Synthesis of an impurity in crude roflumilast

Article abstract of DOI:10.3184/174751914X14061300074410

A simple synthetic method has been developed for the synthesis of 3,4-bis(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl) benzamide (an impurity in crude roflumilast) from 3,4-dihydroxybenzaldehyde via alkylation, oxidation, chlorination and acylation reactions. Acetonitrile was used as the solvent in all the three steps for convenient recovery. The oxidation of 3,4-bis(cyclopropylmethoxy)benzaldehyde (purity, 86.2%) by sodium chlorite afforded the corresponding acid with purity of 99.2%. Finally, N-acylation of 3,5-dichloropyridin-4-amine yielded 3,4-bis(cyclopropylmethoxy)-N-(3,5- dichloropyridin-4-yl) benzamide. Without column chromatography, the overall yield of the target compound was about 70%.

Full text of DOI:10.3184/174751914X14061300074410

JOURNAL OF CHEMICAL RESEARCH 2014
VOL. 38 AUGUST, 507–509
RESEARCH PAPER 507
Synthesis of an impurity in crude roflumilast
Hankang Zhanga, Yan Linb, Yan Lia, Kai Dongc, Ligong Chenb and Donghua Wanga*
aSchool of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, P.R. China
bSchool of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, P.R. China
cDepartment of Pharmaceutical synthesis, Tianjin Chase Sun Pharmaceutical Co., Ltd, Tianjin 301700, P.R. China
A simple synthetic method has been developed for the synthesis of 3,4-bis(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)
benzamide (an impurity in crude roflumilast) from 3,4-dihydroxybenzaldehyde via alkylation, oxidation, chlorination and
acylation reactions. Acetonitrile was used as the solvent in all the three steps for convenient recovery. The oxidation of
3,4-bis(cyclopropylmethoxy)benzaldehyde (purity, 86.2%) by sodium chlorite afforded the corresponding acid with purity of
99.2%. Finally, N-acylation of 3,5-dichloropyridin-4-amine yielded 3,4-bis(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)
benzamide. Without column chromatography, the overall yield of the target compound was about 70%.
Keywords: phosphodiesterase 4 inhibitor, purification, N‑acylation, acetonitrile, impurity
Phosphodiesterases (PDEs) play an important role in various
biological processes through decreasing the concentration
of cAMP and cGMP.1–3 Phosphodiesterase 4 (PDE 4) is
responsible for the degradation of cAMP in many cell types and
has been proposed as an attractive target in various diseases
including chronic obstructive pulmonary disease (COPD) and
asthma.4–7 Roflumilast (Fig. 1), acting as the inhibitor of the
PDE 4, was developed by Altana AG and became the first
drug approved for the treatment of COPD in Europe.8,9 Further
attention has been paid to the pharmacology, synthesis and
analysis of roflumilast in the last decade.10–13 It was reported
that 3,4‑bis(cyclopropylmethoxy)‑N‑(3,5‑dichloropyridin‑4‑yl)
benzamide (1) (Fig. 1) is one of the impurities in the synthesis
of roflumilast [14]. However, the synthesis of the impurity 1 has
rarely been mentioned in the literature. Here, a simple synthetic
method is described for the preparation of the impurity 1
from 3,4‑dihydroxybenzaldehyde via alkylation, oxidation
and acylation reactions (Scheme 1). Reaction parameters were
optimised and acetonitrile was selected as the solvent in all the
three steps to make the solvent recovery easier. The total yield
of the four‑step sequence was about 70%.
the reaction at higher temperature to accelerate the reaction. KI
was also chosen as the catalyst to improve the conversion and
selectivity of the reaction. The effect of KI to this reaction was
clear in methanol, ethanol and acetone, but not in acetonitrile.
Several bases were evaluated and the results indicated
that potassium carbonate exhibited the best performance.
Cyclopropyl methyl bromide was added gradually to avoid
hydrolysis side reaction. As mentioned above, the reaction
parameters were optimised for this nucleophilic substitution.
Compound 4 was used directly in the next oxidation step
without further purification.
The oxidation of aldehydes to the corresponding carboxylic
acids in the presence of sodium chlorite has been widely
reported.15–19
It was claimed that sulfamic acid was used for
the chlorine scavenger.20,21 Methanol, ethanol, t‑butanol or
acetonitrile as the solvent for the oxidation were found to afford
similar results. Since acetonitrile was used in the first step, we
chose acetonitrile as the reaction solvent. Compound 5 was
recrystallised from toluene in 99.2% purity to avoid impurities
into the next step.
The nucleophilic ability of 3,5‑dichloropyridin‑4‑amine
was low due to the electronic and steric effects, so sodium
hydride was chosen as the base to form the amino anion to
enhance its reactivity.18,22 Acetonitrile, consistent with the
previous reactions, was chosen as the solvent for this reaction.
3,4‑Bis(cyclopropylmethoxy)‑N‑(3,5‑dichloropyridin‑4‑yl)
benzamide was obtained as a white solid by the N‑acylation
of the created anion with the benzoyl chloride 6. Finally the
Results and discussion
The O‑alkylation of 3,4‑dihydroxybenzaldehyde
2 with
cyclopropylmethyl bromide 3 gave compound 4 mono‑ and
di‑alkylated products were expected. In order to increase the
yield of the desired compound, several solvents were examined
for this reaction. It was found that acetonitrile was promising.
It is a polar aprotic solvent, which enhances nucleophilic
substitution; and its high boiling point made it possible to carry
1
purified compound 1 was characterised by IR, H NMR, 13C
NMR and high‑resolution mass spectra (HR‑MS).
Cl
Cl
N
O
N
O
O
O
O
O
N
F
N
H
H
Cl
Cl
F
Roflumilast
formula: C17H14Cl2F2N2O3
impurity 1
Fig. 1 The structure of Roflumilast and the impurity 1.
* Correspondent. E‑mail: dhwang022@163.com
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508 JOURNAL OF CHEMICAL RESEARCH 2014
HO
HO
CHO
K
NH2SO3H, NaClO2
2CO3
r
B
H
C O
O
O
O
O
COOH
CH3CN, reflux
CH3CN, H2O, 5~10°C
.
82 5
%
)
(
2
5
3
4
without purification
Cl
NH2
N
O
SOCl2, DMF
NaH
l
C
l
C
O
COCl
O
O
N
CH3CN, -5~0°C
(85.3%)
toluene, reflux
H
l
C
N
O
7
6
impurity 1
Scheme 1 The synthesis of the impurity 1.
OCH2), 3.85 (d, J=6.0 Hz, 2 H, OCH2), 1.25 (m, 2 H, CH), 0.58 (t,
4 H, CH2), 0.35 (t, 4 H, CH2). 13C NMR (151 MHz, DMSO‑d6): δ 167.1
(C=O), 152.3, 147.6, 123.2, 122.7, 113.8, 112.3 (6 C on benzene), 72.9
(2 C on OCH2), 10.0, 10.1 (2 C on CH), 3.2 (4 C on CH2).
Experimental
Reagents and solvents used in this study were commercially
available. All reactions were monitored by TLC using commercial
silica gel plates. The purity of product was detected by HPLC on
Agilent 1,100 series. IR spectra were obtained from KBr disk on the
FT‑IR Bruker Tensor 27. NMR spectra were recorded on Avance III
400 or 600 NMR spectrometer with tetramethylsilane as an internal
reference. Melting points were observed on a YRT‑3 Melting Point
Tester and uncorrected. HR‑MS were recorded with a Bruker
micrOTOF‑QII spectrometer in electrospray ionisation (ESI) mode.
3,4-Bis(cyclopropylmethoxy)benzaldehyde (4): Potassium
carbonate (4.5 g, 32.56 mmol) was added to the solution of
3,4‑dihydroxybenzaldehyde 2 (1.5 g, 10.86 mmol) in acetonitrile
(25 mL) with magnetic stirring. It was heated to reflux and stirred for
30 minutes. Then, cyclopropyl methyl bromide 3 (4.4 g, 32.56 mmol)
was added dropwise to the reaction mixture and stirred at reflux
till no starting material was left (TLC). The reaction mixture was
then cooled to 20 °C. After filtration, the filtrate was evaporated
to give 4 (2.58 g) as yellow oil with the purity of 86.2%. It was used
in the next step without further purification. IR (KBr, νmax/cm–1):
3085–3002 (ν CH on benzene), 2922 (ν CH on cyclopropyl), 2819, 2784
(ν CH on CHO), 1694 (ν C=O), 1589, 1517, 1433 (ν C=C), 1277, 1238
(ν C–O–Ar), 1132, 1121, 1032, 845, 830 (ν CH on benzene). 1H NMR
(600 MHz, DMSO‑d6): δ 9.59 (s, 1 H, CHO), 7.29 (dd, J=1.8, 8.2 Hz,
1 H, CH on benzene), 7.16 (d, J=1.8 Hz, 1 H, CH on benzene), 6.92 (d,
J=8.3 Hz, 1 H, CH on benzene), 3.73 (d, J=7.0 Hz, 2 H, OCH2), 3.67
(d, J=7.0 Hz, 2 H, OCH2), 1.05 (m, 2 H, CH), 0.37 (t, 4 H, CH2), 0.13
(t, 4 H, CH2). 13C NMR (151 MHz, DMSO‑d6): δ 191.3 (C=O), 153.9,
148.5, 129.5, 125.8, 112.6, 111.5 (6 C on benzene), 73.0, 72.9 (2 C on
OCH2), 10.0 (2 C on CH), 3.2 (4 C on CH2).
3,4-Bis(cyclopropylmethoxy)benzoyl chloride (6): Compound
5
(1.49 g, 5.68 mmol) in toluene (48 mL) was heated to reflux until it
dissolved and water was removed by Dean–Stark apparatus. Then
the solution was cooled to 85 °C. After that, three drops of DMF
and thionyl chloride (1.01 g, 8.49 mmol) were added dropwise to
the solution. The mixture was stirred at reflux for 3 h (monitored
by TLC). Then toluene was evaporated to give a brown oil of
3,4‑bis(cyclopropylmethoxy)benzoyl chloride 6. The residue was
dissolved in anhydrous (8 mL) acetonitrile and used for the next step
directly. IR (KBr, νmax/cm–1): 3082, 3068 (ν CH on benzene), 2930,
2876 (ν CH on cyclopropyl), 1757 (ν C=O), 1688 (ν C=O), 1583, 1517,
1466 (ν C=C), 1277, 1240 (ν C–O–Ar), 1174, 1132, 1029, 832, 807 (δ
CH on benzene). 1H NMR (600 MHz, CDCl3): δ 7.79 (dd, J=2.2,
8.3 Hz, 1 H, CH on benzene), 7.57 (d, J=2.2 Hz, 1 H, CH on benzene),
6.91 (d, J=8.6 Hz, 1 H, CH on benzene), 3.97 (d, J=6.9 Hz, 2 H,
OCH2), 3.92 (d, J=6.8 Hz, 2 H, OCH2), 1.34 (m, 2 H, CH), 0.66 (t, 4 H,
CH2), 0.40 (t, 4 H, CH2). 13C NMR (151 MHz, CDCl3): δ 167.2 (C=O),
155.7, 148.7, 127.3, 125.2, 116.3, 112.4 (6 C on benzene), 74.4, 73.9
(2 C on OCH2), 10.2 (2 C on CH), 3.4 (4 C on CH2). HR‑MS (ESI) m/z:
[M+H]+ calcd for C15H17ClO3 +H+ 263.1283; found 263.1274.
3,4-Bis(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)
benzamide (1): A suspension of sodium hydride (0.50 g, 12.50 mmol)
in anhydrous (17 mL) acetonitrile was stirred at –5–0 °C for
20 minutes, then 3,5‑dichloropyridin‑4‑amine 7 (2.33 g, 14.20 mmol)
was added to the solution (CAUTION: hydrogen gas is liberated).
After that, compound 6 dissolved in acetonitrile was added dropwise
to the mixture, and the temperature remained unchanged for an hour
(monitored by TLC). Then the mixture was filtered, concentrated
and dissolved in dichloromethane. The organic phase was washed
with 1 M aqueous solution of hydrochloric acid, saturated sodium
hydrogen carbonate and brine, then dried with magnesium sulfate.
The organic phase was concentrated to give a yellow solid. Then it was
recrystallised in methanol to give 3,4‑bis(cyclopropylmethoxy)‑N‑
(3,5‑dichloropyridin‑4‑yl)benzamide 1 (1.97 g, 85.3% yield) as a white
solid. M.p. 206–207 °C; IR (KBr, νmax/cm–1): 3283 (ν NH), 3085, 3010
(ν CH on benzene or pyridine), 2913, 2871 (ν CH on cyclopropyl), 1656
(ν C=O), 1598, 1586 (ν C=C), 1558, 1548 (δ NH), 1500 (ν C=C), 1461
(ν C=C), 1399 (ν C=N), 1303 (ν CONHR), 1278, 1251 (ν C–O–Ar),
3,4-Bis(cyclopropylmethoxy)benzoic acid (5): Compound 4 (2.58 g,
10.68 mmol) was dissolved in acetonitrile (20 mL) and added to a
solution of sulfamic acid (1.48 g, 15.24 mmol) in water (10 mL). Then,
sodium chlorite (1.53 g, 15.24 mmol) in water (10 mL) was added
dropwise to the above reaction mixture at 5–10 °C. Subsequently, the
ice bath was removed and the mixture was stirred at room temperature
for two hours (monitored by TLC). Then the solvent was evaporated
to give a white solid. It was then recrystallised from toluene as white
solid 5 (2.35 g, 82.5% yield). M.p. 155–156 °C; IR (KBr, νmax/cm–1):
3079, 3003 (ν CH on benzene), 2952–2550 (ν OH on COOH), 2921,
2877 (ν CH on cyclopropyl), 1680 (ν C=O), 1600, 1586, 1519, 1445
(ν C=C), 1270, 1225 (ν C–O–Ar), 1135–1003, 844, 812 (ν CH on
1
1
1239–1001, 868, 807 (δ CH on benzene), 750 (δ CH on pyridine). H
benzene). H NMR (600 MHz, DMSO‑d6): δ 12.64 (s, 1 H, COOH),
7.52 (d, J=8.3 Hz, 1 H, CH on benzene), 7.42 (s, 1 H, CH on benzene),
7.01 (d, J=8.4 Hz, 1 H, CH on benzene), 3.90 (d, J=6.0 Hz, 2 H,
NMR (400 MHz, DMSO‑d6): δ 10.43 (s, 1 H, NH), 8.74 (s, 2 H, CH on
pyridine), 7.64 (d, J=8.4 Hz, 1 H, CH of benzene), 7.57 (s, 1 H, CH of
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JOURNAL OF CHEMICAL RESEARCH 2014 509
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