Methods of synthesis of Pimavanserin: the first drug approved for the treatment of Parkinson’s disease psychosis (PDP )

Pimavanserin (Nuplazid TM ) is the first FDA atypical antipsychotic drug approved for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis (PDP). Pimavanserin displays a unique pharmacological profile with nanomolar potency as a 5-HT 2A receptor inverse agonist. Due to the importance of Pimavanserin for the field of neurological disorder, numerous reports have appeared in the literature dealing with the synthesis of Pimavanserin. In this article we collect, summarize and discuss the various synthetic strategies and judge their applicability for larger scale drug synthesis.


Introduction
3][4] Many PD patients also develop non-motor deficits that are equally disturbing to the well-being of patients and their daily functional activities including autonomic dysfunctions, sensory disturbances and psychosis.The deteriorations associated with Parkinson's disease (PD) are comorbid medical conditions (e.g.][7][8][9][10] Unfortunately, over the course of the disease the majority of patients are also affected by Parkinson's disease psychosis (PDP), which occurs in up to 60% of individuals. 11PDP causes them to see, hear, or experience things that are not real (hallucinations), 12,13 or believe things that are not true (delusions). 55][16] Therefore, psychotic symptoms in patients with PD require treatment.There are many antipsychotic medications on the market, and they differ in potency in relation to dopaminergic and serotonin receptor types.The first generation or typical antipsychotics [17][18][19] (Scheme 1) were examined as potential drugs.However, the clinical studies showed the use of typical antipsychotics in patients with PD is complicated due to their ability to block dopaminergic D2 receptors and cause profound dopamine D2 antagonism and druginduced Parkinsonism symptoms 20 such as dyskinesia which usually accompanied with worsened motor symptoms. 21Therefore, atypical antipsychotics (AAP); also known as second generation antipsychotics (SGAs) are commonly used. 22Among these drugs are Olanzapine, Risperidone, Quetiapine and Clozapine (Scheme 2).It is generally accepted that second-generation antipsychotics (SGAs) are safer in patients with PD due to their lower D2 antagonism but they also can cause extrapyramidal side effects, 23,24,21 even in lower rates, in comparison with first-generation antipsychotics (FGAs). 25Recently Barry et al. have published a tutorial review that summarized the synthesis, mode of action, effectiveness and limitations of some of the most clinically used typical and atypical antipsychotics.The treatment of psychosis in PD is therefore a complex task and the choice of atypical antipsychotic is based on patient-specific parameters, potential benefit, and side effects. 27Accordingly, there is an urgent need to develop novel effective, safer and better-tolerated drugs for improved treatment of PDP. 28The only antipsychotic with clear evidence regarding efficacy in PD patients is Pimavanserin (Figure 1).Pimavanserin (Nuplazid TM ) is a first medication approved by the FDA for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis (PDP).It was originally developed by Acadia Pharmaceuticals [29][30][31][32][33] (CAS No. [706779-91-1], April 2016).Pimavanserin is a first-in-class atypical antipsychotic that does not induce clinically significant antagonism of dopaminergic, adrenergic, histaminergic, or muscarinic receptors. 34Throughout the clinical trial program, Pimavanserin appeared to be safe and welltolerated, particularly with respect to its lack of deleterious effects on motor function. 29,35Collective reviews that discuss the pharmacology, pharmacodynamics, pharmacokinetics and clinical trials assessing its efficacy and safety have been reported. 30,362][33] As a consequence, to summarize and to discuss the innovative and challenging synthetic strategies of Pimavanserin is crucial.The only article that has described the synthesis methods of Pimavanserin was published in the Chinese language by Gan and Hu. 37The aim of this review is to describe, discuss, and provide a selection of the most commonly used routes for Pimavanserin synthesis based on many literature sources including patents.Furthermore, from this study, it will be possible to establish or to judge whether novel methods and transformations developed are most frequently employed and which ones are not applicable in large-scale syntheses.We believe that this summary will give an enlightening overview of the chemical methodologies adopted for the synthesis of Pimavanserin as a novel drug candidate for Parkinson's disease psychosis (PDP).

Synthesis Methods to Pimavanserin (Nuplazid TM )
Pimavanserin, is a member of the class of ureas in which three of the four hydrogens are replaced by 4fluorobenzyl, 1-methylpiperidin-4-yl, and 4-(isopropyloxy) benzyl groups (Figure 1).The following schemes illustrate the methods used for synthesis of Pimavanserin. 32einer et al. 32 devised an efficient production method for the synthesis of Pimavanserin.Their route was improved and developed for the compound's large scale manufacture.The refined process route (Scheme 3) is based on the condensation of readily available N-methylpiperidone 1 with p-fluorobenzylamine 2 followed by reduction to offer the precursor S1 quantitatively.Alkylation of commercially available 4-hydroxyphenylacetate ester 3 gave compound 4. Hydrolysis of ester 4 gave the corresponding acid 5. Heating the carboxylic acid 5 with diphenylphosphoryl azide (DPPA) 38,39 in the presence of base such as 1,8-bis(dimethylamino)naphthalene 40 produced acyl azides, which thermally underwent the Curtius rearrangement to afford the key isocyanate S2. 41 The isocyanate S2 thus formed reacts with amine S1 to furnish the target Pimavanserin (Scheme 3).Scheme 3 2.2.Method B (Acadia Pharmaceuticals Company, 2006) 33 Thygesen et al. 33 have developed an attractive alternative method for synthesis a wide variety of carbamides and their tartrate salt derivatives including Pimavanserin for large scale manufacture (Scheme 4).Reductive amination between compounds 1 and 2 was accomplished smoothly by using sodium triacetoxyborohydride to generate the key fragment secondary amine S1.Treatment of phenol 6 with isobutylbromide in the presence of K2CO3 gave the corresponding ether derivative 7. Subsequent oximation of 7 produced the oxime 8. Reduction of oxime group and subsequent hydrolysis of ammonium salt formed, yielded the desired primary amine 9. Treatment of amine 9 with phosgene 42,43 provided the corresponding isocyanate 41 S2.Coupling the key synthon S2 with secondary amine S1 furnished the target carbamide derivative (Pimavanserin) in high yield (Scheme 4).

Method A (Acadia Pharmaceuticals Company, 2004)
However, both of the above processes for the preparation of Pimavanserin suffer from low process safety, they often utilize hazardous reagents like phosgene 44 or diphenylphosphoryl azide. 45Accordingly, there was still a need for additional processes allowing the efficient and safe synthesis of Pimavanserin.

Scheme 4
In 2016, TEVA Pharmaceutical Industries 46 developed various methods for the production of Pimavanserin.
In their patent work it was shown that the highly toxic phosgene and DPPA reagents can be readily substituted by less toxic and less expensive intermediates.The routes of synthesis were based on coupling of readily prepared N-(4-fluorobenzyl)-l-methylpiperidin-4-amine S1 with urea or carbamate derivatives (Scheme 5 and Scheme 6).

Method C (TEVA Pharmaceutical
Industries, 2016) 46 The first route starts with the readily available 4-cyanophenol 10.Compound 10 was alkylated with isobutyl bromide in the presence of K2CO3 to form the corresponding cyanophenyl ether 11.Catalytic hydrogenation of cyanophenyl ether 11 with Raney nickel afforded the key intermediate 4-isobutyloxybenzylamine 9. Coupling of amine 9 with 1,1-carbonyldiimidazole (CDI) 47 in acetonitrile produced the urea synthon S3.The urea derivative S3 was found to be an efficient coupling partner and reaction with N-(4-fluorobenzyl)-l-methylpiperidin-4-amine S1 in a mixture of CH3CN and DMF led smoothly to the desired Pimavanserin in an overall yield of 82%.(Scheme 5) In general, the reaction conditions are convenient for purification, and the reactions proceed with complete conversion.The method is thus convenient for large scale manufacture. 46 modified approach (Scheme 6) from the same stable involved an alternative synthesis of the isobutyloxybenzonitrile 11 from 4-fluorobenzonitrile and isobutanol, and formation of the urea unit via the nitrophenyl carbamate S4, giving Pimavanserin, but only in unsatisfactory yield, and furthermore long reaction times were required. 46

Scheme 6
However, the above-mentioned methods (C and D) have disadvantageous features.One particular disadvantage is the formation of l,3-bis-(4-isobutoxybenzyl)urea 13 as a side product.Removal of compound 13 leads to considerable loss from the total weight of crude products.

Method E. Comparative method
Another possible approach introduced different conditions for the synthesis of Pimavanserin.Initially, the condensation of the readily available p-fluorobenzaldehyde 14 with aminopiperidine 15 followed by reduction with Pd/C under hydrogen produced S1 in one step (route 1).Alternatively, condensation of N-methylpiperidone 1 with p-fluorobenzylamine 2 followed by reduction with NaCNBH3 in the presence of acetic acid led to the formation of the same precursor S1 quantitatively (the second route was described in Method A (Scheme 3).The developed approach was based on the direct coupling of S1 with 1,1-carbonyldiimidazole (CDI) in presence of Et3N and CH2Cl2 to produce the substituted urea S6.The fully elaborated urea component S6 was then heated with the primary amine 5 in the presence of DMAP and DMF at 100 °C to furnish the desired Pimavanserin in good yield (58%) for the final step (Scheme 7).It is noteworthy that the method involves a different approach to Pimavanserin synthesis, but the yield is very low, also using catalyst with extra heating discourages the use of this approach in comparison with the previous methods.

Method F: An environmentally friendly route
A novel and eco-friendly method was developed by Mulakayala et al. 48The synthesis developed from the key starting material 4-isobutyloxybenzylamine 9.The primary amine 9 was transformed into the corresponding isothiocyanate derivative 16 using thiophosgene in water as the solvent.Coupling of the readily available S1 intermediate with isothiocyanate 16 produced the thiourea 17.Compound 17 was desulfurized by silver carbonate to furnish the title compound Pimavanserin.(Scheme 8) This procedure provides the advantages of easy workup, good yields of products, and use or water as the solvent.No column purification was required for the isolation of the product.However, thiophosgene was used to prepare compound 16 which is considered highly toxic, and the use of silver carbonate, and the formation of silver precipitates as byproducts, tends to the impracticability of the method.

Conclusions
In April 2016, FDA approved Pimavanserin (NuplazidTM) as the first drug indicated for treatment of PDP.Pimavanserin has a unique pharmacological profile with its high and selective affinity for 5-HT2A and 5-HT2C receptors and potent inverse agonist activity at 5-HT2A receptors.The drug has minimal affinity and does not interact with dopaminergic, muscarinic, adrenergic and histaminergic receptor subtypes.Pimavanserin may also be useful for treating psychotic conditions associated with other neurodegenerative diseases and therefore a study in Alzheimer's disease psychosis (ADP) has recently been initiated by ACADIA pharmaceutical company to explore this possibility. 49Based on the data that collected from different literature resources, a number of observations can be drawn for the syntheses of Pimavanserin,.For example, it is established that the most applicable method used is based on coupling of readily prepared N-(4-fluorobenzyl)-lmethylpiperidin-4-amine S1 with urea derivatives in general.Specifically, CDI reagent is used as powerful coupling agent (Scheme 5).This can be rationalized by considering the efficiency and the safe synthesis routes in comparison with the highly toxic phosgene and DPPA reagents that are used in scheme 3 and 4. Other robust method such as coupling of carbamate derivative to a secondary amine (Scheme 7), appear to be rarely used.The reasons for this might be the low yield product, in addition to the need of catalyst with extra heating.In conclusion, the development and approval of Pimavanserin will encourage the medical arsenal in discovering novel 5-HT2A inverse agonists for improved treatment of psychotic symptoms in psychiatric as specific and neurological disorders as a general.Undoubtedly, many other developed strategies will be discovered in the near future and further applied economic steps will become elaborated in total synthesis of Pimavanserin and various analogs. 50,51In summary, this article may be helpful to the field of pharmaceutical industry, researchers and scholars working the field of antipsychotic medicines and health care specialists.