A practical synthesis of 3-chloro-2,4-difluoro-5-hydroxybenzoic acid

Article abstract of DOI:10.1177/1747519820932259

A new and practical synthesis of 3-chloro-2,4-difluoro-5-hydroxybenzoic acid, a key intermediate for preparing antimicrobial 3-quinolinecarboxylic acid drugs, is synthesized from 2,4-difluoro-3-chlororobenzoic acid. The protocol involves nitration, esteri

Full text of DOI:10.1177/1747519820932259

932259CHL0010.1177/1747519820932259Journal of Chemical ResearchZhang et al.
research-article2020
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Journal of Chemical Research
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A practical synthesis of 3-chloro-2,4-difluoro-5-
hydroxybenzoic acid
https://doi.org/10.1177/1747519820932259
DOI: 10.1177/1747519820932259
journals.sagepub.com/home/chl
Mingguang Zhang1,2, Zhongbao Bi2, Yunyun Wang1, Yuxun Zhao1,
Yang Yang2, Yongqiang Zhu2,3 and Shifa Wang1
Abstract
A new and practical synthesis of 3-chloro-2,4-difluoro-5-hydroxybenzoic acid, a key intermediate for preparing
antimicrobial 3-quinolinecarboxylic acid drugs, is synthesized from 2,4-difluoro-3-chlororobenzoic acid. The protocol
involves nitration, esterification, reduction of NO2, diazotization, and hydrolysis with a 70% overall yield. The structures
of the synthesized compounds are determined by infrared spectroscopy, nuclear magnetic resonance spectroscopy, and
high-resolution electrospray ionization mass spectrometry. The advantages of this developed synthetic strategy include
an improved overall yield and readily controllable reaction conditions.
Keywords
3-Chloro-2,4-difluoro-5-hydroxybenzoic acid, 3-quinolinecarboxylic acid derivatives, diazotization, hydrolysis, synthesis
Date received: 31 March 2020; accepted: 15 May 2020
O
F
O
F
O
F
O
F
O
F
H2N
F
HO
F
O2N
F
O2N
F
H2/Pd-C
H2SO4 , NaNO2
OH HNO3
OH
O
OH
OH
O
H
2SO4
H3PO2 , 30% NaOH
F
Cl
Cl
Cl
Cl
Cl
afforded impurities in the target final intermediates that
made the purification difficult. In this study, compounds 2
and 3 have been synthesized following the route shown in
Scheme 1. 3-Chloro-2,4-difluoro-5-hydroxybenzoic acid
(1) was used as the starting material, followed by benzyla-
tion, condensation with diethyl malonate, hydrolysis with
p-toluenesulfonic acid, condensation with ethyl orthofor-
mate, cyclopropylamine substitution, cyclization, ester
hydrolysis, and debenzylation to afford the key quinolone
intermediate 1h. Compounds 2 and 3 were prepared by the
condensation of 1h with cyclic amines. Overall, the syn-
Introduction
Synthetic fluoroquinolone (FQ) antibiotics such as nali-
dixic acid and piromidic acid are effective antibacterial
agents for treating infections caused by Gram-negative
microorganisms. As a new generation of FQs, 3-quinoline-
carboxylic acid derivatives such as norfloxacin, ofloxacin,
moxifloxacin, and besifloxacin are well known for their
strong antimicrobial activities and broad spectrum of anti-
bacterial activities, including activity against Gram-positive
bacteria.1,2 Developing new 3-quinolinecarboxylic acid
derivatives as novel antimicrobial agents with improved
activity, superior pharmacokinetic properties, and satisfac-
tory bacterial resistance is important in pharmaceutical
research.3–7 1-Cyclopropyl-7-amine-6-hydroxy-8-chloro-
1,4-dihydro-4-oxo-quinoline-3-carboxylic acid derivatives
have been developed for improving antibacterial effects.
The novel antibacterial compounds 2 and 3 have been syn-
thesized from 2,4-difluoro-bromobenzene by aromatic
chlorination, carboxylation, nitration, and so on with 11
steps in total.8,9 However, the overall procedure is compli-
cated with many reaction steps, and the carboxylation con-
ditions are harsh requiring n-butyllithium below −78°C.
Besides, the reduction of NO2 and the diazotization of NH2
1College of Chemical Engineering, Nanjing Forestry University, Nanjing,
People’s Republic of China
2Jiangsu Chia Tai Fenghai Pharmaceutical Co., Ltd, Nanjing, People’s
Republic of China
3College of Life Science, Nanjing Normal University, Nanjing, People’s
Republic of China
Corresponding author:
Shifa Wang, College of Chemical Engineering, Nanjing Forestry
University, Nanjing 210037, People’s Republic of China.
Email: wangshifa65@163.com

2
Journal of Chemical Research 00(0)
O
O
O
O
F
O
F
O
O
O
Br
O
S
OH
HO
F
Ph
O
F
Ph
O
F
OH
OH
O
O
O
H2O
O
DMF, K2CO3, HCl
Mg, CCl4
F
Cl
Cl
Cl
1b
1a
1
O
O
F
O
O
O
O
O
O
O
O
Ph
O
NH2
EtOH
Ph
O
Ph
O
F
O
O
O
Ac2O
F
NH
F
F
F
Cl
Cl
Cl
1e
1c
1d
O
O
O
N
O
O
O
HO
Ph
Ph
O
O
OH
O
OH
5% Pd-C, H2
CH3OH
HCl
AcOH
K
2CO3
F
N
F
F
N
Cl
Cl
Cl
1h
1f
1g
O
O
O
O
O
O
HO
HO
N
HO
F
OH
OH
OH
H2N
N
N
N
N
Cl
Cl
Cl
H2N
1h
2
3
Scheme 1. Synthetic route to compounds 2 and 3 staring from compound 1.
O
O
O
O
O
F
OH
O
O
O
F
F
F
F
c
F
a
d
b
Cl
Li
Cl
COOH
Cl
Li
F
F
F
F
6
7
5
1
4
Scheme 2. Reported synthetic route toward compound 1.
Reagents and conditions: (a) sec-BuLi in THF, −75°C, 2h, 83%; (b) 1,1,2-trichloro-1,2, 2-trifluoroethane, 82%; (c) LITMP in THF, −75°C, 2h; and (d)
1—excess dry ice, 2—HCl, 75%.
thetic method is more efficient and does not use n-butyllith- (THF) at −75°C to give (2,6-difluoro-3-methoxymethoxy-
ium (Scheme 1).
phenyl)lithium (5) in 83% yield. 2-Chloro-1,3-difluoro-4-
Some FQs are also photolabile compounds which lead methoxymethoxybenzene (6) was obtained in 82% yield by
to phototoxicity as a side effect. The intrinsic photostability treating compound 5 with 1,1,2-trichloro-1,2,2-trifluoroeth-
characteristics should be evaluated to demonstrate that light ane. Compound 1 could be prepared through Li-substitution
exposure does not result in unacceptable changes.10 and carboxylation of 6 in 75% yield. However, this method
Hydroxylation of FQs at the 6-position is one of the main uses dangerous alkyllithium reagents at extremely low tem-
photodegradation pathways, affording 6-hydroxyciproflox- peratures which limits the large-scale preparation using this
acin and 6-hydroxysarafloxacin impurities.11 For quality route. Furthermore, the overall yield for the synthetic route
control of FQ drug substances, it is necessary to synthesize was only 51%.
these impurities, which can be prepared from the deriva-
tives of compound 1.
Thus, it is important to develop a more practical and effi-
cient synthetic method for the preparation of compound 1.
The synthesis of 3-chloro-2,4-difluoro-5-hydroxybenzoic
acid (1) was critical for developing new FQs and the quality
control of drug substances. However, there is only one
reported method for the preparation of the title compound 1
(Scheme 2).12 2,4-Difluoro-1-(methoxymethoxy)benzene
(4) was reacted with sec-butyllithium in tetrahydrofuran
Results and discussion
Amino hydrolysis of an aryl amine can be used for preparing
phenols.13–16 As shown in Scheme 3, the retrosynthetic analy-
sis suggests that compound 1 can be synthesized by the

Zhang et al.
3
O
F
O
F
O
F
O
F
HO
F
COOH
F
N
F
O2
NaO3SN2
F
H2N
F
OH
OH
OH
OH
F
Cl
1
Cl
Cl
Cl
10
Cl
11
8
9
Scheme 3. Retrosynthetic analysis of compound 1.
O
O
F
O
F
O
HO
F
H2SO4
H2N
F
O2N
H2/Pd-C
OH HNO3
OH
OH
OH
H SO 94%
,
4
F
F
2
F
F
Cl
11
Cl
10
Cl
9
Cl
1
86%
OH
O
O
O2N
F
NaO3SN2
F
OH
O
F
F
Cl
12
Cl
8
97%
H2/Pd-C
H2N
F
O
H3PO2, 30% NaOH
90%
H2SO4
NaNO2
O
F
Cl
13
Scheme 4. The new synthetic strategy toward compound 1.
hydrolysis of diazonium salt 8, which is the typical method for of 10, compound 12 was obtained in a good yield of 86%.
introducing a hydroxy group into an aromatic ring. Compound The hydrogenation of 12 catalyzed by Pd/C gave ethyl
8 could be obtained by the diazotization of compound 9, which 5-amino-3-chloro-2,4-difluorobenzoate (13) in an excellent
occurs rapidly in concentrated sulfuric acid. Compound 9 yield of 97.0%. Finally, compound 13 was converted into
would be prepared by the reduction of 3-chloro-2,4-difluro- the target compound 1 in 90% yield by diazotization and
5-nitrobenzoic acid (10) with hydrogen in the presence of hydrolysis with H3PO2/H2O in one step.
Pd/C, while 10 can be synthesized by the nitration of commer-
cially available 2,4-difluro-3-chlorobenzoic acid (11).
With optimized reaction conditions in hand, we sought
to evaluate the suitable conditions for the reduction of com-
Based on the retrosynthetic analysis of compound 1, pound 12. 2% Raney Ni and 3 equiv. of hydrazine hydrate
preliminary experiments were performed to verify the fea- (80%) in ethanol were initially used. The result demon-
sibility of this scheme. However, the critical intermediate strated low activity, giving a 45% yield of 13 after reaction
compound 8 could not be separated from water because of for 9h (Table 1, entry 1). The numbers of equivalents of
its high solubility. Further optimization was achieved by hydrazine hydrate (80%) was increased to 4.0 and the reac-
introducing an ester group into benzoic acid to reduce the tion temperature was increased to 78°C; the highest yield
solubility. The new synthetic strategy is illustrated in was 62%, after reacting for 12h (entries 2 and 3). By fur-
Scheme 4. Compound 1 was obtained by the nitration of 11, ther optimizing the additive (entries 4−6), the yield of com-
which was followed by esterification, reduction of NO2, pound 13 was significantly improved (entry 6, 82%).
diazotization, and hydrolysis of 13. The structures of the Compared to Raney Ni and hydrazine hydrate (80%), using
intermediates and products were characterized by infrared 5% Pd/C (66% water) and H2 improved the yield to 72%
1
(IR) spectroscopy, H nuclear magnetic resonance (NMR) (entry 7). The additive ratios were also optimized, and the
spectroscopy, 13C NMR spectroscopy, and mass spectrom- highest yield (97%) was obtained (entries 8−11). On
etry (MS).
increasing the pressure to 0.8−1.0MPa, the reactions were
In this new synthetic route, compound 11 was treated complete within 5h, and the highest yield of 97% was
with concentrated nitric acid to give 3-chloro-2,4-difluoro- obtained.
5-nitrobenzoic acid (10) in 94% yield. The nitration of
In the fourth step, concentrated sulfuric acid was first
compound 11 was slow because of the electron-withdraw- employed as the solvent for the hydrolysis of compound 13;
ing effects of the F and COOH groups. The reaction however, the reaction did not occur. Further experiments
required a high temperature and the inclusion of excess showed that compound 1 could be afforded by diazotization
concentrated HNO3 as an additive. Following esterification with NaNO2 and hydrolysis with 50% H3PO2 to give 13. For

4
Journal of Chemical Research 00(0)
Table 1. Optimization of the reduction reaction conditions.
O
O
F
O2N
H2N
F
additive, solvent
O
O
temperature, time
F
F
Cl
12
Cl
13
Entry
Additive (w/w, equiv., H2 pressure)a
Solvent
Temperature (°C)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
Raney Ni (0.02), NH2NH2 (3.0)
Raney Ni (0.02), NH2NH2 (4.0)
Raney Ni (0.03), NH2NH2 (4.0)
5% Pd-C (0.02), NH2NH2 (3.0)
5% Pd-C (0.02), NH2NH2 (3.0)
5% Pd-C (0.03), NH2NH2 (4.0)
5% Pd-C (0.02), H2 (0.1MPa)
5% Pd-C (0.03), H2 (0.1MPa)
5% Pd-C (0.02), H2 (0.5MPa)
5% Pd-C (0.02), H2 (0.8MPa)
5% Pd-C (0.03), H2 (1MPa)
Ethanol
Ethanol
Ethanol
Ethanol
Methanol
Methanol
Ethanol
60
70
78
60
68
68
60
78
30
40
40
9
9
12
9
9
9
9
6
5
5
45
53
62
63
75
82
72
85
93
97
97
Ethanol
9
10
11
Methanol
Methanol
Methanol
5
aEntries 1–3: Raney Ni (w/w); entries 4–11: 5% Pd-C (dry weight/w).
bIsolated yield.
Table 2. Optimization of the diazotization and hydrolysis reaction conditions.a
O
O
F
H2N
F
HO
F
1) H2SO4, NaNO2
2) H3PO2
O
OH
F
Cl
13
Cl
1
Entry
NaNO2 (equiv.)
H2SO4 (equiv.)
Temperature (°C)
Time (h)
Yield (%)b
1
2
3
4
5
6
1.0
1.0
1.2
1.25
1.25
1.25
2.5
3.0
3.0
3.0
4.0
4.0
10
10
5
5
0
4
3
3
3
2
2.5
48
50
57
63
89
90
0
aCompound 13 (10mmol), H2O (50mL), 50% H3PO2 (30mmol).
bIsolated yield.
optimizing the reaction conditions, the equivalents of NaNO2 reagents and low reaction temperatures are avoided to
and H2SO4 were studied (Table 2). Equivalents of NaNO2 decrease the formation of byproducts. In addition, this new
from 1.0 to 1.25 were screened and the results showed that synthetic route has the advantages of readily available rea-
NaNO2 equivalents below 1.2 gave only moderate yields gents and a high overall yield of 70%. The described strat-
(Table 1, entries 1−3). Subsequently, by decreasing the reac- egy is also suitable for the synthesis of derivatives of
tion temperature from 10°C to 0°C, it was found that 1.25 compound 1.
equiv. of NaNO2 in 4.0 equiv. of H2SO4 successfully
improved the yield from 57% to 90% (Table 2, entries 4−6).
Experimental
2,4-Difluoro-3-chlororobenzoic acid (11) was purchased
from Aladdin (Shanghai) with 98% purity. Unless other-
Conclusion
In summary, a novel and practical process for the synthesis wise mentioned, all solvents, reagents, and materials were
of 3-chloro-2,4-difluoro-5-hydroxybenzoic acid (1), a key purchased from commercial suppliers and used without fur-
intermediate for preparing antimicrobial 3-quinolinecar- ther purification. All reactions were monitored by thin-
boxylic acid derivatives, has been developed. The synthetic layer chromatography (TLC) on silica gel plates (GF-254;
strategy involved the nitration of 2,4-difluoro-3-chlo- Qingdao Ocean Chemical Company, China) and products
rorobenzoic acid (11), esterification, reduction of NO2, were purified by silica gel column chromatography
diazotization, and hydrolysis. Hazardous alkyllithium (200−300 mesh; Qingdao Marine Chemical Industry

Zhang et al.
5
Corporation, China). Melting points (m.p.) were deter- 127.3 (t, J=2.2Hz), 116.3 (dd, J=11.7, 4.5Hz), 114.6 (dd,
mined on a YRT-3 melting point apparatus using the capil- J=22.3, 20.0Hz), 62.8, 14.1; HRMS (ESI): m/z [M+H]+
lary method without correction. IR spectra were obtained calcd for C9H7ClF2NO4: 266.0032; found: 266.0049.
on an Avatar 330FT-IR (Thermo Nicolet) spectrometer,
using the attenuated total reflectance (ATP) method.
Ethyl 5-amino-3-chloro-2,4-
Nuclear magnetic resonance (NMR) spectra were recorded
difluorobenzoate (13)
on a Bruker Avance DPX 300MHz instrument in CDCl3 or
DMSO-d6 with tetramethylsilane (TMS) as an internal ref- Compound 12 (10. 0g, 37.73mmol), Pd/C (10%, 0.2g),
erence. Chemical shifts (δ) are reported in parts per million and methanol (100 mL) were placed in an autoclave (250
(ppm). High-resolution mass spectra (HRMS) were mL). H2 was purged into the autoclave three times to
obtained from Agilent 1100 LC/MS Spectrometry Services. remove air, and the reaction mixture was stirred at 40°C for
5h under a pressure between 0.8 and 1.0MPa. After the
reaction was complete, the resulting mixture was trans-
3-Chloro-2,4-difluoro-5-nitrobenzoic acid
ferred to a tube and filtered to recycle the catalyst. The sol-
(10)
vent was removed under reduced pressure to afford 13 as a
A solution of concentrated HNO3 (65%, 15.0g) and H2SO4 gray solid (8.6g, 97%); m.p. 115.2–115.9°C; IR (KBr)/
(98%, 8.0g) was added dropwise to 2,4-difluoro-3-chlo- cm−1: 3431, 3410, 3351, 3216, 3072, 3011, 2972, 1713,
robenzoic acid (11) (15.0g, 78.13mmol) and concentrated 1496, 1284, 1018, 779; 1H NMR (300MHz, CDCl3):
H2SO4 (98%, 32.0g) at ice-bath temperature. The tempera- δ=7.27 (m, 1 H), 4.37 (q, J=7.1Hz, 2 H), 3.76 (s, 2 H, D2O
ture was kept below 20°C during the addition process. After exchangeable), 1.38 (t, J=7.1Hz, 3 H); 13C NMR (75MHz,
the addition was complete, the mixture was stirred for 2h at CDCl3): δ=163.4 (d, J=4.3Hz), 150.9 (d, J=253.5Hz),
70–75°C until TLC (40% ethyl acetate in hexane) showed 149.9 (d, J=248.9Hz), 131.3 (dd, J=12.8, 3.1Hz), 115.8
the starting materials had disappeared. The mixture was (d, J=5.4Hz), 115.3 (dd, J=10.9, 3.7Hz), 111.2 (dd,
cooled to room temperature, poured into ice-water (180g), J=22.9, 18.6Hz), 61.6, 14.0; HRMS (ESI): m/z [M-H]−
stirred for another 1h at 0–5°C, filtered, and washed with calcd for C9H7ClF2NO2: 234.0133; found: 234.0128.
water to afford a gray solid. The crude product was purified
by recrystallization from hexane to afford 10 as a white
3-Chloro-2,4-difluoro-5-hydroxybenzoic
acid (1)
solid (17.38g, 94%); m.p. 122.3–124.1°C, (123–124°C);17
1
IR (KBr)/cm−1: 3269, 3055, 1692, 1533, 1322, 891; H
NMR (300MHz, DMSO-d6): δ=13.67 (br s, 1 H, D2O A mixture of compound 13 (2.35g, 10mmol) and H2O (45
exchangeable), 8.52–8.57 (m, 1 H); 13C NMR (75MHz, mL) was cooled to 0°C, concentrated sulfuric acid (98%,
DMSO-d6): δ=161.9 (d, J=3.8Hz), 160.3 (dd, J=268.4, 4.0g) was added dropwise, and the temperature was kept
2.7Hz), 154.4 (dd, J=268.1, 3.7Hz), 133.9, 127.4, 116.8 below 5°C. A white solid precipitated during the process,
(dd, J=12.1, 4.1Hz), 113.2 (t, J=22.5Hz); HRMS (ESI): and the mixture was stirred for 30min. To this emulsion, a
m/z [M-H]− calcd for C7HClF2NO4: 235.9562; found: solution of NaNO2 (0.86g, 12.5mmol) in H2O (5.0mL)
235.9559.
was added dropwise to the cooled reaction mixture. Stirring
was continued for another 30min during which the reaction
mixture became a clear solution. A solution of 50%
hypophosphorous acid (3.96g, 30mmol) was added drop-
wise below 0°C, and the mixture was stirred at 0°C for
Ethyl 3-chloro-2,4-difluoro-5-
nitrobenzoate (12)
A mixture of compound 10 (12.0g, 50.6mmol), ethanol 2.5h. Then, the pH of the reaction mixture was adjusted to
(200 mL), and H2SO4 (98%, 7.5g) was stirred under reflux 9–10 with 30% NaOH and stirred for another 1h at 50°C
for 3h until the starting materials had disappeared (TLC (the reaction was monitored by TLC (25% ethyl acetate,
detection, 10% ethyl acetate, 90% hexane). After cooling, 5% acetic acid in hexane)). The reaction mixture was
the solvent was removed under reduced pressure, the resi- cooled to room temperature and extracted with dichlo-
due cooled to 5°C, and the pH value was adjusted to neutral romethane (2×300mL), and the combined organic phases
with 10% sodium carbonate solution (70 mL). The mixture were decolorized with activated charcoal and dried over
was extracted twice with ethyl acetate (60 mL×2) and the anhydrous Na2SO4. The solvent was removed under
combined organic layer was dried with Na2SO4. The sol- reduced pressure to afford a white solid. The crude product
vent was removed on a rotary evaporator, and the crude was washed with a mixture of hexane (10mL) and ethyl
product was purified by column chromatography using 5% acetate (2mL), and then dried between 50 and 55°C for 5h.
ethyl acetate:9% petroleum ether as an eluent. The solvent The product was obtained as a white solid (1.87g, 90%);
was removed under reduced pressure to afford 12 as a light m.p. 194.7–195.9°C, (195–197°C);12 IR (KBr)/cm−1: 3566,
1
yellow solid (11.5g, 86%); m.p. 127–129°C; IR (KBr)/ 3506, 3257, 3048, 1698, 1597, 1495, 1459, 1088, 932; H
1
cm−1: 3145, 3081, 2967, 2875, 1716, 1534, 1327, 901; H NMR (300MHz, DMSO-d6): δ=13.47 (br, s, 1 H, D2O
NMR (400MHz, CDCl3): δ=8.68 (t, J=7.2Hz, 1 H), 4.47 exchangeable), 10.66 (br, s, 1 H, D2O exchangeable), 7.43
(q, J=7.1Hz, 2 H), 1.45 (t, J=7.1Hz, 3 H); 13C NMR (dd, J=9.09, 7.32Hz, 1 H); 13C NMR (75MHz, DMSO-d6):
(100MHz, CDCl3): δ=160.9 (d, J=3.4Hz), 161.1 (dd, δ=163.6 (d, J=3.6Hz), 150.2 (d, J=252.9Hz), 149.7 (d,
J=204.2, 2.2Hz), 155.1 (dd, J=272.3, 3.8Hz), 134.0, J=252.4Hz), 141.8 (dd, J=11.6, 2.9Hz), 117.1 (d,

6
Journal of Chemical Research 00(0)
3. Hu YQ, Xu Z, Qiang M, et al. J Heterocyclic Chem 2018; 55:
J=4.3Hz), 115.5 (dd, J=11.1, 3.8Hz), 110.4 (dd, J=22.9,
18.4Hz); 19F NMR (376MHz, DMSO-d6): δ=−122.5,
−127.6; HRMS (ESI): m/z [M−H]− calcd for C7H2ClF2O3:
206.9661; found: 206.9672.
187.
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Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
7. Natalini B, Sardella R, Massari S, et al. Talanta 2011; 85:
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8. Benoit L, Hu X, Eric Almstead J, et al. WO2004014893,
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Funding
9. Benoit L, Kim AJ and Jeffrey G. US2002049192, 2002.
10. Ge LK, Chen JW, Wei XX, et al. Environ Sci Technol 2010;
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: This
study was supported by the Natural National Science Foundation
of China (No. 31470592).
44: 2400.
11. Guo HG, Gao NY and Chu WH. Environ Sci Pollut Res
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ORCID iD
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Shifa Wang
https://orcid.org/0000-0001-8578-9845
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2003; 7: 762.
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Supplemental material for this article is available online.
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