Method for producing naldemedine
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- PROCOS SPA
- Filing Date
- 2024-05-13
- Publication Date
- 2026-06-11
Smart Images
Figure 2026518990000021 
Figure 2026518990000022 
Figure 2026518990000023
Abstract
Claims
1. A method for producing naldemedine or a salt thereof, a) A step of reacting naltrexone (II) with diethyl pyrocarbonate (DEPC) and treating with a base to obtain compound (III), 【Chemistry 1】 b) A step of condensing compound (III) with compound (IV) to form an amide bond and obtain naldemedine (I), 【Chemistry 2】 A manufacturing method that includes the following features.
2. The aforementioned step a) is, a1) A sub-step in which naltrexone (II) and diethyl pyrocarbonate (DEPC) are reacted according to the following reaction scheme to obtain intermediate (V), followed by two intermediates (VI) and (VII), 【Transformation 3】 a2) A sub-step of treating the intermediates (VI) and (VII) with a base to obtain compound (III), 【Chemistry 4】 The manufacturing method according to claim 1, comprising:
3. The reaction a) is carried out continuously without separating the intermediates (V), (VI), and (VII). The manufacturing method according to claim 2.
4. In step a) / a1), the reaction between naltrexone(II) and diethyl pyrocarbonate (DEPC) is carried out at a temperature in the range of 70°C to 150°C. The manufacturing method according to any one of claims 1 to 3.
5. In step a) / a1), the reaction between naltrexone(II) and diethyl pyrocarbonate (DEPC) is carried out at a temperature in the range of 100°C to 130°C. The manufacturing method according to claim 4.
6. In step a) / a1), the reaction between naltrexone(II) and diethyl pyrocarbonate (DEPC) is carried out under reduced pressure. The manufacturing method according to any one of claims 1 to 5.
7. Use diethyl pyrocarbonate in an amount of 2 to 12 equivalents per 1 equivalent of naltrexone. The manufacturing method according to any one of claims 1 to 4.
8. Use 4 to 10 equivalents of diethyl pyrocarbonate per 1 equivalent of naltrexone. The manufacturing method according to claim 7.
9. Use 5 to 8 equivalents of diethyl pyrocarbonate per 1 equivalent of naltrexone. The manufacturing method according to claim 8.
10. In the above steps a) / a2), the treatment with the base is carried out at a temperature in the range of -20°C to 40°C. The manufacturing method according to any one of claims 1 to 9.
11. In the above steps a) / a2), the treatment with the base is performed at a temperature in the range of 0°C to 20°C. The manufacturing method according to claim 10.
12. The base in step a) / a2) is selected from the group consisting of sodium ethoxide, potassium ethoxide, and lithium hexamethyldisilazide. The manufacturing method according to any one of claims 1 to 11.
13. The base in step a) / a2) is sodium ethoxide. The manufacturing method according to claim 12.
14. The base in steps a) / a2) is sodium ethoxide in an ethanol solution, preferably 21% by weight of ethanol. The manufacturing method according to claim 13.
15. The compound (III) obtained in step a) is preferably separated in the form of a solvate and subsequently crystallized. The manufacturing method according to any one of claims 1 to 14.
16. Step b) is performed at a temperature in the range of 110°C to 180°C. The manufacturing method according to any one of claims 1 to 15.
17. Step b) is preferably carried out at a temperature in the range of 150°C to 170°C. The manufacturing method according to claim 16.
18. Step b) is preferably carried out at a temperature in the range of 130°C to 160°C. The manufacturing method according to claim 17.
19. Step b) is carried out under reduced pressure conditions. The manufacturing method according to any one of claims 1 to 18.
20. The condensation step b) is carried out using compound (IV) in an amount of 1.0 to 4.0 equivalents per equivalent of compound (III). The manufacturing method according to any one of claims 1 to 19.
21. The condensation step b) is carried out using compound (IV) in an amount of 1.5 to 2.5 equivalents per equivalent of compound (III). The manufacturing method according to claim 20.
22. The reaction in step b) is carried out without a solvent, or in the presence of a suitable protic polar solvent. The manufacturing method according to any one of claims 1 to 21.
23. The appropriate protic polar solvent is selected from the group consisting of ethanol, isopropanol, and butanol. The manufacturing method according to claim 22.
24. The reaction time for step b) is 2 to 5 hours. The manufacturing method according to any one of claims 1 to 23.
25. The reaction time for step b) is approximately 3 hours. The manufacturing method according to claim 24.
26. The naldemedine (I) obtained in step b) above can be obtained as a free base or as a salt. The manufacturing method according to any one of claims 1 to 25.
27. The naldemedine(I) obtained as a free base is dissolved by heating in an organic solvent. The manufacturing method according to any one of claims 1 to 26.
28. The aforementioned organic solvent is toluene or xylene. The manufacturing method according to claim 27.
29. Naldemedine(I) is extracted from an organic solution with a basic aqueous solution. The manufacturing method according to claim 27 or 28.
30. The basic aqueous solution is selected from aqueous sodium hydroxide solution and aqueous potassium hydroxide solution. The manufacturing method according to claim 29.
31. Naldemedine(I) is crystallized as a free base by adding an acid selected from the group consisting of p-toluenesulfonic acid, hydrochloric acid, and acetic acid. The manufacturing method according to any one of claims 1 to 30.
32. The acid is hydrochloric acid. The manufacturing method according to claim 31.