A new approach to the synthesis of 2,6-dichloro-3-fluorobenzonitrile: A useful pharmaceutical intermediate

Article abstract of DOI:10.3184/174751911X13129873455321

A highly efficient manufacturing-scale process for the preparation of 2,6-dichloro-3-fluorobenzonitrile, utilising industrial by-product 2,6-dichloro-3-fluoroacetophenone as starting material, has been developed. The overall yield was 77%.

Full text of DOI:10.3184/174751911X13129873455321

474 RESEARCH PAPER
AUGUST, 474–476
JOURNAL OF CHEMICAL RESEARCH 2011
A new approach to the synthesis of 2,6-dichloro-3-fluorobenzonitrile:
a useful pharmaceutical intermediate
Zhiwei Chen, Lidong Zheng and Weike Su*
Key Laboratory of Pharmaceutical Engineering of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of
Technology, Hangzhou 310014, P. R. China
A highly efficient manufacturing-scale process for the preparation of 2,6-dichloro-3-fluorobenzonitrile, utilising indus-
trial by-product 2,6-dichloro-3-fluoroacetophenone as starting material, has been developed. The overall yield was
77%.
Keywords: 2,6-dichloro-3-fluoroacetophenone, 2,6-dichloro-3-fluorobenzonitrile, synthesis
2,6-Dichloro-3-fluorobenzonitrile 1 is a useful intermediate
in the synthesis of pharmaceuticals and plant protection
agents.1 Itaru et al.2 reported a synthesis from 3-chloro-2,4-
difluoronitrobenzene in which the fluorine atom at position
2 was replaced with cyanide to give 2-chloro-3-fluoro-6-
nitrobenzonitrile and converted by chlorolysis of the nitro
group into compound 1 (Scheme 1, route 1). Hagedorn et al.1
described a process in which an isomeric mixture of 2,
4-dichloro-5-fluorotoluene and 2,6-dichloro-3-fluorotoluene
was subjected to ammoxidation with ammonia, air and steam
in the gas phase at a temperature of 550°C. The resultant
formed mixture of 2,4-dichloro-5-fluorobenzonitrile and
2,6-dichloro-3-fluorobenzonitrile was separated by reduced
pressure fractional distillation to give product 1 (Scheme 1,
route 2). Lantzsch et al.3 indicated that the target molecule
could be prepared from 1-fluoro-3-methylbenzene via a five
or seven-step synthetic route (Scheme 1, route 3). Most of these
methods have their own merits. However, each suffered either
from employing expensive catalyst, low yield, or especially
high temperature and high material pollution of the equipment
which was used thus limiting their industrial applications.
In the production of 2,4-dichloro-5-fluoroacetophenone, a
key intermediate for the preparation of the fluoroquinolone
antimicrobial agents,4 2,6-dichloro-3-fluoro acetophenone 2
is unavoidably generated as a by-product.5 This isomeric
by-product exists in the form of a mixture called “crystallisa-
tion mother liquor” mainly containing these two isomers,
obtained in the purification stage. Since there were no efficient
and economical ways to separate these two isomers because
of the tiny differences of physicochemical properties, this
“crystallisation mother liquor” was treated as industrial waste
and burned. This not only raised air pollution, but also wasted
resources. In our previous work6, the isomers were success-
fully separated chemically (Scheme 2), utilising a difference
in the reactivity of the carbonyl groups due to the steric
hindrance.
As part of our interest in developing the uses for this “crys-
tallisation mother liquor”, we now report a highly efficient and
convenient method for the preparation of 1 utilising a starting
material isolated from this industrial by-product. The synthetic
route is shown in Scheme 3.
Scheme 1
* Correspondent. E-mail: pharmlab@zjut.edu.cn.

JOURNAL OF CHEMICAL RESEARCH 2011 475
Scheme 2
Scheme 3
A conventional way for the synthesis of compound 4 could
be achieved by oxidation of 2 to a benzoic acid by an oxidant,
followed by halogenation and then ammonolysis. Unfortu-
nately, the oxidation reaction of 2 yielded the corresponding
benzoic acid in a very low yield (< 30% at best) due to lack
of selectivity, when KMnO4 was used as the oxidant. Though
the haloform reaction is effective in oxidative degradations of
methyl ketones to carboxylic acids,7,8 strongly basic conditions
are required, accompanied by a large quantity of waste water.
As a modification and simplification for preparation of 4,
we have adopted a method that involved of tri-chlorination
at the methyl group of 2, and ammonolysis of the resultant
compound 3. Satisfyingly, 3 was obtained in nearly quantita-
tive yield (98%) by treating 2 with chlorine gas in a NaOAc/
AcOH system. Moreover, 3 was smoothly transformed in
good yield (97%) into 4 by ammonolysis with ammonia gas in
ethanol which was used as a suitable green solvent.
A conventional dehydration reaction employs toxic reagents
such as POCl3 and SOCl2 that are harmful to human health
and hazardous to the environment.9 Previously, we reviewed
bis-(trichloromethyl) carbonate (BTC) as a mild, safe, easily
handled, highly efficient and environmentally benign reagent.10
It is convenient for use as a substitute for traditional reagents
such as POCl3, SOCl2, phosgene, trichloromethyl chloroformate

476 JOURNAL OF CHEMICAL RESEARCH 2011
solid (79.1 g, 97%). m.p. 181–185°C (183−186°C3). 1H NMR (DMSO-
d6) δ: 7.50(t, J = 8.8 Hz, 1H), 7.56 (dd, J = 4.8, 8.8 Hz, 1H), 7.88–8.02
(brs, 1H), 8.08–8.24 (brs, 1H). 13C NMR (DMSO-d6) δ: 117.3 (d,
J = 22 Hz), 118.0 (d, J = 20 Hz), 125.7, 129.5, 129.6, 138.7, 156.2 (d,
J = 247 Hz), 164.3. EI-MS (m/z, %): 207 (M+, 35), 191(100), 163(42),
128(19), 93(16), 74(6).
(TCF, diphosgene). Here, BTC was employed as a dehydrating
reagent with DMF as a catalyst in the conversion of 4 to 1. After
optimisation of the solvent, temperature and catalyst mole
ratio, the reaction was carried out in EtOAc between 60°C and
reflux with 20 mol% DMF, to afford 1 in a yield of 81%.
In conclusion, a highly efficient new approach to the
synthesis of 2,6-dichloro-3-fluorobenzonitrile has been devel-
oped. The attractive features of this protocol are simple reac-
tion procedure, high yield, and mild reaction conditions. As
a highlight, an industrial by-product is utilised as the starting
material, making this production method economically
advantageous and beneficial for environment- protection.
Synthesis of 2,6-dichloro-3-fluorobenzonitrile (1): Compound
4 (79.1 g, 380.3 mmol), BTC (48.9 g 164.8 mmol), and DMF (5.6 g,
76 mmol) were added to EtOAc (250 mL). The temperature was
raised to 60°C, and after completion of the reaction, the reaction mix-
ture was cooled to r.t. and washed with water until it was neutral. The
solution was then dried over Na2SO4 and evaporated under reduced
pressure to give crude product 1. Further purification by vacuum
distillation at 130°C/20 mmHg yielded 1 as white solid (58.5 g, 81%).
1
m.p. 74–75°C (70−72°C3). H NMR (CDCl3) δ: 7.39(t, J = 8.8 Hz,
Experimental
1H), 7.45 (dd, J = 4.4, 8.8 Hz, 1H). 13C NMR (CDCl3) δ: 112.4 (d,
J = 2 Hz), 115.7, 121.5 (d, J = 22 Hz), 125.8 (d, J = 21 Hz), 129.2 (d,
J = 7 Hz), 133.4 (d, J = 4 Hz), 156.9 (d, J = 251 Hz). EI-MS (m/z, %):
189 (M+, 100), 154(39), 118(13), 99(8).
1H NMR and 13C NMR spectra were measured on a Varian 400
(400 MHz) spectrometer (chemical shifts in δ ppm) using TMS as
internal standard. Mass spectra (EI-MS) were determined on a Thermo
Finnigan LCQ-Advantage. Melting points were measured on a Büchi
B-540 capillary melting point apparatus.
Received 28 July 2011; accepted 9 August 2011
Paper 100817 doi: 10.3184/174751911X13129873455321
Published online: 29 August 2011
Synthesis of α,α,α,2,6-pentachloro-3-fluoroacetophenone (3): Chlo-
rine gas was slowly bubbled into a solution of 2 (82.8 g, 400.0 mmol)
in AcOH (250 mL) in a flask equipped with a condenser while stirring
at 60°C for 5 h. The products were 2,6,α-trichloro-3-fluoroacetophe-
none and 2,6,α,α-tetrachloro-3-fluoroacetophenone with a mole ratio
of approximately 2:1. NaOAc (65.6 g, 800.0 mmol) was added, the
temperature was raised to 100°C and the chlorine gas was passed in
for a further 1h. Excess chlorine was swept out with nitrogen, the
mixture was cooled, and NaCl formed in the reaction was filtered.
After removal of the solvent AcOH, the residue was dissolved in
EtOAc (250 mL), washed with water, dried over Na2SO4 and concen-
trated in vacuo to give intermediate compound 3 as light yellow oil
(121.7 g, 98%).
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