Convenient synthesis of tolcapone, a selective catechol-O-methyltransferase inhibitor

Article abstract of DOI:10.1080/00397910701821077

A convenient and efficient synthesis of tolcapone from commercial 4-benzyloxy-3-methoxybenzaldehyde is presented. Grignard reaction of 4-benzyloxy-3-methoxybenzaldehyde (1) with p-tolylmagnesium bromide followed by Oppenauer oxidation of the hydroxyl func

Full text of DOI:10.1080/00397910701821077

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Convenient Synthesis of Tolcapone, a
Selective Catechol‐O‐methyltransferase
Inhibitor
Govindarajan Manikumar a , Chunyang Jin a & Kenneth S. Rehder a
a Organic and Medicinal Chemistry, Science and Engineering Group ,
Research Triangle Institute , North Carolina, USA
Published online: 15 Feb 2008.
To cite this article: Govindarajan Manikumar , Chunyang Jin & Kenneth S. Rehder (2008) Convenient
Synthesis of Tolcapone, a Selective Catechol‐O‐methyltransferase Inhibitor, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:5, 810-815, DOI:
10.1080/00397910701821077
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Synthetic Communicationsw, 38: 810–815, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701821077
Convenient Synthesis of Tolcapone,
a Selective Catechol-O-methyltransferase
Inhibitor
Govindarajan Manikumar, Chunyang Jin, and
Kenneth S. Rehder
Organic and Medicinal Chemistry, Science and Engineering Group,
Research Triangle Institute, North Carolina, USA
Abstract: A convenient and efficient synthesis of tolcapone from commercial
4-benzyloxy-3-methoxybenzaldehyde is presented. Grignard reaction of 4-benzyloxy-
3-methoxybenzaldehyde (1) with p-tolylmagnesium bromide followed by Oppenauer
oxidation of the hydroxyl functionality and subsequent O-debenzylation gave phenol
5. Compound 5 was regioselectively nitrated and then subjected to O-demethylation to
produce tolcapone in 60% overall yield.
Keywords: catechol-O-methyltransferase, nitration, tolcapone
INTRODUCTION
Tolcapone is a highly potent and selective peripheral and central
catechol-O-methyltransferase (COMT) inhibitor used as an adjunct to the
levodopa/carbidopa medication of Parkinson’s disease, a dopamine-
deficiency disorder.[1] Tolcapone potentiates and prolongs the effect of
levodopa in the central nervous system (CNS) by enhancing levodopa’s
transport into the CNS and slowing the metabolism of brain dopamine.
Unfortunately, because of concerns about its liver toxicity, tolcapone was
recently withdrawn from the market in some countries.[2] The cause of
Received in the USA September 14, 2007
Address correspondence to Kenneth S. Rehder, Organic and Medicinal Chemistry,
Science and Engineering Group, Research Triangle Institute, P. O. Box 12194,
Research Triangle Park, NC 27709, USA. E-mail: krehder@rti.org
810

Synthesis of Tolcapone
811
tolcapone’s liver toxicity is currently not fully understood. To further
investigate the mechanism of tolcapone’s toxicity and obtain a more
potent, selective, and safe COMT inhibitor, tolcapone and its 3-nitro-
catechol-based derivatives continue to be investigated.[3]
The synthesis of tolcapone was first reported in a patent by Bernauer et al.[4]
However, their synthesis involved a low-temperature reaction (2708C for
addition of p-tolyl-lithium to 4-benzyloxy-3-methoxybenzaldehyde) and
toxic (e.g., pyridinium chlorochcamate (PCC) for oxidation) and corrosive
(e.g., HBr for O-dealkylation) reagents, which are neither environmentally
friendly nor suitable for large-scale preparation. In addition, the experimental
details and characterization data of key intermediates, as well as tolcapone,
were not well reported.[4] In this article, an efficient, economical, and environ-
mentally acceptable synthesis of tolcapone from commercially available
4-benzyloxy-3-methoxybenzaldehyde is described. The full characterization
data of all intermediates and tolcapone are also presented for future comparison.
RESULTS AND DISCUSSION
Synthesis of tolcapone was accomplished following the route outlined in
Scheme 1. Treatment of commercial 4-benzyloxy-3-methoxybenzaldehyde
(1)[5] with p-tolylmagnesium bromide (2) in tetrahydrofuran (THF) at 08C
gave the Grignard adduct 3 in 91% yield. Oppenauer oxidation[6] of 3 using
sodium tert-butoxide as the base and cylcohexanone as a hydrogen acceptor
afforded an 89% yield of ketone 4. This Oppenauer oxidation is more con-
venient than PCC oxidation[4] both in terms of operational simplicity and
use of inexpensive and nontoxic reagents. Palladium-catalyzed deprotection
Scheme 1.

812
G. Manikumar, C. Jin, and K. S. Rehder
of the benzyl protecting group using ammonium formate as a hydrogen donor
provided phenol 5 in 92% yield. Regioselective nitration of 5 was first tried
following the literature procedure.[4] However, addition of 70% nitric acid to
the solution of 5 in acetic acid at room temperature gave only a small
1
amount of desired product 6, along with other unidentified by-products. H
NMR analysis of the major by-product suggested that it was a dinitrated
compound, but a full characterization of this by-product was not conducted
to confirm its structural assignment. The nitric acid addition was observed to
generate a significant amount of heat, possibly contributing to the low yield
and by-product profile. Therefore, the procedure was modified by using a
lower reaction temperature (08C) and a more dilute nitric acid solution. As a
result of these modifications, the nitro compound 6 was obtained in 88%
yield after recrystallization from ethanol.
According to the procedure of Bernauer et al.,[4] the methyl ether cleavage
was achieved with moderate yield under standard forcing conditions (48%
HBr, acetic acid, and reflux). Recently, Learmonth and coworkers[7] have
reported an improved O-demethylation of nitro catechol methyl ethers using
aluminum chloride and pyridine in warm ethyl acetate, which is suitably
mild and appropriate for large-scale demethylation of 6. Accordingly,
treatment of 6 with aluminum chloride and pyridine in ethyl acetate at
reflux for 2 h furnished tolcapone (7) in 91% yield.
In summary, we have developed an efficient and economical synthesis of
tolcapone in 60% overall yield from commercial 4-benzyloxy-3-methoxyben-
zaldehyde (1). No column purifications were needed for this synthesis. Our
synthesis of tolcapone is potentially applicable to other biologically active
3-nitrocatechol analogues.
EXPERIMENTAL
Reagents were obtained from Aldrich Chemical Company and used as received.
Melting points were determined on a Mel-Temp II capillary melting-point
apparatus and are uncorrected. NMR (1H and 13C) spectra were obtained
using a Bruker Avance DPX 300-MHz or a Varian Unity Inova 500-MHz
NMR spectrometer. Chemical shifts are reported in parts per million (ppm)
with reference to internal solvent. Mass spectra (MS) were recorded on a
Perkin-Elmer Sciex APR 150 EX mass spectrometer. Elemental analysis was
done by Atlantic Microlab, Inc., Norcross, GA. Analytical thin-layer chromato-
graphy (TLC) was carried out using EMD silica-gel 60 F254 TLC plates.
1-(4-Benzyloxy-3-methoxyphenyl)-1-(4-methylphenyl)methanol (3)
A solution of 4-benzyloxy-3-methoxybenzaldehyde (1) (30.0 g, 0.12 mol)
in THF (120 mL) was slowly added to a stirred 1 M solution of

Synthesis of Tolcapone
813
p-tolylmagnesium bromide (2) (150 mL, 0.15 mol) in THF at 08C under
nitrogen. After being stirred at room temperature for 1 h, the reaction
mixture was concentrated in vacuo. The residue was dissolved in Et2O
(450 mL) and cooled to 08C, and a 2 N HCl solution (50 mL) was carefully
added. The phases were separated, and the aqueous phase was extracted
with Et2O (100 mL). The combined organic extract was washed with brine
(100 mL), dried, (Na2SO4), and concentrated in vacuo. The resultant crude
product was recrystallized from CH2Cl2–petroleum ether to give 3 (37.6 g,
91% yield) as a white solid: mp 101–1038C (lit.[4] oil); 1H NMR
(300 MHz; CDCl3) d 2.19 (1H, d, J ¼ 3.5 Hz), 2.32 (3H, s), 3.84 (3H, s),
5.11 (2H, s), 5.72 (1H, d, J ¼ 3.5 Hz), 6.79–7.42 (12H, m); 13C NMR
(75 MHz; DMSO-d6) d 20.9, 55.8, 70.4, 74.2, 110.8, 113.8, 118.6, 126.4,
128.0, 128.1, 128.4, 128.7, 128.8, 129.2, 135.9, 137.6, 139.3, 143.2, 146.9,
149.2.
1-(4-Benzyloxy-3-methoxyphenyl)-1-(4-methylphenyl)methanone (4)
Sodium tert-butoxide (11.7 g, 0.12 mol) was added to a stirred suspension of 3
(26.0 g, 0.08 mol) in toluene (350 mL) at room temperature under nitrogen,
followed by cyclohexanone (47.7 g, 0.49 mol). After being refluxed for 1 h,
the reaction mixture was cooled to 508C, and H2O (60 mL) was slowly
added with stirring. The phases were separated, and the aqueous phase was
extracted with EtOAc (60 mL). The combined organic extract was washed
with brine (100 mL), dried, (Na2SO4), and concentrated in vacuo. The
resultant crude product was recrystallized from 95% EtOH (75 mL) to give
1
4 (23.1 g, 89% yield) as a white solid: mp 70–728C (lit.[4] 79–818C); H
NMR (300 MHz; CDCl3) d 2.43 (3H, s), 3.94 (3H, s), 5.23 (2H, s), 6.88–
7.68 (12H, m); 13C NMR (75 MHz; CDCl3) d 23.3, 56.1, 70.8, 112.0,
112.7, 125.0, 127.2, 128.0, 128.6, 128.8, 130.0, 130.8, 131.5, 135.4, 136.4,
142.6, 149.4, 152.0, 195.4; MS (ESI) m/z 333.5 [M þ H]þ.
1-(4-Hydroxy-3-methoxyphenyl)-1-(4-methylphenyl)methanone (5)
A mixture of 4 (19.5 g, 0.06 mol), 10% Pd-C (1.00 g), and ammonium formate
(17.6 g, 0.28 mol) in MeOH (200 mL) was refluxed under nitrogen for 30 min.
After being cooled to 08C, H2O (70 mL) and concentrated HCl (20 mL) were
slowly added, followed by additional H2O (80 mL) and CH2Cl2 (300 mL).
The mixture was filtered through a short pad of Celitew, and the filter cake
was washed with CH2Cl2 (60 mL). The organic phase of the filtrate was
separated, washed with brine (100 mL), dried, (Na2SO4), and concentrated
in vacuo. The resultant crude product was recrystallized from CH2Cl2–
petroleum ether to give 5 (13.0 g, 92% yield) as a white solid: mp
1
98–1008C (lit.[4] 103–1058C); H NMR (300 MHz; CDCl3) d 2.43 (3H, s),

814
G. Manikumar, C. Jin, and K. S. Rehder
3.94 (3H, s), 6.24 (1H, br s), 6.93 (1H, d, J ¼ 8.2 Hz), 7.28–7.35 (3H, m), 7.49
(1H, s), 7.67 (2H, d, J ¼ 8.2 Hz); 13C NMR (75 MHz; CDCl3) d 21.6, 56.1,
111.9, 113.5, 126.3, 128.8, 129.0, 129.1, 135.5, 142.5, 146.6, 149.9, 195.3;
MS (ESI) m/z 243.4 [M þ H]þ.
1-(4-Hydroxy-3-methoxy-5-nitrophenyl)-1-(4-methylphenyl)
methanone (6)
A mixture of 70% HNO3 (1.5 mL) and acetic acid (2 mL) was slowly added to a
stirred solution of 5 (2.40 g, 0.01 mol) in acetic acid (20 mL) at 08C under
nitrogen. After being stirred at 08C for 30 min, the reaction mixture was
poured into ice water. The resultant precipitate was collected by filtration and
washed with cold H2O. The crude product was recrystallized from EtOH to
give 6 (2.50 g, 88% yield) as a white solid: mp 135–1378C (lit.[4] 137–
1398C); 1H NMR (300 MHz; CDCl3) d 2.47 (3H, s), 4.03 (3H, s), 7.33 (2H, d,
J ¼ 8.0 Hz), 7.69 (2H, d, J ¼ 8.0 Hz), 7.71 (1H, d, J ¼ 1.5 Hz), 8.10 (1H, d,
J ¼ 1.5 Hz); 13C NMR (75 MHz; DMSO-d6) d 21.4, 57.0, 115.6, 119.6, 127.3,
129.1, 129.5, 129.7, 129.9, 134.3, 136.5, 143.4; MS (ESI) m/z 288.4 [M þ H]þ.
1-(3,4-Dihydroxy-5-nitrophenyl)-1-(4-methylphenyl)methanone
(Tolcapone) (7)
AlCl3 (3.50 g, 0.026 mol) was added to a stirred suspension of 6 (6.00 g,
0.021 mol) in EtOAc (60 mL) at room temperature under nitrogen, followed
by pyridine (6.60 g, 0.084 mol). The red solution was refluxed for 2 h and
then cooled to 608C, whereupon the reaction mixture was carefully added to
a mixture of ice and concentrated HCl (24 mL). After being stirred at 508C
for 1 h, the mixture was kept in the refrigerator overnight. The resultant pre-
cipitate was collected by filtration, washed with cold H2O, and dried in vacuo
for 10 h at 608C to give 7 (5.20 g, 91% yield) as a yellow solid: mp 141–
1
1438C (lit.[4] 146–1488C); H NMR (500 MHz; DMSO-d6) d 2.42 (3H, s),
7.37 (2H, d, J ¼ 8.0 Hz), 7.47 (1H, d, J ¼ 1.5 Hz), 7.64 (2H, d,
J ¼ 8.0 Hz), 7.66 (1H, d, J ¼ 1.5 Hz); 13C NMR (75 MHz; DMSO-d6) d
21.1, 117.7, 119.1, 127.0, 129.1, 129.5, 134.2, 136.6, 142.9, 145.7, 147.7,
192.7; MS (ESI) m/z 274.5 [M þ H]þ; Anal. calcd. for C14H11NO5: C,
61.54; H, 4.06; N, 5.13. Found: C, 61.83; H, 4.05; N, 5.19.
ACKNOWLEDGMENT
This work was supported by the National Institute of Mental Health under
Contract N01-MH-32005.

Synthesis of Tolcapone
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