A novel and facile method for synthesis of 2,4-dichloro-3-cyano-5- fluorobenzoic acid

Article abstract of DOI:10.3184/174751912X13371855044778

A two-step facile process for the preparation of 2,4-dichloro-3-cyano-5- fluorobenzoic acid, starting from easily available 2,6-dichloro-3- fluorobenzonitrile, has been developed. The overall yield was 58%.

Full text of DOI:10.3184/174751912X13371855044778

JOURNAL OF CHEMICAL RESEARCH 2012
RESEARCH PAPER 411
JULY, 411–412
A novel and facile method for synthesis of 2,4-dichloro-3-cyano-5-
fluorobenzoic acid
Zhiwei Chen, Lidong Zheng and Weike Su*
Key Laboratory for Green PharmaceuticalTechnologies and Related Equipment of Ministry of Education, College of Pharmaceutical
Sciences, Zhejiang University ofTechnology, Hangzhou 310014, P. R. China
A two-step facile process for the preparation of 2,4-dichloro-3-cyano-5-fluorobenzoic acid, starting from easily avail-
able 2,6-dichloro-3-fluorobenzonitrile, has been developed. The overall yield was 58%.
Keywords: 2,4-dichloro-3-cyano-5-fluorobenzoic acid, 2,6-dichloro-3-fluorobenzonitrile, synthesis
2,4-Dichloro-3-cyano-5-fluorobenzoic acid is the key interme-
diate for synthesis of finafloxacin hydrochloride (BAY35-
3377), a novel fluoroquinolone antibiotic that is currently in
clinical trial.1 M. Schriewer et al. reported a synthetic method
from a 2,4-dichloro-5-fluorobenzoic acid that involved nitra-
tion, reduction, diazotisation and a Sandmeyer reaction to give
final product 1 (Scheme 1, route 1).2 The main disadvantage of
this process is, in particular, the Sandmeyer reaction, which
proceeds with poorly reproducible yield and employs three
extra equivalents of cyanide thus resulting in considerable
hazard potential. The objective compound 1 was also prepared
by Marhold and Wolfrum3 from 5-fluoro-1,3-xylene, via a
five-step synthetic route (Scheme 2, route 2). But it also
suffered from disadvantages of low overall yield (less than
30%) and complicated manipulations.
(Table 1, entries 1–4). KBrO3 was successful in carrying out
bromination of 2 in the presence of a strong acid e.g. sulfuric
acid (Table 1, entry 6), but unfortunately the yield was not
satisfactory, as the reaction was accompanied by a consider-
able amount of by-product due to the strong oxidisability
of KBrO3. But by employing NBS as brominating agent in
concentrated sulfuric acid5 (Table 1, entry 8), 2 was smoothly
brominated into 2,6-dichloro-3-fluoro-5-bromobenzonitrile 3
in high yield (97%).
The preparation of polyfunctional organometallics has long
been an active research field, especially the functionalised
Grignard reagents which are key organometallics in organic
synthesis. Recently, Knochel’s group reported an interesting
Recently, we reported a highly efficient new approach to the
synthesis of 2,6-dichloro-3-fluorobenzonitrile 2, an important
intermediate used in the synthesis of pharmaceuticals and
plant protection agents.4 As part of our attempt focused on
developments of pharmaceutical intermediates, we now report
a novel and facile method for preparing 1 starting from this
commercially available material, as shown in Scheme 2.
Results and discussion
For bromination of 2, a series of methods were investigated.
Compound 2 failed to be brominated by the common bromin-
ating agent Br2 in the presence of Lewis acids or protonic
acids, owing to the weakly electrophilic benzene nucleus of 2
Scheme 2
Scheme 1
* Correspondent. E-mail: pharmlab@zjut.edu.cn

412 JOURNAL OF CHEMICAL RESEARCH 2012
Table 1 Bromination of 2,6-dichloro-3-fluorobenzonitrile
Entry
Brominating agent
Solvent
Catalyst
Temperature /°C
Reaction time /h
Yield /%
1
2
3
4
5
6
7
8
Br2
Br2
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
AcOH
AlCl3
Reflux
Reflux
Reflux
Reflux
Reflux
r.t.
24
24
24
24
24
30
24
36
NA
NA
NA
NA
NA
42b
NA
97
FeCl3
Br2
Fe
H2SO4
Br2
KBrO3
KBrO3
NBS
NBS
AcOH
/
/
/
/
AcOH/H2SO4a
F3CCO2H
H2SO4
Reflux
r.t.
a Vol/vol 7:3.
b The best yield at optimised condition.
112.1 (d, J = 3 Hz), 116.5, 122.1 (d, J = 9 Hz), 125.1 (d, J = 20 Hz),
125.2 (d, J = 24 Hz), 134.0 (d, J = 4 Hz), 156.0 (d, J = 254 Hz). EI-MS
(m/z, %): 269 (M+, 100), 188 (24), 153 (16). EI-HRMS: m/z (M+)
Calcd for C7HBrCl2FN: 266.8653; found: 266.8672.
method for preparation of functionalised Grignard reagents by
the direct insertion of magnesium in the presence of LiCl.6 But
since the cyano group in substrate 3 was highly sensitive,
applying this method to compound 3 failed badly as reduction
and coupling products formed as the main products, accompa-
nied by large amount of products from reaction of the cyano
group with the highly reactive magnesium intermediate.
Other methods for preparing polyfunctional Grignard
reagents includes I/Mg exchange and Br/Mg exchange
reactions.7–10 Since aryl and heteroaryl bromides are cheaper
and more readily available as starting materials, they are more
commonly used as the substrates. Thus 3 was treated with
i-PrMgCl, a commercially available reagent that could be effi-
ciently used to carry out Br/Mg exchange, and 2,6-dichloro-3-
fluoro-5-bromo-benzyl-magnesium reagent was successfully
generated. This Grignard reagent was further subjected to
carboxylation with CO2, followed by acidification to afford
target compound 1 with a yield of 60%.
2,4-Dichloro-3-cyano-5-fluorobenzoic acid (1): i-PrMgCl (116.5 mL,
116.5 mmol, 1 M in THF) was cooled to –50 °C and to this solution
was slowly added 3 (26.1 g, 97.1 mmol) with vigorous stirring, while
maintaining this temperature. The Br/Mg exchange reaction was
complete after 1 h, and dry CO2 was then slowly bubbled in for a fur-
ther 1 h with the temperature being raised to –5 °C. After acidification
by aqueous HCl solution (1 M), THF was evaporated, and the aqueous
phase was extracted with EtOAc, dried over Na2SO4, and concentrated
in vacuo. Further purification by recrystallisation from toluene yielded
pure product 1 as light yellow crystals (13.6 g, 60%). m.p. 204–
206 °C (lit.2 203−205 °C); 1H NMR (400 MHz, DMSO-d6) δ 8.18 (d,
J = 9.2 Hz, 1 H), 14.23 (brs, 1 H); 13C NMR (100 MHz, DMSO-d6)
δ 112.8 (d, J = 3 Hz), 116.1, 122.5 (d, J = 24 Hz), 126.6 (d, J = 21 Hz),
130.7 (d, J = 3 Hz), 134.1 (d, J = 6 Hz), 155.7 (d, J = 248 Hz), 163.9.
ESI-MS (m/z, %): 233 ([M-H]−, 100), 189 (30).
In conclusion, a two-step and efficient novel approach to the
synthesis of 2,4-dichloro-3-cyano-5-fluorobenzoic acid, which
could be extended to large-scale production, was developed.
The attractive features of this protocol are simple reaction
procedure, high overall yield and avoiding employing highly
toxic reagents.
Received 5 March 2012; accepted 10 April 2012
Paper 1201193 doi: 10.3184/174751912X13371855044778
Published online: 26 June 2012
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