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

A kind of fluorophenylmethyl, methyl propoxy technology, applied in the field of medicine and chemistry

Active Publication Date: 2018-03-27
ACADIA PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

While the pathway described is sufficient to produce pimavanserin, there may be other pathways that offer other opportunities

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  • 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
  • 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
  • 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

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[0250] Experimental Procedures and Instruments

[0251] Examples of devices and methods useful in assisting in the preparation of the compounds described herein are:

[0252] NMR equipment: VARIAN INOVA 400mhz.

[0253] GC-MS equipment: TRACE GC THERMO FINNIGAN (method: column: ZB-5MS, 30x 0.25mm, 0.25μm. Temperature gradient: 50°C for 2min, then rise to 320°C at 20°C / min. Hold time: 15min. Flow rate : 1.0ml / min, split: 1:50, injection temperature: 200°C. injection volume: 1μL. diluent: acetonitrile).

[0254] LC-MS equipment: AGILENT 6530ACCURATE-MASS Q-TOF (Method: Column: ACQUITYUPLC BEHC18, 100x 2.1mm, 1.7μm. Eluent A: 0.1% HFo in acetonitrile. Eluent B: 0.1% HFo in h 2 O middle. Gradient: 10% A 90% B at 0 min, 95% A 5% B at 15 min, 95% A 5% B at 20 min. Flow rate: 0.25ml / min, temperature: 40°C. Injection volume: 1 μL. Diluent: Acetonitrile. ); or LCQ ADVANTAGE THERMO FINNIGAN (Method: Column: Symmetry Shield RP18, 150 x 3.0 mm, 3.5 μm, Eluent A: 0.05% TFA in Ace...

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Abstract

Disclosed herein are methods for obtaining N-(4-fluorobenzyl)-N-(l-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 substitutedor 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-(l-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide and methods for obtaining the salt.

Description

[0001] background technical field [0002] This disclosure relates to the fields of medicine and chemistry. More specifically, the present disclosure relates to one or more methods for obtaining N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methyl Propoxy)-phenylmethyl)urea, its tartrate salts and polymorphs, methods of intermediates, and their synthesis and use. Background technique [0003] N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropoxy)-phenylmethyl)urea (also known as pimavanserin) is described in WO 2004 / 064738, WO 2006 / 037043, WO 2007 / 124136 and WO 2008 / 144326, each of which is incorporated herein by reference in its entirety. These publications describe routes to the preparation of pimavanserin. While the pathway described is sufficient to produce pimavanserin, there may be other pathways that offer other opportunities. Contents of the invention [0004] Disclosed herein include methods of preparing pimavanserin. [0005] Also dis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/58
CPCC07D211/58C07B2200/13A61K31/4468C07C233/00C07D211/98
Inventor 马龙·卡洛斯萨冈·坦德尔R·奥尔森米卡尔·希尔格伦马修·J·弗莱明安德烈亚斯·菲利普·布迪耶贝亚特·T·韦伯
Owner ACADIA PHARMA INC
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