Methods for preparing N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and polymorphic form C

• US 10,597,363 B2
• Filed: 07/19/2016
• Issued: 03/24/2020
• 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.
• Primary Examiner(s): Chandrakumar, Nizal S
• Application Number:
  US15/744,636
• Publication Number:
  US 20190047955A1
• Time in Patent Office: 1,344 Days
• Field of Search: 546224
• 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-fluorobenzyl)-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 isobutyl alcohol with 4-fluorobenzonitrile to produce 4-isobutoxybenzonitrile;

converting the 4-isobutoxybenzonitrile to (4-isobutoxyphenyl)methanamine;

contacting the (4-isobutoxyphenyl)methanamine with

2. The method according to claim 1, wherein R₁ is methyl, ethyl, propyl, butyl, pentyl, trifluoroethyl or phenyl.

3. The method according to claim 2, wherein R₁ is phenyl.

4. The method according to claim 1, wherein the hydrogenated (4-isobutoxyphenyl)methanamine is contacted with diphenyl carbonate or phenyl chloroformate and the intermediate according to Formula (A2) is phenyl (4-isobutoxybenzyl)carbamate.

5. The method according to claim 1, wherein pimavanserin is contacted with (L)-tartaric acid to produce a pimavanserin tartrate salt.

6. The method according to claim 5, wherein the tartrate salt is a hemi-tartrate salt.

7. The method according to claim 5, wherein pimavanserin is contacted with (L)-tartaric in methyl ethyl ketone and dried to produce a pimavanserin tartrate salt 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).

8. The method according to claim 7, wherein the DSC shows no peak between 120 and 140°

C.

9. The method according to claim 5, wherein pimavanserin (N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide) is isolated prior to being contacted with (L)-tartaric acid to produce the pimavanserin tartrate salt.

10. The method according to claim 5, wherein pimavanserin (N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide) is not isolated prior to being contacted with (L)-tartaric acid to produce the pimavanserin tartrate salt.

11. 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.

12. The method according to claim 11, 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.

13. The method according to claim 12, wherein the pyridine or alkali metal carbonates are sodium carbonate or potassium carbonate.

14. The method according to claim 4, wherein the intermediate according Formula (A2) is contacted with the intermediate according to Formula (B2) in the presence of potassium carbonate.

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

-(4-(2-methylpropyloxy)phenylmethyl)carbamide) comprising;

contacting an intermediate according to Formula (A2),