Improved method for demethylation of nitro-catechol methyl ethers

Article abstract of DOI:10.1081/SCC-120002413

Several nitro-catechol compounds, useful as inhibitors of COMT were obtained in excellent yield and purity via an improved procedure for demethylation of the corresponding methyl ethers using aluminium chloride and pyridine in ethyl acetate.

Full text of DOI:10.1081/SCC-120002413

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IMPROVED METHOD FOR DEMETHYLATION OF NITRO-
CATECHOL METHYL ETHERS
David A. Learmonth a & Paula C. Alves a
a Laboratory of Chemical Research, Department of Research and Development,
Laboratórios BIAL, S. Mamede do Coronado, 4745-457, Portugal
Published online: 16 Aug 2006.
To cite this article: David A. Learmonth & Paula C. Alves (2002) IMPROVED METHOD FOR DEMETHYLATION OF NITRO-
CATECHOL METHYL ETHERS, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 32:4, 641-649, DOI: 10.1081/SCC-120002413
To link to this article: http://dx.doi.org/10.1081/SCC-120002413
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SYNTHETIC COMMUNICATIONS, 32(4), 641–649 (2002)
IMPROVED METHOD FOR
DEMETHYLATION OF NITRO-
CATECHOL METHYL ETHERS
David A. Learmonth* and Paula C. Alves
Laboratory of Chemical Research, Department of
Research and Development, Laboratorios BIAL,
4745-457 S. Mamede do Coronado, Portugal
ABSTRACT
Several nitro-catechol compounds, useful as inhibitors of
COMT were obtained in excellent yield and purity via an
improved procedure for demethylation of the corresponding
methyl ethers using aluminium chloride and pyridine in ethyl
acetate.
BIA 3-202, [1-(3,4-Dihydroxy-5-nitrophenyl)-2-phenyl-ethanone] (1),
is a potent and highly selective inhibitor of the enzyme catechol-O-methyl-
transferase which is currently under clinical development for the treatment
of Parkinson’s disease.1 These clinical studies have necessitated the produc-
tion of multi-kilogramme quantities of BIA 3-202 of sufficient chemical
purity to be tested in human patients.
The original five-step synthesis starting from 4-O-benzyl vanillin (2) is
shown in Scheme 1.
*Corresponding author.
641
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

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642
LEARMONTH AND ALVES
Reagents: i. a) ArCH2Cl, Mg, Et2O/THF b) H3O+, (95%); ii. Na2Cr2O7, H2SO4,
CH2Cl2, H2O, Bu4N+BrÀ, (96%); iii. 30% HBr in AcOH, CH2Cl2, (91%); iv. 70%
HNO3, AcOH (72%); v. 48% HBr/AcOH (68%).
Scheme 1. Original synthesis of BIA 3-202.
While efficient, economical and environmentally acceptable alterna-
tive procedures for steps ii–iv were subsequently developed for scale-up
and synthesis of multi-kilogramme (1–50 kg) batches of BIA 3-202,
step v., involving cleavage of the 3-O-methyl group of the nitro-catechol
methyl ether (6) was a principal cause of concern, primarily due to
the use of large volumes of corrosive hydrobromic acid, harsh condi-
tions and the relatively low reaction yield. An operationally simple, scale-
able, cheap and high-yielding procedure for the demethylation of (6) was
sought.
The cleavage of aryl methyl ethers to liberate the corresponding
phenolic compounds has been reviewed in the literature.2–4 The apparent
simplicity of this commonly found protecting group belies its sheer rugged-
ness and organic chemists over many decades have been challenged to
develop improved methods for its removal. However, the presence of
the relatively sensitive nitro-group of the nitro catechol methyl ether (6)
precludes the use of many of the routine reagents for this transformation
and surprisingly, few methods were considered both suitably mild and
appropriate for large-scale demethylation of (6). In fact complex reaction
mixtures were obtained from the attempted demethylation of (6) with pyr-
idinium hydrochloride,5 boron tribromide,6 sodium cyanide/DMSO7 or
thiophenolate anion.8
Notwithstanding, the successful cleavage of aromatic methyl ethers
with aluminium chloride alone9 and some alkyl ortho-hydroxyphenyl

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NITRO-CATECHOL METHYL ETHERS
643
ethers such as vanillin using an aluminium chloride-pyridine mixture have
been reported.10 However, the latter reactions were usually run in dichloro-
methane and required refluxing for 24 h to achieve good conversion and
product yields. Alternative solvents utilised such as benzene, carbon tetra-
chloride, ethylene chloride and ethyl bromide must be considered unsuitable
for the production of pharmaceutical products intended for human use
(residual levels of Class 1 solvents in medicinal products are severely lim-
ited11 at ꢀ5 ppm). Of course, even for routine applications, it would be
preferable to avoid such toxic solvents.
We therefore undertook a reinvestigation of this reaction with respect
to its suitability for the large-scale demethylation of the nitro-catechol
methyl ether (6) and now report on its general utility for the demethylation
of related compounds.
Table 1 summarises the results from these experiments. Using initially
chlorinated solvents, it was found that temperature had a profound
effect on reaction rate. Whereas the reaction was incomplete in dichloro-
methane (b.p. 40ꢁC) after reflux over 24 h, the use of either 1,2-dichlor-
oethane at reflux (b.p. 83ꢁC) or 1,1,2,2-tetrachloroethane at 100ꢁC
(b.p. 147ꢁC) provided complete conversion of (6) to BIA 3-202 in 2 h
(no significant by-products or even starting material was found in the
crude product by HPLC analysis in each case indicating the ‘clean’ nature
of the reaction). The molar ratio of reactants to reagents was thereafter
investigated, and although the ratio 4 : 1.2 : 1 (pyridine : aluminium
chloride : (6)) was routinely employed, pyridine could be satisfactorily
reduced to under three molar equivalents without deleterious effect on
Table 1. Demethylation of Nitro-Catechol Ether (6) to BIA 3-202
Isolated
Yield
(%)
Purity BIA
3-202 %
(HPLC)a
B.P.
(ꢁC)
Time
(h)
Run
Solvent
1
2
3
4
5
6
7
8
Dichloromethane
1,2-Dichloroethane
1,1,2,2-Tetrachloroethane
Pyridine
Methyl ethyl ketone
Acetone
1,4-Dioxan
40
83
147
115
80
56
100
77
24
2
2
0.5
3.5
5
2
1.5
79
87
85
79
78
72
70
99
94
>99
>99
>98
>98
>98
>97
>99
Ethyl acetate
aSee Experimental section.