Modafinil synthesis process
View Patent ↗The invention relates to a process for preparing modafinil having a defined granulometry which comprises the steps of: a) preparing a solution of DMSAM; b) contacting the solution obtained with NH3 at a predetermined temperature and a predetermined stirring; and c) isolating the modafinil formed, wherein said temperature and said stirring are predetermined in order to obtain said defined granulometry.
1. Process for preparing modafinil having a defined granulometry which comprises the steps of:
a) preparing a solution of DMSAM in a solvent;
b) contacting the solution obtained with NH 3 at a predetermined temperature and under a predetermined stirring; and
c) isolating the modafinil formed,
wherein said temperature and said stirring are predetermined in order to obtain modafinil having a granulometry wherein the ratio of median to mean is from 1:3 to 1:0.3 and of median to mode is from 1:3 to 1:0.3.
2. Process according to claim 1 , wherein the solvent is a protic polar solvent.
3. Process according to claim 2 , wherein the solvent is an alcohol.
4. Process according to claim 3 , wherein the solvent is methanol.
5. Process according to claim 4 , wherein the solution of DMSAM has a concentration of DMSAM of between 1 and 1.25 mol L −1 .
6. Process according to claim 1 , wherein the temperature in step b) is held between 15 and 65° C.
7. Process according to claim 1 , wherein the predetermined stirring speed in step b) is chosen such that the modafinil isolated in step c) has a granulometric median of between 2 and 60 μm.
8. Process according to claim 1 , wherein in step b), the solution of DMSAM is contacted with 3 to 6 molar equivalent of NH 3 .
9. Process according to claim 8 , wherein, in step b), the solution of DMSAM is contacted with 3.2 and 5 molar equivalent of NH 3 .
10. Process according to claim 1 , wherein, in step b), the NH 3 is introduced into the solution over a sufficient time to obtain a complete dissolution of NH 3 .
11. Process according to claim 10 , wherein, in step b), the NH 3 is introduced into the solution over a time of between 2 h and 6 h.
12. Process according to claim 11 , wherein, in step b), the NH 3 is introduced into the solution over a time of between 3 h and 4.5 h.
13. Process according to claim 1 , wherein, in step b), the solution is contacted after the introduction of the NH 3 for a contact time sufficient to allow the polymorphic transformation of form III to form I.
14. Process according to claim 13 , wherein the contact time is between 8 and 12 h.
15. Process according to claim 1 , wherein the solution obtained after step b) is further maintained at a temperature lower than the predetermined temperature of step b) for a time sufficient to obtain complete crystallization of modafinil.
16. Process according to claim 15 , wherein the solution is further maintained at a temperature lower than the temperature of step b) for a time of from 1 h to 4 h.
17. Process according to claim 15 , wherein the temperature is between −20° C. and 0° C.
18. Process according to claim 1 , wherein the modafinil is isolated in step c) by filtration.
19. Process according to claim 1 , wherein the solvent in step a) comprises water.
20. Process according to claim 19 , wherein the solvent contains from 5% to 20% by volume of water.
21. Process according to claim 19 , wherein the NH 3 is introduced into the solution in step b) over a time of between 4 h and 5 h.
22. Process according to claim 19 , wherein, in step b), the solution of DMSAM is contacted with 5 to 5.5 molar equivalent of NH 3 .
23. Process according to claim 1 , which does not include a recrystallization step after step c).
24. Process according to claim 1 , which does not include a grinding step after step c).
25. Process according to claim 1 , wherein the predetermined temperature and stirring speed are chosen such that particles of modafinil form I of which at least:
50% have a diameter of less than 45 μm, and
80% have a diameter of less than 110 μm, and
95% have a diameter of less than 220 μm, are isolated in step c).
26. Process according to claim 1 , wherein the modafinil isolated in step c) is modafinil form III.
27. Process according to claim 1 , wherein the modafinil isolated in step c) is modafinil form I.
28. Process according to claim 1 , wherein modafinil with a granulometric median of between 1 μm and 1 mm is isolated in step c).
29. Process according to claim 1 , wherein the levorotary enantiomer of DMSAM is employed in step a).
30. Process according to claim 1 , wherein the dextrorotary enantiomer of DMSAM is employed in step a).
31. Process according to claim 7 , wherein the predetermined stirring speed in step b) is chosen such that the modafinil isolated in step c) has a granulometric median of between 15 and 45 μm.