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-10981871-B2
Application number	US-202016786809-A
Country	US
Kind code	B2
Filing date	Feb 10, 2020
Priority date	Jul 20, 2015
Publication date	Apr 20, 2021
Grant date	Apr 20, 2021

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 2a R 2b ; R 3 is hydrogen or substituted or unsubstituted heteroalicyclyl, R 4 is substituted or unsubstituted aralkyl; X is —OR 22 or —NR 23 R 24 ; (wherein R 22 is hydrogen or substituted or unsubstituted C 1-6 alkyl and one of R 23 and R 24 is hydrogen and the other is hydrogen or N-methylpiperidin-4-yl); and R 21 is —OCH 2 CH(CH 3 ) 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 i) isobutyl methanesulfonate or isobutyl p-toluenesulfonate with 4-hydroxybenzaldehyde, or ii) contacting isobutanol with 4-fluorobenzaldehyde, thereby producing (4-isobutoxyphenyl)methanamine;
contacting (4-isobutoxyphenyl)methanamine with carbonyldiimidazole to produce the intermediate according to Formula (I6);

contacting the intermediate according to Formula (I6) or a salt thereof with an intermediate according to Formula (B2),

or a salt thereof, to produce pimavanserin or a salt thereof.

2. The method according to claim 1 , wherein the produced intermediate according to Formula (I6) is isolated prior to being contacted by the intermediate according to Formula (B2).

3. The method according to claim 1 , wherein the (4-isobutoxyphenyl)methanamine is contacted by carbonyldiimidazole to produce the intermediate according to Formula (I6), which is subsequently contacted by the intermediate according to Formula (B2) in a telescoping synthesis.

4. 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.

5. The method according to claim 4 , wherein the pimavanserin tartrate salt is a hemi-tartrate salt.

6. The method according to claim 4 , wherein the produced pimavanserin is contacted with (L)-tartaric acid in methyl ethyl ketone 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).

7. The method according to claim 6 , wherein the DSC shows no peak between 120 and 140° C.

8. The method according to claim 4 , wherein the produced pimavanserin is isolated prior to being contacted with (L)-tartaric acid to produce the pimavanserin tartrate salt.

9. The method according to claim 4 , wherein the produced pimavanserin is not isolated prior to being contacted with (L)-tartaric acid to produce the pimavanserin tartrate salt.

10. The method according to claim 1 , wherein the intermediate according to Formula (I6) is contacted with the intermediate according to Formula (B2) in the presence of a base.

11. The method according to claim 10 , 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.

12. The method according to claim 11 , wherein the base is sodium carbonate or potassium carbonate.

13. The method according to claim 11 , 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

• C07C233/00

  Carboxylic acid amides · 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

• C07D211/98

  Nitrogen atom · CPC title