Process for preparing hydromorphone and derivatives thereof

1. A process for the preparation of a compound of formula I,

or a pharmaceutically acceptable salt thereof;

wherein:

R 1 represents hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 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 R 1a is defined according to R 1 ,

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,

X 1 —S—X 2   III

wherein X 1 and X 2 each independently represent hydrogen, phenyl, —C(O)R 3 or a C 1-12 alkyl group, wherein the phenyl, R 3 and alkyl are each independently optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, —NH 2 , phenyl, —O—C 1-4 alkyl, —C(O)R 4 and —S(O) m —C 1-4 alkyl;

R 3 and R 4 independently represent —OH, —C 1-4 alkyl or —O—C 1-4 alkyl; and

m represents from 0 to 2.

2. The process as claimed in claim 1 , wherein R 1 represents methyl, ethyl, propyl, butyl, benzyl or —CH 2 -cyclopropyl.

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

4. The process as claimed in claim 1 , wherein the sulfonic acid is a sulfonic acid of formula V,

R 5 —SO 2 —OH  V

wherein R 5 represents a C 1-6 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 C 1-4 alkyl group and a halogen atom.

5. 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.

6. 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.

7. 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,

X 1 —S—X 2   III

wherein X 1 and X 2 each independently represent hydrogen, phenyl, —C(O)R 3 or a C 1-12 alkyl group, wherein the phenyl, R 3 and alkyl are each independently optionally substituted by one or more substituents selected from the group consisting of halogen, —NH 2 , phenyl, —C(O)R 4 and —S(O) m —C 1-4 alkyl);

R 3 and R 4 independently represent —OH, —C 1-4 alkyl or —O—C 1-4 alkyl; and

m represents from 0 to 2.

8. 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.

9. 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.

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

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

12. 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.

13. 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.

14. 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.

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

16. 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.

17. 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.

18. 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 R 1b is defined according to R 1a ,

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.

19. The process as claimed in claim 18 , wherein the rhodium complex is prepared from a [Rh(COD)(CH 3 CN) 2 ](BF 4 ) and a phosphine derivative, wherein the COD is 1,5-cyclooctadiene.

20. 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 .

21. A process for preparing a salt of a compound of formula I,

wherein:

R 1 represents hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 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.

22. A process for preparing a pharmaceutical formulation comprising a compound of formula I,

or a pharmaceutically acceptable salt thereof;

wherein:

R 1 represents hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 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.

23. A process for preparing a prodrug of a compound of formula I,

or a pharmaceutically acceptable salt thereof;

wherein:

R 1 represents hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 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.