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

Patent metadata

Field	Value
Publication number	US-11840515-B2
Application number	US-202117203266-A
Country	US
Kind code	B2
Filing date	Mar 16, 2021
Priority date	Jul 20, 2015
Publication date	Dec 12, 2023
Grant date	Dec 12, 2023

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 —ORi or —NR2aR2b; 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 C1-6alkyl 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.

First claim

What is claimed is:

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),

or a salt thereof, with an intermediate according to Formula (B2),

or a salt thereof, to produce pimavanserin or a salt thereof, wherein:
Y is —OR 1 or —NR 2a R 2b ;
R 1 , R 2a , R 2b , independently of each other are selected from the group consisting of hydrogen, substituted or unsubstituted C 1-6 alkyl, and substituted or unsubstituted aryl; or
R 2a and R 2b taken together with the nitrogen to which they are attached form a substituted or unsubstituted heteroalicyclyl, or a substituted or unsubstituted heteroaryl.

2. The method according to claim 1 , wherein R 1 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, trifluoroethyl and phenyl.

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

4. The method according to claim 3 , wherein R 1 is methyl, ethyl, propyl, butyl, pentyl, trifluoroethyl and phenyl.

5. The method according to claim 1 , additionally comprising contacting isobutyl alcohol with 4-fluorobenzonitrile to produce a compound according to Formula (A).

6. The method according to claim 5 , wherein the 4-isobutoxybenzonitrile produced by contacting isobutyl alcohol and 4-fluorobenzonitrile is hydrogenated to produce a compound according to Formula (A2).

7. The method according to claim 5 , wherein the compound according to Formula (A2) is phenyl (4-isobutoxybenzyl)carbamate.

8. The method according to claim 1 , further comprising contacting the pimavanserin produced from the previous step with (L)-tartaric acid to produce a pimavanserin tartrate salt.

9. The method according to claim 8 , wherein the tartrate salt is the hemi-tartrate salt.

10. The method according to claim 1 , wherein the produced pimavanserin is contacted with (L)-tartaric in methyl ethyl ketone to produce a pimavanserin tartrate salt obtained as polymorphic Form C characterized by having an endotherm with an onset of between 167 and 177 C° as obtained by differential scanning calorimetry (DSC).

11. The method according to claim 10 , wherein the DSC shows no peak between 120 and 140° C.

12. The method according to claim 8 , 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.

13. The method according to claim 8 , wherein pimavanserin (N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide) is not isolated prior to being contact with (L)-tartaric acid to produce the pimavanserin tartrate salt.

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

15. The method according to claim 14 , wherein the base is selected from the group consisting of triethyl amine, diisopropyl amine, pyridine, alkali metal carbonates, sodium hydroxide, potassium hydroxide, sodium phosphate and potassium phosphate.

16. The method according to claim 15 , wherein the base is sodium carbonate or potassium carbonate.

17. The method according to claim 15 , wherein the base is potassium carbonate.

Assignees

• Acadia Pharm Inc

Inventors

• Carlos Marlon
• Tandel Sagun
• Olsson Roger
• Hillgren Mikael
• Fleming Matthew J
• Boudier Andreas Philipp
• Weber Beat T

Classifications

• C07D211/58 Primary

  attached in position 4 · CPC title

• C07D211/98

  Nitrogen atom · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61K31/4468

  having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl · CPC title

• C07C233/00

  Carboxylic acid amides · CPC title