyl or —CH2-cyclopropyl.

### Claim 3 (depends on 1)

The process as claimed in claim 1, wherein R1 represents methyl.

### Claim 4 (depends on 1)

The process as claimed in claim 1, wherein the sulfonic acid is a sulfonic acid of formula V,
R5—SO2—OH V
wherein R5 represents a C1-6 alkyl group that is optionally substituted by one or more halogen atoms, or an aryl group that is optionally substituted by one or more substituents selected from the group consisting of a C1-4 alkyl group and a halogen atom.

### Claim 5 (depends on 4)

The process as claimed in claim 4, wherein the sulfonic acid is selected from the group consisting of methane sulfonic acid, trifluoromethane sulfonic acid, toluenesulfonic acid, and mixtures thereof.

### Claim 6 (depends on 1)

The process as claimed in claim 1, wherein the sulfonic acid is present at from about 1 to about 10 equivalents relative to the compound of formula II.

### Claim 7 (depends on 1)

The process as claimed in claim 1, wherein the sulfide compound is:
(a) a monocyclic aromatic compound containing one or more sulfur atoms within the aromatic ring;
(b) a compound of formula IV
wherein n represents from 0 to 3; or
(c) a sulfide of formula III,
X1—S—X2 III
wherein X1 and X2 each independently represent hydrogen, phenyl, —C(O)R3 or a C1-12 alkyl group, wherein the phenyl, R3 and alkyl are each independently optionally substituted by one or more substituents selected from the group consisting of halogen, —NH2, phenyl, —C(O)R4 and —S(O)m—C1-4 alkyl);
R3 and R4 independently represent —OH, —C1-4 alkyl or —O—C1-4 alkyl; and
m represents from 0 to 2.

### Claim 8 (depends on 7)

The process as claimed in claim 7, wherein the sulfide compound is selected from the group consisting of dioctyl sulfide, dibutyl sulfide, dipropyl sulfide, diethyl sulfide, dimethyl sulfide, dodecyl methyl sulfide, and mixtures thereof.

### Claim 9 (depends on 1)

The process as claimed in claim 1, wherein the sulfide compound is present in an amount of at least 1 equivalent relative to the compound of formula II.

### Claim 10 (depends on 1)

The process as claimed in claim 1, wherein the carboxylic acid has a pKa of 5 or below.

### Claim 11 (depends on 1)

The process as claimed in claim 1, wherein the carboxylic acid is acetic acid, or a halogenated derivative thereof.

### Claim 12 (depends on 11)

The process as claimed in claim 11, wherein the carboxylic acid is selected from the group consisting of trifluoroacetic acid, trichloroacetic acid, difluoroacetic acid, dichloroacetic acid, fluoroacetic acid, chloroacetic acid, and mixtures thereof.

### Claim 13 (depends on 1)

The process as claimed in claim 1, wherein the carboxylic acid is present in an amount of from 1 to 20 volumes relative to the compound of formula II.

### Claim 14 (depends on 1)

The process as claimed in claim 1, wherein the water is present in an amount ranging from 2% to 50% by weight relative to the combined weight of the water and the compound of formula II.

### Claim 15 (depends on 1)

The process as claimed in claim 1, wherein the reaction is performed at a temperature of from about 30° C. to about 70° C.

### Claim 16 (depends on 1)

The process as claimed in claim 1, wherein the compound of formula I is hydromorphone or a salt thereof, the compound of formula II is hydrocodone or a salt thereof, and:
(i) the carboxylic acid is selected from the group consisting of trifluoroacetic acid, trichloroacetic acid, difluoroacetic acid, dichloroacetic acid, fluoroacetic acid, chloroacetic acid, and mixtures thereof;
(ii) the sulfonic acid is selected from the group consisting of methane sulfonic acid, trifluoromethane sulfonic acid, toluenesulfonic acid, and mixtures thereof; and
(ii) the sulfide compound is selected from the group consisting of dioctyl sulfide, dibutyl sulfide, dipropyl sulfide, diethyl sulfide, dimethyl sulfide, dodecyl methyl sulfide and mixtures thereof.

### Claim 17 (depends on 2)

The process as claimed in claim 2, wherein the compound of formula II is hydrocodone or a salt thereof and wherein the process further comprises a preceding step of converting codeine to the hydrocodone.

### Claim 18 (depends on 1)

The process as claimed in claim 1, wherein the compound of formula II is formed by a process comprising reacting a compound of formula VII,
wherein R1b is defined according to R1a,
with a rhodium complex in an aqueous solvent system; and
optionally the compound of formula VII and the rhodium complex are mixed together with an organic additive selected from the group consisting of acetone, isopropanol, tert-butanol and mixtures thereof.

### Claim 19 (depends on 18)

The process as claimed in claim 18, wherein the rhodium complex is prepared from a [Rh(COD)(CH3CN)2](BF4) and a phosphine derivative, wherein the COD is 1,5-cyclooctadiene.

### Claim 20 (depends on 1)

A process for forming hydromorphone, wherein the process comprises:
(i) converting thebaine to hydrocodone; and
(ii) converting said hydrocodone to hydromorphone according to a process as claimed in claim 1.

### Claim 21 (depends on 1)

A process for preparing a salt of a compound of formula I,
wherein:
R1 represents hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl or C3-12 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are each independently optionally substituted by one or more halogen atoms or phenyl groups;
the process comprises the steps of:
(i) preparing a compound of formula I in accordance with the process defined in claim 1;
(ii) optionally isolating and/or purifying the compound of formula I obtained from the process;
(iii) bringing into association the compound of formula I formed from step (i) or (ii) with an acid; and
(iv) optionally converting the product from step (iii) into a different salt.

### Claim 22 (depends on 1)

A process for preparing a pharmaceutical formulation comprising a compound of formula I,
or a pharmaceutically acceptable salt thereof;
wherein:
R1 represents hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl or C3-12 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are each independently optionally substituted by one or more halogen atoms or phenyl groups;
the process comprises the steps of:
(i) preparing a compound of formula I or a salt thereof in accordance with a process as defined in claim 1;
(ii) optionally isolating and/or purifying the compound of formula I or a salt thereof obtained from the process; and
(iii) bringing into association the compound of formula I or a salt thereof formed from step (i) or (ii) with one or more pharmaceutically-acceptable excipients, adjuvants, diluents or carriers.

### Claim 23 (depends on 1)

A process for preparing a prodrug of a compound of formula I,
or a pharmaceutically acceptable salt thereof;
wherein:
R1 represents hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl or C3-12 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted by one or more halogen atoms or phenyl groups;
the process comprises the steps of:
(i) preparing a compound of formula I in accordance with the process as defined in claim 1;
(ii) optionally isolating and/or purifying the compound of formula I obtained from the process; and
(iii) converting the compound of formula I obtained from step (i) or (ii) into a prodrug of the compound of formula I by reacting with a reagent that is capable to react with a hydroxyl functional group, an enol tautomer, a carboxyl functional group, or an amine group to form the prodrug of the compound of formula I, wherein the product is an ester derivative, a carbamate derivative, an N-acyl derivative, or an N-Mannich base derivative of the compound of formula I.