Sequential synthesis of a new analogue of amlodipine bearing a short amino polyethyleneglycol chain

Article abstract of DOI:10.1016/j.tet.2007.08.111

3-Ethyl 5-methyl 2-[(2-(2-(2-aminoethoxy)ethoxy)ethoxy)methyl]-4-(2-chlorophenyl)-6-methy l-1,4-dihydropyridine-3,5-dicarboxylate as new analogue of amlodipine was prepared in five steps with an overall yield of 22%. The 1,4-dihydropyridine nucleus was built in two steps via Knoevenagel reaction and the amino group of this analogue has been prepared in good yield by Staudinger reduction of the azido 1,4-dihydropyridine precursor in the last step.

Full text of DOI:10.1016/j.tet.2007.08.111

Tetrahedron 63 (2007) 12081–12086
Sequential synthesis of a new analogue of amlodipine bearing
a short amino polyethyleneglycol chain
Jean Christophe Legeay,a Jean Jacques Vanden Eyndeb and Jean Pierre Bazureaua,
*
a
´
´
´
Universite de Rennes 1, Laboratoire Sciences Chimiques de Rennes, UMR 6226, Groupe Ingenierie Chimique & Molecules pour le
´ ´
Vivant (ICMV), Ba^t. 10A, Campus de Beaulieu, Avenue du General Leclerc, CS 74205, 35042 Rennes Cedex, France
b
´
´
´
´
Universite de Mons-Hainaut, Academie Universitaire Wallonie-Bruxelles, Faculte des Sciences, Departement de Chimie Organique,
20 Place du Parc, 7000 Mons, Belgium
Received 5 July 2007; revised 28 August 2007; accepted 31 August 2007
Available online 6 September 2007
Abstract—3-Ethyl 5-methyl 2-[(2-(2-(2-aminoethoxy)ethoxy)ethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicar-
boxylate as new analogue of amlodipine was prepared in five steps with an overall yield of 22%. The 1,4-dihydropyridine nucleus was built
in two steps via Knoevenagel reaction and the amino group of this analogue has been prepared in good yield by Staudinger reduction of the
azido 1,4-dihydropyridine precursor in the last step.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
ischaemia. In the 1990s, progress has been made in the
search for new 1,4-DHPs with wider applicability, mainly
characterized by a longer duration of action.
Many 1,4-dihydropyridine (1,4-DHP) derivatives have been
studied as a consequence of their pharmacological profile
and as the most important calcium channel blockers.1 The
original lead compound in the class of 1,4-DHP is nifedi-
pine2 (Fig. 1), which is widely used today for the treatment
of cardiovascular disease. 1,4-DHPs have undergone several
changes to optimize their efficacy and safety. 1,4-DHPs can
be classified according to their kinetic properties and/or
pharmacodynamic properties. Lacidipine and lercanidipine
(Fig. 1) represent the 1,4-DHPs of the fourth generation
and these highly lipophilic agents3 provide a real degree of
therapeutic comfort in terms of stable activity in myocardial
Amlodipine4 (Fig. 1) is comparable from a dynamic point of
view to nifedipine5 and is in late stage clinical evaluation for
the once-daily treatment of angina and hypertension.6 Amlodi-
pine differed from the other 1,4-DHP drugs in possessing a basic
side chain7 linked to the DHP 2-methyl group via an ether oxy-
genatomandstronglyinfluencestheionizationandlipophilicity
profiles of the drug. Recent structure relationship of new gener-
ation of 1,4-DHPs indicated that the presence of oxypropanol-
amine moiety on phenyl ring at the 4-position8 of the DHP
nucleus exhibit the b- or a-/b-adrenoceptor blocking activities.9
NO2
Cl
CO2Et
CO2tBu
CO2Et
O
NO2
CO2Me
MeO2C
Me
MeO2C
Me
MeO2C
Me
MeO2C
Me
O
N
Me
O
N
H
NH2
N
H
Me
N
H
Me
N
H
Me
Amlodipine
Nifedipine
Lacidipine
Lercanidipine
Figure 1. Chemical structures of amlodipine, nifedipine, lacidipine and lercanidipine.
Keywords: Analogue of amlodipine; Knoevenagel reaction; 1,4-Dihydropyridine; Staudinger reduction.
* Corresponding author. Fax: +33 (0)2 23 23 63 74; e-mail: jean-pierre.bazureau@univ-rennes1.fr
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.111

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J. C. Legeay et al. / Tetrahedron 63 (2007) 12081–12086
2-chloro
benzaldehyde
Cl
HO
O
Cl
O
Cl
O
MeO2C
Me
CO2Et
X
MeO2C
Me
CO2Et
O
O
NH3
"ammonia"
NH2
O
N
O
NH2
H
β-keto ester
(X = Cl, Br)
analogue of Amlodipine
amino crotonate
Figure 2. Components used for the synthesis of a new analogue of amlodipine.
Taking into consideration that nearly all the DHP drugs were
essentially neutral molecules with low aqueous solubility and
lipophilicity, we chose to focus on a basic DHP derivative
with a short amino polyethyleneglycol chain appended to
the DHP 2-methylgroup. Our aim in thisstudy was to develop
a convenient, robust and high yielding reaction protocol for
the preparation of this new derivative of amlodipine (Fig. 2).
ester, 2-chlorobenzaldehyde and methyl 3-methylamino-
crotonate as building blocks afforded low yield. To circum-
vent this drawback, we decided to develop a sequential
approach via solution-phase organic synthesis for this new
lipophilic derivative of amlodipine. As shown in Scheme
1, the key step of our strategy towards the 1,4-DHP nucleus
is based on the product 6 by Knoevenagel reaction.14
In the first step, we chose commercially available 2-chloro
alcohol 1 as a spacer building block. Complete transforma-
tion of the chloro alcohol 1 into azide 2 was accomplished
after 38 h in refluxed EtOH with the presence of NaI15
according to a modified known procedure16 that gave the
desired stable17 azido compound 2 in 97% yield.
2. Results and discussion
Most of the 1,4-DHPs were prepared by a procedure first de-
scribed by Hantzsch in 1882. Experimentally, the preparation
of the 1,4-DHPs involves a three component, one-step cyclo-
condensation, because multicomponent reactions (MCRs)
constitute an attractive synthetic strategy for rapid and effi-
cient library generation due to the fact that the products are
formed in a single step, and the diversity can be simply
achieved by varying the reacting components. Owing to their
productivity and convergence, the MCRs have attracted con-
siderable attention from the point of view of combinatorial
chemistry.10 For this project, the 1,4-DHP moiety can be built
(Fig. 2) from methyl 3-methylaminocrotonate, ethyl 4-halo-
geno-3-oxo-butanoateasb-ketoester, 2-chlorobenzaldehyde,
2-[2-(2-chloroethoxy)ethoxy)]ethanol as precursor of the
short amino polyethyleneglycol side chain of the 1,4-DHP
nucleus, ammonia or a synthetic equivalent of ammonia.
Next, the preparation of the required b-keto ester 4 started
with 2-[2-(2-azidoethoxy)ethoxy]ethanol 2. Initially, our
studies started by the reaction of azido compound 2 and ethyl
4-chloro-3-oxobutanoate 3 as b-keto ester at 20 ꢀC using
various solvents (MeCN, THF) and various quantities of
NaH and NaI (Table 1). Among the conditions studied (entry
4), we found that an equimolecular mixture of compounds 2
and 3 with the presence of NaH18 (3 equiv) in THF gave
good conversion (4: 77%) after 24 h.
With the ethyl 4-{2-[2-(2-azidoethoxy)ethoxy]ethoxy}-3-
oxo butanoate 4 in hand, we have examined two experimen-
tal protocols for the synthesis of the Knoevenagel building
block 6 in step 3. As illustrated in Table 2, the two methods
investigated for the preparation of the Knoevenagel product
6 are presented. In the first method7 (A), the azido b-keto
In the original synthesis of amlodipine by the Pfizer group,11
the construction of the 1,4-DHP moiety12 by a three compo-
nent Hantzsch condensation13 from 2-azidoethoxy b-keto
O
O
O
N3
O
O
i
ii
EtO
O
HO
O
N3
N3
HO
Cl
2
2
2
EtO2C
Cl
1
2 (97%)
4 (77%)
O
3
O
O
Cl
CO2Et
iii
iv
MeO2C
7
EtO
O
MeO2C
Me
2
Me
O
5
O
N3
N
O
Cl
NH2
6 (76%)
H
Cl
2
8 (53%)
Cl
CO2Et
v
MeO2C
Me
9 (74%)
overall
yield: 22%
O
O
N
H
O
NH2
Scheme 1. Reagents and reaction conditions: (i) NaN3 (2 equiv), NaI (2 equiv), abs EtOH, reflux, 38 h; (ii) NaH (60% mineral oil), THF, 1.5 h at 0 ꢀC then 3
(1 equiv), 25 ꢀC, 24 h; (iii) 5, piperidine, Me2CHOH, 40 ꢀC, 1 h, glacial AcOH, 0 ꢀC then 25 ꢀC, 19 h; (iv) 7 (1 equiv), abs EtOH, reflux, 60 h; (v) Ph3P
(1.3 equiv), THF, 25 ꢀC, 2 h, deionized H2O (25 equiv), reflux, 48 h.

J. C. Legeay et al. / Tetrahedron 63 (2007) 12081–12086
12083
Table 1. Results of reaction conditions evaluated for the preparation of ethyl
4-{2-[2-(2-azidoethoxy)ethoxy]ethoxy}-3-oxo butanoate 4
gel and was eluted with CH2Cl2/AcOEt (9:1, 8: Rf¼0.4) in
moderate yield (53%). The structure of the 1,4-DHP 8 was
ascertained by high-resolution mass spectrometry, proton
and carbon NMR confirming that the major compound is
the expected 1,4-DHP.
Entry
Solvent
Reaction time
(hour)
NaH
(equiv)
NaI
(equiv)
Yielda
(%)
b
1
2
3
4
MeCN
THF
THF
16
24
24
24
2
2
3
3
0
0
1
0
—
30
68
77
For the last step, our focus was the transformation of the azi-
do 1,4-DHP 8 into amino derivative 9 of amlodipine. To the
best of our knowledge, all the common methods for reduction
of azides are based on hydride20 (LiAlH4 in THF), tin(II)
chloride21 or zinc dust12 in methanol, or palladium-catalyzed
hydrogenolysis.7,22 This implies that specific tedious syn-
thetic protocol has to be devised for each new compound.
In 1919, Staudinger and Meyer reported that azides react
smoothly with triaryl phosphanes to form iminophosphor-
anes.23,24 If the Staudinger reaction is carried out in aque-
ous solvent, the readily formed iminophosphorane is
hydrolyzed rapidly to generate a primary amine and phos-
phane(V) oxide. The so-called Staudinger reaction is a fre-
quently used method25 for the smooth reduction of azides
to amines. On the basis of the recent works of the Shiba-
saki26 and Cho27 groups, the reduction of the azido group
of 8 was tried under several experimental conditions
(Table 4). The best results (entry 3) were encountered
by reaction of 1.3 equiv of triphenylphosphine with azido
product 8 in tetrahydrofuran, followed by addition of
25 equiv of deionized water and heating under reflux for
48 h. Pure amino 1,4-DHP 9 was obtained at this stage by
chromatography on alumina gel with CH2Cl2/AcOEt (9:1) as
eluent. The final 3-ethyl 5-methyl 2-[(2-(2-(2-aminoethoxy)-
ethoxy)ethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-
dihydropyridine-3,5-dicarboxylate 9 was obtained in 74%
yield.
THF
a
Isolated yield.
Decomposition.
b
Table 2. Results for the preparation of Knoevenagel product 6 according to
the methods A and B
Entry Reaction
Aldehyde 5 Reaction
temperature (ꢀC)
Yieldc (%)
conditions (equiv)
1
2
3
4
Method Aa 1.05
Method A
Method Bb 1.1
Method B 1.1
110
110
20
5
21
2
76
Decomposition
90
a
Method A: piperidinium acetate in C7H8, 110 ꢀC, 24 h.
Method B: (i) piperidine 0.5%, Me2CHOH, 40 ꢀC, 2 h. (ii) AcOH 9%,
0 ꢀC, 1 h. (iii) 25 ꢀC, 19 h.
b
c
Isolated yield.
ester 4 was coupled with 2-chlorobenzaldehyde 5 in the pres-
ence of piperidinium acetate (10%) in toluene at 110 ꢀC for
24 h. In the second method18 (B), a mixture constituted by
b-keto ester 4, 1.1 equiv of 2-chlorobenzaldehyde 5 and
a catalytic amount of piperidine (4.5%) in isopropanol was
heated at 40 ꢀC for 1 h, followed by addition of glacial acetic
acid (9%) at 0 ꢀC. Then the reaction mixture is mixed at
room temperature over a period of 19 h.
Table 4. Reaction conditions used for Staudinger reaction
Entries 1 and 2 (method A) show that at a high temperature
(110 ꢀC) low yield for 6 is associated to the formation of un-
desired by-products according to H NMR analysis of the
Entry Reaction
Reaction time PPh3
(equiv) (equiv)
Deionized water Yieldc
(%)
1
conditions (hour)
crude reaction mixture. It can be observed that the optimal
reaction conditions were obtained with the method B at
25 ꢀC (entry 3), to produce the desired product 6 in good
yield (76%) as a mixture of stereoisomers Z/E (1/1).
1
2
3
Method Aa 48
1.5
2
1.3
25
25
25
14
30
74
Method Aa 24
Method Bb 48
a
b
c
Method A: stirred mixture of 8 with PPh3 and deionized water at room
temperature.
Method B: (i) 8, PPh3 (1.3 equiv), THF, 2 h, 25 ꢀC. (ii) deionized water
(25 equiv), reflux, 48 h.
Isolated yield.
In the fourth step, we have evaluated the reactivity of the
Knoevenagel product 6 and methyl 3-methylaminocrotonate
7 for the preparation of the 1,4-DHP 8 with various quantities
of 7 in isopropanol19 or EtOH at 90 and 79 ꢀC, respectively
(Table 3). The reactions were conveniently monitored by
1H NMR or by TLC and among the conditions studied (entry
3), we found that reaction of 6 with 1 equiv of crotonate 7 in
EtOH at 79 ꢀC gave good conversion after 60 h. The crude
1,4-DHP was purified by column chromatography on silica
3. Conclusion
In summary, we developed the synthesis of new analogue of
amlodipine in five steps with an overall yield28 of 22% start-
ing from 2-[2-(2-chloroethoxy)ethoxy]ethanol 1. The key
steps of this sequential solution-phase organic synthesis
are the Knoevenagel condensation in step 3 (76%) and trans-
formation of the azido 1,4-DHP 8 into new amino analogue
of amlodipine 9 by smooth Staudinger reduction conditions
(74%). This useful approach may be used as an alternative
route to provide a new 1,4-dihydropyridine bearing a short
amino polyethyleneglycol side chain as new analogue amlo-
dipine drug. We are currently exploring the scope of this
methodology for the preparation of new 1,4-dihydropyridines
derived from amlodipine that will be much more reliable
for biological screening.
Table 3. Optimization of reaction conditions used for the preparation of azi-
do 1,4-DHP 8
Entry Solvent
Reaction
Reaction time
7
Yielda
(equiv) (%)
temperature (ꢀC) (hour)
1
2
3
Me2CHOH 90
Me2CHOH 90
48
64
60
1
1.1
1
39
20
53
EtOH
79
a
Isolated yield.

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J. C. Legeay et al. / Tetrahedron 63 (2007) 12081–12086
4. Experimental
was dispersed in freshly dry tetrahydrofuran (10 mL). To
this slurry was added dropwise 2-[2-(2-azidoethoxy)ethoxy]-
ethanol 2 (1.375 g, 7.85 mmol, dissolved in 5 mL of tetrahy-
drofuran) at 0 ꢀC over a period of 60 min. The mixture was
stirred for 30 min at 0 ꢀC, after which ethyl 4-chloro-3-oxo-
butanoate 3 (1.05 mL, 7.85 mmol dissolved in 5 mL of dry
tetrahydrofuran) was added dropwise at 0 ꢀC over 30 min.
The reaction mixture was stirred at 25 ꢀC over a period of
24 h. After elimination of the solvent in a rotary evaporator
under reduced pressure, the residue was poured in water
(20 mL) and it was acidified at pH 3 with 1 M hydrochloric
acid. The mixture was transferred to a separating funnel and
was extracted with dichloromethane (3ꢁ20 mL). The com-
bined organic phases were dried over MgSO4, filtered and
the solvent was eliminated in vacuo. The residue was puri-
fied by column chromatography (silica gel 60 F 254 Merck,
column dimensions 16.0ꢁ2.4 cm, AcOEt/CH2Cl2 (1:1) as
eluent). The desired product 4 was obtained as a yellowish
oil after pooling and evaporation of the appropriate fractions
(Rf¼0.63) and was further dried under high vacuum
(10ꢂ2 Torr) at 25 ꢀC for 4 h (yield¼77%). 1H NMR
(300 MHz, CDCl3) d: 1.28 (t, 3H, J¼7.1 Hz, CH2CH3);
3.39 (t, 2H, J¼4.9 Hz, H-13); 3.54 (s, 2H, H-4); 3.68 (m,
10H, H-6, H-7, H-9, H-10, H-12); 4.19 (m, 4H, J¼7.1 Hz,
H-2, CH2CH3). 13C NMR (75 MHz, acetone-d6) d: 13.86
(CH3CH2); 45.63 (C-2); 50.41 (C-13); 61.11 (CH2CH3);
69.81–70.42–70.88 (C-12, C-7, C-6, C-9, C-10), 76.00 (C-
4); 166.83 (C-1); 201.80 (C-3). HRMS m/z: found
4.1. General
Thin-layer chromatography (TLC) was accomplished on
0.2-mm precoated plates of silica gel 60 F-254 (Merck) or
neutral alumina oxide gel 60 F-254 (Merck). Visualization
was made with ultraviolet light (254 and 365 nm) or with
a fluorescence indicator. For preparative column chromato-
graphy, silica gel 60F 254 Merck (230–240 mesh ASTM)
1
and neutral alumina oxide gel 90 (Merck) were used. H
NMR spectra were recorded on BRUKER AC 300 P
(300 MHz) and BRUKER ARX 200 (200 MHz) spectrome-
ters, 13C NMR spectra on BRUKER AC 300 P (75 MHz)
spectrometer. Chemical shifts are expressed in parts per mil-
lion downfield from tetramethylsilane as an internal stan-
dard. Data are given in the following order: d value,
multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; br, broad), number of protons, coupling constants
J (in hertz). The mass spectra (HRMS) were taken, respec-
tively, on a MS/MS ZABSpec TOF Micromass (EBE TOF
geometry) at an ionizing potential of 8 eVor on a VARIAN
MAT 311 at an ionizing potential of 70 eV in the Centre
ꢀ
Regional de Mesures Physiques de l’Ouest (CRMPO, Ren-
nes). Acetonitrile was distilled over calcium chloride after
standing overnight and stored over molecular sieves (3 A).
Solvents were evaporated with a BUCHI rotary evaporator.
All reagents were purchased from Acros, Aldrich Chimie,
Fluka France and used without further purification.
˚
ꢃ
303.1330 (calculated for C12H21N3O6 [M+ ] requires
303.1447).
4.2. 2-[2-(2-Azidoethoxy)ethoxy]ethanol (2)
4.4. Ethyl 4-{[2-[2-(2-azidoethoxy)ethoxy]ethoxy]-
acetyl}-3-(2-chlorophenyl)acrylate (6)
In a 100 mL two-necked round-bottomed flask, provided
with a magnetic stirrer and reflux condenser, 2-[2-(2-chloro-
ethoxy)ethoxy]ethanol 1 (4.053 g, 23.07 mmol) and sodium
azide (3.030 g, 46.12 mmol, 2 equiv) were dispersed in
absolute ethanol (30 mL). To this mixture, sodium iodide
NaI (6.920 g, 46.16 mmol) was added portion wise and the
reaction mixture was stirred at room temperature. The result-
ing yellowish solution was heated at 79 ꢀC for 38 h under
vigorous magnetic stirring, then cooled down to room tem-
perature. The solvent was evaporated in vacuo. The residue
was poured in water (100 mL) and was extracted with meth-
ylene chloride (2ꢁ100 mL). The combined organic phases
were dried over MgSO4, filtered and the solvent was elimi-
nated in a rotary evaporator under reduced pressure. After
evaporation, the desired azido alcohol 2 was further dried
under high vacuum (10ꢂ2 Torr) at 25 ꢀC for 4 h and was ob-
In a 25 mL round-bottomed flask, provided with a magnetic
stirrer, ethyl 4-{2-[2-(2-azidoethoxy)ethoxy]ethoxy}-3-oxo
butanoate 4 (428 mg, 1.41 mmol) and 2-chlorobenzaldehyde
5 (175 mL, 1.54 mmol) were mixed in isopropanol p.a.
(5 mL). To this solution was added dropwise a solution of pi-
peridine (15 mL, 13 mg, 0.15 mmol) in 5 mL of isopropanol
p.a. over a period of 2 h. A reflux condenser was then fitted
and the reaction mixture was heated at 40 ꢀC for 1 h. After
cooling down to 0 ꢀC, glacial acetic acid (17 mL, 17.7 mg,
0.3 mmol) was added in one portion. After stirring at room
temperature for 19 h, the crude reaction mixture was submit-
ted to purification by column chromatography on silica gel
with CH2Cl2/AcOEt (9:1) as eluent. Pooling and evaporation
of the solvent in vacuo afforded the expected product 6 as
a yellowish oil. The mixture of the stereoisomers Z/E29
(1:1) was dried under high vacuum (10ꢂ2 Torr) for 4 h at
25 ꢀC. Yield¼76%. E-isomer: 1H NMR (300 MHz,
CDCl3) d: 1.33 (t, 3H, J¼7.1 Hz, CH2CH3); 3.36 (t, 2H,
J¼4.9 Hz, H-1300); 3.61 (m, 10H, H-600, H-700, H-900, H-
1000, H-1200); 4.18 (s, 2H, H-400); 4.31 (q, 2H, J¼7.1 Hz,
CH2CH3); 7.22–7.44 (m, 4H, H-60, H-50, H-40, H-30); 8.05
(s, 1H, H-3). 13C NMR (75 MHz, acetone-d6) d: 13.75
(CH3CH2); 50.25 (C-1300); 61.39 (CH2CH3); 69.61–70.14–
70.21–70.50 (C-120, C-70, C-60, C-90, C-100); 76.00 (C-400);
126.75–129.53–129.85–131.01 (C-60, C-50, C-40, C-30);
131.27 (C-10); 133.39 (C-20); 134.11 (C-2); 139.40 (C-3);
163.40 (C-1); 201.54 (C-300). Z-isomer: 1H NMR
(300 MHz, CDCl3) d: 1.33 (t, 3H, J¼7.1 Hz, CH2CH3);
3.36 (t, 2H, J¼4.9 Hz, H-1300); 3.58 (m, 10H, H-600, H-700,
1
tained as a mobile colourless oil in 97% yield. H NMR
(300 MHz, CDCl3) d: 2.32 (br s, 1H, OH); 3.39 (t, 2H,
J¼5.2 Hz, H-9); 3.60 (t, 2H, J¼5 Hz, H-8); 3.67 (m, 6H,
H-6, H-5, H-3); 3.73 (t, 2H, J¼4.9, 4.1 Hz, H-2). 13C
NMR (75 MHz, acetone-d6) d: 50.40 (C-9); 61.42 (C-2);
69.78–70.12–70.39–72.35 (C-3, C-5, C-6, C-8). HRMS m/z:
ꢃ
found 119.0705 (calculated for C5H11O3 [Mꢂ CH2N3]+
requires 119.0708).
4.3. Ethyl 4-{2-[2-(2-azidoethoxy)ethoxy]ethoxy}-3-oxo
butanoate (4)
In a 50 mL two-necked round-bottomed flask, provided with
a magnetic stirrer and nitrogen inlet, sodium hydride
(0.945 g of a 60% suspension in mineral oil, 23.63 mmol)

J. C. Legeay et al. / Tetrahedron 63 (2007) 12081–12086
12085
H-900, H-1000, H-1200); 4.13 (q, 2H, J¼7.2 Hz, CH2CH3); 4.45
(s, 2H, H-400); 7.14–7.37 (m, 4H, H-60, H-50, H-40, H-30); 7.90
(s, 1H, H-3). 13C NMR (75 MHz, acetone-d6) d: 13.63
(CH3CH2); 50.56 (C-1300); 61.47 (CH2CH3); 69.92–70.57–
70.98 (C-120, C-70, C-60, C-90, C-100); 74.88 (C-400);
126.56–129.47–129.67–131.15 (C-60, C-50, C-40, C-30);
132.26 (C-10); 133.69 (C-20); 134.53 (C-2); 139.90 (C-3);
166.07 (C-1); 194.44 (C-300).
4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-di-
carboxylate 9 in 74% yield as a yellowish oil. H NMR
1
(300 MHz, CDCl3) d: 1.11 (t, 3H, J¼7.1 Hz, OCH2CH3);
2.07 (br s, 2H, NH2); 2.29 (s, 3H, CH3); 2.84 (br s, 2H, H-
16); 3.48 (br s, 2H, H-15); 3.54 (s, 3H, OCH3); 3.61–3.64
(m, 8H, H-9, H-10, H-12, H-13); 3.97 (dq, 2H, J¼7.2,
1.3 Hz, OCH2CH3); 4.62 (d, 1H, J¼16.4 Hz, H-7); 4.73 (d,
1H, J¼16.5 Hz, H-7); 5.34 (s, 1H, H-4); 6.97 (dt, 1H,
J¼7.7, 1.6 Hz, H-40); 7.06 (dt, 1H, J¼7.4, 1.2 Hz, H-50);
7.16 (dd, 1H, J¼7.9, 1 Hz, H-30); 7.31 (dd, 1H, J¼7.7,
1.5 Hz, H-60); 7.51 (br s, 1H, NH). 13C NMR (75 MHz, ace-
tone-d6) d: 14.10 (OCH2CH3); 18.96 (CH3); 37.07 (C-4);
41.42 (C-16); 50.55 (OCH3); 59.55 (OCH2CH3); 67.72 (C-
7); 69.99–70.44–70.46 (C-9, C-10, C-12, C-13); 72.82 (C-
15); 101.35 (C-5); 103.53 (C-3); 126.66–127.11–129.00–
131.32 (C-60, C-50, C-40, C-30); 132.10 (C-20); 144.30 (C-
2); 145.53 (C-6); 145.70 (C-10); 167.04 (CO2CH3); 167.89
(CO2Et). HRMS m/z: found 497.2054 (calculated for
C24H34 N2O735Cl [M+H]+ requires 497.2055).
4.5. 3-Ethyl 5-methyl 2-[(2-(2-(2-azidoethoxy)ethoxy)-
ethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-
dihydropyridine-3,5-dicarboxylate (8)
In a 50 mL round-bottomed flask fitted with a reflux
condenser, a solution of ethyl 4-{[2-[2-(2-azidoethoxy)eth-
oxy]ethoxy]acetyl}-3-(2-chlorophenyl)acrylate 6 (392 mg,
0.92 mmol) and methyl 3-methylaminocrotonate 7 (110 mg,
0.92 mmol) in absolute ethanol (10 mL) was refluxed under
vigorous magnetic stirring for 60 h. The solvent was elimi-
nated in a rotary evaporator under reduced pressure and the
crude residue was purified by column chromatography on sil-
ica gel with CH2Cl2/AcOEt (9:1) as eluent. Pooling of the ap-
propriate fractions (Rf¼0.4) and evaporation in vacuo
afforded a residue in 53% yield containing the desired com-
pound 8 as a yellowish oil. 1H NMR (300 MHz, CDCl3) d:
1.11 (t, 3H, J¼7.1 Hz, OCH2CH3); 2.28 (s, 3H, CH3); 3.32
(t, 2H, J¼4.9 Hz, H-16); 3.55 (s, 3H, OCH3); 3.58–3.67
(m, 10H, H-9, H-10, H-12, H-13, H-15); 3.97 (dq, 2H,
J¼7.2, 1.4 Hz, OCH2CH3); 4.64 (d, 1H, J¼16.8 Hz, H-7);
4.73 (d, 1H, J¼16.8 Hz, H-7); 5.36 (s, 1H, H-4); 6.97 (dt,
1H, J¼7.7, 1.7 Hz, H-40); 7.06 (dt, 1H, J¼7.6, 1.3 Hz, H-
50); 7.16 (dd, 1H, J¼7.8, 1.3 Hz, H-30); 7.30 (dd, 1H,
J¼7.7, 1.7 Hz, H-60); 7.36 (br s, 1H, NH). 13C NMR
(75 MHz, acetone-d6) d: 14.07 (OCH2CH3); 19.11 (CH3);
37.04 (C-4); 50.42 (C-16); 50.53 (OCH3); 59.51
(OCH2CH3); 67.76 (C-7); 69.84–70.06–70.42–70.57 (C-9,
C-10, C-12, C-13, C-15); 101.07 (C-5); 103.60 (C-3);
126.64–127.10–128.97–131.30 (C-60, C-50, C-40, C-30);
132.07 (C-20); 144.11 (C-2); 145.59 (C-6); 145.65 (C-10);
166.97 (CO2CH3); 167.86 (CO2Et). HRMS m/z: found
521.1801 (calculated for C24H30 N4O735Cl [MꢂH]+ requires
521.1803).
Acknowledgements
ꢁ
One of us (J.C.L.) wishes to thank the ‘Ministere de la
Recherche et de l’Enseignement Superieur’ for a research
ꢀ
ꢀ
fellowship. We also thank Dr. Pierre Guenot (CRMPO) for
the mass spectrometry measurements.
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