Method for the preparation of morphine compounds

1. A process for the preparation of morphine compounds of the formula (I):

wherein:

R1 is selected from the group consisting of a hydrogen atom and a hydroxyl group;

and R2 is selected from the group consisting of a hydrogen atom, (C 1 -C 6 )alkyl group, cyclo(C 3 -C 6 )alkyl group and (C 2 -C 6 )alkenyl group;

comprising a low content of α,β-unsaturated compounds, comprising the stages of:

(i) bringing the crude morphine compound into contact with a base, at a pH of greater than 13, under conditions which make possible the Michael addition reaction on the α,β-unsaturated compound(s) present;

(ii) separating the morphine compound from the reaction mixture; and

(iii) if appropriate, separating the addition product formed from the morphine compound.

2. The process according to claim 1 , comprising, as subsequent stage:

(iv) converting the morphine compound to a corresponding pharmaceutically acceptable salt.

3. The process according to claim 1 , in which stage (i) is carried out by introducing the crude morphine compound into the base.

4. The process according to claim 1 , in which in stage (ii) the morphine product is separated by precipitation by addition of a neutralizing agent.

5. The process according to claim 2 , in which stage (iii) is carried out at the same time as stage (iv).

6. The process according to claim 1 , in which the morphine compound is naloxone and the α,β-unsaturated compound is 7,8-didehydronaloxone.

7. The process according to claim 2 , in which the morphine compound is naloxone and the α,β-unsaturated compound is 7,8-didehydronaloxone.

8. The process according to claim 6 , in which stage (i) is carried out at a temperature of 20 to 25° C.

9. The process according to claim 6 , in which stage (i) is carried out with a contact time of less than one hour.

10. A composition comprising at least 99% by dry weight of a morphine compound of the formula (I);

wherein:

R1 is selected from the group consisting of a hydrogen atom and a hydroxyl group;

and R2 is selected from the group consisting of a hydrogen atom, (C i -C 6 )alkyl group, cyclo(C 3 -C 6 )alkyl group and (C 2 -C 6 )alkenyl group;

or a pharmaceutically acceptable salt thereof and an α,β-unsaturated compound in a content of less than 100 ppm and additionally comprising at least one compound resulting from an aldol condensation or crotonization reaction.

11. The composition according to claim 10 , comprising at least 99.5% by dry weight of morphine compound or a pharmaceutically acceptable salt thereof.

12. The composition according to claim 10 , which contains less than 50 ppm of α,β-unsaturated compound.

13. The composition according to claim 10 , in which the content of the compound resulting from the aldol condensation reaction is less than 1000 ppm.

14. The composition according to claim 10 , in which the content of the compound resulting from the crotonization reaction is less than 1000 ppm.

15. The composition according to claim 10 , in which the morphine compound is naloxone and the α,β-unsaturated compound is 7,8-didehydronaloxone.

16. The composition according to claim 10 , in which the pharmaceutically acceptable salt of the morphine compound is naloxone hydrochloride and the α,β-unsaturated compound is 7,8-didehydronaloxone.

17. The composition according to claim 10 , in which the pharmaceutically acceptable salt of the morphine compound is naloxone hydrochloride dihydrate and the α,β-unsaturated compound is 7,8-didehydronaloxone.

18. The composition according to claim 15 , additionally comprising 6′,7-naloxol-naloxone.

19. The composition according to claim 15 , additionally comprising the 6′,7′-olefin of 6′,7-naloxol-naloxone.