Method for producing N-methylnaltrexone bromide

1. Process for the preparation of N-methylnaltrexone bromide, wherein a compound of the general formula (I):

wherein

X − represents an anion selected from HSO 4 − ; SO 4 2− ; [—O—S(O) 2 —O—(C 1-4 )alkyl]; [—O—S(O) 2 —(C 1-4 ) alkyl];

[—O—S(O) 2 —CF 3 ]; or [—O—S(O) 2 -phenyl], wherein the phenyl ring is optionally substituted;

R represents hydrogen or a leaving group,

(i) is dissolved or dispersed in a suitable polar solvent, said solvent being selected from the group consisting of water, polar organic solvents, aprotic dipolar solvents, and alcohols or a mixture thereof;

(ii) the solution or dispersion is mixed with a compound containing bromide anions, and the resulting reaction mixture is stirred until N-methylnaltrexone bromide has formed and crystallised, wherein, in the case where R represents a leaving group, that group is removed during or after the reaction.

2. Process according to claim 1 , wherein X − represents:

HSO 4 − ; SO 4 2− ; [—O—S(O) 2 —O—CH 3 ];

[—O—S(O) 2 —CH 3 ];

[—O—S(O) 2 -phenyl]; or [—O—S(O) 2 -tolyl].

3. Process according to claim 1 , wherein X − represents:

HSO 4 − ; SO 4 2− ; [—O—S(O) 2 —O—CH 3 ];

[—O—S(O) 2 —CH 3 ]; or [—O—S(O) 2 -phenyl].

4. Process according to claim 1 , wherein R represents hydrogen.

5. Process according to claim 1 , wherein R represents a leaving group selected from the group consisting of (C 1 -C 8 )-alkyloxycarbonyl, phenyloxycarbonyl, and trialkylsilyl.

6. Process according to claim 1 , wherein R represents a leaving group selected from the group comprising ester groupings.

7. Process according to claim 1 , wherein the solvent is selected from the group consisting of water, water/methanol, water/ethanol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, acetone/dimethylformamide, and acetone/dimethylacetamide, aliphatic alcohols and mixtures of such polar organic solvents with water.

8. Process according to claim 1 , wherein the compound of formula (I) is reacted with a compound containing bromide anions.

9. Process according to claim 1 , wherein the compound containing bromide anions is selected from the group consisting of inorganic and organic medically approved compounds.

10. Process according to claim 1 , wherein the anion exchange reaction is carried out at an acid value (pH value) in the range from zero to 9 (nine), the acid value preferably being established by adding hydrogen bromide (HBr) to the reaction mixture.

11. Process for the preparation of N-methylnaltrexone bromide, wherein a compound of formula (I) according to claim 1 is prepared in a first step by reacting the free naltrexone base with a compound containing the substituent X, the phenolic hydroxyl group of the free naltrexone base optionally being provided beforehand with a leaving group, and then, in a second step, the resulting compound of the general formula (I) is dissolved or dispersed in a suitable polar solvent, the solution or dispersion is mixed with a compound containing bromide anions, and the reaction mixture, or the solution or dispersion, is stirred until N-methylnaltrexone bromide has formed and crystallised, wherein, in the case where R represents a leaving group, that group is removed during or after the reaction, wherein said leaving group is selected from the group consisting of (C 1 -C 8 -alkyloxycarbonyl, phenyloxycarbonyl, trialkylsilyl, and ester groupings;

wherein said solvent is selected from the group consisting of water, water/methanol, water/ethanol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, acetone/dimethylformamide, and acetone/dimethylacetamide, aliphatic alcohols and mixtures of such polar organic solvents with water; and

wherein said compound containing bromide anions is selected from the group consisting of inorganic and organic medically approved compounds.

12. Process according to claim 11 , wherein the compound containing the substituent X is selected from the group consisting of dimethyl sulfate [CH 3 —O—S(O) 2 —O—CH 3 ]; (C 1-4 ) alkylsulfonic acid methyl ester [CH 3 —O—S(O) 2 —(C 1-4 )alkyl]; trifluoromethylsulfonic acid methyl ester [CH 3 —O—S(O) 2 —CF 3 ];

and phenylsulfonic acid methyl ester [CH 3 —O—S(O) 2 -phenyl], wherein the phenyl ring is optionally substituted.

13. Process according to claim 12 , wherein the resulting compound of formula (I) is isolated by means of a precipitation reaction.

14. Process for the preparation of N-methylnaltrexone bromide as a one-pot process, wherein a compound of the general formula (I) according to claim 1 is prepared by reacting the free naltrexone base with a methylating agent containing the substituent X, the phenolic hydroxyl group of the free naltrexone base optionally being provided beforehand with a protecting group, and then, the excess methylating agent present in the reaction mixture is decomposed in the presence of water, at a neutral or acid pH value (pH≦7) or at an acid pH value, and at elevated temperature, so that a protecting group that may be present, bonded to the phenolic group, is removed at the same time; and then a compound containing bromide anions is added to the reaction mixture and stirring is carried out until N-methyl-naltrexone bromide has formed and crystallised.

15. Process according to claim 14 , wherein the decomposition of the excess methylating agent present in the reaction mixture is carried out at an elevated acid value (pH 8-12).

16. Process according to claim 1 , wherein the resulting N-methylnaltrexone bromide crude product is recrystallised from a suitable solvent.

17. Process according to claim 10 , wherein the anion exchange reaction is carried out at a temperature in the range of 20° C. to 80° C., until the N-methylnaltrexone bromide has formed in a quantitative amount.

18. Process according to claim 16 , wherein the resulting N-methylnaltrexone bromide crude product is recrystallised from aqueous ethanol or methanol, containing from 1% to 99% water, based on the total weight of water and methanol.