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WO2019087069A2 - Pimavanserin tartrate impurities, processes for their preparation, and their use as reference standards - Google Patents

Pimavanserin tartrate impurities, processes for their preparation, and their use as reference standards Download PDF

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Publication number
WO2019087069A2
WO2019087069A2 PCT/IB2018/058498 IB2018058498W WO2019087069A2 WO 2019087069 A2 WO2019087069 A2 WO 2019087069A2 IB 2018058498 W IB2018058498 W IB 2018058498W WO 2019087069 A2 WO2019087069 A2 WO 2019087069A2
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Prior art keywords
formula
methylpropoxy
phenyl
benzyl
sample
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WO2019087069A3 (en
Inventor
Sairab Khan
Kaushal Nayyar
Mohan Prasad
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Sun Pharmaceutical Industries Ltd
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Sun Pharmaceutical Industries Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/62—Detectors specially adapted therefor
    • G01N2030/621—Detectors specially adapted therefor signal-to-noise ratio
    • G01N2030/625—Detectors specially adapted therefor signal-to-noise ratio by measuring reference material, e.g. carrier without sample
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
    • G01N2030/8872—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample impurities
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86

Definitions

  • the present disclosure provides impurities of pimavanserin tartrate, processes for the preparation of the disclosed impurities, and the use of the disclosed impurities as reference standards in a chromatographic method for analyzing the purity of pimavanserin tartrate, or a dosage form comprising pimavanserin tartrate.
  • Nuplazid® an atypical antipsychotic, contains pimavanserin tartrate of Formula I.
  • Pimavanserin tartrate is chemically known as urea, N-[(4-fluorophenyl)methyl]-N-(l- methyl-4-piperidinyl)-N'-[[4-(2-methylpropoxy)phenyl]methyl]- (2R,3R)-2,3- dihydroxybutanedioate 2: 1).
  • CN 105153016 CN 1051 1 1 135; CN 104961672; CN 104844502; CN 105906551 ; CN 105820110; CN 106518751 ; and CN 105906531.
  • the present disclosure provides impurities of pimavanserin tartrate, processes for the preparation of the disclosed impurities, and the use of the disclosed impurities as reference standards in a chromatographic method for analyzing the purity of pimavanserin tartrate, or a dosage form comprising pimavanserin tartrate.
  • a first aspect of the present disclosure provides N-[4-(2-methylpropoxy)benzyl]-l- [4-(2-methylpropoxy)phenyl]methanamine of Formula II.
  • a second aspect of the present disclosure provides a process for the preparation of N-[4-(2-methylpropoxy)benzyl] - 1 -[4-(2-methylpropoxy)phenyl]methanamine of Formula
  • a third aspect of the present disclosure provides a method for analyzing the purity of pimavanserin tartrate comprising the use of N-[4-(2-methylpropoxy)benzyl]-l-[4-(2- methylpropoxy)phenyl]methanamine of Formula II
  • a fourth aspect of the present disclosure provides a chromatographic method for testing the purity of a sample comprising pimavanserin tartrate by determining the presence of the N-[4-(2-methylpropoxy)benzyl]-l-[4-(2- methylpropoxy)phenyl]methanamine of Formula II in the sample comprising the steps of:
  • a fifth aspect of the present disclosure provides N,N-bis[4-(2- methylpropoxy)benzyl]- l-[4-(2-methylpropoxy)phenyl]methanamine of Formula V.
  • a sixth aspect of the present disclosure provides a process for the preparation of N,N-bis[4-(2-methylpropoxy)benzyl] - 1 -[4-(2-methylpropoxy)phenyl]methanamine of Formula V
  • a seventh aspect of the present disclosure provides a method for analyzing the purity of pimavanserin tartrate comprising the use ofN,N-bis[4-(2- methylpropoxy)benzyl] - l-[4-(2-methylpropoxy)phenyl]methanamine of Formula V
  • An eighth aspect of the present disclosure provides a chromatographic method for testing the purity of a sample comprising pimavanserin tartrate by determining the presence of the N,N-bis[4-(2-methylpropoxy)benzyl]-l-[4-(2- methylpropoxy)phenyl]methanamine of Formula V in the sample comprising the steps of: i) dissolving pimavanserin tartrate in a solvent to obtain a sample solution; ii) dissolving a sample of the N,N-bis[4-(2-methylpropoxy)benzyl]-l-[4-(2- methylpropoxy)phenyl]methanamine of Formula V in a solvent to make a reference standard solution;
  • a ninth aspect of the present disclosure provides [4-(2- methylpropoxy)phenyl]methanol of Formula VI.
  • a tenth aspect of the present disclosure provides a process for the preparation of [4-(2-methylpropoxy)phenyl]methanol of Formula VI
  • An eleventh aspect of the present disclosure a method for analyzing the purity of pimavanserin tartrate comprising the use of [4-(2-methylpropoxy)phenyl]methanol of Formula VI
  • a twelfth aspect of the present disclosure provides a chromatographic method for testing the purity of a sample comprising pimavanserin tartrate by determining the presence of the [4-(2-methylpropoxy)phenyl]methanol of Formula VI in the sample comprising the steps of:
  • a thirteenth aspect of the present disclosure provides l-(4-fluorobenzyl)-3-[4-(2- methylpropoxy)benzyl]urea of Formula VII.
  • a fourteenth aspect of the present disclosure provides a process for the preparation of l-(4-fluorobenzyl)-3-[4-(2-methylpropoxy)benzyl]urea of Formula VII
  • a fifteenth aspect of the present disclosure provides a method for analyzing the purity of pimavanserin tartrate comprising the use of l-(4-fluorobenzyl)-3-[4-(2- methylpropoxy)benzyl]urea of Formula VII
  • a sixteenth aspect of the present disclosure provides a chromatographic method for testing the purity of a sample comprising pimavanserin tartrate by determining the presence of the l-(4-fluorobenzyl)-3-[4-(2-methylpropoxy)benzyl]urea of Formula VII in the sample comprising the steps of:
  • ambient temperature refers to a temperature in the range of about 20°C to about 35°C.
  • solvent refers to aromatic hydrocarbons, esters, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, alcohols, or combinations thereof.
  • aromatic hydrocarbons include toluene and xylene.
  • esters include ethyl acetate, w-propyl acetate, isopropyl acetate, and «-butyl acetate.
  • halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane.
  • ketones include acetone and methyl ethyl ketone.
  • ethers include diethyl ether, methyl teri-butyl ether, and tetrahydrofuran.
  • polar aprotic solvents include N,N-dimethylformamide, N,N- dimethylacetamide, dimethylsulphoxide, acetonitrile, andN-methylpyrrolidone.
  • alcohols include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, and 2-butanol.
  • reference standard refers to the compounds of Formula II, V, VI, or VII that can be used both for quantitative and qualitative analysis of different components of a mixture comprising pimavanserin tartrate in a chromatographic method, such as, HPLC (High-Performance Liquid Chromatography), LC-MS (Liquid
  • the preparation ofN-[4-(2-methylpropoxy)benzyl]-l-[4-(2- methylpropoxy)phenyl]methanamine of Formula II is carried out by reacting 4-(2- methylpropoxy)benzaldehyde of Formula III with l-[4-(2- methylpropoxy)phenyl]methanamine of Formula IV in the presence of a reducing agent in an inert atmosphere.
  • a reducing agent inert atmosphere.
  • sodium borohydride is used as reducing agent.
  • lithium aluminum hydride is used.
  • diisobutylaluminum hydride is used.
  • sodium triacetoxy borane is used.
  • borane is used.
  • the reaction of the compound of Formula III with the compound of Formula IV is carried out in the presence of a solvent selected from aromatic hydrocarbons, esters, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, alcohols, or combinations thereof.
  • a solvent selected from aromatic hydrocarbons, esters, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, alcohols, or combinations thereof.
  • a halogenated hydrocarbon solvent is used.
  • dichloromethane is used.
  • chloroform is used.
  • 1,2-dichloroethane is used.
  • an aromatic hydrocarbon is used.
  • an ester solvent is used.
  • a ketone solvent is used.
  • an ether solvent is used.
  • a polar aprotic solvent is used.
  • an alcohol solvent is used.
  • the reaction of the compound of Formula III with the compound of Formula IV is carried out at a temperature of about 10°C to the reflux temperature of the solvent. In one embodiment, the reaction is carried out at a temperature of about 10°C to about 20°C. In another embodiment, the reaction is carried out at ambient temperature. In another embodiment, the reaction is carried out at the reflux temperature of the solvent.
  • the reaction of the compound of Formula III with the compound of Formula IV is carried out for a period of about 30 minutes to about 10 hours. In one embodiment, the reaction is carried out for about 30 minutes to about 2 hours. In another embodiment, the reaction is carried out for about 2 hours to about 5 hours. In another embodiment, the reaction is carried out for about 5 hours to about 8 hours. In another embodiment, the reaction is carried out for about 8 hours to about 10 hours.
  • Isolation can be carried out by concentration, precipitation, cooling, filtration, centrifugation, or combinations thereof, followed by optional purification, and drying. Purification can be carried out using column chromatography or crystallization.
  • N-[4-(2-methylpropoxy)benzyl]-l-[4-(2- methylpropoxy)phenyl]methanamine of Formula II is purified using column
  • N-[4-(2-methylpropoxy)benzyl]- l-[4-(2- methylpropoxy)phenyl]methanamine of Formula II is purified by crystallization.
  • N-[4-(2-methylpropoxy)benzyl]-l-[4-(2- methylpropoxy)phenyl]methanamine of Formula II is purified by crystallization from mixture of dichloromethane and diisopropyl ether.
  • Drying can be carried out using any suitable method, such as, drying under reduced pressure, air drying, or vacuum tray drying. In one embodiment, drying is carried out under reduced pressure. In another embodiment, air drying is carried out. In another embodiment, vacuum tray drying is carried out. Drying can be carried out at a temperature of about 35°C to about 70°C. In one embodiment, drying is carried out at about 35°C to about 45°C. In another embodiment, drying is carried out at about 45°C to about 55°C. In another embodiment, drying is carried out at about 55°C to about 70°C. Drying is carried out for a period of about 2 hours to about 24 hours. In one embodiment, drying is carried out for about 2 hours to about 5 hours. In another embodiment, drying is carried out for about 5 hours to about 10 hours.
  • drying is carried out for about 10 hours to about 15 hours. In another embodiment, drying is carried out for about 15 hours to about 20 hours. In another embodiment, drying is carried out for about 20 hours to about 24 hours.
  • the preparation of N,N-bis[4-(2-methylpropoxy)benzyl]- l-[4-(2- methylpropoxy)phenyl]methanamine of Formula V is carried out by reacting N-[4-(2- methylpropoxy) benzyl] -l-[4-(2-methylpropoxy)phenyl] methanamine of Formula II with 4-(2-methylpropoxy)benzaldehyde of Formula III in the presence of a reducing agent in an inert atmosphere.
  • sodium borohydride is used as reducing agent.
  • lithium aluminum hydride is used.
  • diisobutylaluminum hydride is used.
  • sodium triacetoxy borane is used.
  • borane is used.
  • the reaction of the compound of Formula II with the compound of Formula III is carried out in the presence of a solvent selected from aromatic hydrocarbons, esters, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, alcohols, or combinations thereof.
  • a solvent selected from aromatic hydrocarbons, esters, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, alcohols, or combinations thereof.
  • a halogenated hydrocarbon solvent is used.
  • dichloromethane is used.
  • chloroform is used.
  • 1,2-dichloroethane is used.
  • an aromatic hydrocarbon is used.
  • an ester solvent is used.
  • a ketone solvent is used.
  • an ether solvent is used.
  • a polar aprotic solvent is used.
  • an alcohol solvent is used.
  • the reaction of the compound of Formula II with the compound of Formula III is carried out in the presence of a catalytic amount of a carboxylic acid.
  • the carboxylic acid is selected from formic acid, acetic acid, and propionic acid. In one embodiment, formic acid is added. In another embodiment, acetic acid is added. In another embodiment, propionic acid is added.
  • the reaction of the compound of Formula II with the compound of Formula III is carried out at a temperature of about 10°C to the reflux temperature of the solvent. In one embodiment, the reaction is carried out at a temperature of about 10°C to about 20°C. In another embodiment, the reaction is carried out at ambient temperature. In another embodiment, the reaction is carried out at the reflux temperature of the solvent.
  • the reaction of the compound of Formula II with the compound of Formula III is carried out for a period of about 10 hours to about 72 hours. In one embodiment, the reaction is carried out for a period of about 10 hours to about 24 hours. In another embodiment, the reaction is carried out for a period of about 24 hours to about 48 hours. In another embodiment, the reaction is carried out for a period of about 48 hours to about 72 hours.
  • Isolation can be carried out by concentration, precipitation, cooling, filtration, centrifugation, or combinations thereof, followed by optional purification, and drying. Purification can be carried out using column chromatography or crystallization.
  • N,N-bis[4-(2-methylpropoxy)benzyl]-l-[4-(2- methylpropoxy)phenyl]methanamine of Formula V is purified using column
  • N,N-bis[4-(2-methylpropoxy)benzyl]-l-[4-(2- methylpropoxy)phenyl]methanamine of Formula V is purified by column chromatography using a mixture of ethyl acetate and hexane as eluent.
  • N,N-bis[4- (2-methylpropoxy)benzyl]-l-[4-(2-methylpropoxy)phenyl]methanamine of Formula V is purified by crystallization.
  • Drying can be carried out using any suitable method, such as, drying under reduced pressure, air drying, or vacuum tray drying. In one embodiment, drying is carried out under reduced pressure. In another embodiment, air drying is carried out. In another embodiment, vacuum tray drying is carried out. Drying can be carried out at a temperature of about 35°C to about 70°C. In one embodiment, drying is carried out at about 35°C to about 45°C. In another embodiment, drying is carried out at about 45°C to about 55°C. In another embodiment, drying is carried out at about 55°C to about 70°C. Drying is carried out for a period of about 2 hours to about 24 hours. In one embodiment, drying is carried out for about 2 hours to about 5 hours. In another embodiment, drying is carried out for about 5 hours to about 10 hours. In another embodiment, drying is carried out for about 10 hours to about 15 hours. In another embodiment, drying is carried out for about 15 hours to about 20 hours. In another embodiment, drying is carried out for about 20 hours to about 24 hours.
  • the preparation of [4-(2-methylpropoxy)phenyl]methanol of Formula VI is carried out by reacting 4-(2-methylpropoxy)benzaldehyde of Formula III with a reducing agent in an inert atmosphere.
  • a reducing agent in one embodiment, sodium borohydride is used as reducing agent.
  • lithium aluminum hydride is used.
  • diisobutylaluminum hydride is used.
  • sodium triacetoxy borane is used.
  • borane is used.
  • the reduction is carried out in the presence of a solvent selected from aromatic hydrocarbons, esters, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, alcohols, or combinations thereof.
  • an alcohol solvent is used.
  • methanol is used. In another embodiment, ethanol is used.
  • 1-propanol is used. In another embodiment, 2-propanol is used.
  • 1-butanol is used. In another embodiment, 2-butanol is used.
  • an aromatic hydrocarbon is used. In another embodiment, an ester solvent is used. In another embodiment, a halogenated hydrocarbon solvent is used. In another embodiment, dichloromethane is used. In another embodiment, chloroform is used. In another embodiment, 1,2-dichloroethane is used. In another embodiment, a ketone solvent is used. In another embodiment, an ether solvent is used. In another embodiment, a polar aprotic solvent is used.
  • the reduction of the compound of Formula III is carried out at a temperature of about 10°C to the reflux temperature of the solvent. In one embodiment, the reaction is carried out at a temperature of about 10°C to about 20°C. In another embodiment, the reaction is carried out at ambient temperature. In another embodiment, the reaction is carried out at the reflux temperature of the solvent.
  • the reaction mass is cooled to a temperature of about -10°C to 10°C. In one embodiment, the reaction mass is cooled to a temperature of about -10°C to 0°C. In another embodiment, the reaction mass is cooled to a temperature of 0°C to 10°C.
  • Isolation can be carried out by concentration, precipitation, cooling, filtration, centrifugation, or combinations thereof, followed by optional purification, and drying. Purification can be carried out using column chromatography or crystallization.
  • [4-(2-methylpropoxy)phenyl]methanol of Formula VI is purified using column chromatography. In another embodiment, [4-(2- methylpropoxy)phenyl]methanol of Formula VI is purified by crystallization.
  • Drying can be carried out using any suitable method, such as, drying under reduced pressure, air drying, or vacuum tray drying. In one embodiment, drying is carried out under reduced pressure. In another embodiment, air drying is carried out. In another embodiment, vacuum tray drying is carried out. Drying can be carried out at a temperature of about 35°C to about 70°C. In one embodiment, drying is carried out at about 35°C to about 45°C. In another embodiment, drying is carried out at about 45°C to about 55°C. In another embodiment, drying is carried out at about 55°C to about 70°C. Drying is carried out for a period of about 2 hours to about 24 hours. In one embodiment, drying is carried out for about 2 hours to about 5 hours. In another embodiment, drying is carried out for about 5 hours to about 10 hours. In another embodiment, drying is carried out for about 10 hours to about 15 hours. In another embodiment, drying is carried out for about 15 hours to about 20 hours. In another embodiment, drying is carried out for about 20 hours to about 24 hours.
  • the preparation of l-(4-fluorobenzyl)-3-[4-(2-methylpropoxy)benzyl]urea of Formula VII is carried out by reacting l-[4-(2-methylpropoxy)phenyl]methanamine of Formula IV with l-[4-(fluoromethyl)phenyl]methanamine of Formula VIII in an inert atmosphere.
  • reaction of Formula IV with Formula VIII is carried out in the presence of a coupling agent selected from carbonyldiimidazole, phosgene, triphosgene, or
  • phenylchloroformate In one embodiment, carbonyldiimidazole is used. In another embodiment, phosgene is used. In another embodiment, triphosgene is used. In another embodiment, phenylchloroformate is used.
  • the reaction of the compound of Formula IV with the compound of Formula VIII is carried out in the presence of an organic or an inorganic base.
  • organic base include ethylamine, propyl amine, isopropylamine, and triethylamine.
  • inorganic base include hydroxides, carbonates and bicarbonates of alkali and alkaline metals, for example, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, barium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, and magnesium bicarbonate.
  • ethylamine is used.
  • propylamine is used.
  • isopropyl amine is used.
  • triethylamine is used.
  • the reaction of the compound of Formula IV with the compound of Formula VIII is carried out in a solvent selected from aromatic hydrocarbons, esters, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, alcohols, or combinations thereof.
  • a solvent selected from aromatic hydrocarbons, esters, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, alcohols, or combinations thereof.
  • a polar aprotic solvent is used.
  • N,N- dimethylformamide is used.
  • N,N-dimethylacetamide is used.
  • dimethylsulphoxide is used.
  • acetonitrile is used.
  • N-methylpyrrolidone is used.
  • an alcohol solvent is used.
  • an aromatic hydrocarbon is used.
  • an ester solvent is used.
  • a halogenated hydrocarbon solvent is used.
  • dichloromethane is used.
  • chloroform is used.
  • 1,2-dichloroethane is used.
  • a ketone solvent is used.
  • an ether solvent is used.
  • the reaction of the compound of Formula IV with the compound of Formula VIII is carried out at a temperature of about 10°C to the reflux temperature of the solvent. In one embodiment, the reaction is carried out at a temperature of about 10°C to about 20°C. In another embodiment, the reaction is carried out at ambient temperature. In another embodiment, the reaction is carried out at the reflux temperature of the solvent.
  • the reaction of the compound of Formula IV with the compound of Formula VIII is carried out in a period of about 10 hours to about 48 hours. In one embodiment, the reaction is carried out in about 10 to about 15 hours. In another embodiment, the reaction is carried out in about 15 to about 20 hours. In another embodiment, the reaction is carried out in about 20 to about 30 hours. In another embodiment, the reaction is carried out in about 30 to about 48 hours.
  • Isolation can be carried out by concentration, precipitation, cooling, filtration, centrifugation, or combinations thereof, followed by optional purification, and drying. Purification can be carried out using column chromatography or crystallization.
  • l-(4-fluorobenzyl)-3-[4-(2-methylpropoxy)benzyl]urea of Formula VII is purified using column chromatography.
  • l-(4- fluorobenzyl)-3-[4-(2-methylpropoxy)benzyl]urea of Formula VII is purified by crystallization.
  • l-(4-fluorobenzyl)-3-[4-(2- methylpropoxy)benzyl]urea of Formula VII is purified by dissolving the crude material in dichloromethane and adding diisopropyl ether to the solution.
  • Drying can be carried out using any suitable method, such as, drying under reduced pressure, air drying, or vacuum tray drying. In one embodiment, drying is carried out under reduced pressure. In another embodiment, air drying is carried out. In another embodiment, vacuum tray drying is carried out. Drying can be carried out at a temperature of about 35°C to about 70°C. In one embodiment, drying is carried out at about 35°C to about 45°C. In another embodiment, drying is carried out at about 45°C to about 55°C. In another embodiment, drying is carried out at about 55°C to about 70°C. Drying is carried out for a period of about 2 hours to about 24 hours. In one embodiment, drying is carried out for about 2 hours to about 5 hours. In another embodiment, drying is carried out for about 5 hours to about 10 hours. In another embodiment, drying is carried out for about 10 hours to about 15 hours. In another embodiment, drying is carried out for about 15 hours to about 20 hours. In another embodiment, drying is carried out for about 20 hours to about 24 hours.
  • the NMR spectrum was recorded using a Bruker Avance III 400 MHz NMR spectrometer.
  • HPLC purity was determined using an Sunniest C18 (150 mm x 4.6 mm), 2.7 ⁇ column with a flow rate of 0.5-0.6 mL/minute; Column oven temperature: 35°C; Sample tray temperature: 10°C; Detector UV: 270 nm; Injection volume: 10 ⁇ ; Run time: 110 minutes.
  • the crude material was purified by treating with mixture of dichloromethane and diisopropyl ether, followed by filtration, and drying at a temperature of 40°C under reduced pressure to pure obtain N-[4- (2-methylpropoxy)benzyl] - 1 -[4-(2-methylpropoxy)phenyl]methanamine .
  • the crude material was purified using column chromatography using a mixture of ethyl acetate and hexane as eluent, followed by filtration, and drying at a temperature of 40°C under reduced pressure to obtain pure N,N-bis[4-(2-methylpropoxy)benzyl]-l-[4-(2- methylpropoxy)phenyl]methanamine .
  • Triethylamine (3 mL) was added in 10 minutes into a reaction vessel containing 1- [4-(2-methylpropoxy)phenyl]methanamine (2g; Formula IV) in N,N-dimethylformamide (10 mL) at ambient temperature. Carbonyldiimidazole (1.8 g) was added. The reaction mass was stirred for 2 hours. l(4-fluorophenyl)methanamine (1.39 g; Formula VIII) was added. The reaction mass was stirred for 18 hours. The reaction mass was concentrated at a temperature of 40°C under reduced pressure.
  • the crude material was purified by dissolving in dichloromethane and adding diisopropyl ether to the solution, followed by filtration, and drying at a temperature of 45 °C under reduced pressure to obtain pure l-(4- fluorobenzyl) -3 - [4-(2-methylpropoxy)benzy 1] urea.

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Abstract

The present disclosure provides impurities of pimavanserin tartrate, processes for the preparation of the disclosed impurities, and the use of the disclosed impurities as reference standards in a chromatographic method for analyzing the purity of pimavanserin tartrate, or a dosage form comprising pimavanserin tartrate.

Description

PIMAVANSERIN TARTRATE IMPURITIES, PROCESSES FOR THEIR PREPARATION, AND THEIR USE AS REFERENCE STANDARDS
Field of the Invention
The present disclosure provides impurities of pimavanserin tartrate, processes for the preparation of the disclosed impurities, and the use of the disclosed impurities as reference standards in a chromatographic method for analyzing the purity of pimavanserin tartrate, or a dosage form comprising pimavanserin tartrate.
Background of the Invention
Nuplazid®, an atypical antipsychotic, contains pimavanserin tartrate of Formula I. Pimavanserin tartrate is chemically known as urea, N-[(4-fluorophenyl)methyl]-N-(l- methyl-4-piperidinyl)-N'-[[4-(2-methylpropoxy)phenyl]methyl]- (2R,3R)-2,3- dihydroxybutanedioate 2: 1).
Figure imgf000002_0001
Formula I
Processes for the preparation of pimavanserin tartrate are disclosed in U.S. Patent No. 7,601,740; PCT Publication Nos. WO 2017/054786; WO 2017/036432; and WO 2017/015272; and Chinese Publication Nos. CN 105481757; CN 105418460;
CN 105153016; CN 1051 1 1 135; CN 104961672; CN 104844502; CN 105906551 ; CN 105820110; CN 106518751 ; and CN 105906531.
Summary of the Invention
The present disclosure provides impurities of pimavanserin tartrate, processes for the preparation of the disclosed impurities, and the use of the disclosed impurities as reference standards in a chromatographic method for analyzing the purity of pimavanserin tartrate, or a dosage form comprising pimavanserin tartrate. A first aspect of the present disclosure provides N-[4-(2-methylpropoxy)benzyl]-l- [4-(2-methylpropoxy)phenyl]methanamine of Formula II.
Figure imgf000003_0001
Formula II
A second aspect of the present disclosure provides a process for the preparation of N-[4-(2-methylpropoxy)benzyl] - 1 -[4-(2-methylpropoxy)phenyl]methanamine of Formula
Figure imgf000003_0002
Formula II
comprising reacting 4-(2-methylpropoxy)benzaldehyde of Formula III
Figure imgf000003_0003
Formula III
with l-[4-(2-methylpropoxy)phenyl]methanamine of Formula IV
Figure imgf000003_0004
Formula IV
the presence of a reducing agent. A third aspect of the present disclosure provides a method for analyzing the purity of pimavanserin tartrate comprising the use of N-[4-(2-methylpropoxy)benzyl]-l-[4-(2- methylpropoxy)phenyl]methanamine of Formula II
Figure imgf000004_0001
Formula II
as a reference standard.
A fourth aspect of the present disclosure provides a chromatographic method for testing the purity of a sample comprising pimavanserin tartrate by determining the presence of the N-[4-(2-methylpropoxy)benzyl]-l-[4-(2- methylpropoxy)phenyl]methanamine of Formula II in the sample comprising the steps of:
dissolving pimavanserin tartrate in a solvent to obtain a sample solution; ii) dissolving a sample of the N-[4-(2-methylpropoxy)benzyl]-l-[4-(2- methylpropoxy)phenyl]methanamine of Formula II in a solvent to make a reference standard solution;
iii) subjecting the sample solution and the reference standard solution to a chromatographic technique; and
iv) determining the presence of the N-[4-(2-methylpropoxy)benzyl]- 1-[4-(2- methylpropoxy)phenyl]methanamine of Formula II in the sample of pimavanserin tartrate using the reference standard solution.
A fifth aspect of the present disclosure provides N,N-bis[4-(2- methylpropoxy)benzyl]- l-[4-(2-methylpropoxy)phenyl]methanamine of Formula V.
Figure imgf000005_0001
Formula V
A sixth aspect of the present disclosure provides a process for the preparation of N,N-bis[4-(2-methylpropoxy)benzyl] - 1 -[4-(2-methylpropoxy)phenyl]methanamine of Formula V
Figure imgf000005_0002
Formula V
comprising reacting N-[4-(2-methylpropoxy) benzyl]-l-[4-(2-methylpropoxy)phenyl] methanamine of Formula II
Figure imgf000006_0001
Formula II
with 4-(2-methylpropoxy)benzaldehyde of Formula III
Figure imgf000006_0002
Formula III
in the presence of a reducing agent.
A seventh aspect of the present disclosure provides a method for analyzing the purity of pimavanserin tartrate comprising the use ofN,N-bis[4-(2- methylpropoxy)benzyl] - l-[4-(2-methylpropoxy)phenyl]methanamine of Formula V
Figure imgf000006_0003
Formula V
as a reference standard. An eighth aspect of the present disclosure provides a chromatographic method for testing the purity of a sample comprising pimavanserin tartrate by determining the presence of the N,N-bis[4-(2-methylpropoxy)benzyl]-l-[4-(2- methylpropoxy)phenyl]methanamine of Formula V in the sample comprising the steps of: i) dissolving pimavanserin tartrate in a solvent to obtain a sample solution; ii) dissolving a sample of the N,N-bis[4-(2-methylpropoxy)benzyl]-l-[4-(2- methylpropoxy)phenyl]methanamine of Formula V in a solvent to make a reference standard solution;
iii) subjecting the sample solution and the reference standard solution to a chromatographic technique; and
iv) determining the presence of the N,N-bis[4-(2-methylpropoxy)benzyl]-l-[4- (2-methylpropoxy)phenyl]methanamine of Formula V in the sample of pimavanserin tartrate using the reference standard solution.
A ninth aspect of the present disclosure provides [4-(2- methylpropoxy)phenyl]methanol of Formula VI.
Figure imgf000007_0001
Formula VI
A tenth aspect of the present disclosure provides a process for the preparation of [4-(2-methylpropoxy)phenyl]methanol of Formula VI
Figure imgf000007_0002
Formula VI
comprising reacting 4-(2-methylpropoxy)benzaldehyde of Formula III
Figure imgf000008_0001
Formula III
with a reducing agent.
An eleventh aspect of the present disclosure a method for analyzing the purity of pimavanserin tartrate comprising the use of [4-(2-methylpropoxy)phenyl]methanol of Formula VI
Figure imgf000008_0002
Formula VI
as a reference standard.
A twelfth aspect of the present disclosure provides a chromatographic method for testing the purity of a sample comprising pimavanserin tartrate by determining the presence of the [4-(2-methylpropoxy)phenyl]methanol of Formula VI in the sample comprising the steps of:
i) dissolving pimavanserin tartrate in a solvent to obtain a sample solution; ii) dissolving a sample of the [4-(2-methylpropoxy)phenyl]methanol of
Formula VI in a solvent to make a reference standard solution;
iii) subjecting the sample solution and the reference standard solution to a chromatographic technique; and
iv) determining the presence of the [4-(2-methylpropoxy)phenyl]methanol of Formula VI in the sample of pimavanserin tartrate using the reference standard solution.
A thirteenth aspect of the present disclosure provides l-(4-fluorobenzyl)-3-[4-(2- methylpropoxy)benzyl]urea of Formula VII.
Figure imgf000009_0001
A fourteenth aspect of the present disclosure provides a process for the preparation of l-(4-fluorobenzyl)-3-[4-(2-methylpropoxy)benzyl]urea of Formula VII
Figure imgf000009_0002
Formula VII
comprising reacting l-[4-(2-methylpropoxy)phenyl]methanamine of Formula IV
Figure imgf000009_0003
Formula IV
with l-[4-(fluoromethyl)phenyl]methanamine of Formula VIII in the presence of a coupling agent.
Figure imgf000009_0004
Formula VIII
A fifteenth aspect of the present disclosure provides a method for analyzing the purity of pimavanserin tartrate comprising the use of l-(4-fluorobenzyl)-3-[4-(2- methylpropoxy)benzyl]urea of Formula VII
Figure imgf000010_0001
Formula VII
as a reference standard.
A sixteenth aspect of the present disclosure provides a chromatographic method for testing the purity of a sample comprising pimavanserin tartrate by determining the presence of the l-(4-fluorobenzyl)-3-[4-(2-methylpropoxy)benzyl]urea of Formula VII in the sample comprising the steps of:
i) dissolving pimavanserin tartrate in a solvent to obtain a sample solution; ii) dissolving a sample of the l-(4-fluorobenzyl)-3-[4-(2- methylpropoxy)benzyl]urea of Formula VII in a solvent to make a reference standard solution;
iii) subjecting the sample solution and the reference standard solution to a chromatographic technique; and
iv) determining the presence of the l-(4-fluorobenzyl)-3-[4-(2- methylpropoxy)benzyl]urea of Formula VII in the sample of pimavanserin tartrate using the reference standard solution.
Detailed Description of the Invention
Various aspects and embodiments of the present invention are described hereafter.
The term "about" as used herein, refers to any value which lies within the range defined by a variation of up to ± 10% of the value .
The term "ambient temperature" as used herein, refers to a temperature in the range of about 20°C to about 35°C.
The term "solvent" as used herein, refers to aromatic hydrocarbons, esters, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, alcohols, or combinations thereof. Examples of aromatic hydrocarbons include toluene and xylene. Examples of esters include ethyl acetate, w-propyl acetate, isopropyl acetate, and «-butyl acetate. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. Examples of ketones include acetone and methyl ethyl ketone. Examples of ethers include diethyl ether, methyl teri-butyl ether, and tetrahydrofuran. Examples of polar aprotic solvents include N,N-dimethylformamide, N,N- dimethylacetamide, dimethylsulphoxide, acetonitrile, andN-methylpyrrolidone. Examples of alcohols include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, and 2-butanol.
The term "reference standard" as used herein, refers to the compounds of Formula II, V, VI, or VII that can be used both for quantitative and qualitative analysis of different components of a mixture comprising pimavanserin tartrate in a chromatographic method, such as, HPLC (High-Performance Liquid Chromatography), LC-MS (Liquid
Chromatography-Mass Spectrometry), or on a TLC (Thin Layer Chromatography) plate.
The preparation ofN-[4-(2-methylpropoxy)benzyl]-l-[4-(2- methylpropoxy)phenyl]methanamine of Formula II is carried out by reacting 4-(2- methylpropoxy)benzaldehyde of Formula III with l-[4-(2- methylpropoxy)phenyl]methanamine of Formula IV in the presence of a reducing agent in an inert atmosphere. In one embodiment, sodium borohydride is used as reducing agent. In another embodiment, lithium aluminum hydride is used. In another embodiment, diisobutylaluminum hydride is used. In another embodiment, sodium triacetoxy borane is used. In another embodiment, borane is used.
The reaction of the compound of Formula III with the compound of Formula IV is carried out in the presence of a solvent selected from aromatic hydrocarbons, esters, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, alcohols, or combinations thereof. In one embodiment, a halogenated hydrocarbon solvent is used. In another embodiment, dichloromethane is used. In another embodiment, chloroform is used. In another embodiment, 1,2-dichloroethane is used. In another embodiment, an aromatic hydrocarbon is used. In another embodiment, an ester solvent is used. In another embodiment, a ketone solvent is used. In another embodiment, an ether solvent is used. In another embodiment, a polar aprotic solvent is used. In another embodiment, an alcohol solvent is used.
The reaction of the compound of Formula III with the compound of Formula IV is carried out at a temperature of about 10°C to the reflux temperature of the solvent. In one embodiment, the reaction is carried out at a temperature of about 10°C to about 20°C. In another embodiment, the reaction is carried out at ambient temperature. In another embodiment, the reaction is carried out at the reflux temperature of the solvent.
The reaction of the compound of Formula III with the compound of Formula IV is carried out for a period of about 30 minutes to about 10 hours. In one embodiment, the reaction is carried out for about 30 minutes to about 2 hours. In another embodiment, the reaction is carried out for about 2 hours to about 5 hours. In another embodiment, the reaction is carried out for about 5 hours to about 8 hours. In another embodiment, the reaction is carried out for about 8 hours to about 10 hours.
Isolation can be carried out by concentration, precipitation, cooling, filtration, centrifugation, or combinations thereof, followed by optional purification, and drying. Purification can be carried out using column chromatography or crystallization.
In one embodiment, N-[4-(2-methylpropoxy)benzyl]-l-[4-(2- methylpropoxy)phenyl]methanamine of Formula II is purified using column
chromatography. In another embodiment, N-[4-(2-methylpropoxy)benzyl]- l-[4-(2- methylpropoxy)phenyl]methanamine of Formula II is purified by crystallization. In another embodiment, N-[4-(2-methylpropoxy)benzyl]-l-[4-(2- methylpropoxy)phenyl]methanamine of Formula II is purified by crystallization from mixture of dichloromethane and diisopropyl ether.
Drying can be carried out using any suitable method, such as, drying under reduced pressure, air drying, or vacuum tray drying. In one embodiment, drying is carried out under reduced pressure. In another embodiment, air drying is carried out. In another embodiment, vacuum tray drying is carried out. Drying can be carried out at a temperature of about 35°C to about 70°C. In one embodiment, drying is carried out at about 35°C to about 45°C. In another embodiment, drying is carried out at about 45°C to about 55°C. In another embodiment, drying is carried out at about 55°C to about 70°C. Drying is carried out for a period of about 2 hours to about 24 hours. In one embodiment, drying is carried out for about 2 hours to about 5 hours. In another embodiment, drying is carried out for about 5 hours to about 10 hours. In another embodiment, drying is carried out for about 10 hours to about 15 hours. In another embodiment, drying is carried out for about 15 hours to about 20 hours. In another embodiment, drying is carried out for about 20 hours to about 24 hours. The preparation of N,N-bis[4-(2-methylpropoxy)benzyl]- l-[4-(2- methylpropoxy)phenyl]methanamine of Formula V is carried out by reacting N-[4-(2- methylpropoxy) benzyl] -l-[4-(2-methylpropoxy)phenyl] methanamine of Formula II with 4-(2-methylpropoxy)benzaldehyde of Formula III in the presence of a reducing agent in an inert atmosphere. In one embodiment, sodium borohydride is used as reducing agent. In another embodiment, lithium aluminum hydride is used. In another embodiment, diisobutylaluminum hydride is used. In another embodiment, sodium triacetoxy borane is used. In another embodiment, borane is used.
The reaction of the compound of Formula II with the compound of Formula III is carried out in the presence of a solvent selected from aromatic hydrocarbons, esters, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, alcohols, or combinations thereof. In one embodiment, a halogenated hydrocarbon solvent is used. In another embodiment, dichloromethane is used. In another embodiment, chloroform is used. In another embodiment, 1,2-dichloroethane is used. In another embodiment, an aromatic hydrocarbon is used. In another embodiment, an ester solvent is used. In another embodiment, a ketone solvent is used. In another embodiment, an ether solvent is used. In another embodiment, a polar aprotic solvent is used. In another embodiment, an alcohol solvent is used.
The reaction of the compound of Formula II with the compound of Formula III is carried out in the presence of a catalytic amount of a carboxylic acid. The carboxylic acid is selected from formic acid, acetic acid, and propionic acid. In one embodiment, formic acid is added. In another embodiment, acetic acid is added. In another embodiment, propionic acid is added.
The reaction of the compound of Formula II with the compound of Formula III is carried out at a temperature of about 10°C to the reflux temperature of the solvent. In one embodiment, the reaction is carried out at a temperature of about 10°C to about 20°C. In another embodiment, the reaction is carried out at ambient temperature. In another embodiment, the reaction is carried out at the reflux temperature of the solvent.
The reaction of the compound of Formula II with the compound of Formula III is carried out for a period of about 10 hours to about 72 hours. In one embodiment, the reaction is carried out for a period of about 10 hours to about 24 hours. In another embodiment, the reaction is carried out for a period of about 24 hours to about 48 hours. In another embodiment, the reaction is carried out for a period of about 48 hours to about 72 hours.
Isolation can be carried out by concentration, precipitation, cooling, filtration, centrifugation, or combinations thereof, followed by optional purification, and drying. Purification can be carried out using column chromatography or crystallization.
In one embodiment, N,N-bis[4-(2-methylpropoxy)benzyl]-l-[4-(2- methylpropoxy)phenyl]methanamine of Formula V is purified using column
chromatography. In another embodiment, N,N-bis[4-(2-methylpropoxy)benzyl]-l-[4-(2- methylpropoxy)phenyl]methanamine of Formula V is purified by column chromatography using a mixture of ethyl acetate and hexane as eluent. In another embodiment, N,N-bis[4- (2-methylpropoxy)benzyl]-l-[4-(2-methylpropoxy)phenyl]methanamine of Formula V is purified by crystallization.
Drying can be carried out using any suitable method, such as, drying under reduced pressure, air drying, or vacuum tray drying. In one embodiment, drying is carried out under reduced pressure. In another embodiment, air drying is carried out. In another embodiment, vacuum tray drying is carried out. Drying can be carried out at a temperature of about 35°C to about 70°C. In one embodiment, drying is carried out at about 35°C to about 45°C. In another embodiment, drying is carried out at about 45°C to about 55°C. In another embodiment, drying is carried out at about 55°C to about 70°C. Drying is carried out for a period of about 2 hours to about 24 hours. In one embodiment, drying is carried out for about 2 hours to about 5 hours. In another embodiment, drying is carried out for about 5 hours to about 10 hours. In another embodiment, drying is carried out for about 10 hours to about 15 hours. In another embodiment, drying is carried out for about 15 hours to about 20 hours. In another embodiment, drying is carried out for about 20 hours to about 24 hours.
The preparation of [4-(2-methylpropoxy)phenyl]methanol of Formula VI is carried out by reacting 4-(2-methylpropoxy)benzaldehyde of Formula III with a reducing agent in an inert atmosphere. In one embodiment, sodium borohydride is used as reducing agent. In another embodiment, lithium aluminum hydride is used. In another embodiment, diisobutylaluminum hydride is used. In another embodiment, sodium triacetoxy borane is used. In another embodiment, borane is used. The reduction is carried out in the presence of a solvent selected from aromatic hydrocarbons, esters, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, alcohols, or combinations thereof. In one embodiment, an alcohol solvent is used. In another embodiment, methanol is used. In another embodiment, ethanol is used. In another embodiment, 1-propanol is used. In another embodiment, 2-propanol is used. In another embodiment, 1-butanol is used. In another embodiment, 2-butanol is used. In another embodiment, an aromatic hydrocarbon is used. In another embodiment, an ester solvent is used. In another embodiment, a halogenated hydrocarbon solvent is used. In another embodiment, dichloromethane is used. In another embodiment, chloroform is used. In another embodiment, 1,2-dichloroethane is used. In another embodiment, a ketone solvent is used. In another embodiment, an ether solvent is used. In another embodiment, a polar aprotic solvent is used.
The reduction of the compound of Formula III is carried out at a temperature of about 10°C to the reflux temperature of the solvent. In one embodiment, the reaction is carried out at a temperature of about 10°C to about 20°C. In another embodiment, the reaction is carried out at ambient temperature. In another embodiment, the reaction is carried out at the reflux temperature of the solvent.
The reaction mass is cooled to a temperature of about -10°C to 10°C. In one embodiment, the reaction mass is cooled to a temperature of about -10°C to 0°C. In another embodiment, the reaction mass is cooled to a temperature of 0°C to 10°C.
Isolation can be carried out by concentration, precipitation, cooling, filtration, centrifugation, or combinations thereof, followed by optional purification, and drying. Purification can be carried out using column chromatography or crystallization.
In one embodiment, [4-(2-methylpropoxy)phenyl]methanol of Formula VI is purified using column chromatography. In another embodiment, [4-(2- methylpropoxy)phenyl]methanol of Formula VI is purified by crystallization.
Drying can be carried out using any suitable method, such as, drying under reduced pressure, air drying, or vacuum tray drying. In one embodiment, drying is carried out under reduced pressure. In another embodiment, air drying is carried out. In another embodiment, vacuum tray drying is carried out. Drying can be carried out at a temperature of about 35°C to about 70°C. In one embodiment, drying is carried out at about 35°C to about 45°C. In another embodiment, drying is carried out at about 45°C to about 55°C. In another embodiment, drying is carried out at about 55°C to about 70°C. Drying is carried out for a period of about 2 hours to about 24 hours. In one embodiment, drying is carried out for about 2 hours to about 5 hours. In another embodiment, drying is carried out for about 5 hours to about 10 hours. In another embodiment, drying is carried out for about 10 hours to about 15 hours. In another embodiment, drying is carried out for about 15 hours to about 20 hours. In another embodiment, drying is carried out for about 20 hours to about 24 hours.
The preparation of l-(4-fluorobenzyl)-3-[4-(2-methylpropoxy)benzyl]urea of Formula VII is carried out by reacting l-[4-(2-methylpropoxy)phenyl]methanamine of Formula IV with l-[4-(fluoromethyl)phenyl]methanamine of Formula VIII in an inert atmosphere.
The reaction of Formula IV with Formula VIII is carried out in the presence of a coupling agent selected from carbonyldiimidazole, phosgene, triphosgene, or
phenylchloroformate. In one embodiment, carbonyldiimidazole is used. In another embodiment, phosgene is used. In another embodiment, triphosgene is used. In another embodiment, phenylchloroformate is used.
The reaction of the compound of Formula IV with the compound of Formula VIII is carried out in the presence of an organic or an inorganic base. Examples of an organic base include ethylamine, propyl amine, isopropylamine, and triethylamine. Examples of an inorganic base include hydroxides, carbonates and bicarbonates of alkali and alkaline metals, for example, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, barium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, and magnesium bicarbonate. In one embodiment, ethylamine is used. In another embodiment, propylamine is used. In another embodiment, isopropyl amine is used. In another embodiment, triethylamine is used.
The reaction of the compound of Formula IV with the compound of Formula VIII is carried out in a solvent selected from aromatic hydrocarbons, esters, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, alcohols, or combinations thereof. In one embodiment, a polar aprotic solvent is used. In another embodiment, N,N- dimethylformamide is used. In another embodiment, N,N-dimethylacetamide is used. In another embodiment, dimethylsulphoxide is used. In another embodiment, acetonitrile is used. In another embodiment, N-methylpyrrolidone is used. In another embodiment, an alcohol solvent is used. In another embodiment, an aromatic hydrocarbon is used. In another embodiment, an ester solvent is used. In another embodiment, a halogenated hydrocarbon solvent is used. In another embodiment, dichloromethane is used. In another embodiment, chloroform is used. In another embodiment, 1,2-dichloroethane is used. In another embodiment, a ketone solvent is used. In another embodiment, an ether solvent is used.
The reaction of the compound of Formula IV with the compound of Formula VIII is carried out at a temperature of about 10°C to the reflux temperature of the solvent. In one embodiment, the reaction is carried out at a temperature of about 10°C to about 20°C. In another embodiment, the reaction is carried out at ambient temperature. In another embodiment, the reaction is carried out at the reflux temperature of the solvent.
The reaction of the compound of Formula IV with the compound of Formula VIII is carried out in a period of about 10 hours to about 48 hours. In one embodiment, the reaction is carried out in about 10 to about 15 hours. In another embodiment, the reaction is carried out in about 15 to about 20 hours. In another embodiment, the reaction is carried out in about 20 to about 30 hours. In another embodiment, the reaction is carried out in about 30 to about 48 hours.
Isolation can be carried out by concentration, precipitation, cooling, filtration, centrifugation, or combinations thereof, followed by optional purification, and drying. Purification can be carried out using column chromatography or crystallization.
In one embodiment, l-(4-fluorobenzyl)-3-[4-(2-methylpropoxy)benzyl]urea of Formula VII is purified using column chromatography. In another embodiment, l-(4- fluorobenzyl)-3-[4-(2-methylpropoxy)benzyl]urea of Formula VII is purified by crystallization. In another embodiment, l-(4-fluorobenzyl)-3-[4-(2- methylpropoxy)benzyl]urea of Formula VII is purified by dissolving the crude material in dichloromethane and adding diisopropyl ether to the solution.
Drying can be carried out using any suitable method, such as, drying under reduced pressure, air drying, or vacuum tray drying. In one embodiment, drying is carried out under reduced pressure. In another embodiment, air drying is carried out. In another embodiment, vacuum tray drying is carried out. Drying can be carried out at a temperature of about 35°C to about 70°C. In one embodiment, drying is carried out at about 35°C to about 45°C. In another embodiment, drying is carried out at about 45°C to about 55°C. In another embodiment, drying is carried out at about 55°C to about 70°C. Drying is carried out for a period of about 2 hours to about 24 hours. In one embodiment, drying is carried out for about 2 hours to about 5 hours. In another embodiment, drying is carried out for about 5 hours to about 10 hours. In another embodiment, drying is carried out for about 10 hours to about 15 hours. In another embodiment, drying is carried out for about 15 hours to about 20 hours. In another embodiment, drying is carried out for about 20 hours to about 24 hours.
Methods:
The Mass spectrum was recorded using an Q TRAP LC/MS/MS system.
The NMR spectrum was recorded using a Bruker Avance III 400 MHz NMR spectrometer.
The HPLC purity was determined using an Sunniest C18 (150 mm x 4.6 mm), 2.7 μ column with a flow rate of 0.5-0.6 mL/minute; Column oven temperature: 35°C; Sample tray temperature: 10°C; Detector UV: 270 nm; Injection volume: 10 μί; Run time: 110 minutes.
While the present disclosure has been described in terms of its specific embodiments, certain modifications and equivalents can be apparent to those skilled in the art and are intended to be included within the scope of the present disclosure.
Examples
Example 1 : Preparation of N-[4-(2-methylpropoxy)benzyl]-l-[4-(2- methylpropoxy)phenvHmethanamine (Formula II)
l-[4-(2-Methylpropoxy)phenyl]methanamine (2g; Formula IV) and sodium triacetoxy borane (3.6g) were added into a reaction vessel containing 4-(2- methylpropoxy)benzaldehyde (2g; Formula III) in 1,2-dichloroethane (20 mL) at ambient temperature under nitrogen atmosphere. The reaction mass was stirred for 3 hours. The reaction mass was quenched with a saturated aqueous solution of sodium bicarbonate. The reaction mass was extracted with ethyl acetate (2 x 100 mL). The organic layer was concentrated at a temperature of 50°C under reduced pressure. The crude material was purified by treating with mixture of dichloromethane and diisopropyl ether, followed by filtration, and drying at a temperature of 40°C under reduced pressure to pure obtain N-[4- (2-methylpropoxy)benzyl] - 1 -[4-(2-methylpropoxy)phenyl]methanamine .
Yield: 80.94%
Mass: 342.5 [M + H]+
Ms Ms: 342.2, 163.0, 107.0.
1HNMR Spectrum (400 mHz in CDCb) δ 1.02 (d, 12H J=6.6 Hz), 2.08 (m, 2H), 3.70 (d, 4H J= 6.4 Hz), 3.76 (s, 4H), 6.86 (d, 4H, J= 7.2 Hz), 7.24 (m, 4H).
Example 2: Preparation of N,N-bis[4-(2-methylpropoxy)benzyl]-l-[4-(2- methylpropoxy)phenvHmethanamine (Formula V)
4-(2-Methylpropoxy)benzaldehyde (0.8 g; Formula III) and sodium triacetoxy borane (3.8 g) were added into a reaction vessel containing a solution of N-[4-(2- methylpropoxy) benzyl] -l-[4-(2-methylpropoxy)phenyl] methanamine (1 g; Formula II) in 1,2-dichloroethane (20 mL) at ambient temperature under nitrogen atmosphere. Acetic acid (0.5 mL) was added. The reaction mass was stirred for 48 hours. The reaction mass was concentrated under reduced pressure at a temperature of 40°C. The crude material was purified using column chromatography using a mixture of ethyl acetate and hexane as eluent, followed by filtration, and drying at a temperature of 40°C under reduced pressure to obtain pure N,N-bis[4-(2-methylpropoxy)benzyl]-l-[4-(2- methylpropoxy)phenyl]methanamine .
Yield: 62.16%
Mass: 504.7 [M + H]+
Ms Ms: 504.3, 163.0, 107.2.
¾ NMR Spectrum (400 mHz in CDCb) δ 1.01(d, 18H, J= 5.6 Hz), 2.06 (m, 3H), 3.44 (s, 6H), 3.69 (d, 6H, J= 5.6 Hz), 6.83 (d, 6H J=7.2 Hz), 7.25(m, 6H). Example 3 : Preparation of r4-(2-methylpropoxy)phenyllmethanol (Formula VI)
4-(2-Methylpropoxy)benzaldehyde (1 g; Formula III) was dissolved in methanol (20 mL) at ambient temperature. Sodium borohydride (0.6 g) was added to the solution in 30 minutes. The reaction mass was stirred for 2 hours. The reaction mass was cooled to 0°C to 5°C. Acetone (20 mL) was added. The reaction mass was concentrated under reduced pressure at a temperature of 40°C. Water (10 mL) was added. The reaction mass was extracted with ethyl acetate (20 mL) followed by removal of the solvent under reduced pressure at a temperature of 50°C to obtain [4-(2- methylpropoxy)phenyl]methanol .
Yield: 97.02%
¾ NMR Spectrum (400 mHz in CDCb) δ 1.02 (d, 6H, J= 6.6 Hz), 2.08 (m, 1H), 3.72 (d, 2H, J= 6.6 Hz), 4.61 (m, 2H), 6.89 (d, 2H, J= 8.4 Hz), 7.27(m, 2H).
Example 4: Preparation of l-(4-fluorobenzyl)-3-r4-(2-methylpropoxy)benzvHurea (Formula VII)
Triethylamine (3 mL) was added in 10 minutes into a reaction vessel containing 1- [4-(2-methylpropoxy)phenyl]methanamine (2g; Formula IV) in N,N-dimethylformamide (10 mL) at ambient temperature. Carbonyldiimidazole (1.8 g) was added. The reaction mass was stirred for 2 hours. l(4-fluorophenyl)methanamine (1.39 g; Formula VIII) was added. The reaction mass was stirred for 18 hours. The reaction mass was concentrated at a temperature of 40°C under reduced pressure. The crude material was purified by dissolving in dichloromethane and adding diisopropyl ether to the solution, followed by filtration, and drying at a temperature of 45 °C under reduced pressure to obtain pure l-(4- fluorobenzyl) -3 - [4-(2-methylpropoxy)benzy 1] urea.
Yield: 86.96%
Mass: Mass: 331.5 [M + H]+
Ms Ms: 331.4, 181.0, 163.0, 106.9.
1ΗΝΜΡν Spectrum (400 mHz in CDCb) δ 1.01 (d, 6H, J=6.2Hz), 2.06 (m, 1H), 3.68 (d, 2H, J=6.4 Hz) 4.27 (m, 4H), 4.85(br, 1H), 6.82 (d, 2H, J=7.3 Hz), 6.95-7.26(m, 6H).

Claims

We Claim:
1. N-[4-(2-methylpropoxy)benzyl]-l-[4-(2-methylpropoxy)phenyl]methanamine of Formula II.
Figure imgf000021_0001
Formula II
2. A process for the preparation of N-[4-(2-methylpropoxy)benzyl]-l-[4-(2- methylpropoxy)pheny l]methanamine of Formula II
Figure imgf000021_0002
Formula II
comprising reacting 4-(2-methylpropoxy)benzaldehyde of Formula III
Figure imgf000021_0003
Formula III
with l-[4-(2-methylpropoxy)phenyl]methanamine of Formula IV
Figure imgf000021_0004
Formula IV
in the presence of a reducing agent.
3. A method for analyzing the purity of pimavanserin tartrate comprising the use of N-[4-(2-methylpropoxy)benzyl] - 1 -[4-(2-methylpropoxy)phenyl]methanamine of Formula II
Figure imgf000022_0001
Formula II
as a reference standard.
4. A chromatographic method for testing the purity of a sample comprising pimavanserin tartrate by determining the presence of the N-[4-(2-methylpropoxy)benzyl]- l-[4-(2-methylpropoxy)phenyl]methanamine of Formula II in the sample comprising the steps of:
i) dissolving pimavanserin tartrate in a solvent to obtain a sample solution; ii) dissolving a sample of the N-[4-(2-methylpropoxy)benzyl]-l-[4-(2- methylpropoxy)phenyl]methanamine of Formula II in a solvent to make a reference standard solution;
iii) subjecting the sample solution and the reference standard solution to a chromatographic technique; and
iv) determining the presence of the N-[4-(2-methylpropoxy)benzyl]- 1-[4-(2- methylpropoxy)phenyl]methanamine of Formula II in the sample of pimavanserin tartrate using the reference standard solution.
5. N,N-bis[4-(2-methylpropoxy)benzyl]-l-[4-(2-methylpropoxy)phenyl]methanamine of Formula V.
Figure imgf000023_0001
Formula V
6. A process for the preparation of N,N-bis[4-(2-methylpropoxy)benzyl]-l-[4-(2- methylpropoxy)phenyl]methanamine of Formula V
Figure imgf000023_0002
Formula V
comprising reacting N-[4-(2-methylpropoxy) benzyl]- l-[4-(2-methylpropoxy)phenyl] methanamine of Formula II
Figure imgf000023_0003
Formula II
with 4-(2-methylpropoxy)benzaldehyde of Formula III
Figure imgf000024_0001
Formula III
in the presence of a reducing agent.
7. A method for analyzing the purity of pimavanserin tartrate comprising the use of N,N-bis[4-(2-methylpropoxy)benzyl] - 1 -[4-(2-methylpropoxy)phenyl]methanamine of Formula V
Figure imgf000024_0002
Formula V
as a reference standard.
8. A chromatographic method for testing the purity of a sample comprising pimavanserin tartrate by determining the presence of the N,N-bis[4-(2- methylpropoxy)benzyl]-l-[4-(2-methylpropoxy)phenyl]methanamine of Formula V in the sample comprising the steps of:
i) dissolving pimavanserin tartrate in a solvent to obtain a sample solution; ii) dissolving a sample of the N,N-bis[4-(2-methylpropoxy)benzyl]-l-[4-(2- methylpropoxy)phenyl]methanamine of Formula V in a solvent to make a reference standard solution: iii) subjecting the sample solution and the reference standard solution to a chromatographic technique; and
iv) determining the presence of the N,N-bis[4-(2-methylpropoxy)benzyl]-l-[4 (2-methylpropoxy)phenyl]methanamine of Formula V in the sample of pimavanserin tartrate using the reference standard solution.
[4-(2-Methylpropoxy)phenyl]methanol of Formula VI.
Figure imgf000025_0001
Formula VI
A process for the preparation of [4-(2-methylpropoxy)phenyl]methanol of Formula
Figure imgf000025_0002
Formula VI
comprising reacting 4-(2-methylpropoxy)benzaldehyde of Formula III
Figure imgf000025_0003
Formula III
with a reducing agent.
11. A method for analyzing the purity of pimavanserin tartrate comprising the use of [4-(2-methylpropoxy)phenyl]methanol of Formula VI
Figure imgf000026_0001
Formula VI
as a reference standard.
12. A chromatographic method for testing the purity of a sample comprising pimavanserin tartrate by determining the presence of the [4-(2- methylpropoxy)phenyl]methanol of Formula VI in the sample comprising the steps of: i) dissolving pimavanserin tartrate in a solvent to obtain a sample solution; ii) dissolving a sample of the [4-(2-methylpropoxy)phenyl]methanol of Formula VI in a solvent to make a reference standard solution;
iii) subjecting the sample solution and the reference standard solution to a chromatographic technique; and
iv) determining the presence of the [4-(2-methylpropoxy)phenyl]methanol of Formula VI in the sample of pimavanserin tartrate using the reference standard solution.
13. The process according to any of the claims 2, 6 or 10, wherein the reducing agent is selected from sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, sodium triacetoxy borane , or borane.
14. l-(4-Fluorobenzyl)-3-[4-(2-methylpropoxy)benzyl]urea of Formula VII.
Figure imgf000026_0002
Formula VII
15. A process for the preparation of l-(4-fluorobenzyl)-3-[4-(2- methylpropoxy)benzyl]urea of Formula VII
Figure imgf000027_0001
Formula VII
comprising reacting l-[4-(2-methylpropoxy)phenyl]methanamine of Formula IV
Figure imgf000027_0002
Formula IV
with l-[4-(fluoromethyl)phenyl]methanamine of Formula VIII
Figure imgf000027_0003
Formula VIII
in the presence of a coupling agent.
16. The process according to claim 15, wherein the coupling agent is selected from carbonyldiimidazole, phosgene, triphosgene, or phenylchloroformate.
17. A method for analyzing the purity of pimavanserin tartrate comprising the use of 1- (4-fluorobenzyl)-3-[4-(2-methylpropoxy)benzyl]urea of Formula VII
Figure imgf000027_0004
Formula VII as a reference standard.
18. A chromatographic method for testing the purity of a sample comprising pimavanserin tartrate by determining the presence of the l-(4-fluorobenzyl)-3-[4-(2- methylpropoxy)benzyl]urea of Formula VII in the sample comprising the steps of:
i) dissolving pimavanserin tartrate in a solvent to obtain a sample solution; ii) dissolving a sample of the l-(4-fluorobenzyl)-3-[4-(2- methylpropoxy)benzyl]urea of Formula VII in a solvent to make a reference standard solution;
iii) subjecting the sample solution and the reference standard solution to a chromatographic technique; and
iv) determining the presence of the l-(4-fluorobenzyl)-3-[4-(2- methylpropoxy)benzyl]urea of Formula VII in the sample of pimavanserin tartrate using the reference standard solution.
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WO2019087069A3 (en) * 2017-10-30 2019-08-29 Sun Pharmaceutical Industries Limited Pimavanserin tartrate impurities, processes for their preparation, and their use as reference standards
CN117142963A (en) * 2022-05-23 2023-12-01 扬子江药业集团有限公司 Preparation methods of pimavanserin tartrate, pimavanserin and intermediates thereof

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EP3271018B1 (en) * 2015-03-02 2020-12-23 Pliva Hrvatska D.O.O. Processes and intermediates for the preparation of pimavanserin
CZ2015601A3 (en) * 2015-09-02 2017-03-15 Zentiva, K.S. A method of producing 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidine-4-yl) of urea and its deuterated analogues not containing dimeric impurities
WO2019087069A2 (en) * 2017-10-30 2019-05-09 Sun Pharmaceutical Industries Limited Pimavanserin tartrate impurities, processes for their preparation, and their use as reference standards

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WO2019087069A3 (en) * 2017-10-30 2019-08-29 Sun Pharmaceutical Industries Limited Pimavanserin tartrate impurities, processes for their preparation, and their use as reference standards
CN117142963A (en) * 2022-05-23 2023-12-01 扬子江药业集团有限公司 Preparation methods of pimavanserin tartrate, pimavanserin and intermediates thereof

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