706779-91-1

Basic information

• Product Name: Pimavanserin
• Synonyms: Pimavanserin;1-(4-Fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)urea;PIMAVANSERIN/1-(4-FLUOROBENZYL)-3-(4-ISOBUTOXYBENZYL)-1-(1-METHYLPIPERIDIN-4-YL)UREA;Unii-jz963p0dik;Pimavamserin;1-[(4-fluorophenyl)Methyl]-1-(1-Methylpiperidin-4-yl)-3-{[4-(2-Methylpropoxy)phenyl]Methyl}urea;N-(4-Fluorobenzyl)-N-(1-Methylpiperidin-4-yl)-N'-[[4-(2-Methylpropyloxy)phenyl]Methyl]carbaMide;N-[(4-Fluorophenyl)Methyl]-N-(1-Methyl-4-piperidinyl)-N'-[[4-(2-Methylpropoxy)phenyl]Methyl]urea
• CAS NO: 706779-91-1
• Molecular Formula: C₂₅H₃₄FN₃O₂
• Molecular Weight: 427.55
• EINECS: 1806241-263-5
• Product Categories: Intermediates & Fine Chemicals;Pharmaceuticals;Inhibitors
• Mol File: 706779-91-1.mol
• Article Data: 39

Chemical Properties

• Boiling Point: 604.222 °C at 760 mmHg
• Flash Point: 319.222 °C
• Appearance: /
• Density: 1.15 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.576
• Storage Temp.: Refrigerator
• Solubility: Methanol (Slightly)
• PKA: 13.52±0.46(Predicted)
• CAS DataBase Reference: Pimavanserin(CAS DataBase Reference)
• NIST Chemistry Reference: Pimavanserin(706779-91-1)
• EPA Substance Registry System: Pimavanserin(706779-91-1)

Safety Data

• Hazard Codes: Xi
• Safety Statements: 24/25
• Hazardous Substances Data: 706779-91-1(Hazardous Substances Data)

Usage

Parkinson's treatment

Pimavanserin is a kind of novel oral administrated drug for treatment of Parkinson’s psychosis developed by Acadia pharmaceutical Company (US) with the trade name being Pimavanserin. In September 3rd 2014, it has been granted by the US Food and Drug Administration (FDA) for breakthrough therapy certification. Breakthrough therapy certification is created by the FDA for accelerating the development and review of new drugs for treatment of serious or life-threatening diseases. Currently there are about seven millions to ten million of patients of Parkinson's disease worldwide with China contributing 2.6 million, ranking first in the world with 100,000 new patients emerging every year. More than 50% of patients of Parkinson's disease have had psychiatric symptoms (PDP). These psychiatric symptoms are mainly manifested as hallucinations and delusions, bringing greater challenge to the treatment and care for patients of Parkinson's disease. Dopamine is the primary target for the treatment of Parkinson's disease because most antipsychotics drugs will block the dopamine in the brain of the patients of Parkinson’s disease, making their situation of motor dysfunction be even worse, and thus currently not being suitable for these patients. Parkinson's disease psychosis is the major reason why patients of Parkinson disease enter into the elderly-care apartment. There is currently no other drugs except low-dose clozapine (Clozaril) that have been approved for the treatment of Parkinson's disease psychosis. So once approved, the drug should be able to significantly improve the standard therapy. Clozapine has serious security risks that can lead to a dangerous decline in the number of white blood cells and also has another side effect of causing drowsiness. Pimavanserin is a novel first-line drug of antipsychotic symptoms belongs to non-dopaminergic neurotransmitters with the drug targets being serotonin 2A receptor (5-HT2A), which can selectively block the 5-HT 2A receptor without affecting the action of dopamine with the routine administration being treatment via oral administration once daily. There are evidences showing that the drug is quite effective in the treatment of Parkinson's disease psychosis with well tolerance. Moreover, it does not block the dopamine receptors, and therefore does not lead to worsening of symptoms of Parkinson's disease. A 6-week-lasting randomized, double-blind, placebo-controlled trial has included 199 patients and evaluated the safety and efficacy of pimavanserin.Patients in the pimavanserin group, in the Parkinson's disease-adapted scale for assessment of positive symptoms (SAPS-PD) for evaluating the positive symptom, have their average scores drop by 5.79 points while the placebo group have the average score drop only by 2.73 points, the difference between these two groups was statistically significant (P = 0.001). In addition, pimavanserin group also have greater improvement in the Clinical Global Impression Scale and caregiver burden scale. Pimavanserin can be well tolerated and does not aggravate the symptoms of motion. The secondary endpoints for the study is the exercise tolerance in patients, it is through the assessment of the second part and third part of the unified Parkinson's disease rating scale (UPDRS). From this perspective, pimavanserin treatment enables the patient to receive a significant therapeutic benefit. In the improvement aspect on the Clinical Global Impression Scale scores, patients in the group of the Clinical Global Impression Scale have been also significantly improved. In some exploratory detection indicators, patients in the pimavanserin treatment group had also obtained significant improvement such as night sleep time, wake time during the day, and the total cost of care and so on. During the course of treatment, the most common adverse events are urinary tract infection (11.7% in the placebo group, 13.5% in the pimavanserin group) and falls (8.5% in the placebo group; 10.6% in the pimavanserin group), but the vast majority are mild to moderate adverse reactions. Moreover, for patients who have been subject to completion of all tests and treatment benefit, 90% are chosen to participate in the further pimavanserin extension study. Figure 1 the chemical structure formula of Pimavanserin The above information is edited by the lookchem of Dai Xiongfeng.

Uses

Different sources of media describe the Uses of 706779-91-1 differently. You can refer to the following data:
1. Drug used in the treatment of Parkinson disease psychosis.
2. Drug used in the treatment of Parkinson’s disease psychosis.
3. Drug used in the treatment of Parkinson’s disease and psychosis.

Description

Pimavanserin is an inverse agonist of the serotonin (5-HT) receptor subtype 5-HT2A (IC50 = 1.86 nM; Ki = 0.5 nM). It is selective for 5-HT2A over a panel of 65 ion channels, enzymes, and receptors (Kis = >100 nM). Pimavanserin reduces head-twitch behavior and prepulse inhibition deficits induced by the 5-HT2A receptor agonist DOI in rats at doses of 3 mg/kg, p.o. and 1-10 mg/kg, s.c., respectively. It also exhibits antipsychotic-like activity, reducing hyperactivity induced by (+)-MK-801 in mice. Pimavanserin acts synergistically with haloperidol or risperidone to suppress (+)-MK-801-induced hyperactivity and attenuates haloperidol- and risperidone-induced catalepsy in rats. Formulations containing pimavanserin have been used for the treatment of psychosis in Parkinson''s disease.

Chemical Properties

Yellow Solid

Definition

ChEBI: A member of the class of ureas in which three of the four hydrogens are replaced by 4-fluorobenzyl, 1-methylpiperidin-4-yl, and 4-(isopropyloxy)benzyl groups. An atypical antipsychotic that is used (in the form of its tartrate salt) for treatment of halluc nations and delusions associated with Parkinson's disease.

Enzyme inhibitor

This orally active atypical non-dopaminergic antipsychotic[ (FWfree-base = 427.56 g/mol; CAS 706779-91-1 (free base) and 706782-28-7 (tartrate salt)), also known as ACP-103, Nuplazid? and N-(4-fluorophenylmethyl)- N-(1-methyl-piperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenyl-methyl)carbamide, is a potent inverse agonist and antagonist at serotonin 5-HT2A receptors (Ki = 0.087 nM) and less so at serotonin 5-HT2C receptors (Ki = 0.44 nM). Pimavanserin shows low binding to σ1 receptors (Ki = 120 nM), with no appreciable affinity (Ki > 300 nM) to serotonin 5-HT2B, dopaminergic (including D2), muscarinic, histaminergic, or adrenergic receptors, or to calcium channels. 5-HT2A receptor dysregulation is implicated in both the etiology and treatment of schizophrenia, and the same receptor plays an active role in the regulation of sleep architecture. Nuplazid is specifically indicated in its FDA approval (April, 2016) for the treatment of hallucinations and delusions associated with Parkinson disease. Significantly, 5-HT2A serotonin receptor antagonists differentially regulate 5-HT2A receptor protein level in vivo. See also Ketanserin; RH-34; Risperidone; Ritanserin; Setoperone; Volinanserin.

InChI:InChI=1/C25H34FN3O2/c1-19(2)18-31-24-10-6-20(7-11-24)16-27-25(30)29(23-12-14-28(3)15-13-23)17-21-4-8-22(26)9-5-21/h4-11,19,23H,12-18H2,1-3H3,(H,27,30)

Synthetic route

1-[4-(2-methylpropyloxy)phenyl]methanamino acetate + C18H24FN4O(1+)*I(1-) → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
In toluene at 50℃; for 15h;	100%

N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (359878-47-0) + 1-[4-(2-methylpropyloxy)phenyl]methanamine (4734-09-2) + 1,1'-carbonyldiimidazole (530-62-1) → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
Stage #1: 1-[4-(2-methylpropyloxy)phenyl]methanamine; 1,1'-carbonyldiimidazole In toluene at 20℃; for 1h; Stage #2: N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine In toluene at 50℃; for 15h;	96%
Stage #1: 1-[4-(2-methylpropyloxy)phenyl]methanamine; 1,1'-carbonyldiimidazole In dichloromethane at 0 - 5℃; for 0.5h; Stage #2: N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine In dichloromethane at 18 - 22℃; for 12h; Temperature;	85%

N-(4-(2-methylpropyloxy)phenylmethyl)imidazol-1-ylcarboxamide + N-(4-fluorobenzyl)-1-methylpiperidine-4-amine dihydrochloride → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
With potassium carbonate at 65 - 70℃; for 18h;	95.6%

N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (359878-47-0) + di(succinimido) carbonate (74124-79-1) + 1-[4-(2-methylpropyloxy)phenyl]methanamine (4734-09-2) → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
Stage #1: N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine; di(succinimido) carbonate With 4-methyl-morpholine In dichloromethane at -5 - 25℃; for 5h; Stage #2: 1-[4-(2-methylpropyloxy)phenyl]methanamine In dichloromethane at 25℃; for 10h; Solvent; Temperature; Time;	95%

1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)thiourea → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
With silver carbonate In acetonitrile at 20℃; for 24h; Reagent/catalyst; Green chemistry;	94.2%

N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (359878-47-0) + N-(4-isobutoxybenzyl)carbamic acid phenyl ester → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
With potassium carbonate In toluene at 90℃; for 24h; Reagent/catalyst; Temperature;	92%
With triethylamine In ethanol for 6h; Reflux;	91%
With triethylamine In ethanol for 12h; Reflux; Green chemistry;	84.5%

1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea + 4-isobutoxybenzaldehyde (18962-07-7) → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
Stage #1: 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea; 4-isobutoxybenzaldehyde With titanium(IV) isopropylate In tetrahydrofuran at 20℃; for 10h; Stage #2: With sodium tetrahydroborate at -5 - 0℃; for 6h;	92%
With 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid In toluene for 24h; Reagent/catalyst; Solvent; Time; Inert atmosphere;	82%

4-isobutoxybenzylamine acetate + N-(4-fluorobenzyl)-1-methylpiperidin-4-amine oxalate + 1,1'-carbonyldiimidazole (530-62-1) → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
Stage #1: 4-isobutoxybenzylamine acetate; 1,1'-carbonyldiimidazole With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 5℃; for 0.5h; Stage #2: N-(4-fluorobenzyl)-1-methylpiperidin-4-amine oxalate With N-ethyl-N,N-diisopropylamine In dichloromethane at 15 - 25℃; for 10h;	90.4%

N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (359878-47-0) + 4-isobutoxybenzylamine acetate + 1,1'-carbonyldiimidazole (530-62-1) → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
Stage #1: 4-isobutoxybenzylamine acetate; 1,1'-carbonyldiimidazole With triethylamine In dichloromethane at 0 - 5℃; for 0.5h; Stage #2: N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine In dichloromethane at 15 - 25℃; for 8h;	90.3%

1-[4-(2-methylpropyloxy)phenyl]methanamine (4734-09-2) + phenyl (4-fluorobenzyl)(1-methylpiperidin-4-yl)carbamate → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
With N,N'-bis(4-isobutoxybenzyl)urea; potassium carbonate In toluene at 65 - 80℃; for 5h; Reagent/catalyst; Temperature;	90%
With triethylamine In acetonitrile at 50 - 60℃; for 12h;	75%

N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (359878-47-0) + (4-Isobutoxy-phenyl)-acetic acid hydrazide (61904-59-4) → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
With hydrogenchloride; sodium hydroxide; sodium nitrite In dichloromethane; water at 15 - 110℃; under 11251.1 Torr; for 0.0611111h; Time; Solvent; Temperature;	90%

potassium cyanate (590-28-3) + N-(4-fluorobenzyl)-1-methylpiperidine-4-amine dihydrochloride + 4-isobutoxybenzaldehyde (18962-07-7) → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
Stage #1: potassium cyanate; N-(4-fluorobenzyl)-1-methylpiperidine-4-amine dihydrochloride In methanol for 4h; Stage #2: 4-isobutoxybenzaldehyde With 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid for 4h; Reflux;	88%

N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (359878-47-0) + N-(4-(2-methylpropyloxy)phenylmethyl)imidazol-1-ylcarboxamide → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
In toluene at 25 - 55℃; for 15h;	83.19%
In tetrahydrofuran at 60℃; for 4h;	70%
In toluene Solvent; Reflux;
In N,N-dimethyl-formamide; acetonitrile at 60℃; for 2h; Temperature; Solvent; Sealed tube;	704.3 mg
With potassium tert-butylate In toluene at 25 - 55℃; for 15h; Reflux;	16 g

N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (359878-47-0) + 1-(4-isobutoxybenzyl)urea → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
at 120 - 130℃; for 12h; Green chemistry;	83.1%
In toluene

1-[4-(2-methylpropyloxy)phenyl]methanamino acetate + C18H24FN4O(1+)*I(1-) → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
In toluene at 50℃; for 15h;	100%

N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (359878-47-0) + 1-[4-(2-methylpropyloxy)phenyl]methanamine (4734-09-2) + 1,1'-carbonyldiimidazole (530-62-1) → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
Stage #1: 1-[4-(2-methylpropyloxy)phenyl]methanamine; 1,1'-carbonyldiimidazole In toluene at 20℃; for 1h; Stage #2: N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine In toluene at 50℃; for 15h;	96%
Stage #1: 1-[4-(2-methylpropyloxy)phenyl]methanamine; 1,1'-carbonyldiimidazole In dichloromethane at 0 - 5℃; for 0.5h; Stage #2: N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine In dichloromethane at 18 - 22℃; for 12h; Temperature;	85%

N-(4-(2-methylpropyloxy)phenylmethyl)imidazol-1-ylcarboxamide + N-(4-fluorobenzyl)-1-methylpiperidine-4-amine dihydrochloride → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
With potassium carbonate at 65 - 70℃; for 18h;	95.6%

N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (359878-47-0) + di(succinimido) carbonate (74124-79-1) + 1-[4-(2-methylpropyloxy)phenyl]methanamine (4734-09-2) → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
Stage #1: N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine; di(succinimido) carbonate With 4-methyl-morpholine In dichloromethane at -5 - 25℃; for 5h; Stage #2: 1-[4-(2-methylpropyloxy)phenyl]methanamine In dichloromethane at 25℃; for 10h; Solvent; Temperature; Time;	95%

1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)thiourea → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
With silver carbonate In acetonitrile at 20℃; for 24h; Reagent/catalyst; Green chemistry;	94.2%

N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (359878-47-0) + N-(4-isobutoxybenzyl)carbamic acid phenyl ester → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
With potassium carbonate In toluene at 90℃; for 24h; Reagent/catalyst; Temperature;	92%
With triethylamine In ethanol for 6h; Reflux;	91%
With triethylamine In ethanol for 12h; Reflux; Green chemistry;	84.5%

1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea + 4-isobutoxybenzaldehyde (18962-07-7) → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
Stage #1: 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea; 4-isobutoxybenzaldehyde With titanium(IV) isopropylate In tetrahydrofuran at 20℃; for 10h; Stage #2: With sodium tetrahydroborate at -5 - 0℃; for 6h;	92%
With 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid In toluene for 24h; Reagent/catalyst; Solvent; Time; Inert atmosphere;	82%

4-isobutoxybenzylamine acetate + N-(4-fluorobenzyl)-1-methylpiperidin-4-amine oxalate + 1,1'-carbonyldiimidazole (530-62-1) → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
Stage #1: 4-isobutoxybenzylamine acetate; 1,1'-carbonyldiimidazole With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 5℃; for 0.5h; Stage #2: N-(4-fluorobenzyl)-1-methylpiperidin-4-amine oxalate With N-ethyl-N,N-diisopropylamine In dichloromethane at 15 - 25℃; for 10h;	90.4%

N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (359878-47-0) + 4-isobutoxybenzylamine acetate + 1,1'-carbonyldiimidazole (530-62-1) → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
Stage #1: 4-isobutoxybenzylamine acetate; 1,1'-carbonyldiimidazole With triethylamine In dichloromethane at 0 - 5℃; for 0.5h; Stage #2: N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine In dichloromethane at 15 - 25℃; for 8h;	90.3%

1-[4-(2-methylpropyloxy)phenyl]methanamine (4734-09-2) + phenyl (4-fluorobenzyl)(1-methylpiperidin-4-yl)carbamate → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
With N,N'-bis(4-isobutoxybenzyl)urea; potassium carbonate In toluene at 65 - 80℃; for 5h; Reagent/catalyst; Temperature;	90%
With triethylamine In acetonitrile at 50 - 60℃; for 12h;	75%

N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (359878-47-0) + (4-Isobutoxy-phenyl)-acetic acid hydrazide (61904-59-4) → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
With hydrogenchloride; sodium hydroxide; sodium nitrite In dichloromethane; water at 15 - 110℃; under 11251.1 Torr; for 0.0611111h; Time; Solvent; Temperature;	90%

potassium cyanate (590-28-3) + N-(4-fluorobenzyl)-1-methylpiperidine-4-amine dihydrochloride + 4-isobutoxybenzaldehyde (18962-07-7) → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
Stage #1: potassium cyanate; N-(4-fluorobenzyl)-1-methylpiperidine-4-amine dihydrochloride In methanol for 4h; Stage #2: 4-isobutoxybenzaldehyde With 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid for 4h; Reflux;	88%

N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (359878-47-0) + N-(4-(2-methylpropyloxy)phenylmethyl)imidazol-1-ylcarboxamide → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
In toluene at 25 - 55℃; for 15h;	83.19%
In tetrahydrofuran at 60℃; for 4h;	70%
In toluene Solvent; Reflux;
In N,N-dimethyl-formamide; acetonitrile at 60℃; for 2h; Temperature; Solvent; Sealed tube;	704.3 mg
With potassium tert-butylate In toluene at 25 - 55℃; for 15h; Reflux;	16 g

N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (359878-47-0) + 1-(4-isobutoxybenzyl)urea → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
at 120 - 130℃; for 12h; Green chemistry;	83.1%
In toluene

N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (359878-47-0) + 1-[4-(2-methylpropyloxy)phenyl]methanamine (4734-09-2) + phenyl chloroformate (1885-14-9) → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
Stage #1: 1-[4-(2-methylpropyloxy)phenyl]methanamine; phenyl chloroformate With triethylamine In acetonitrile at 0 - 20℃; for 2h; Stage #2: N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine With triethylamine In acetonitrile at 60℃; for 12h;	83%

N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (359878-47-0) + di-tert-butyl dicarbonate (24424-99-5) + 1-[4-(2-methylpropyloxy)phenyl]methanamine (4734-09-2) → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
Stage #1: di-tert-butyl dicarbonate; 1-[4-(2-methylpropyloxy)phenyl]methanamine With dmap; triethylamine In dichloromethane at -18 - -5℃; Stage #2: N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine In dichloromethane at -5 - 35℃; for 0.5h;	83%
Stage #1: di-tert-butyl dicarbonate; 1-[4-(2-methylpropyloxy)phenyl]methanamine With dmap In acetonitrile at -10℃; Stage #2: N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine In toluene at 50℃; for 15h;

bis(trichloromethyl) carbonate (32315-10-9) + N-(4-fluorobenzyl)-1-methylpiperidin-4-amine p-toluenesulfonate + 4-isobutoxybenzylamine hydrochloride → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
Stage #1: bis(trichloromethyl) carbonate; 4-isobutoxybenzylamine hydrochloride With N-ethyl-N,N-diisopropylamine In chloroform at -5 - 5℃; for 1h; Stage #2: N-(4-fluorobenzyl)-1-methylpiperidin-4-amine p-toluenesulfonate With N-ethyl-N,N-diisopropylamine In chloroform at 15 - 25℃; for 6h;	82.4%

N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (359878-47-0) + C16H20N2O5 → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
With potassium carbonate In Isopropyl acetate at 50 - 60℃; for 6h; Solvent; Temperature;	82%
at 80℃; for 3h;	20.3 g

1-(isocyanatomethyl)-4-(2-methylpropoxy)benzene (639863-75-5) + N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (359878-47-0) → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
In dichloromethane at 20℃; for 2h; Large scale;	81.6%
In tetrahydrofuran at 25℃; for 16h; Solvent;	63.8%
In tetrahydrofuran at 20℃; for 16h;	60.4%

N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (359878-47-0) + bis(trichloromethyl) carbonate (32315-10-9) + 1-[4-(2-methylpropyloxy)phenyl]methanamine (4734-09-2) → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
Stage #1: bis(trichloromethyl) carbonate; 1-[4-(2-methylpropyloxy)phenyl]methanamine With triethylamine In dichloromethane at -5 - 5℃; for 1h; Stage #2: N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine In dichloromethane at 15 - 25℃; for 5h; Temperature; Solvent;	81.6%

N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (359878-47-0) + 4-nitrophenyl (4-isobutoxybenzyl)carbamate → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
With triethylamine In acetonitrile at 0 - 20℃; for 2h;	81%

1-[4-(2-methylpropyloxy)phenyl]methanamine (4734-09-2) + (4-fluorobenzyl)(1-methylpiperidin-4-yl)carbamoyl chloride → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
With dmap In 1,4-dioxane at 75℃; for 15h; Solvent; Reagent/catalyst; Temperature;	78.5%

4-isobutoxybenzylamine acetate + N-(4-fluorobenzyl)-1-methylpiperidin-4-amine oxalate + 4-Nitrophenyl chloroformate (7693-46-1) → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
Stage #1: 4-isobutoxybenzylamine acetate; 4-Nitrophenyl chloroformate With triethylamine In dichloromethane at 0 - 5℃; for 0.5h; Stage #2: N-(4-fluorobenzyl)-1-methylpiperidin-4-amine oxalate With triethylamine In dichloromethane at 15 - 25℃; for 10h;	78.1%

N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (359878-47-0) + N-(4-isobutoxybenzyl)formamide → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
Stage #1: N-(4-isobutoxybenzyl)formamide With bis(trichloromethyl) carbonate; triethylamine In dichloromethane at 0 - 20℃; Green chemistry; Stage #2: With trifluoromethylsulfonic anhydride; dimethyl sulfoxide at -65 - -60℃; Inert atmosphere; Green chemistry; Stage #3: N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine In dichloromethane at -65 - 20℃; Inert atmosphere; Green chemistry;	77.7%

N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (359878-47-0) + 1-[4-(2-methylpropyloxy)phenyl]methanamine (4734-09-2) + 4-Nitrophenyl chloroformate (7693-46-1) → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
Stage #1: 1-[4-(2-methylpropyloxy)phenyl]methanamine; 4-Nitrophenyl chloroformate With triethylamine In acetonitrile at 0 - 20℃; for 2h; Stage #2: N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine With triethylamine In acetonitrile at 0 - 20℃; for 12h; Cooling with ice;	74%

1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea + sodium hydroxy(4-isobutoxyphenyl)methanesulfonate → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
With triethylsilane; trifluoroacetic acid In acetonitrile at 50℃; for 24h; Inert atmosphere;	74%

N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (359878-47-0) + 1-[4-(2-methylpropyloxy)phenyl]methanamine (4734-09-2) → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
Stage #1: 1-[4-(2-methylpropyloxy)phenyl]methanamine With dmap; di-tert-butyl dicarbonate; triethylamine In dichloromethane at -5 - 5℃; Stage #2: N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine In dichloromethane at 0 - 5℃; for 2h; Reagent/catalyst; Further stages;	72%

1-[4-(2-methylpropyloxy)phenyl]methanamine (4734-09-2) + 4-((-4-fluorobenzyl)benzyloxycarbonylamino)-1-methylpiperidine → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 40℃; for 10h;	71.8%

N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (359878-47-0) + methyl (4-isobutoxybenzyl)carbamate → N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1)

Conditions	Yield
Stage #1: methyl (4-isobutoxybenzyl)carbamate With triethylamine In toluene at 0 - 10℃; for 0.5h; Stage #2: N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine In toluene at 80℃; for 12h;	71%
at 120℃; for 0.24h; Time; Temperature;	22%
With potassium tert-butylate In toluene for 5h; Reflux;	14 g

N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1) + L-Tartaric acid (87-69-4) → 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)urea L-hemitartrate

Conditions	Yield
In n-heptane; acetone at 20 - 50℃; for 10h; Solvent;	99%
In ethanol at -5 - 50℃; for 16h;	85%
In ethanol at 20 - 50℃; for 17h;	104.6 g
In ethanol at 20 - 50℃; for 2h;	21.9 g

N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1) + toluene-4-sulfonic acid (104-15-4) → C25H34FN3O2*C7H8O3S*H2O

Conditions	Yield
In ethyl acetate at 20 - 42℃; for 5h;	97.9%

N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1) + L-Tartaric acid (87-69-4) → Pimavanserin tartrate

Conditions	Yield
In tert-butyl methyl ether; acetone at 50 - 55℃; for 1h;	95%
In dichloromethane; isopropyl alcohol at 70℃; for 5h; Inert atmosphere;	93%
In dichloromethane; isopropyl alcohol at 0 - 70℃; for 7h; Inert atmosphere;	93%

N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1) + cyclohexylsulfamic acid (100-88-9) → C25H34FN3O2*H2O*C6H13NO3S

Conditions	Yield
In ethyl acetate at 20 - 42℃; for 5h;	93.7%

N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1) + L-Tartaric acid (87-69-4) → pimavanserin tartrate

Conditions	Yield
In ethanol at 30 - 50℃; for 2h;	85%

N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxyl)phenylmethyl)carbamide (706779-91-1) + D-tartaric acid (147-71-7) → N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropoxy)phenylmethyl)urea hemi-tartrate

Conditions	Yield
In ethanol	85%

Upstream product

• 359878-47-0 N- [(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine 
• 4734-09-2 1-[4-(2-methylpropyloxy)phenyl]methanamine 
• 1885-14-9 phenyl chloroformate 
• 7693-46-1 4-Nitrophenyl chloroformate 
• 140-75-0 para-fluorobenzylamine 
• 1445-73-4 1-Methyl-4-piperidone 
• 530-62-1 1,1'-carbonyldiimidazole 
• 24424-99-5 di-tert-butyl dicarbonate 
• 1194-02-1 4-fluorobenzonitrile 
• 459-57-4 4-fluorobenzaldehyde 
• 5203-15-6 4-(2-methylpropoxy)benzonitrile 

Downstream Products

• 882035-24-7 N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide phosphate 
• 882035-19-0 N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide maleate 
• 882035-26-9 N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide succinate 
• 882035-17-8 N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide citrate 
• 882035-28-1 N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide sulphate 
• 1080491-31-1 N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N’-(4-(2-methylpropyloxy)phenylmethyl)carbamide tartaric acid 
• 1134815-71-6 N-(4-fluorobenzyl)-N-(1-methyl-1-oxopiperidin-4-yl)-N'-(4-isobutoxybenzyl)carbamide 
• 706782-28-7 2C₂₅H₃₄FN₃O₂*0.5C₄H₆O₆ 
• 706782-28-7 Pimavanserin tartrate 
• 706782-28-7 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)urea L-hemitartrate 
• 706782-28-7 N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropoxy)phenylmethyl)urea hemi-tartrate 

Relevant articles and documents

Application of pimavanserin in preparation of antitumor drugs

The invention relates to application of pimavanserin in preparation of antitumor drugs, belongs to the technical field of medicines, and particularly relates to novel application of pimavanserin in preparation of antitumor drugs. The structural formula of the pimavanserin is shown in the formula I. The biological activity test of the compound shows that the compound has antitumor activity and is a novel antitumor drug.

A PHARMACEUTICAL INTERMEDIATE

This invention relates to4-(4-fluorobenzylamino)-1-methylpiperidine trihydrateand a process for the preparation of 4-(4-fluorobenzylamino)-1-methylpiperidine trihydrate comprising treating 4-(4- fluorobenzylamino)-1-methylpiperidine with water. The invention also relates toa process for the preparation of pimavanserin comprising reacting 4-(4- fluorobenzylamino)-1-methylpiperidine trihydrate with 1-isobutoxy-4-(isocyanatomethyl)benzene; toa process for the preparation of a pimavanserin acid addition salt comprising reacting 4-(4- fluorobenzylamino)-1-methylpiperidine trihydrate with 1-isobutoxy-4-(isocyanatomethyl)benzene and converting pimavanserin into a pimavanserinacid additionsalt, pimavanserin and pimavanserin acid addition salts obtainable by the process, and to the use of 4-(4-fluorobenzylamino)-1-methylpiperidine trihydrate for preparing pimavanserin or an acid additionsalt thereof.

PROCESS FOR THE PREPARATION OF A PHARMACEUTICAL AGENT

This invention relates to a process for the preparation of pimavanserin comprising: (i) providing an acid addition salt of pimavanserin; (ii) dissolving the acid addition salt of pimavanserin in an aqueous solvent to form an aqueous solution; (ill) washing the aqueous solution obtained in step (ii) with an organic solvent; and (iv) adding a base to the washed aqueous solution to form pimavanserin. The invention also relates to a process for the preparation of an acid addition salt of pimavanserin additionally comprising step (v) of converting pimavanserin into an acid addition salt of pimavanserin. The invention also relates to pimavanserin or an acid addition salt thereof obtainable by the process, and to the use of pimavanserin hydrochloride, pimavanserin hydrogen sulfate or pimavanserin acetate for preparing pimavanserin or an acid addition salt thereof.