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
Inventors
Carlos, Marlon • Tandel, Sagun • Olsson, Roger • Hillgren, Mikael • Fleming, Matthew J. • Boudier, Andreas Philipp • Weber, Beat T.
Assignees
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Publication Number
US-11840515-B2
Publication Date
2023-12-12
Expiration Date
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.
Core Innovation
The invention relates to a method of preparing pimavanserin or a salt thereof by contacting an intermediate according to Formula (A2) with an intermediate according to Formula (B2). The contacting produces pimavanserin or a salt thereof, with Y defined as —OR1 or —NR2aR2b and R1, R2a, and R2b independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted aryl, with R2a and R2b optionally forming a substituted or unsubstituted heteroalicyclyl or heteroaryl with the nitrogen.
The disclosure also describes carbamate intermediates derived from SM1 and SM2, including SM2b, and carbonate-based carbamate formation using dimethyl carbonate and diphenyl carbonate with catalysts or co-catalysts such as NaOtBu, Zr(OtBu)4, 2-hydroxypyridine, and 4-methyl-2-hydroxyquinoline. It further includes preparation of an intermediate such as phenyl 4-isobutoxybenzyl carbamate and conversion with SM1 to form pimavanserin.
The document additionally describes pimavanserin tartrate, including hemi-tartrate and polymorphic Form C, and characterizes the tartrate salt by differential scanning calorimetry behavior. It also notes an integrated approach to form the tartrate salt without isolating intermediate pimavanserin.
Claims Coverage
The independent claim coverage centers on a method of preparing pimavanserin or a salt by contacting intermediates of Formula (A2) and Formula (B2), with one inventive feature focused on the structural definitions of Y, R1, R2a, and R2b. Additional claim features refine the contacting conditions, the base, and the formation of pimavanserin tartrate salt polymorphic Form C. In total, six inventive features are identified.
Contacting formula a2 with formula b2 to produce pimavanserin
A method of preparing pimavanserin or a salt thereof by 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 —OR1 or —NR2aR2b and R1, R2a, and R2b are defined by the stated substituent options.
Contacting the formula a2 and formula b2 intermediates in the presence of a base
The method further includes contacting the intermediate of Formula (A2) with the intermediate of Formula (B2) in the presence of a base.
Using a base selected from a defined list
The base is selected from triethyl amine, diisopropyl amine, pyridine, alkali metal carbonates, sodium hydroxide, potassium hydroxide, sodium phosphate, or potassium phosphate.
Selecting the base as sodium carbonate or potassium carbonate
The base is sodium carbonate or potassium carbonate.
Forming pimavanserin tartrate salt with (L)-tartaric acid without isolating pimavanserin
Pimavanserin is contacted with (L)-tartaric acid to form a pimavanserin tartrate salt without isolating pimavanserin beforehand.
Forming pimavanserin tartrate salt polymorphic form c defined by dsc onset
A pimavanserin tartrate salt polymorphic Form C is characterized by a differential scanning calorimetry endotherm onset between 167 and 177 °C.
Overall claim coverage focuses on producing pimavanserin or a salt by contacting intermediates according to Formula (A2) and Formula (B2), with defined substituent options. The dependent features add the presence and identity of a base and further define formation of pimavanserin tartrate salt, including non-isolation of pimavanserin and polymorphic Form C characterization by DSC onset.
Stated Advantages
Safety, economic, and environmental benefits are stated in the context of avoiding toxic phosgene and avoiding isobutyl bromide.
High-purity and pH-solubility advantages are discussed for salts and pharmaceutical formulations.
Avoidance of phosgene is stated as an emphasis in the disclosed carbamate-intermediate formation approach.
Documented Applications
Preparation of pimavanserin by converting disclosed intermediates and subsequent formation of pimavanserin tartrate salt, including polymorphic Form C, with an option for integrated formation without isolating intermediate pimavanserin.
Pharmaceutical formulations and salts.
Manufacturing/preparing pimavanserin and pimavanserin salts, including pimavanserin tartrate and polymorphic Form C tartrate, using intermediate coupling between Formula (A2) and Formula (B2) and subsequent salt formation with (L)-tartaric acid.
Producing and characterizing carbamate intermediates (from SM1 and SM2 or SM2 freebase) and using DSC characterization (including for carbamate intermediate I1.1).
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