An improved process for the preparation of pimavanserin tartrate

Abstract

A practical synthetic route to pimavanserin tartrate, in which the target compound was obtained with 99.84% purity and in 46% total yield via a 5-step synthesis starting from 4-hydroxybenzaldehyde and (4-fluorophenyl)methanamine, is reported. The main advantages of the route include inexpensive starting materials, mild reaction conditions and an acceptable overall yield.

Keywords

optimization Parkinson’s disease pimavanserin tartrate synthesis

Introduction

Pimavanserin has been administered as its tartrate salt (ACP-103, P) (Figure 1) and was used as a novel inverse agonist of 5-HT_2A receptors. It was independently developed by Acadia Pharmaceuticals and approved by the US Food and Drug Administration (FDA) in 2016 for the treatment of psychosis and other neuropsychiatric indications.^1,2

Figure 1.

Chemical structure of pimavanserin tartrate (1).

The reported routes to 1 are depicted in Scheme 1. Initially, Acadia Pharmaceuticals disclosed a method for its synthesis in the early stage of drug discovery (Route A).³ In this method, 4-hydroxybenzaldehyde was used as a starting material in 6-step process to provide 1 with a total yield of 11%. The main drawbacks of this approach were that the use of toxic phosgene and H₂/Pd-C as a reducing reagent under high pressure, which seriously hampered its large-scale production. Gant and Sarshar⁴ developed another method (Route B) to provide 1 from methyl-2-(4-hydroxyphenyl) acetate in five steps with a total yield of 21%. However, unsafe N,N,N’,N’-tetramethylnaphthalene-1,8-diamine and diphenyl phosphorazidate were used in this route. To avoid the application of toxic phosgene, the groups of Wang and Cheng reported another two novel synthetic routes by using 4-hydroxybenzylamine (Route C, in <16% total yield)⁵ and 4-fluorobenzylamine (Route D, in <52% total yield),⁶ respectively, as starting materials. However, the reagents phenyl chloroformate and benzyl chloroformate have certain toxicity and corrosiveness. Moreover, 4-hydroxybenzylamine and 4-fluorobenzylamine are relatively expensive.

Scheme 1.

Synthetic routes toward pimavanserin tartrate or pimavanserin.

Accordingly, we discuss our attempts to develop a safe and scalable process for the synthesis of 1 and seek to define a more efficient and cost-effective route that is appropriate for more sustainable long-term supply of the drug (Scheme 2). The new synthesis started from commercially available p-hydroxybenzaldehyde (2), which was converted into ether 4 via reaction with 1-chloro-2-methylpropane. Subsequently, ether 4 was transformed into amine 5 via reductive amination reaction using Raney-nickel. Reaction of amine 5 and with bis(trichloromethyl)carbonate (BTC) yielded isocyanate 6, which upon treatment with fluoro compound 9 furnished pimavanserin. Finally, pimavanserin was reacted with tartaric acid to afford pimavanserin tartrate (1).

Scheme 2.

Our an alternative synthetic route to pimavanserin tartrate (1).

Results and discussion

During the process for the assembly of 5, we found that a small quantity of an impurity, a light oil, that was identified 5a formed (Table 1 ). Efforts to improve the conversion rate and to reduce the yield of 5a by controlling the temperature and amount of catalyst were unsuccessful. As 5a did not affect the next synthetic step, the reduced product was directly used in the next step without any further purification.

Table 1.

Optimization of the reduction reaction^a.


Entry	Ni (%)^b	Temperature (^oC)	Yield^c (%)
Entry	Ni (%)^b	Temperature (^oC)	5 . . . 5a
1	5	30	26 . . . 0
2	5	50	43 . . . 1
30	10	30	35 . . . 1
4	10	50	46 . . . 1
5	15	30	37 . . . 1
6	15	50	80 . . . 1
7	20	50	81 . . . 2
8	25	50	81 . . . 2

Standard conditions: 4 (200 mmol), 10% w/v solution of ammonia in methanol (150 mL).

Based on the quality of 4.

Isolated yield after chromatography.

The main methods to synthesize isocyanates are as follow: amines reacting with phosgene,³ using carboxylic acids in Curtius rearrangements in the presence of azide,⁴ and utilizing N,N’-carbonyldiimidazole (CDI) as an activated amide.⁷ Unfortunately, CDI readily formed the self-condensation byproduct A-1 (Figure 2). Consequently, we chose BTC (bis(trichloromethyl)carbonate) to synthesize isocyanates in order to reduce the generation of impurity A-1.⁸

Figure 2.

Chemical structures of A-1 and A-2.

Interestingly, it was found that the order of addition had a significant influence on the reaction. When BTC was added to 5 in dichloromethane (DCM), a large quantity of A-1 was observed. It is speculated that this was due to 5 being present in excess compared to BTC in the reaction mixture. This problem was solved by adding 5 to a mixture of BTC in DCM in a dose-controlled manner. During further study on the synthesis of pimavanserin, it was found that the order of addition had a significant influence on the reaction results. When 9 was added to a mixture of 6 in DCM, impurity A-2 (Figure 2) was readily formed. If 6 was added to a mixture of 9 in DCM, A-2 was not detected.

On this basis, the effects of the amount of BTC, the solvent and the temperature were investigated. As shown in Table 2, the reaction temperature of the first step had a significant influence on the yield. It was found that slow, dropwise addition of a mixture of 5 and Et₃N at -10 ^oC to the solution of BTC (1.5 equiv with respect to phosgene) in DCM was optimum. After the reaction was complete, the precipitates were removed and the filtrate was added dropwise to a solution of 9. The reaction mixture was stirred for 3 h at room temperature and the total yield of the two steps was 70% (entry 8).

Table 2.

Optimization of the amount of BTC, the solvent and the temperature on the yield of pimavanserin^a.

Entry	BTC (equiv)	Solvent	Temperature 1^b (^oC)	Temperature^c 2 (^oC)	Yield (%)
1	1.2	THF	25	25	20
2	1.5	THF	25	25	41
3	1.5	THF	0	25	51
4	1.5	THF	−10	25	69
5	1.5	THF	−10	50	68
6	1.5	THF	−20	50	66
7	1.8	THF	−10	50	68
8	01.5	DCM	−10	25	70
9	1.5	DCM	−20	25	69
10	1.5	DCM	−10	reflux	69

BTC: bis(trichloromethyl)carbonate; DCM:dichloromethane; THF:tetrahydrofuran.

Standard conditions: 5 (100 mmol), Et₃N (290 mmol).

Temperature for the reaction of 5 and BTC.

Temperature for the reaction of 6 and 9.

An attempt to increase the purity and yield by changing the recrystallization solvents proved successful. It was found that a yield of 70% could be obtained by recrystallization from ethyl acetate (Table 3).

Table 3.

Effect of the solvent on the yield of recrystallization^a.

Standard conditions: Pimavanserin (93.6 mmol).

Finally, salt formation process was carried out in ethyl acetate, when ethyl acetate was used as solvent, the reaction mixture was stirred for 1 h at 50 ^oC, an acceptable yield of 89% could be obtained.

Conclusion

In summary, we have provided an alternative method for the production of pimavanserin tartrate. The modified route avoids several drawbacks of the original synthesis such as removal of highly toxic and expensive reagents. The method also reduces the cost and improves the yield. The procedure involves in five linear steps with an overall yield of 46% and a 99.84% high-performance liquid chromatography (HPLC) purity of the target compound.

Experimental

General

Reagents and solvents were obtained from commercial suppliers and used without further purification. Melting points were determined with a Yanaco apparatus and were uncorrected. ¹H and ¹³C nuclear magnetic resonance (NMR) spectra were recorded using a Bruker ARX-400 apparatus (Billerica, MA, USA) with tetramethylsilane (TMS) as an internal standard. Electrospray ionization mass spectrometry (ESI-MS) data were obtained using an AlliAnce+Quattromicro^TM Series liquid chromatography-tandem quadrupole mass spectrometer. The reactions were monitored by thin-layer chromatography (TLC; HG/T2354-92, GF254), and compounds were visualized on TLC with ultraviolet (UV) light. HPLC analyses were performed on a Shimadzu LC-20, column, Shimadzu Inertsil-SP C18 (5 µm; 250 mm × 4.6 mm).

Preparation of 4-isobutoxybenzaldehyde (4): Potassium carbonate (69.0 g, 500 mmol) and potassium iodide (6.6 g, 40 mmol), 4-hydroxybenzaldehyde (2) (24.4 g, 200 mmol) and isobutyl chloride (3) (36.8 g, 400 mmol) were added to dimethylformamide (DMF) (140 mL). After being stirred at reflux for 18 h, the mixture was cooled to ambient temperature filtered under vacuum. The filtrate was concentrated in vacuo to remove DMF. The residue was dissolved in EtOAC (100 mL) and H₂O (100 mL). The layers were separated, and the aqueous layer extracted with EtOAC (100 mL). The organic phase was collected, washed with brine (100 mL) and then dried over anhydrous sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo to afford 4 as a yellow oil (34.3 g, 96%). Crude 4 was used directly in the next step. A sample of 4 was analyzed as follows. ESI-MS m/z: 179.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): δ (ppm) 9.88 (s, 1H), 7.82 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 8.7 Hz, 2H), 3.80 (d, J = 6.5 Hz, 2H), 2.15–2.08 (m, 1H), 1.04 (d, J = 6.7 Hz, 6H).

Preparation of (4-isobutoxyphenyl) methanamine (5): 4-isobutoxybenzaldehyde (4) (28 g, 200 mmol), Raney-nickel (4.2 g, 15%, 47% w/w) and a 10% w/v solution of ammonia in methanol (150 mL) were stirred at 50–55 °C for 8 h at a hydrogen pressure of 2.02 kg/cm². The reaction mixture was cooled to ambient temperature and isolated by vacuum filtration. The filtrate was concentrated in vacuo to afford 5 as a light yellow oil (22.6 g, 80%). ESI-MS m/z: 180.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.23–7.19 (m, 2H), 6.89–6.84 (m, 2H), 3.80 (s, 2H), 3.71 (d, J = 6.6 Hz, 2H), 2.12–2.02 (m, 1H), 1.02 (d, J = 6.7 Hz, 6H). Impurity 5a (yield: 1.5%). ESI MS m/z: 342.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.30–7.26 (m, 4H), 6.91–6.86 (m, 4H), 4.61 (s, 4H), 3.72 (d, J = 6.6 Hz, 4H), 2.08 (dt, J = 13.3, 6.7 Hz, 2H), 1.02 (d, J = 6.7 Hz, 12H).

Preparation of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (9): (4- fluorophenyl)methanamine (7) (15.0 g, 120 mmol), 1-methylpiperidin-4-one (8) (13.6 g, 120 mmol), and zinc chloride (3.3 g, 24 mmol) were added to methanol (200 mL). The mixture was cooled below 0 °C, and sodium cyanoborohydride (11.3 g, 180 mmol) was slowly added. The mixture was stirred at 40 °C for 4 h, then cooled to ambient temperature and concentrated in vacuo to remove methanol. The residue was dissolved in DCM (300 mL), washed with 10% sodium hydroxide (450 mL) and brine (200 mL), and then dried over anhydrous sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo to 9 as a yellow oil (25.9 g, 97.1%). ESI-MS m/z: 223.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.31–7.26 (m, 2H), 7.03–6.97 (m, 2H), 3.78 (s, 2H), 2.85–2.80 (m, 2H), 2.51–2.46 (m, 1H), 2.27 (s, 3H), 2.03–1.97 (m, 2H), 1.93–1.87 (m, 2H), 1.50–1.41 (m, 2H).

Preparation of Pimavanserin tartrate (1): A solution of BTC (14.6 g, 150 mmol) in DCM (80 mL) was stirred at −10 °C, followed by the dropwise addition of (4-isobutoxyphenyl) methanamine (5) (17.6 g, 100 mmol) and Et₃N (29.8 g, 290 mmol) in DCM (80 mL) while maintaining the temperature below 10 °C. When the addition was complete (0.5 h), the reaction mixture was isolated by vacuum filtration. The filtrate 6 was added dropwise to a mixture of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (9) (21.8 g, 100 mmol) and DCM (80 mL) over 2.5 h. The mixture was then stirred at 25 °C for 3 h. The reaction mixture was extracted with H₂O (720 mL) and the combined aqueous layer was extracted with DCM (240 mL). The organic phase was collected, washed with brine (300 mL) and then dried over anhydrous sodium sulfate. The sodium sulfate was filtered off, and the filtrate was concentrated in vacuo to afford a brown oil (40.0 g). The crude material was recrystallized form EtOAC (160 mL) to afford pimavanserin as a beige solid (29.4 g, 70%). Recrystallization process: crude pimavanserin was dissolved by heating in EtOAC and cooled for 30 min. The mixture was then filtered to obtain pure pimavanserin. A sample of purified pimavanserin was analyzed as follows. M.p. 119–122 ^oC (Lit.,⁹ m.p.124 ^oC). ESI-MS m/z: 428.3 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃): δ (ppm) 7.18 (dd, J = 8.4, 5.3 Hz, 2H, ArH), 6.99 (m, 4H, ArH), 6.78 (d, J = 8.6 Hz, 2H, ArH), 4.50 (t, J = 5.5 Hz, 1H, NH), 4.34 (s, 2H, CH₂), 4.33-4.31 (m, 1H, CH), 4.27 (d, J = 5.4 Hz, 2H, CH₂), 3.68 (d, J = 6.6 Hz, 2H, CH₂), 2.88-2.85 (m, 2H, CH₂), 2.26 (s, 3H, CH₃), 2.09-2.05 (m, 3H, CH and CH₂), 1.73-1.65 (m, 4H, CH₂), 1.01 (d, J = 6.7 Hz, 6H, CH). ¹³C NMR (400 MHz, DMSO-d₆): δ (ppm) 162.54, 160.14, 158.03, 157.92, 137.55, 133.57, 128.85, 128.78, 128.61, 115.29, 115.08, 114.53, 74.24, 55.38, 52.85, 46.29, 44.43, 43.59, 30.45, 28.19, 19.52. HRMS (ESI) calcd for C₂₅H₃₄FN₃O₂ [M+H]⁺: 428.2635, found: 428.2728. Impurity A-1: ESI-MS m/z: 385.4 [M+H]⁺, 407.4 [M+Na]⁺. ¹H NMR (400 MHz, CDCl₃): δ(ppm) 7.14 (d, J = 8.5 Hz, 4H), 6.81 (d, J = 8.6 Hz, 4H), 4.69 (s, 2H), 4.24 (d, J = 5.3 Hz, 4H), 3.67 (d, J = 6.6 Hz, 4H), 2.11–2.01 (m, 2H), 1.01 (d, J = 6.7 Hz, 12H). Impurity A-2: ESI-MS m/z: 633.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ(ppm) 7.17–7.15 (m, 2H), 7.07–7.03 (m, 4H), 6.87–6.77 (m, 6H), 5.96 (t, J = 5.2 Hz, 1H), 4.70 (s, 2H), 4.29 (s, 2H), 4.28 (d, J=5.4 Hz, 2H), 3.70 (d, J = 6.6 Hz, 2H), 3.68 (d, J = 6.6 Hz, 2H), 3.65–3.63 (m, 1H), 2.77 (d, J=11.2 Hz, 2H), 2.23 (s, 3H), 2.11–2.03 (m, 2H), 1.86 (d, J=11.4 Hz 2H), 1.73–1.64 (m, 2H), 1.28 (d, J=10.8 Hz, 2H), 1.02 (d, J = 6.7 Hz, 12H).

Pimavanserin (20 g, 46.8 mmol) in EtOAC (200 mL) was stirred at 50 °C. Then L-(+)-tartaric acid (3.6 g, 24.0 mmol) was added to the mixture which was stirred at 50 ^oC for 1 h. The mixture was cooled to −15 °C, stirred for 0.5 h and then was filtered. The residue was washed with cold EtOAC (40 mL) and dried at 45–55 °C under vacuum to afford 1 as a white solid (22.4 g, 95%, based on pimavanserin). Crude 1 was recrystallized from ethanol (60 mL) to afford pimavanserin tartrate (1) as a white solid (20.8 g, 89%, based on pimavanserin). Recrystallization process: crude pimavanserin tartrate was dissolved by heating in ethanol and then cooled to ambient temperature and isolated by vacuum filtration to obtain pure pimavanserin tartrate. M.p. 129–131 ^oC (Lit.,⁹ m.p.133–135 ^oC). ESI-MS m/z: 428.3 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 7.24 (dd, J = 8.3, 5.5 Hz, 4H, ArH), 7.14–7.09 (m, 8H, ArH), 6.93 (t, J = 5.7 Hz, 2H, NH), 6.84 (d, J = 8.2 Hz, 4H, ArH), 4.41 (s, 4H, CH₂), 4.18 (d, J = 5.6 Hz, 4H, CH₂), 4.07-4.04 (m, 2H, CH), 4.01 (m, 2H, CH), 3.70 (d, J = 6.6 Hz, 4H, CH₂), 2.99-2.96 (m, 4H, CH₂), 2.36-2.30 (m, 10H, CH₂ and CH₃), 2.01-1.96 (m, 2H, CH), 1.73-1.66 (m, 4H, CH₂), 1.52–1.48 (m, 4H, CH₂), 0.97(d, J = 6.7 Hz, 12H, CH₃).¹³C NMR (600 MHz, DMSO-d₆): δ (ppm) 174.78, 161.36 (d, J = 240 Hz), 157.93, 137.26, 133.43, 128.80 (d, J = 8.0 Hz), 128.61, 115.24 (d, J =21 Hz), 114.54, 74.24, 72.23, 54.48, 51.79, 44.68, 44.55, 43.57, 29.08, 28.17, 19.52. Pimavanserin tartrate 1 with 99.84% (relative area) of HPLC purity (eluent, acetonitrile/water = 55/45; flow rate = 1 mL/min; temperature 40 ^oC; wavelength 231 nm. The HPLC analysis data are reported in relative area % and was not adjusted to weight %).

Supplemental Material

Revised_Supplementary_information – Supplemental material for An improved process for the preparation of pimavanserin tartrate

Supplemental material, Revised_Supplementary_information for An improved process for the preparation of pimavanserin tartrate by Caijiao Wu, Qifan Zhou, Dake Song, Hui Li, Changshun Bao, Xuelong Liu, Xuefei Bao and Guoliang Chen in Journal of Chemical Research

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Guoliang Chen

Supplemental material

¹H spectra, MS spectra, HPLC traces: This material can be found via the “Supplementary Content” section of this article’s web page.

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