Synthesis and spectroscopic characterisation of novel roflumilast analogues

Article abstract of DOI:10.3184/174751913X13782291519608

A series of new N-heterocyclic or phenoxy substituted roflumilast analogues have been designed and synthesised. N-heterocyclic or phenoxy substituted benzaldehydes were first prepared from 3-hydroxy-4-methoxybenzaldehbyde and 1-bromo-3-chloropropane by an

Full text of DOI:10.3184/174751913X13782291519608

JOURNAL OF CHEMICAL RESEARCH 2013
OCTOBER, 583–585
RESEARCH PAPER 583
Synthesis and spectroscopic characterisation of novel roflumilast
analogues
Gangchun Sun*, Yuhui Si, Ge Song, Wenpeng Mai and Zhicheng Li
Chemistry and Chemical Engineering School, Henan University of Technology, Zhengzhou 450001, P. R. China
A series of new N-heterocyclic or phenoxy substituted roflumilast analogues have been designed and synthesised. N-heterocyclic
or phenoxy substituted benzaldehydes were first prepared from 3-hydroxy-4-methoxybenzaldehbyde and 1-bromo-3-
chloropropane by an alkylation reaction. The roflumilast analogues were then obtained by oxidation, acylation, amidation and
alkylation reactions. These compounds were characterised by 1H NMR, IR, ESI-MS and elemental analyses.
Keywords: roflumilast analogue, 3-hydroxy-4-methoxybenzaldehyde
Roflumilast is a phosphodiesterase 4 (PDE4) inhibitor which
was marketed in the European Union for the treatment of
chronic bronchitis in 2009, and in the USA in 2012, for the
treatment of chronic obstructive pulmonary disease (COPD).1,2
In addition to the treatment of COPD, it is used to treat
many inflammation related diseases2 including emphysema,3
asthma,4 diabetes mellitus5 and allergic rhinitis.6 However, it
still has some slight side effects, such as gastrointestinal upsets,
headache, and weight loss,7 which limit its therapeutic potential.
It is therefore important to discover novel PDE4 inhibitors with
a better therapeutic index.
In this study, we have synthesised a series of benzamide
compounds mostly starting from the archetypical inhibitor
roflumilast by introducing N-heterocyclic or substituted
phenoxy groups. We found that these compounds were a good
matchwiththePDE4enzymesbyusingthedrugdesignsoftware
Autodock Vina.12 We expect that these novel roflumilast
analogues will exhibit biological activity and this study is
ongoing. The structure of target molecules was confirmed by
IR and 1H NMR spectroscopy, mass spectrometry and element
analyses.
Results and discussion
The pharmacophores of roflumilast were a catechol ring,
pyridine group and two chlorine atoms (Fig. 1). In docking
with the PDE4 enzymes, the catechol ring is placed at the
hydrophobic clamp and the 3, 5-dichloropyridine group
extends to the divalent metal–ion site and forms a hydrogen
bond to a water molecule that is coordinated to Mg2+. The two
chlorine atoms also form additional hydrophobic interactions
with residues in the metal binding pocket.2 Research with
PDE4 inhibitors, including the chemical structures within the
pharmacophore models, showed that some heterocyclic groups,
such as morpholine, pyridine, piperidine, and piperazine could
play a major role in their biological activity.8–11
The synthetic strategies used for the preparation of the
“N-heterocyclic” type roflumilast analogues are illustrated
in Scheme 1. As shown in this Scheme, 1 was obtained
from 1-bromo-3-chloropropane and with 3-hydroxy-4-
methoxybenzaldehyde by an alkylation reaction. Then after
oxidation and acylation, 3 reacted with 3,5-dichloropyridin-4-
amine to give the key intermediate 4. Reaction with either an
N-heterocyclic or substituted phenol gave the products 5–10.
The conditions for the preparation of the key intermediate 4
was investigated using several methods. When we used DCC as
the dehydrating agent, the reaction was not successful. When
3 reacted with 3,5-dichloropyridin-4-amine, three conditions
were examined. The key intermediate 4 was obtained in high
yield when NaH was used as a base in anhydrous THF, but the
reaction did not proceed with CaH2 or without any base. This
indicated that the nucleophilic substitution activity of the amine
was reduced by the pyridine and by steric hindrance from the
two chlorine atoms at the ortho-position.
l
C
N
O
O
O
N
H
l
C
F
F
Fig. 1 Structure of roflumilast.
O
O
O
l
C
O
O
H
O
l
C
O
O
H
O
H
H
a
b
O
2
1
4
c
l
C
l
C
N
N
O
O
O
R
l
C
l
C
O
O
O
O
N
N
l
C
e
d
H
H
l
C
l
C
O
O
3
-
5 10
O
N
5
N
:
R
Reagents and conditions: (a) K2CO3, DMF, 75 °C, 10h; (b) CH3COOH,
HSO3NH2, NaClO2, 0–5 °C, 1h; (c)SOCl2, reflux; (d)NaH, DMF,
15–25 °C, 5h; (e): K2CO3, KI, DMF, 75 °C, 10h.
N
N
N
6
8
7
O
N
O2
Scheme 1 Synthesis of roflumilast analogues.
O
O
10
9
* Correspondent. E-mail: sungangchun@163.com
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584 JOURNAL OF CHEMICAL RESEARCH 2013
in thionyl chloride (15 mL) and the reaction mixture was refluxed
for 2 h. Then the excess thionyl chloride was evaporated to dryness
under vacuum to give intermediate 3. This was dissolved in dry
tetrahydrofuran (5 mL), and then added dropwise to a magnetically
stirred solution of 3,5-dichloropyridin-4-amine (1.46 g, 8.96 mmol)
and sodium hydride (4.04 g, 60% suspension) in dry tetrahydrofuran
(10 mL) at 0 °C. The reaction mixture was stirred for 5 h at 15–25 °C and
acidified to pH 2 with hydrochloric acid (1 mol), and then extracted with
ethyl acetate (25 mL×3). The combined layer was washed with sodium
hydroxide solution (20 mL, 5%) and water (10 mL) and then dried over
anhydrous sodium sulfate and concentrated in vacuo. The crude product
was purified by column chromatography using PE-EA (4:1 in v:v)
as eluent to afford a white solid (0.81 g, 25% yield), m.p. 143–144 °C.
1H NMR (CDCl3, 400 MHz) δ 8.57 (1H, s), 7.68 (1H, s), 7.57 (1H, d,
J=7.3 Hz), 7.54 (1H, s), 6.98 (1H, d, J=8.6 Hz), 4.28 (2H, t, J= 5.4 H z),
3.96 (3H, s), 3.81 (2H, t, J=6.2 Hz), 2.36 (2H, q, J=6.1 Hz). IR (KBr) ν
(cm−1): 3226 (NH), 2933(–CH3), 1676 (CO). MS (m/z): 388.8 (M–). Anal.
Calcd for C16H15Cl3N2O3: C, 49.32; H, 3.88; N, 7.19. Found: C, 49.11; H,
3.86; N, 7.28%.
The reactions of 4 with piperidine, pyrrolidine were relatively
easy, but difficult with N-methyl piperazine or morpholine, and
when reacted with 2,6-dimethylpiperidine the corresponding
product could not be obtained. This showed that the activity of
heterocyclic ring was reduced by the greater steric hindrance of
the methyl groups.
The IR spectra of the products showed the N–H stretching
absorption at 3236–3217 cm–1, CH2 at 2970–2924 cm–1,
CO at 1726–1680 cm–1. The 1H NMR spectra showed the
pyridine proton resonance at a chemical shift δ ~8.55 ppm,
benzamide NH proton resonance at a chemical shift between
δ 7.78–7.61 ppm as a broad singlet, except for 5. The 2-proton
resonance of the benzene ring in most products appeared at δ
7.57–7.54 ppm. This was a doublet signal because of long range
coupling. The 6-proton resonance was a doublet–doublet signal
at δ 7.55–7.50 ppm, while the 5-proton resonance appeared at
δ 7.08–6.93 ppm as a doublet. The methyl proton resonance
always appeared at δ 3.94 ppm as a singlet. The structure of the
products was further proved by mass spectroscopic data.
N-(3,5-Dichloropyridin-4-yl)-4-methoxy-3-(3-morpholinopropoxy)
benzamide (5): A mixture of 4 (1.25 g, 3.21 mmol), potassium carbonate
(0.53 g, 3.85 mmol) and potassium iodide (0.33 g) in DMF (7 mL) was
stirred at room temperature for 30 min. Morpholine (0.56 g, 6.42 mmol)
was added dropwise over 5 min. Then the mixture was heated to 75 °C
for 10 h. The reaction mixture was poured onto ice water (50 mL) and
extracted with dichloromethane (20 mL×2). The combined organic layer
was washed with water (50 mL×2). It was then dried over anhydrous
sodium sulfate and concentrated in vacuo. The crude product was
purified by chromatography using PE-EA (3:1–1:1) as eluent to afford 5
as a yellow solid (0.29 g, 21% yield), m.p. 146–147 °C. 1H NMR (CDCl3,
400 MHz) δ 8.56 (2H, s), 7.74 (1H,s), 7.55 (1H, d, J =1.9 Hz), 7.53 (1H,
dd, J=8.4 Hz, 1.8 Hz), 6.96 (1H, d, J=8.4 Hz), 4.19 (2H, t, J = 6.6 H z),
3.94 (3H, s), 3.72 (4H, m), 2.56 (6H, m), 2.07 (2H, m). IR (KBr) ν (cm−1):
3236 (NH), 2933(–CH3), 1726 (CO). MS (m/z): 438.5 (M–). Anal. Calcd
for C20H23Cl2N3O4: C, 54.55; H, 5.26; N, 9.54. Found: C, 54.95; H, 5.51;
N, 9.38%.
Experimental
Melting points were determined by microscope melting point apparatus
and were uncorrected. 1H NMR spectra were recorded on a Bruker-400
spectrometer, using CDCl3 as the solvent and TMS as internal reference,
coupling constants J are given in Hz. IR spectra were recorded on
Prestige-21 Shimadzu IR Spectrophotometer in KBr pellets and
reported in cm–1. MS (ESI) spectra were collected using an Agilent LC-
MS 6310EV. Elemental analyses were measured with a Flash EA 1112
elemental analyser.
3-(3-Chloropropoxy)-4-methoxybenzaldehyde (1):
A
mixture
of 3-hydroxy-4-methoxy benzaldehyde (2.00 g, 13.14 mmol) and
potassium carbonate (2.20 g, 15.95 mmol) in DMF 15 mL was stirred
at room temperature for 30 min. 1-Bromo-3-chloropropane (1.69 mL,
17.09 mmol) was added dropwise over 5 min. Then the mixture was
heated to 75 °C for 10 h. After 3-hydroxy-4-methoxybenzaldehyde has
disappeared by analytical TLC (PE-EA, 2:1 in v:v), the reaction mixture
was poured onto ice water (50 mL) and extracted with dichloromethane
(25 mL×3). The combined organic layer was washed with sodium
hydroxide solution (30 mL, 8%), water (200 mL×3), then dried over
anhydrous sodium sulfate and concentrated in vacuo. The crude product
was purified by column chromatography using PE-EA (7:1 in v:v) as
eluent to afford 1 as a faint yellow solid (2.26 g, 75.3% yield), m.p. 52–
54 °C. 1H NMR (CDCl3, 400 MHz) δ 9.91 (1H, s), 7.54 (1H, dd, J= 8.1 H z,
1.8 Hz), 7.49 (1H, d, J=1.7 Hz), 7.05 (1H, d, J=8.2 Hz), 4.30 (2H, t,
J=5.9 Hz), 4.00 (3H, s), 3.85 (2H, t, J=6.3 Hz), 2.40 (2H, m). IR (KBr)
ν (cm−1): 2937 (–CH3), 1689 (CO), 1593, 1583, 1441 (Ph). MS (m/z): 227.8
(M–). Anal. Calcd for C11H13ClO3: C, 57.78; H, 5.73. Found: C, 57.49; H,
5.86%.
N-(3,5-dichloropyridin-4-yl)-4-methoxy-3-(3-(piperidin-1-yl)
propoxy)benzamide (6): The synthetic method followed that of 5 to give
1
a yellow solid 0.40 g,(yield 51%), m.p. 159–160 °C. H NMR (CDCl3,
400 MHz) δ 8.55 (2H, s), 7.78 (1H, s), 7.53 (1H, s), 7.51 (1H, d, J= 2.1 H z),
6.95 (1H, d, J=8.0 Hz), 4.16 (2H, t, J=6.7 Hz), 3.94 (3H, s), 2.50 (2H, t,
J=7.3 Hz), 2.39 (4H, s), 2.07 (2H, m), 1.60 (4H, m), 1.43 (2H, m). IR (KBr)
ν (cm−1): 3263 (NH), 2933 (–CH3), 1651 (CO). MS (m/z):436.8 (M–). Anal.
Calcd for C21H25Cl2N3O3: C, 57.54; H, 5.75; N, 9.59. Found: C, 57.07; H,
5.78; N, 9.72%.
N-(3,5-Dichloropyridin-4-yl)-4-methoxy-3-(3-(4-methylpiperazin-
1-yl)propoxy)benzamide (7): The synthetic method followed that of 5 to
give a yellow solid 0.42 g,(yield 36%), m.p. 162–163 °C. 1H NMR (CDCl3,
400 MHz) δ 8.56 (2H, s), 8.02 (1H,s), 7.54 (1H, d, J=1.8 Hz), 7.53 (1H,
dd, J=8.2 Hz, 1.8 Hz), 6.95 (1H, d, J=8.3 Hz), 4.17 (2H, t, J=6.6 Hz), 3.94
(3H, s), 2.57–2.48 (10H, m), 2.28 (3H, s). 2.07–2.03 (2H, m). IR (KBr)
ν (cm−1): 3246 (NH), 2937 (–CH3), 2790 (–CH2), 1647 (CO). MS (m/z):
451.8 (M–). Anal. Calcd for C21H26Cl2N4O3: C, 55.63; H, 5.78; N, 12.36.
Found: C, 55.26; H, 5.85; N, 12.49%.
3-(3-Chloropropoxy)-4-methoxybenzoic acid (2): Compound 1 (2.00 g,
8.75 mmol) was added to a solution of sulfamic acid (1.38 g, 14.21 mmol)
in acetic acid (9 mL). A solution of sodium chloride (1.23 g, 13.60 mmol)
in 4 mL of water was added slowly to this mixture with vigorous stirring,
whilst keeping the temperature in the range of 0–5 °C under ice-bath
conditions for 1 h. The reaction mixture was poured on water (100 mL),
and a milky precipitate appeared. After vigorous stirring for 5 min, and
then boiling for 20 min, the solid precipitate which was obtained was
collected by filtration, dried and then recrystallised from acetonitrile and
PE (1:1 in v:v) to give 2 as a white solid (1.96 g, 91.6% yield), m.p. 140–
N-(3,5-Dichloropyridin-4-yl)-4-methoxy-3-(3-(pyrrolidin-1-yl)
propoxy)benzamide (8): The synthetic method followed that of 5 to give
1
a white solid 0.56 g, (yield 36%), m.p. 160–161 °C. H NMR (CDCl3,
400 MHz) δ 8.56 (2H, s), 7.55 (1H, d, J=2.0 Hz), 7.54 (1H, dd, J= 8.7 H z,
2.5 Hz), 6.95 (1H, d, J=8.1 Hz), 4.19 (2H, t, J=6.8 Hz), 3.95 (3H, s),
2.65 (2H, t, J=7.3 Hz), 2.52 (4H, s), 2.12 (2H, m), 1.81 (4H, m). IR (KBr)
ν (cm−1): 3222 (NH), 2954 (–CH3), 2790 (–CH2), 1647 (CO). MS (m/z):
422.9 (M–). Anal. Calcd for C20H23Cl2N3O3: C, 56.61; H, 5.46; N, 9.90.
Found: C, 56.05; H, 5.54; N, 9.97%.
1
143 °C. H NMR (CDCl3, 400 MHz) δ 7.80 (1H, dd, J= 8.4H z, 1.8 H z),
7.63 (1H, d, J=1.8 Hz), 6.94 (1H, d, J=8.5 Hz), 4.23 (2H, t, J= 5.4 H z),
3.94 (3H, s), 3.80 (2H, t, J=6.1 Hz), 2.33 (2H, m). IR (KBr) ν (cm−1): 2918
(–CH3), 1685 (CO), 1597, 1583, 1437 (Ph). MS (m/z): 243.7 (M–). Anal.
Calcd for C11H13ClO4: C, 54.00; H, 5.36. Found: C, 53.79; H, 5.51%.
3-(3- Chloropropox y)-N-(3,5- dichloropyridin- 4-yl)- 4-
methoxybenzamine (4): Compound 2 (2.00 g, 8.17 mmol) was dissolved
N-(3,5-Dichloropyridin-4-yl)-4-methoxy-3-(3-(4-nitrophenoxy)
propoxy)benzamide (9): The synthetic method followed that of 5 to give
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JOURNAL OF CHEMICAL RESEARCH 2013 585
a faint yellow solid 0.27 g (yield 21%), m.p. 194–195 °C.1H NMR (CDCl3,
400 MHz) δ 8.57 (2H, s), 8.30 (1H, d, J=1.9 Hz), 8.18 (1H, d, J= 1.7 H z),
7.64 (1H, s),7.57 (1H, d, J=2.1 Hz), 7.54 (1H, dd, J=8.2 Hz, 2.0 Hz), 6.99
(1H, d, J=2.1 Hz), 6.97 (1H, d, J=1.7 Hz), 6.95 (1H, s), 4.32 (4H, m), 3.94
(3H, s), 2.42 (2H, m). IR (KBr) ν (cm−1): 3176 (NH), 2924 (–CH3), 1668,
1647 (CO). MS (m/z): 490.6 (M–). Anal. Calcd for C22H19Cl2N3O6: C,
53.67; H,3.89; N,8.54. Found: C, 53.12; H, 3.96;N, 8.93%.
3-(3-(4-Acetylphenoxy)propoxy)-N-(3,5-dichloropyridin-4-yl)-4-
methoxybenzamide (10): The synthetic method followed that of 5 to give
a white solid 0.36 g (yield 28.80%), m.p. 152–153 °C. 1H NMR (CDCl3,
400 MHz) δ 8.55 (2H, s),7.92 (1H, s), 7.90 (1H, s), 7.69 (1H, s), 7.57 (1H,
d, J=2.0 Hz), 7.55 (1H, dd, J=8.4 Hz, 1.8 Hz), 6.96 (3H, m), 4.32 (2H,
t, J=6.1 Hz), 4.27 (2H, t, J=6.0 Hz), 3.94 (3H, s), 2.54 (3H, s). 2.40 (2H,
m), IR (KBr) ν (cm−1): 3176 (NH), 2924 (–CH3), 2854 (–CH3), 1680, 1650
(CO). MS (m/z): 488.0 (M–). Anal. Calcd for C24H22Cl2N2O5: C, 58.91; H,
4.53; N, 5.72. Found: C, 58.72; H, 4.6; N, 5.81%.
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Received 30 May 2013; accepted 1 July 2013
Paper 1301978 doi: 10.3184/174751913X13782291519608
Published online: 7 October 2013
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