A Green and Environmentally Friendly, An Improved Synthesis of Pimavanserin (5-HT2A Receptor)

 

Rajesh Kumar Rapolu^{1, 2}, V.V.N.K.V. Prasada Raju¹, Murthy Chavali², Naveen Mulakayala³

¹Granules India Limited – R & D Center, Plot No.56, Road No.5, ALEAP Industrial Area, Pragathinagar, Hyderabad, 5000072, India

²Division of Chemistry, Department of Science and Humanities, Vignan's Foundation for Science Technology and Research University (VFSTRU), Vadlamudi, Guntur 522 213, India

³SVAK Life Sciences, ALEAP Industrial Area, Pragathi Nagar, Hyderabad 500090, India

*Corresponding Author E-mail: rapolu.rajesh@gmail.com

 

 

INTRODUCTION:

Parkinson’s disease¹ is a neurodegenerative disease that affects millions of people worldwide. PD is more common in older people and the number of PD patients is expected to increase with the increasing age of the worldwide population. Psychosis is highly prevalent in Parkinson’s disease patients and is associated with poor prognosis. Until April 2016, there were no licensed drugs available in the United States of America (USA) for the treatment of Parkinson’s disease psychosis (PDP). Pimavanserin² is the first Food and Drug Administration approved medicine for the treatment of hallucinations and delusions associated with PDP.

 

Pimavanserin (Nuplazid) is a drug of selective targeting 5-HT2A receptor³， developed by Acadia Pharmaceuticals. In April 29， 2016， it was approved by FDA for the treatment of Parkinson′s disease (PD).

 

It has little or no activity against 2C receptors which may account for its relative lack of adverse effects. The absence of dopamine receptor activity suggested that pimavanserin would be appropriate for patients with Parkinson disease psychosis which is usually resistant to the atypical antipsychotic medications and can be worsened by inhibition of dopaminergic transmission⁴.  Clinical studies demonstrated its effectiveness in Parkinson disease psychosis and it was approved for this use in the United States in 2016.  Pimavanserin is available in tablets of 17 mg under the brand name Nuplazid. The typical dose is 34 mg once daily.  Common side effects include somnolence, headache, confusion, hallucinations, and peripheral edema. Rare, but potentially serious adverse events include prolongation of the QT interval and increased risk of death in elderly patients with dementia related psychosis. Pimavanserin is chemically described as N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N’-(4-(2-methylpropyloxy) phenylmethyl) carbamide.

 

 

MATERIAL AND METHODS:

Melting points are uncorrected and were determined in open capillary tubes in sulphuric acid bath. TLC was run on silica gel – G and visualization was done using iodine or UV light. IR spectra were recorded using Perkin – Elmer 1000 instrument in KBr pellets. ¹H NMR spectra were recorded in DMSO – d₆ using TMS as internal standard using 400 MHz spectrometer. Mass spectra were recorded on Agilent-LCMS instrument under CI conditions and given by Q+1 value only.

 

General procedure for preparation of 1-isobutoxy-4-(isothiocyanatomethyl) benzene (2):

A mixture of 4-Isobutoxy benzyl amine (10.0 g), water (7.0 v), and Sodium bicarbonate (18.7 g) were stirred the reaction mixture at room temperature. To this was added thiophosgene (12.8 g) at 0-10^oC and stir for about 4-6 hours. To the resulting reaction mixture was charged 10% Sodium bicarbonate solution (2.0 v) and stirred for 5-10 minutes.  Separated organic layer and was washed with water (3.0 v). The organic layer dried over sodiumsulfate. Evaporated solvent under reduced pressure to get the 1-isobutoxy-4-(isothiocyanatomethyl) benzene.

 

General procedure for preparation of 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methyl piperidin-4-yl) thiourea (4):

A mixture of 1-isobutoxy-4-(isothiocyanatomethyl) benzene (5.0 g) and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (6.0 g) in Ethyl acetate (10.0 v) were stirred at 70-75^oC until the TLC complies (4-5 hours). Solvent was evaporated under reduced pressure and residue was purified by column chromatography (5 % methanol in dichloromethane) to get solid compound 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methyl piperidin-4-yl) thiourea.

 

General procedure for preparation of Pimavanserin (5):

Compound 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methyl piperidin-4-yl) thiourea (1.0 g) and silver carbonate (1.2 g) in acetonitrile (15.0 v) was stirred at room temperature until TLC complies (24-30 hours). Filtered the reaction mass to remove un-dissolved solids and washed the solid with acetonitrile (5.0 v).Evaporated the solvent under reduced pressure and residue was isolated in water (10.0 v) and methanol (2.0 v) mixture at room temperature.

 

General procedure for preparation of 1-(4-isobutoxybenzyl) urea (7):

A mixture of 4-Isobutoxy benzyl amine (5.0 g), urea (10.0 g), sodium hydroxide (0.99 g) heated to 120-130^oC. Reaction mass was stirred for 12-15 hours for the completion of TLC. To this was charged water (10.0 vl) and pH was adjusted to 7.0 with concentrated HCl. Solid was filtered and washed with water (4.0 v) and dried the compound to provide the 1-(4-isobutoxybenzyl) urea.

 

General procedure for preparation of Pimavanserin from 7:

A mixture of 1-(4-isobutoxybenzyl)urea (1.0 g) and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (IV) (1.0 g) were stirred at 120-130^oC until the TLC complies (12 hours). Charged water to reaction mass at room temperature and extracted into ethyl acetate.  Solvent was evaporated under reduced pressure and residue was purified using solvent system 10 % methanol in ethyl acetate to get Pimavanserin.

 

General procedure for Preparation of N-(4-isobutoxybenzyl)formamide (9):

4-Isobutoxy benzyl amine acetate (10.0 g) was stirred in water (3.0 Volumes) at room temperature. Adjusted the reaction mass pH to 11-12 with aqueous ammonia solution. The product was extracted toluene (5.0 V).  Formic acid (2.3 g) was added to the reaction mixture. The resulting reaction mixture was refluxed for 4-9 hours with azeotropic condenser. After the TLC complies, evaporated the solvent under reduced pressure and stripped out with hexane to get N-(4-isobutoxybenzyl)formamide.

 

General procedure for preparation of Pimavanserin from 9:

N-(4-isobutoxybenzyl) formamide (2.0 g) was stirred in DCM (10.0 v). To this was added triethyl amine (3.9 g) at room temperature. Triphosgene (1.98 g) was added in lot wise to above reaction mixture at 0-5^oC. Reaction mass was stirred at room temperature for 2-3 hours. Wash the reaction mixture with water (5.0v) and dried over anhydrous Na₂ SO₄. The organic layer was transferred in to another round bottom flask U/N₂ atmosphere.  Add Dimethyl sulfoxide (DMSO) (0.82 g) to the reaction mixture at room temperature. To this was added Trifloromethanesulfonic anhydride (0.1 ml) at -65 to -60^oC. Reaction mixture was stirred for 10-15min at room temperature. Add (N-(4-fluorobenzyl)-1-methylpiperidin-4-amine)) (2.1 g) in DCM (10.0 v) at -65 to -60^oC. Reaction mixture was stirred at room temperature for 2-3 hours. Washed the reaction mixture with water (5.0v) and dried the organic layer over Na₂SO₄. Evaporated the solvent under reduced pressure and residue was purified by column chromatography (10 % methanol in ethyl acetate) to give Pimavanserin.

 

RESULTS AND DISCUSSIONS:

Various procedures were reported by utilizing diphenylphosphorylazide compounds, chloroformate amino protected compounds and carbonyl dimimidazole intermediates as key materials. These substances are hazardous reagents and further may lead to formation of more byproducts which may lead to effect on purity & yield of the final substance.

 

Hence, there still exists a need to have alternate procedures which is industrially feasible. Thus, our efforts in achieving an environmentally friendly, step-wise and one-pot an improved synthetic process for Pimavanserin via efficient intermediates (Isothiocyanate, urea and N-formyl) have been described under green conditions.

 

Initially, the reaction was started with by taking one mole of 4-Isobutoxy benzyl amine (1), thiophosgene and sodium bicarbonate in water was stirred at 0-10^oC for 1 h to yield corresponding 1-isobutoxy-4-(isothiocyanatomethyl)benzene (2). Further treatment of 2 with N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (3) in ethanol refluxing for 1-2 h to give respective thiourea derivative of 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methyl piperidin-4-yl) thiourea (4). Furthermore the above synthesized intermediate compound 4 was stirred with silver carbonate at room temperature for 1-2 h gave final title compound Pimavanserin(5) in excellent yield (96%). The structure of compound was established by its spectral data (ie. IR, ¹H-NMR, ¹³C-NMR and Mass).

 

 

Scheme-1: Synthesis of pimavanserin (5) from Isothiocyanate.

 

 

 

In scheme-2, the reaction was started with taking 4-Isobutoxy benzyl amine (1) with urea (6) and sodium hydroxide solution refluxing for 10-12 hr with continuous stirring. After completion of the reaction the reaction was checked by TLC and P^H adjusted with HCl solution the resulting solid was washed with water to yield is corresponding intermediate compound 1-(4-isobutoxybenzyl)urea (7). Further treatment of 1-(4-isobutoxybenzyl) urea with N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (3) was refluxed for 12 hr at 120-130^oC followed by ethyl acetate extraction to get target compound Pimavanserin(5).

 

Scheme-2: Synthesis of pimavanserin (5) from urea intermediate.

 

 

 

As illustrated in scheme-3, 4-Isobutoxy benzyl amine (1) formaldehyde (8) and water was refluxed for 4-9 hr at 100^oC. After completion the reaction, the reaction mass was extracted with hexane and dried to get intermediate N-(4-isobutoxybenzyl)formamide (9). Further, the formide intermediate 9 was stirred with N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (3) at room temperature for 2-3 hr to get final compound 5.

 

Scheme-3: Synthesis of pimavanserin (5) from formide intermediate (9).

 

 

CONCLUSION:

In summary, we have developed environmentally friendly, an improved synthesis of Pimavanserin (5-HT2A receptor) via efficient intermediates (Isothiocyanate, urea and N-formyl) under green conditions.

 

ACKNOWLEDGEMENT:

Authors are very thankful to the authorities of Granules India Pvt Ltd. Hyderabad for providing laboratory facilities.

 

REFERENCES:

1.        Geralyn MS, Megan KG. Effects of speech therapy and pharmacologic and surgical treatments on voice and speech in parkinson's disease: A review of the literature. Journal of Communication Disorders. 2000; 33: 59-88.

2.        Friedman JH. Pimavanserin for the treatment of Parkinson's disease psychosis. Expert Opinion on Pharmacotherapy. 2013; 14: 1969-1975.

3.        Zhang G, Cinalli D, Stackman RW, Effect of a hallucinogenic serotonin 5-HT2A receptor agonist on visually guided, hippocampal-dependent spatial cognition in C57BL/6J mice. Hippocampus. 2017; 27: 558-569.

4.        Combs BL, Cox AG, Update on the treatment of Parkinson's disease psychosis: role of Pimavanserin. Neuropsychiatric Disease and Treatment. 2017; 13: 737-744

5.        Biljan T, et al. US Patent. US20180037549A1 (2015).

 

 

 

 

 

Received on 23.10.2018                    Modified on 22.12.2018

Accepted on 15.01.2019                   ©AJRC All right reserved