METHODS FOR PREPARING N-(4-FLUOROBENZYL)-N-(1-METHYLPIPERIDIN-4-YL)-N'-(4-(2-METHYLPROPYLOXY)PHENYLMETHYL)CARBAMIDE AND ITS TARTRATE SALT AND POLYMORPHIC FORM

• US 20190047955A1
• Filed: 07/19/2016
• Published: 02/14/2019
• Est. Priority Date: 07/20/2015
• Status: Active Grant

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Carlos, Marlon, Tandel, Sagun, Olsson, Roger, Hillgren, Mikael, Fleming, Matthew J., Boudier, Andreas Philipp, Weber, Beat T.
• Granted Patent: US 10,597,363 B2
• Time in Patent Office: Days
• CPC Class Codes: C07D 211/58 attached in position 4
• CPC Class Codes: C07D 211/98 Nitrogen atom

Abstract

Disclosed herein are methods for obtaining N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl) carbamide (pimavanserin) comprising the step of contacting an intermediate according to Formula (A) or a salt thereof, with an intermediate Formula B, or a salt thereof, to produce pimavanserin or a salt thereof wherein Y is —OR_i or —NR_2aR_2b; R₃ is hydrogen or substituted or unsubstituted heteroalicyclyl, R₄ is substituted or unsubstituted aralkyl; X is —OR₂₂ or —NR₂₃R₂₄; (wherein R₂₂ is hydrogen or substituted or unsubstituted C_1-6alkyl and one of R₂₃ and R₂₄ is hydrogen and the other is hydrogen or N-methylpiperidin-4-yl); and R₂₁ is —OCH₂CH(CH₃)₂ or F; Also disclosed herein is the tartrate salt of N-(4-fluoroben-zyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl) carbamide and methods for obtaining the salt.

Claims

1. A method of preparing pimavanserin (N-(4-fluorophenylmethyl)-N-(1 -methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide) or a salt thereof, the method comprising;

contacting an intermediate according to Formula (A2),

11. The method according to claim 1, wherein Y is —

OR₁.

12. The method according to claim 11, wherein R₁ is a substituted or unsubstituted C_1≢

alkyl selected from methyl, ethyl, propyl, butyl, pentyl, trifluoroethyl and phenyl.

13. The method according to claim 12, wherein R₁ is phenyl.

15. The method according to claim 1 further comprising contacting isobutyl alcohol with 4-fluorobenzonitrile to produce the intermediate according to Formula (A2).

16. The method according to claim 15, wherein 4-isobutoxybenzonitrile is produced by contacting isobutyl alcohol and 4-fluorobenzonitrile, and the 4-isobutoxybenzonitrile is hydrogenated to produce the intermediate according to Formula (A2).

17. The method according to claim 15, wherein the intermediate according to Formula (A2) is phenyl (4-isobutoxybenzyl)carbamate.

18. The method according to claim 1, wherein a tartrate salt of (N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N-(4-(2-methylpropyloxy)phenylmethyl)carbamide) is prepared.

19. The method according to claim 18, wherein the tartrate salt is a hemi-tartrate salt.

20. The method according to claim 1, wherein pimavanserin is obtained as a polymorphic Form C characterized by having an endotherm with an onset of between 167 and 177°

C. as obtained by differential scanning calorimetry (DSC) in accordance with USP <

891>

, using a 4-6 mg sample under nitrogren nitrogen at a heating rate of 10°

C./min between 80-210°

C.

21. The method according to claim 20, wherein the DSC shows no peak between 120 and 140°

C.

22. The method according to claim 18, wherein pimavanserin (N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide) is isolated prior to forming a tartrate salt thereof.

23. The method according to claim 18, wherein pimavanserin (N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide) is not isolated prior to forming a tartrate salt thereof.

24. The method according to claim 20, wherein the polymorphic Form C is obtained by direct formation from (N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide).

25. The method according to claim 1, wherein the intermediate according Formula (A2) is contacted with the intermediate according to Formula (B2) in the presence of a base.

26. The method according to claim 25, wherein the base is selected from the group consisting of triethyl amine, diisopropyl amine, pyridine or alkali metal carbonates, sodium hydroxide, potassium hydroxide, sodium phosphate and potassium phosphate.

27. The method according to claim 26, wherein the pyridine or alkali metal carbonates are sodium carbonate or potassium carbonate.

2-10. -10. (canceled)

14. (canceled)