Organic Process Research & Development 1999, 3, 10−16
Oxidative Chlorination, Desulphonation, or Decarboxylation To Synthesize
Pharmaceutical Intermediates: 2,6-Dichlorotoluene, 2,6-Dichloroaniline, and
2
,6-Dichlorophenol
S. Mukhopadhyay and S. B. Chandalia*
Department of Chemical Technology, UniVersity of Mumbai, Matunga, Mumbai-400 019, India
Abstract:
Scheme 1. Oxidative chlorination, decarboxylation, or
desulphonation to synthesize pharmaceutical intermediates
An alternative manufacturing process scheme was developed
for 2,6-dichlorotoluene, 2,6-dichloroaniline, and 2,6-dichlo-
rophenol, involving oxidative chlorination after protection of
the starting material in the para position followed by depro-
tection involving desulphonation or decarboxylation. Oxidative
chlorination of 4-methylbenzenesulphonic acid, 4-methylbenzoic
acid, 4-aminobenzoic acid, and 4-hydroxybenzoic acid by using
2 2
HCl-H O , and their subsequent desulphonation or decar-
boxylation, gave a 60-75% yield of the desired product.
Introduction
2,6-Dichloro-substituted compounds have great relevance
in process industries as intermediates for fine chemicals and
pharmaceuticals. In general, these are synthesized by direct
chlorination of the reactant. But there is always a chance
of getting a mixture of chloro-substituted products, from
which the separation of the desired product itself is a
problem. Chlorine gas is usually used for chlorination. HCl-
H
2
O
2
can also be used by adding hydrogen peroxide in a
Experimental Section
1
2
semibatch manner. Trifluoroacetic acid is used as the
Oxidative Chlorination. The experiments were carried
out in a 250-mL borosilicate glass reactor equipped with a
six-blade turbine impeller, four baffles, a dropping funnel,
and a water condenser. The outgoing gases were passed
through a caustic scrubber. The assembly was kept in a
constant-temperature bath.
2 2
solvent. Oxygen can also be used directly with H O in the
presence of different types of catalysts.3
-5
In this work,
4
-methylbenzenesulphonic acid, 4-methylbenzoic acid, 4-
aminobenzoic acid, and 4-hydroxybenzoic acid were chlo-
rinated by using HCl-H in a less expensive solvent such
2 2
O
as water or acetic acid. 3,5-Dichloro-4-methylbenzenesul-
A predetermined quantity of substrate and 35% hydro-
chloric acid were dissolved in the solvent, and the reaction
mixture was kept at the desired temperature. A measured
quantity of 30% hydrogen peroxide was added dropwise to
the reaction mixture over a predetermined period of time,
maintaining the desired temperature within the specified
range. For 4-methylbenzenesulphonic acid, the reaction
mixture was directly taken for the desulphonation step
without isolation. In the case of benzoic acids, after the
stipulated reaction period, the reaction mixture was cooled
and then filtered to remove the precipitated products. The
products were then dried and taken for the decarboxylation
step.
phonic acid (DCMBSA) was desulphonated in sulphuric acid.
6
7
Hydrochloric acid or phosphoric acid can also be used.
Decarboxylation of aromatic acids can be done under various
8
-12
conditions.
acids were decarboxylated to obtain the desired products
Scheme 1).
In this work, dichloro-substituted aromatic
(
(
(
(
(
(
(
(
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1
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1
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(
(
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Vol. 3, No. 1, 1999 / Organic Process Research & Development
10.1021/op9800515 CCC: $18.00 © 1999 American Chemical Society and Royal Society of Chemistry
Published on Web 11/14/1998