PAPER 57

A Practical, Laboratory-Scale Synthesis of PerampanelLaboratory-Scale Synthesis of PerampanelCharles J. McElhinny Jr., F. I. Carroll, Anita H. Lewin*Research Triangle Institute, 3040 Cornwallis Road, Research Triangle Park, NC 27709, USAFax +1(919)5418868; E-mail: ahl@rti.orgReceived 27 September 2011; revised 5 October 2011

SYNTHESIS 2012, 44, 57–62xx.xx.2011Advanced online publication: 04.11.2011DOI: 10.1055/s-0031-1289587; Art ID: M92511SS© Georg Thieme Verlag Stuttgart · New York

Abstract: The orally active, noncompetitive, selective AMPA re-ceptor antagonist Perampanel, 2-[1¢,6¢-dihydro-6¢-oxo-1-phenyl-(2¢,3¢-bipyridin)-5¢-yl]benzonitrile, has been prepared from readilyavailable, relatively inexpensive starting materials. The synthesiswas carried out on a laboratory scale with no specialized equipment,and involved only two chromatographic purifications.

Key words: AMPA antagonist, Suzuki coupling, palladium con-tent, Stille coupling, trace-metal contamination

Perampanel, 2-[1¢,6¢-dihydro-6¢-oxo-1-phenyl-(2¢,3¢-bi-pyridin)-5¢-yl]benzonitrile (7), an orally active, noncom-petitive, selective AMPA receptor antagonist,1 isundergoing clinical evaluation by Eisai for its effect onpartial seizures in patients with epilepsy. Although it hasbeen prepared on a large scale under GMP conditions;procedures for its preparation are only found scatteredamong various patents. Some of the synthetic steps for alarge-scale preparation are described in United StatesPatent Application 2007/0142640.2 Since this importantcompound is not readily available for basic research stud-ies, we describe in this report a practical, laboratory-scaleprocess for the synthesis of Perampanel.

The patent literature described several alternative ap-proaches to the 1,3,5-triarylpyridin-2-one class of com-pounds. In one approach, the key intermediate was 2-(1-phenyl-5-bromopyridin-2-on-5-yl)benzonitrile (5), whichwas prepared in four steps (Scheme 1). Iodination of com-mercially available 2-amino-5-bromopyridine (1) fol-lowed by diazotization/decomposition of the resulting 2-amino-5-bromo-3-iodopyridine (2) afforded 5-bromo-3-iodopyridin-2-one (3) in quantitative yield. N-Arylationof 3 using phenylboronic acid gave 4 in 52% yield, andcoupling of 4 with 2-(2-cyanophenyl)-1,3,2-dioxabori-nate resulted in the intermediate 5 (52%).3,4 The interme-diate 5 was converted into the tri-n-butylstannanederivative 6 that was coupled, without isolation, to 2-chlo-ropyridine to afford Perampanel (7) in an overall yield of12.5%.3

Alternatively, Perampanel was synthesized via the keysynthetic intermediate 3-(2-cyanophenyl)-5-(2-pyridyl)-2-methoxypyridine (12) (Scheme 2). The details for allthe steps in the synthesis of this intermediate are not avail-able, but it appears that 12 was prepared by treatment ofcommercially available 2,5-dibromopyridine (8) with so-

dium methoxide followed by coupling of with 2-tri-n-bu-tylstannylpyridine (44.6%), bromination with N-bromosuccinimide (79%),3,4 and conversion of the result-ing 3-bromo-5-(2-pyridyl)-1,2-dihydropyridin-2-one (10)into the corresponding methyl ether 11. We have been un-able to find the details for the conversion of 10 into 11;however, such conversions are usually carried out in ac-ceptable yield using diazomethane or iodomethane. Cou-pling of 3-bromo-5-(2-pyridyl)-2-methoxypyridine (11)with 2-(2-cyanophenyl)-1,3,2-dioxaborinate gives the keyintermediate 12 (66%) (Scheme 2).3,4 Hydrolysis of themethyl ether 12 to the dihydropyridone 13 (61%) fol-lowed by coupling with phenylboronic acid proceeds in43% yield3,4 and affords Perampanel in 6% overall yield,assuming a quantitative yield for conversion of the pyri-done 10 into the methyl ether 11.

The most promising approach to the preparation of 7 ap-peared to us to be via 1-phenyl-3-(pyridin-2-yl)pyridin-2-one (18). This key intermediate was reported to have beenprepared by treatment of commercially available 2,5-di-bromopyridine (8) with sodium methoxide (95%),5–7 con-version of the resulting 5-bromo-2-methoxypyridine (14)into the corresponding 2-methoxypyridin-5-ylboronicacid (15) (88%),8–10 coupling of 15 with 2-bromopyridine(87%),11 followed by hydrolysis to 5-pyridin-2-yl-2(1H)pyridone (17) (60%),12 and N-arylation with phe-nylboronic acid (68%)13 (Scheme 3). Alternatively, 5-bro-mo-2-methoxypyridine (14) was coupled to 2-tri-n-butylstannylpyridine, hydrolyzed to the ketone 17(69%),3,4 and then N-arylated with phenylboronic acid(68%)13 (Scheme 3). Treatment of intermediate 18 withN-bromosuccinimide gave 3-bromo-5-pyridin-2-yl-2(1H)pyridone (19) (81–86%)13 that was coupled to 2-(1,3-dioxaborina-2-yl)benzonitrile (65–82%)13 to givePerampanel (7) in 17–23% overall yield.

Our preparation, carried out without optimization of anyof the steps, followed the latter approach with some mod-ifications (Scheme 4). Specifically, we opted to prepare 5-pyridin-2-yl-2(1H)pyridone (17) by coupling of 5-bromo-2-methoxy pyridine (14) with 2-tri-n-butylstannylpyri-dine instead of proceeding via 2-methoxypyridin-5-ylbo-ronic acid (15, cf. Scheme 3), and we combined the firstfour steps in Scheme 3 to shorten the synthesis from a seven-step to a four-step reaction sequence. In addition, wemodified the industrial methodology reported for the N-arylation step to be practical for laboratory scale. Thus, 5-pyridin-2-yl-2(1H)pyridone (17) was prepared in one stepby reacting 2,5-dibromopyridine (8) with sodium methox-ide to give 5-bromo-2-methoxypyridine (14) (86%) that

58 C. J. McElhinny Jr. et al. PAPER

Synthesis 2012, 44, 57–62 © Thieme Stuttgart · New York

was coupled, without purification, with 2-tri-n-butylstan-nylpyridine in the presence of tetrakis(triphenylphos-phine)palladium(0), followed by treatment of 16 with48% hydrobromic acid (42%). The 1H NMR spectrum of17 isolated from this reaction sequence matched exactly tothe patent description.12 While the reported industrial pro-cess for the N-arylation of 5-pyridin-2-yl-2(1H)pyridone(17) utilized triphenylboroxine and required a mixture ofair, nitrogen, and oxygen of very specific proportions, aswell as carefully adjusted temperatures,13 an earlier patentdescribed carrying out the N-arylation of 17 in 68% yieldusing phenylboronic acid and bubbling air through the re-action mixture at a rate of 2 L/min.3 This latter procedurewas followed by bubbling air through a solution of puri-fied 5-pyridin-2-yl-2(1H)pyridone (17) and phenylboron-ic acid containing cupric acetate to produce 18 in 79%isolated yield. The 1H NMR spectrum of the isolated 18was in complete agreement with the spectral data given inthe patent.3 Bromination of the resulting 1-phenyl-5-pyri-din-2-yl-2(1H)pyridone (18) with N-bromosuccinimidegave 3-bromo-1-phenyl-5-pyridin-2-yl-2(1H)pyridone

(19) (99%) with an 1H NMR spectrum identical to thepatent description.3 Suzuki coupling of 19 with 2-(1,3-di-oxaborina-2-yl)benzonitrile proceeded to give Perampanel(7) in 69% isolated yield; starting material 19 was alsorecovered (25%) leading to 91% conversion. Overall, thisunoptimized procedure affords Permapanel in four stepswith a 26% overall yield.

The patent literature describes extensive purification pro-cedures for Perampanel but points out that, even afterthese procedures, the sample retains palladium (15ppm).13 Trace-metal contamination has been recognizedas being a common by-product of organic transformationsutilizing metal complexes. The product prepared by ourprocedure had appearance and 1H NMR matching the datareported in the patent literature,14,15 correct molecularweight (high-resolution MS), and appeared pure by TLC,HPLC, and NMR analysis. However, the sample failed togive a satisfactory elemental analysis. Metal content anal-ysis showed our sample of Perampanel to contain 39 ppmof palladium. In addition, qualitative ICP-MS scan in the

Scheme 1 Literature3,4 preparation of Perampanel (7) via 2-(1-phenyl-5-bromopyridin-2-on-5-yl)benzonitrile (5)

N NH2

Br

N NH2

Br I

NH

O

Br I

N O

Br I

Cu(OAc)2, Et3N

N O

Br

N

N O

Bu3Sn

N

N O

N

N

HIO4, I2 NaNO2, NaOH

B(OH)2

BOO

N

[(n-Bu)2Sn]2(Ph3P)4Pd

N Cl

1 23

456

7

Cs2CO3

52%

52%

46% over 2 steps

ref. 3,4 ref. 3,4

100% overall

ref. 3,4

ref. 3

ref. 3ref. 3,4

(Ph3P)4Pd

PAPER Laboratory-Scale Synthesis of Perampanel 59

© Thieme Stuttgart · New York Synthesis 2012, 44, 57–62

element mass ranges from beryllium through uranium, in-dicated the presence of iodine as well as of trace amounts(<10 ppm) of other elements.

In summary, we have carried out the preparation ofPerampanel on a gram-amount scale by piecing togetherinformation gleaned from several patents. This approach,carried out without any attempts at optimization, gavePerampanel in 24% overall yield. The synthetic protocolutilizes readily available, relatively inexpensive startingmaterials, involves four steps, and includes only two chro-matographic purifications.

Melting points were determined on either a Thomas-Hoover capil-lary tube apparatus or on a Fisher-Johns Model 12-144 meltingpoint apparatus. TLC was carried out using Merck silica gel 60F254TLC plates; visualization was under UV or in an I2 chamber, as ap-propriate. Flash chromatography was conducted on silica gel 60 (40mM). HPLC analyses were carried out on a system comprised of twoVarian ProStar Pumps Model 210 equipped with Degasys modelDG-2410 degasser, a Rheodyne Model 7725i Injector, and a VarianProStar 335 Detector; the system was controlled using Varian StarVersion 6.41. NMR spectra were determined on a Bruker Avance300 MHz NMR spectrometer. High-resolution mass spectral analy-sis was performed at the Mass Spectrometry Facility in the Depart-ment of Chemistry and Biochemistry at the University of SouthCarolina on a Waters Q-Tof 1 quadrupole time-of-flight mass spec-trometer. The ionization mode was electrospray operated in the pos-itive ion mode. The mass reference ions were generated with

sodium trifluoroacetate. The infusion solvent was a 50:50 mix ofH2O–MeCN and 0.1% formic acid. Microanalyses were carried outby Atlantic Microlab, Inc.

5-Pyridin-2-yl-2(1H)pyridone (17)A solution of 2,5-dibromopyridine (8; 22.22 g, 0.094 mol) in 28%methanolic NaOMe (195 mL) was stirred under N2 at 60 °C for 3 h.The reaction mixture was cooled to r.t., poured into H2O (175 mL),and extracted with Et2O (500 mL). The extract was washed withbrine (3 × 100 mL), dried (MgSO4), filtered, and evaporated to give14 as a very pale yellow liquid (15.15 g, 86%).

14: 1H NMR (300 MHz, CDCl3): d = 3.91 (s, 3 H, OCH3), 6.67 (dd,J = 8.8, 0.6 Hz, 1 H, H-3), 7.64 (dd, J = 8.8, 2.6 Hz, 1 H, H-4), 8.20(d, J = 2.4 Hz, 1 H, H-6).

This liquid was dissolved in DMF (110 mL), and (Ph3P)4Pd (1.112g) and tri-n-butyl-(2-pyridyl)tin (50 g, 0.136 mol) were added. Themixture was stirred for 3 h at 120 °C under N2, allowed to cool tor.t., and poured into H2O (200 mL). The mixture was extracted withEt2O (550 mL), and the extract was washed sequentially with sat. aqNaHCO3 (400 mL) and brine (400 mL). The amber liquid fromevaporation of the volatiles was dissolved in 48% aq HBr (45 mL),and the mixture was stirred at 110 °C for 3 h. After allowing themixture to cool to r.t., the solution was washed with Et2O (200 mL).The aqueous phase was poured into ice (175 mL), the pH was ad-justed to 11.0 with 5 N aq NaOH, and the solution was washed withEt2O (200 mL). The pH of the aqueous phase was adjusted to 7.0,and the solution was extracted with CH2Cl2 (3 × 200 mL). The com-bined extracts were dried (Na2SO4) and evaporated, leaving 17 as asolid. Column chromatography (SiO2, 100% CHCl3 using a gradi-ent of 0 → 5% MeOH) gave 17 as an off-white solid (5.85 g, 36%

Scheme 2 Literature3,4 preparation of Perampanel (7) via 3-(2-cyanophenyl)-5-(2-pyridyl)-2-methoxypyridine (12)

N Br

Br

NH

O

N O

N

N

NH

O

N

N

N

NH

O

NBr

N OMe

NBr

N OMe

N

N

TMSCl, NaI

89

101112

13

N SnBu3

N OMe

Br

7

?

BOO

N

B(OH)3

Cu(OAc)2, Et3N

NaOMe (Ph3P)4Pd

NBS

(Ph3P)4Pd

Cs2CO3

44.6% overall

79%

100%(assumed)

66%

61%

43%

ref. 3,4 ref. 3,4

ref. 3,4

ref. 3,4

ref. 3,4

ref. 3,4

60 C. J. McElhinny Jr. et al. PAPER

Synthesis 2012, 44, 57–62 © Thieme Stuttgart · New York

yield from 8); Rf = 0.30 (SiO2, CHCl3–MeOH–concd NH4OH,80:18:2) 1H NMR (300 MHz, CDCl3): d = 6.71 (d, J = 9.5 Hz, 1 H), 7.20 (m,1 H), 7.51 (d, J = 7.9 Hz, 1 H), 7.73 (t, J = 7.9 Hz, 1 H), 8.12–8.19(m, 2 H), 8.61–8.62 (m, 1 H), 12.34 (br s, 1 H, NH).12

1-Phenyl-5-pyridin-2-yl-2(1H)pyridone (18)A mixture of 17 (5.50 g, 0.032 mol), phenylboronic acid (7.8 g,0.064 mol), Cu(OAc)2 (0.584 g, 0.0032 mol), pyridine (5.2 mL),and DMF (45.6 mL) was stirred while bubbling air through it at aflow rate of 500 mL/min. The reaction was monitored by TLC(SiO2; CHCl3–MeOH–concd NH4OH, 90:9:1) to confirm completeconsumption of 17. After 16 h, the reaction was complete. The mix-ture was poured into 10% aq ammonia (110 mL), and the resultingmixture was stirred vigorously for 1 h. The precipitated solid wascollected by filtration and washed thoroughly with H2O leaving 18as a light brown solid that was dried under vacuum (5.65 g, 71%).The filtrate was extracted with CHCl3 (3 × 50 mL). The pooled ex-tracts were dried (Na2SO4), filtered, and concentrated in vacuo, giv-ing a dark brown oil. The oil was passed through a silica plug(gradient elution; CHCl3–MeOH, 100:0 to 95:5) giving additional18 as a brown solid (0.680 g, 8%); Rf = 0.74 (SiO2, CHCl3–MeOH–concd NH4OH, 80:18:2).1H NMR (300 MHz, CDCl3): d = 6.78 (d, J = 9.6 Hz, 1 H), 7.19(ddd, J = 7.5, 4.9, 1.0 Hz, 1 H), 7.42–7.48 (m, 3 H), 7.49–7.55 (m,3 H), 7.72 (ddd, J = 15.5, 7.7, 1.8 Hz, 1 H), 8.04 (dd, J = 9.6, 2.7 Hz,1 H), 8.21 (d, J = 2.5 Hz, 1 H), 8.57–8.59 (m, 1 H).3

MS: m/z = 249.1 (MH+).

3-Bromo-1-phenyl-5-pyridin-2-yl-2(1H)pyridone (19)After stirring at r.t. for 4 h, a solution of 18 (6.00 g, 0.024 mol) andNBS (4.73 g, 0.027 mol) in DMF (5 mL) was poured into H2O (25mL) that was cooled in an ice bath. A precipitate was formed imme-diately, and the mixture was stirred for 1 h. The solid was collectedby filtration and washed thoroughly with H2O, affording 19 as alight brown solid. The solid was dissolved in CHCl3 (100 mL), theresulting layer of H2O was removed, and the CHCl3 was concentrat-ed in vacuo to give 7.80 g of 19 (99%); Rf = 0.65 (SiO2, EtOAc–hex-ane–MeOH–concd NH4OH, 6:3:1:several drops). 1H NMR (300 MHz, CDCl3): d = 7.20–7.24 (m, 1 H) 7.43–7.55 (m,6 H), 7.74 (ddd, J = 15.5, 7.8, 1.7 Hz, 1 H), 8.20 (d, J = 2.4 Hz, 1H), 8.51 (d, J = 2.4 Hz, 1 H), 8.59–8.60 (m, 1 H).3

MS: m/z = 327.3 (MH+), 329.2.

Perampanel (7)A mixture of 19 (2.64 g, 0.008 mol), 2-(1,3-dioxaborina-2-yl)ben-zonitrile (3.12 g, 0.167 mol), Pd(OAc)2 (37.3 mg, 0.166 mmol),Ph3P (174.2 mg, 0.664 mmol), CuI (79 mg, 0.415 mmol), andK2CO3 (1.6 g, 0.012 mol) in 1,2-dimethoxyethane (36 mL) wasstirred and heated to 70 °C under N2 atmosphere. After 30 min, theoil bath temperature was raised to 95 °C, and the mixture was re-fluxed for 5 h. EtOAc (30 mL) was added to the reaction mixture at70 °C, and the mixture was stirred for 10 min. The mixture was fil-tered, and the solid residue was washed with EtOAc (30 mL). Thefiltrate was combined with 12.5% aq ammonia (60 mL), and the so-lution was stirred at 60 °C for 50 min. The aqueous phase was re-moved, and the organic phase was washed with aq 5% NaCl (30

Scheme 3 Literature2,5–10,12 preparation of Perampanel (7) via 1-phenyl-3-(pyridin-2-yl)pyridin-2-one (18)

N Br

Br

N OMe

Br

N OMe

N

NH

O

NN O

N

N O

NBr

N O

N

N

N OMe

(HO)2B

8 14 15

N Br

B(OH)2

1. BuLi2. B(Oi-Pr)33. NaOH

87%

BOO

N

Ph3P, Pd(OAc)2, CuI65–82%ref. 13

161718

19 7

N SnBu3

NaOMe

(Ph3P)4Pd

(Ph3P)4Pd

HBr

NBS

95% 88%

60–69%ref. 10

81–86%

78%

ref. 5–7 ref. 8–10

ref. 3,4

ref. 11

(Ph3P)4Pd68%

ref. 13

ref. 13

PAPER Laboratory-Scale Synthesis of Perampanel 61

© Thieme Stuttgart · New York Synthesis 2012, 44, 57–62

mL), concd NH4OH (60 mL), and aq 5% NaCl (60 mL). The organ-ic extract was concentrated in vacuo to give a yellow solid (3.32 g).Column chromatography (SiO2, EtOAc–hexanes, 1:2) afforded 7 asa light yellow solid14,15 (1.91 g, 69%). Based on recovery of unre-acted starting material 19 (0.71 g), the yield was 91%.The elementalanalysis was not in agreement with the calculated values. Palladiumanalysis showed 7 to contain 0.0039% Pd (see below); mp 175–176 °C; Rf = 0.68 (SiO2, CHCl3–MeOH–concd NH4OH, 90:9:1),Rf = 0.12 (SiO2, EtOAc–hexane, 1:1).

HPLC: Gemini-NX C18 2 × 50 mm, 3 mm, 80 → 90% A over 10min with a 10 min hold at 90%. A: H2O w/0.1% NH4OH; B: MeCN1.0 mL/min; l 290 nm; tR = 5.66 min; >99% purity. 1H NMR (300 MHz, DMSO-d6): d = 7.29–7.33 (m, 1 H), 7.48–7.62(6 H, m), 7.72–7.88 (3 H, m), 7.94 (1 H, d, J = 7.7 Hz), 8.02 (1 H,d, J = 8 Hz), 8.49 (1 H, d, J = 2.5 Hz), 8.55 (1 H, d, J = 2.5 Hz),8.59–8.60 (1 H, m).14,15 13C NMR (75.5 MHz, DMSO-d6): d = 72.17, 112.05, 117.13,118.18, 119.06, 122.12, 126.83, 128.54, 128.66, 129.17, 130.89,132.86, 132.93, 137.24, 138.28, 138.57, 140.42, 140.83, 149.31,152.25, 159.44.

HRMS: m/z calcd for C23H15N3O (MH+): 350.1293; found:350.1299.

Palladium AnalysisAn aliquot (100 mg) of 7 was subjected to charring with high-purityH2SO4 in a MARS-5 microwave oven. The sample was then digest-ed in a closed Teflon vessel in the presence of high-purity HNO3

and H2O2. After the microwave digestion procedure was completed,the sample was brought to a final 25 mL volume with ~18 MW qual-ity deionized H2O after the addition of an ICP-MS internal standardsolution. The digested study sample was analyzed for Pd content us-ing a Thermo X-Series II ICP-MS and, since the Pd concentrationof the sample exceeded that of the highest calibration standard, thesample was diluted five-fold, keeping the acid digestion matrix andinternal standard concentration the same. The analysis showed0.039 mg of Pd/g of 7 (0.0039%).

Metal Content AnalysisThe digested sample of 7 (see above) was also subjected to qualita-tive ICP-MS scan in the element mass ranges from Be through U,skipping only the region impacted by the presence of argon from theplasma discharge. This scan confirmed the presence of Pd, suggest-ed the presence of I2, and the presence of several other elements attrace (<10 ng/mL as measured) elements. It was not possible to es-timate the concentration of I2 because acid digestion is not compat-ible with quantitative I2 measurements by ICP-MS.

Scheme 4 Optimized synthesis of Perampanel (7)

N Br

Br

N OMe

Br28% NaOMe in MeOH

N OMe

N

NH

O

N

N O

N

N O

NBr

N O

N

N

8 14

Sn(Bu)3

16

17

1819

7

BN

48% HBr

B(OH2

Ph3PPd(OAc)2CuI

OO

(Ph3P)4Pd

Cu(OAc)2NBS

79%

99%

91%

36% overall

62 C. J. McElhinny Jr. et al. PAPER

Synthesis 2012, 44, 57–62 © Thieme Stuttgart · New York

Acknowledgment

The work described was supported in part by the National Instituteon Drug Abuse (project N01DA-8-7763).

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