Synthesis and antibacterial activity of novel 15-membered macrolide derivatives: 4″-Carbamate, 11,12-cyclic carbonate-4″-carbamate and 11,4″-di-O-arylcarbamoyl analogs of azithromycin

Article abstract of DOI:10.1016/j.ejmech.2009.04.030

4″-Carbamate, 11,12-cyclic carbonate-4″-carbamate and 11,4″-di-O-arylcarbamoyl analogs of azithromycin were designed, synthesized and evaluated. The 4″-carbamate analogs retained excellent activity against erythromycin-susceptible Staphylococcus pneumonia

Full text of DOI:10.1016/j.ejmech.2009.04.030

European Journal of Medicinal Chemistry 44 (2009) 4010–4020
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antibacterial activity of novel 15-membered
macrolide derivatives: 400-Carbamate, 11,12-cyclic
carbonate-400-carbamate and 11,400-di-O-arylcarbamoyl
analogs of azithromycin
,
b
a
a
a
Shutao Ma a , Ruixin Ma , Zhaopeng Liu , Chenchen Ma , Xuecui Shen
*
a Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, Jinan, Shandong 250012, PR China
b Affiliated Hospital of Medical College, Qingdao University, Qingdao 266003, PR China
a r t i c l e i n f o
a b s t r a c t
400-Carbamate, 11,12-cyclic carbonate-400-carbamate and 11,400-di-O-arylcarbamoyl analogs of azi-
thromycin were designed, synthesized and evaluated. The 400-carbamate analogs retained excellent
activity against erythromycin-susceptible Staphylococcus pneumoniae and showed improved activity
against erythromycin-resistant Staphylococcus pneumoniae. Compared with 400-carbamate analogs,
11,12-cyclic carbonate-400-carbamate analogs exhibited improved activity against erythromycin-resistant
Staphylococcus pneumoniae encoded by the mef gene or the erm and mef genes, and 11,400-di-O-ary-
Article history:
Received 21 February 2009
Received in revised form
16 April 2009
Accepted 20 April 2009
Available online 3 May 2009
lalkylcarbamoyl analogs showed greatly improved activity (0.25–0.5 mg/mL) against erythromycin-
Keywords:
Synthesis
Macrolide
15-Membered macrolide analogs
Antibacterial activity
resistant Staphylococcus pneumoniae encoded by the erm gene. Among them, the novel series of
11,400-di-O-arylalkylcarbamoyl analogs 7a–k exhibited potent and balanced activity against susceptible
and resistant bacteria. In particular, compounds 7f and 7k were the most effective against susceptible
bacteria and resistant bacteria encoded by the erm gene or the mef gene.
Ó 2009 Elsevier Masson SAS. All rights reserved.
1. Introduction
production ofa methyltransferasewhich modifies the key nucleotide,
A2058, in the macrolide–lincosamide–streptogramin
B (MLSB)
Macrolide antibiotics have been used clinically for more than 50
years. They are used for the treatment of infections of the respiratory
tract, skin and soft tissue [1,2]. First-generation macrolides (e.g.,
erythromycin A) readily lose their antibacterial activity under acidic
conditions due to degradation. These degraded products are known
to be responsible for undesirable gastrointestinal side effects [3].
Second-generation macrolide antibioticssuch asazithromycin (Fig.1)
and clarithromycin have been widely prescribed for infections of the
upper and lower respiratory tracts because of their superior anti-
bacterial activity and pharmacokinetic properties compared with
first-generation macrolides [4]. The therapeutic utility of these
macrolides has led to rapid increase in the resistance rates of bacteria
isolated clinically [5]. The molecular mechanisms of macrolide
resistance are diverse, but the commonest mechanism of resistance is
mediated by erm-encoded methylation of 23S rRNA or mef-encoded
efflux. Expression of an erm-resistant determinant in bacteria leads to
binding site, thereby conferring resistance to macrolides [6–8].
Emergence of macrolide resistance has prompted further
research directed towards the discovery of third-generation mac-
rolides (e.g., ketolides) that can effectively address resistance and
other issues associated with current macrolide regimens [9].
Ketolides such as telithromycin and cethromycin may offer alter-
native therapy for Gram-positive infections attributable to resistant
pathogens [10]. Their mechanism of action has been elucidated: the
C-11,12 carbamate side chain or the C-6 side chain in the ketolides
interacts with nucleotide A752 directly in domain II of the 23S rRNA
in addition to the main interaction of the drugs in domain V. This
results in tighter binding to ribosomes [11], and imparts some
activity against methylated ribosomes in some species [12].
Significant efforts have gone into the discovery of increasingly
potent ketolides, but a substantial amount of work has also been
carried out on novel macrolide derivatives. These investigations have
led to the discovery of 11-O-substituted macrolides such as EP-1553
(Fig. 1) and 400-carbamate macrolides such as CP-544372 (Fig. 1)
[13,14]. EP-1553, which has an arylalkyl group tethered to the C-11
position of the erythronolide skeleton, exhibits excellent activity
against macrolide-resistant Staphylococcus aureus, Staphylococcus
* Corresponding author. Tel.: þ86 531 88382009; fax: þ86 531 88911612.
E-mail address: mashutao@sdu.edu.cn (S. Ma).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.04.030

S. Ma et al. / European Journal of Medicinal Chemistry 44 (2009) 4010–4020
4011
N
N
N
O
N
O
N
O
HO
OH
HO
OH
HO
OMe
O
H2N
HO
O
N
O
O
HO
HO
O
O
HO
HO
O
O
O
O
O
O
O
O
O
N
OH
OMe
O
O
O
OH
OMe
O
N
H
OMe
OCH3
Azithromycin
CP-544372
Fig. 1. Structures of azithromycin, EP-1553 and CP-544372.
EP-1553
pneumoniae and Staphylococcus pyogenes. CP-544372 contains a long
anchor group at the C-400 position of the cladinose sugar structure. It
demonstrates good in vitro and in vivo activity against macrolide-
resistant organisms with competitive binding to chloramphenicol,
suggesting that the anchor group reaches the peptidyl transferase
center region, the chloramphenicol-binding site [15,16].
On the basis of the considerations detailed above, we designed
novel structural 15-membered analogs of macrolides comprising
the essential features for addressing macrolide resistance due to
efflux and methylation of the ribosome. By introduction of an ary-
lalkyl or an alkyl group into the 400-position of azithromycin and the
400-position of 11,12-cyclic carbonate azithromycin, the 400-carba-
mate analogs of azithromycin and the 11,12-cyclic carbonate azi-
thromycin were synthesized, respectively. It has been reported
[15,16] that introduction of an arylalkyl group into the 400-position or
the 11-position of 14-membered macrolides enhances antibacterial
activity (particularly anti-resistant activity). Novel 11,400-di-O-aryl-
carbamoyl azithromycin analogs were prepared from 11,12-cyclic
carbonate azithromycin 400-carbamates on the basis of report [19]
that 11,12-cyclic carbonate azithromycin was treated with corre-
sponding amine in the presence of pyridine hydrochloride or
1-methyl-1H-imidazole to provide 11-carbamate of azithromycin.
Numerous chemical modifications of 14-membered macrolides to
overcome bacterial resistance have been investigated over previous
decades. Structure–activity relationships (SARs) of these
14-membered macrolide derivatives lead us to believe that the ary-
lalkyl groups attached to the lactone ring or the C-400 position of the
cladinose sugar structure are essential for overcoming MLSB resis-
tance, whereas the 11,12-cylic carbamate or the 11,12-cylic carbonate
linkage is important for overcoming efflux resistance. The structural
modification of existing antibiotics therefore remains as one of the
most effective approaches for overcoming bacterial resistance.
Azithromycin was the first 15-membered macrolide to have
nitrogen incorporated into the lactone ring. Azithromycin is supe-
rior to erythromycin with regard to having better antibacterial
activity as well as excellent pharmacokinetic properties and safety
profile. It is one of the most widely prescribed antibiotics, but
azithromycin is inactive against resistant bacteria. The azi-
thromycin skeleton is very similar to that of clarithromycin except
that the lactone ring is expanded around the 9-position [15,16].
They share a similar mechanism of action: selective binding to the
50S subunit of bacterial ribosome resulting in inhibition of protein
synthesis. It seems that azithromycin modifications have not been
systemically investigated since it was clinically used [17,18].
2. Chemistry
2.1. Synthesis of 400-carbamate azithromycin analogs
The synthetic method of 400-carbamate azithromycin analogs is
shown in Scheme 1. Protection of the 20-hydroxyl group of
azithromycin with acetic anhydride provided 20-O-acetylazi-
thromycin (2). The treatment of 2 with 1,10-carbonyldiimidazole
(CDI) in toluene at room temperature afforded 20-O-acetyl-400-O-
acylimidazolyl azithromycin (3). Finally, 400-carbamate azithromycin
analogs (4a–m) were prepared by coupling 3 with corresponding
N
O
N
N
O
AcO
OH
AcO
OH
HO
N
O
N
O
N
O
OH
O
a
HO
HO
HO
HO
HO
HO
b
O
O
O
O
O
O
O
O
O
O
O
O
O
OH
OMe
OH
OMe
O
OMe
N
N
3
Azithromycin
2
R1
=
=
=
=
=
=
=
=
4a
4b
4-hydroxyphenethyl
4-methoxybenzyl
4-fluorobenzyl
2-chlorophenethyl
benzyl
R1
N
O
4c R1
4d R1
4e R1
HO
OH
N
c,d
HO
HO
O
R1
4f
phenethyl
R1
4g
3,4-methylenedioxyphenethyl
propyl
4h R1
O
O
O
O
4i R1 = 2-propenyl
R1
4j R1
4k
=
=
=
=
butyl
pentyl
isopropyl
cyclohexyl
O
N
H
O
R1
OMe
R1
4l
4
4m R1
Scheme 1. Reagents and conditions: (a) acetic anhydride, CH2Cl2, Et3N, rt, 24 h; (b) CDI, Et3N, toluene, rt, 48 h; (c) R1NH2, DMF, DBU, rt, 12 h; (d) CH3OH, 55 ꢀC, 20 h.

4012
S. Ma et al. / European Journal of Medicinal Chemistry 44 (2009) 4010–4020
N
O
N
O
AcO
OH
AcO
OH
N
O
N
O
b, c
O
O
a
HO
HO
O
O
O
O
O
O
O
O
O
O
OH
OMe
O
OMe
N
N
2
5
R1 = 4-hydroxyphenethyl
R1 = 4-methoxybenzyl
R1 = 4-fluorobenzyl
R1 = 2-chlorophenethyl
R1 = benzyl
6a
6b
6c
6d
6e
6f
N
O
HO
OH
N
O
O
R1 = phenethyl
O
1 = 3,4-metyhlenedioxyphenethyl
6g
6h
6i
R
O
R1 = propyl
O
R1 = 2-propenyl
R1 = butyl
O
O
O
R1
6j
O
N
H
O
R1 = pentyl
6k
6l
OMe
R1 = isopropyl
1 = cyclohexyl
6
6m
R
Scheme 2. Reagents and conditions: (a) CDI, Et3N, toluene, 75 ꢀC, 24 h; (b) R1NH2, DMF, DBU, rt, 12 h; (c) CH3OH, 55 ꢀC, 20 h.
amines in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),
followed by methanolysis.
1-methyl-1H-imidazole at room temperature for 2–5 days in yields
ranging from 64% to 79%.
2.2. Synthesis of 11,12-cyclic carbonate azithromycin
400-carbamate analogs
3. Antibacterial activity
The antibacterial screening of 400-carbamate, 11,12-cyclic
carbonate-400-carbamate and 11,400-di-O-arylcarbamoyl analogs of
azithromycin prepared above was performed by a standard dilution
assay for the determination of minimal inhibitory concentrations
(MICs). MIC values for all compounds were determined in compar-
ison with azithromycin (AZM) and clarithromycin (CAM) on a panel
of sensitive and resistant Gram-positive bacterial strains. The strains
are Streptococcus pneumoniae ATCC49619 (erythromycin-susceptible
strain), Staphylococcus pneumoniae B1 (erythromycin-resistant
strain encoded by the erm gene), Staphylococcus pneumoniae A22072
(erythromycin-resistant strain encoded by the mef gene) and
Staphylococcus pneumoniae AB11 (erythromycin-resistant strain
encoded by the erm and mef genes).
Scheme 2 describes the synthesis of 11,12-cyclic carbonate azi-
thromycin 400-carbamate analogs starting from 2. 11,12-Carbonate
4-O-acylimidazolide 5 was prepared in toluene at 75 ꢀC by treat-
ment of 2 with CDI in the presence of triethylamine (Et3N). 11,12-
cyclic carbonate azithromycin 400-carbamate analogs (6a–m) were
prepared by treatment of 5 with corresponding amines in the
presence of DBU. This was followed by deprotection of the acetate
protection group with methanol at 55 ꢀC.
2.3. Synthesis of 11,400-di-O-arylalkylcarbamoyl
azithromycin analogs
11,400-Di-O-arylalkylcarbamoyl azithromycin analogs were
prepared from compounds 6a–d (Scheme 3). Compounds 6a–d,
which have an aromatic side chain at the 400-position of their cla-
dinose sugar structures, were readily converted to 11,400-di-O-ary-
lalkylcarbamoyl azithromycin analogs (7a–k) by coupling with the
corresponding amines in the presence of pyridine hydrochloride or
4. Results and discussion
MIC values for 400-carbamate analogs are presented in Table 1.
Most of the 400-carbamate analogs retained excellent activity
against erythromycin-susceptible Staphylococcus pneumoniae and
R1 = 4-hydroxyphenethyl, R2 = butyl
R2
O
7a
N
O
N
NH
7b R1 = 4-hydroxyphenethyl, R2 = 2-chlorophenethyl
HO
OH
HO
OH
7c R1 = 4-hydroxyphenethyl, R2 = benzyl
N
O
N
O
R1 = 4-methoxybenzyl,
R1 = 4-methoxybenzyl,
R1= 4-fluorobenzyl,
R1 = 4-fluorobenzyl,
R2 = pentyl
7d
O
O
O
O
a
O
O
R2 = butyl
7e
7f
O
R2 = phenethyl
R2 = 2-chlorophenethyl
HO
7g
O
O
O
O
O
O
7h R1 = 2-chlorophenethyl, R2 = pentyl
R1
R1
R1 = 2-chlorophenethyl, R2 = benzyl
7i
O
O
N
H
N
O
O
R1 = 2-chlorophenethyl, R2 = 4-fluorobenzyl
H
7j
OMe
OMe
R1 = 2-chlorophenethyl, R2 = 4-hydroxyphenethyl
7k
6
7
Scheme 3. Reagents and conditions: (a) R2NH2, pyridine hydrochloride or 1-methyl-1H-imidazole, rt, 2–5 days.

S. Ma et al. / European Journal of Medicinal Chemistry 44 (2009) 4010–4020
4013
Table 2
showed improved activity against erythromycin-resistant Staphy-
lococcus pneumoniae compared with azithromycin (AZM) and
clarithromycin (CAM). In particular, 400-O-arylalkylcarbamoyl
analogs possessed greatly improved and balanced activity against
erythromycin-resistant Staphylococcus pneumoniae compared with
400-O-alkylcarbamoyl analogs. Among 400-O-arylalkylcarbamoyl
analogs, compounds 4a, 4c, 4e and 4g showed potent activity
against erythromycin-resistant Staphylococcus pneumoniae enco-
In vitro antibacterial activity of 11,12-cyclic carbonate azithromycin 400-carbamate
analogs.
Compound
MICs (mg/mL)
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pneumoniae
ATCC49619a
B1b
A22072c
AB11d
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
<0.03
<0.03
0.06
0.06
<0.03
0.06
<0.03
0.06
0.12
0.12
0.06
8
8
8
8
8
1
4
16
4
2
8
0.25
0.06
0.25
0.12
0.06
0.06
0.12
1
1
8
8
2
ded by the mef gene (0.06–0.5
mg/mL), and compound 4e had the
most potent activity (0.06
m
g/mL). These results suggested that
introduction of the arylalkylcarbamoyl group into the 400-position
of 15-membered macrolides can enhance antibacterial activity
against erythromycin-resistant bacteria.
8
4
2
2
16
64
8
16
16
16
128
64
16
128
16
16
128
32
256
128
Compared with parent 400-carbamate analogs, 11,12-cyclic
carbonate azithromycin 400-carbamate analogs showed similar
activity against erythromycin-susceptible Staphylococcus pneumo-
niae and erythromycin-resistant Staphylococcus pneumoniae enco-
ded by the erm gene, and exhibited improved activity against
erythromycin-resistant Staphylococcus pneumoniae encoded by the
mef gene or the erm and mef genes (Table 2). Almost all of the tested
compounds with 400-O-arylalkylcarbamoyl groups showed
remarkably improved activity against erythromycin-resistant
Staphylococcus pneumoniae encoded by the mef gene or the erm and
mef genes, compared with compounds having 400-O-alkylcarbamoyl
groups. Among them, compounds 6c, 6f and 6g possessed the most
potent activity against erythromycin-resistant Staphylococcus
0.12
0.06
<0.03
<0.03
6m
AZM
CAM
4
4
a
S. pneumoniae ATCC49619: erythromycin-susceptible strain.
b
c
S. pneumoniae B1: erythromycin-resistant strain encoded by the erm gene.
S. pneumoniae A22072: erythromycin-resistant strain encoded by the mef gene.
S. pneumoniae AB11: erythromycin-resistant strain encoded by the erm and mef
d
genes.
suggested that introduction of an arylalkyl group into the
11-position of 400-O-arylalkylcarbamoyl analogs of 15-membered
macrolides greatly enhances their antibacterial activity against
erythromycin-resistant bacteria encoded by the erm gene. Most of
the tested compounds 7a–k (0.06–1
activity to the compounds 6a–d (0.06–1
activity than compounds 4a–d (0.25–4
mycin-resistant Staphylococcus pneumoniae encoded by the mef
gene. That is, most of the compounds 7a–k exhibited potent and
balanced activity against susceptible and resistant bacteria. Among
them, compounds 7f and 7k were the most effective against
susceptible bacteria and resistant bacteria encoded by the erm gene
or the mef gene, and compound 7g had the most potent activity
against susceptible bacteria and resistant bacteria encoded by the
erm and mef genes. These results demonstrate that the arylalkyl
side chain at the 11-position can interact with a new binding site of
nucleotide in domain II of the 23S rRNA, resulting in tighter binding
to ribosomes in macrolide-resistant bacteria.
pneumoniae encoded by the mef gene (0.06 mg/mL), showing 4-fold,
16-fold and 8-fold better activity than their precursors 4c, 4f and
4g, respectively. These results clearly indicated that introduction of
a cyclic carbonate into the 11,12-position of 15-membered macro-
lide 400-carbamate analogs, particularly 400-O-arylalkylcarbamoyl
analogs, dramatically enhance their antibacterial activity against
erythromycin-resistant bacteria encoded by the mef gene. This is
consistent with reports [20,21] that introduction of a cyclic
carbonate or carbamate into the 11,12-position of 14-macrolide
derivatives increases their antibacterial activity.
m
g/mL) retained similar potent
g/mL) and showed better
g/mL) against erythro-
m
m
MIC values for 11,40-di-O-arylalkylcarbamoyl analogs are shown
in Table 3. All the compounds (7a–k) showed greatly improved
activity (0.25–0.5
mg/mL) against erythromycin-resistant Staphylo-
coccus pneumoniae encoded by the erm gene in comparison with
their precursors 6a–d (8
mg/mL) and 4a–d (4–64
mg/mL). This
Table 1
5. Conclusion
In vitro antibacterial activity of 400-carbamate azithromycin analogs.
On the basis of the SARs of 14-membered macrolides, 400-carba-
mate, 11,12-cyclic carbonate-400-carbamate and 11,400-di-O-arylcar-
bamoyl analogs of azithromycin were designed, synthesized and
evaluated. Most of the 400-carbamate analogs retained excellent
activity against erythromycin-susceptible Staphylococcus pneumo-
niae and showed improved activity against erythromycin-resistant
Staphylococcus pneumoniae. In particular, 400-O-arylalkylcarbamoyl
analogs possessed greatly improved activity against erythromycin-
resistant Staphylococcus pneumoniae compared with 400-O-alkyl-
carbamoyl analogs. This suggested that introduction of the
arylalkylcarbamoyl group into the 400-position of 15-membered
macrolides can enhance antibacterial activity against erythromycin-
resistant bacteria. Compared with the parent 400-carbamate analogs,
most of the 11,12-cyclic carbonate-400-carbamate analogs exhibited
improved activity against erythromycin-resistant Staphylococcus
pneumoniae encoded by the mef gene or the erm and mef genes. This
clearly indicated that introduction of a cyclic carbonate into the
11,12-position of 15-membered macrolide analogs, particularly
400-O-arylalkylcarbamoyl analogs, dramatically enhances their
antibacterial activity against erythromycin-resistant bacteria
Compound
MICs (mg/mL)
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pneumoniae
ATCC49619a
B1b
A22072c
AB11d
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
<0.03
0.12
<0.03
<0.03
<0.03
0.06
<0.03
0.12
<0.03
<0.03
<0.03
0.12
4
64
4
8
16
8
0.5
4
0.25
1
0.06
1
0.5
4
1
1
0.5
8
8
2
32
16
8
64
32
8
64
32
128
32
256
128
256
128
8
64
16
8
8
128
32
128
64
4m
AZM
CAM
0.12
<0.03
<0.03
4
4
a
S. pneumoniae ATCC49619: erythromycin-susceptible strain.
b
c
S. pneumoniae B1: erythromycin-resistant strain encoded by the erm gene.
S. pneumoniae A22072: erythromycin-resistant strain encoded by the mef gene.
S. pneumoniae AB11: erythromycin-resistant strain encoded by the erm and mef
d
genes.

4014
S. Ma et al. / European Journal of Medicinal Chemistry 44 (2009) 4010–4020
Table 3
In vitro antibacterial activity of 11,400-di-O-arylalkylcarbamoyl azithromycin analogs.
Strain/compound
MICs (
m
g/mL)
7b
7a
7c
<0.03
0.25
0.12
7d
0.06
0.5
1
7e
7f
7g
7h
7i
7j
7k
AZM
CAM
S. pneumoniae ATCC49619a
S. pneumoniae B1b
<0.03
0.25
1
<0.03
0.25
0.25
16
0.06
0.5
1
<0.03
0.25
0.06
32
<0.03
0.25
0.12
2
<0.03
0.5
0.5
<0.03
0.25
0.25
4
0.06
0.25
0.25
4
<0.03
0.25
0.06
16
<0.03
128
4
<0.03
64
4
S. pneumoniae A22072c
S. pneumoniae AB11d
128
128
32
128
16
256
128
a
S. pneumoniae ATCC49619: erythromycin-susceptible strain.
S. pneumoniae B1: erythromycin-resistant strain encoded by the erm gene.
S. pneumoniae A22072: erythromycin-resistant strain encoded by the mef gene.
b
c
d
S. pneumoniae AB11: erythromycin-resistant strain encoded by the erm and mef genes.
encoded by the mef gene. 11,400-di-O-arylalkylcarbamoyl analogs
showed greatly improved activity (0.25–0.5 g/mL) against eryth-
(3 ꢁ10 mL). The combined organic layers were dried over anhy-
drous Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by flash chromatography (dichloromethane/methanol,
20:1) to afford 1.60 g (95%) of 3 as a white solid: mp 147–150 ꢀC;
Rf ¼ 0.59 (dichloromethane/methanol, 10:1); MS (ESI) m/z calcd. for
C44H76N4O14 884.5; found (M þ Hþ) 885.2.
m
romycin-resistant Staphylococcus pneumoniae encoded by the erm
gene in comparison with their precursors 11,12-cyclic carbonate-400-
carbamate analogs (8 m mg/
g/mL) or 400-carbamate analogs (4–64
mL). This suggested that introduction of an arylalkyl group into the
11-position of 400-O-arylalkylcarbamoyl analogs of 15-membered
macrolides greatly enhanced their antibacterial activity against
erythromycin-resistant bacteria encoded by the erm gene. Among
three series of 15-membered macrolide analogs, the novel series of
11,400-di-O-arylalkylcarbamoyl analogs 7a–k exhibited potent and
balanced activity against susceptible and resistant bacteria. In
particular, compounds 7f and 7k were the most effective against
susceptible bacteria and resistant bacteria encoded by the erm gene
or the mef gene.
6.3. General methods for 400-O-arylalkylcarbamoyl
azithromycin analogs (4a–m)
To a solution of 3 (1.33 g, 1.50 mmol) in DMF (15 mL) at 0 ꢀC was
added DBU (0.33 mL, 2.25 mmol, 1.5 equiv) and corresponding
amine (2.25 mmol, 1.5 equiv). The resulting solution was raised to
room temperature and stirred for 12 h at the same temperature.
The reaction was quenched with water (30 mL) and the aqueous
layer was extracted with ethyl acetate (3 ꢁ15 mL). The combined
organic layers were washed with brine, and dried over anhydrous
Na2SO4, filtered. The filtrate was concentrated in vacuo to afford
a crude product.
A solution of the above crude product in methanol (15 mL) was
heated to 55 ꢀC and stirred for 20 h at the same temperature. After
concentrating the reaction solution in vacuo, the residue was
purified by flash chromatography (dichloromethane/methanol,
5:1) to afford products 4a–m.
6. Experimental
All necessary solvents were purified prior to use, unless noted
otherwise. Reactions were monitored by thin-layer chromatog-
raphy (TLC) using 0.25-mm pre-coated silica gel plates. Flash
chromatography was performed with the indicated solvents using
silica gel 60 (particle size 0.040–0.063 mm). Infrared spectra were
recorded on KBr pellets using Nicolet Nexus 470FT-IR spectrometer.
1H NMR spectra were recorded on Bruker Avance DRX 600 spec-
trometer at ambient temperature. Mass spectra were recorded on
API 4000 instrument. The C, H, N analyses were carried out on PE-
2400 II elemental analyser. Melting points are uncorrected and
were determined on an X-6 melting point apparatus.
6.3.1. 400-O-(4-Hydroxyphenethyl-carbamoyl)azithromycin (4a)
20
White solid, yield 73.5%, mp 159–162 ꢀC, [
a
]
D
¼ ꢂ32.4 (c 0.5,
EtOH), TLC Rf ¼ 0.31 (dichloromethane/methanol, 5:1); IR (KBr):
3435, 2973, 2937, 2878, 1724, 1615, 1516, 1456, 1379, 1356, 1255,
1170,1108, 1072,1035, 1015 cmꢂ1; 1H NMR (600 MHz, CDCl3):
d 7.02
6.1. 20-O-Acetylazithromycin (2)
(d, J ¼ 8.3 Hz, 2H), 6.80 (d, J ¼ 8.0 Hz, 2H), 5.14 (d, J ¼ 4.7 Hz, 1H),
4.71 (d, J ¼ 9.9 Hz, 1H), 4.54 (d, J ¼ 7.3 Hz, 1H), 4.48 (d, J ¼ 9.8 Hz,
1H), 4.38 (m, 1H), 4.27 (m, 2H), 4.23 (m, 1H), 3.68 (s, 1H), 3.62–3.59
(m, 2H), 3.55 (m, 2H), 3.35 (s, 3H), 2.80–2.70 (m, 3H), 2.55
(d, J ¼ 10.5 Hz,1H), 2.46 (s, 6H), 2.39 (d, J ¼ 15.2 Hz,1H), 2.32 (s, 3H),
2.10 (m, 1H), 2.01 (m, 2H), 1.90 (m, 2H), 1.73 (d, J ¼ 14.6 Hz, 1H), 1.65
(m, 1H), 1.47 (m, 2H), 1.28 (s, 3H), 1.25 (m, 2H), 1.24–1.20 (m, 6H),
1.16 (d, J ¼ 8.6 Hz, 3H),1.11–1.09 (m, 6H),1.03 (d, J ¼ 7.5 Hz, 3H), 0.97
(d, J ¼ 7.2 Hz, 3H), 0.92–0.89 (m, 6H); MS (ESI) m/z calcd. for
C47H81N3O14 912.2; found (M þ Hþ) 913.1; Anal. calcd (%) for
C47H81N3O14: C 61.89, H 8.95, N 4.61. Found: C 61.77, H 8.94, N 4.56.
To a solution of azithromycin (2.0 g, 2.67 mmol) in dichloro-
methane (20 mL) at room temperature was added acetic anhydride
(0.5 mL, 5.34 mmol, 2.0 equiv) and Et3N (1.48 mL, 10.68 mmol,
4.0 equiv). The resulting solution was allowed to stir for 24 h at the
same temperature. The reaction was quenched with 5% aqueous
NaHCO3 (20 mL) and the aqueous layer was extracted with
dichloromethane (3 ꢁ10 mL). The combined organic layers were
dried over anhydrous Na2SO4, filtered, and concentrated in vacuo.
The residue was crystallized from acetone–water (2:1) to afford
1.84 g (92%) of 2 as a white solid: mp 167–170 ꢀC; Rf ¼ 0.52
(dichloromethane/methanol, 10:1); MS (ESI) m/z calcd. for
C40H74N2O13 791.0; found (M þ Hþ) 792.3.
6.3.2. 400-O-(4-Methoxybenzyl-carbamoyl)azithromycin (4b)
20
White solid, yield 71.0%, mp 140–143 ꢀC, [
a
]
D
¼ ꢂ41.2 (c 0.5,
EtOH), TLC Rf ¼ 0.32 (dichloromethane/methanol, 5:1); IR (KBr):
3457, 2972, 2936, 2833, 1727, 1613, 1514, 1457, 1424, 1379, 1249,
1173, 1108, 1094, 1073, 1034, 1015 cmꢂ1; 1H NMR (600 MHz, CDCl3):
6.2. 20-O-Acetyl-400-O-acylimidazolyl azithromycin (3)
To a solution of 2 (1.5 g, 1.90 mmol) in toluene (20 mL) was
added Et3N (0.68 mL, 4.33 mmol, 2.3 equiv) and CDI (0.67 g,
3.80 mmol, 2.0 equiv). The resulting solution was stirred at room
temperature for 48 h. The reaction was quenched with saturated
NaHCO3 (20 mL) and the aqueous layer was extracted with toluene
d
7.22 (d, J ¼ 8.2 Hz, 2H), 6.87 (d, J ¼ 8.6 Hz, 2H), 5.13 (d, J ¼ 4.6 Hz,
1H), 4.72 (d, J ¼ 9.0 Hz, 1H), 4.60–4.56 (m, 2H), 4.38–4.31 (m, 3H),
4.27 (m, 1H), 3.81 (s, 3H), 3.74 (m, 1H), 3.70 (s, 1H), 3.66
(d, J ¼ 6.8 Hz, 1H), 3.31(s, 3H), 2.87–2.72 (m, 3H), 2.55
(d, J ¼ 10.6 Hz, 1H), 2.48 (s, 6H), 2.41 (d, J ¼ 7.1 Hz, 1H), 2.32 (s, 3H),

S. Ma et al. / European Journal of Medicinal Chemistry 44 (2009) 4010–4020
4015
2.10 (m, 1H), 2.02 (m, 2H), 1.90 (m, 2H), 1.75 (d, J ¼ 14.6 Hz, 1H), 1.67
(dd, J ¼ 15.0 Hz, J ¼ 5.0 Hz, 1H), 1.48 (m, 1H), 1.31(s, 3H), 1.29 (m,
1H), 1.27 (m, 2H), 1.24 (d, J ¼ 6.2 Hz, 3H), 1.22 (d, J ¼ 7.4 Hz, 3H), 1.19
(s, 3H), 1.16–1.12 (m, 6H), 1.09 (s, 3H), 1.05 (d, J ¼ 7.5 Hz, 3H), 0.94–
0.90 (m, 6H); MS (ESI) m/z calcd. for C47H81N3O14 912.1; found
(M þ Hþ) 913.1; Anal. calcd (%) for C47H81N3O14: C 61.89, H 8.95, N
4.61. Found: C 61.98, H 8.99, N 4.66.
1.04 (d, J ¼ 7.5 Hz, 3H), 0.93–0.88 (m, 6H); 13C NMR (600 MHz,
CDCl3): d 178.4, 156.5, 138.5, 128.3, 127.4, 102.2, 95.1, 79.4, 78.3, 77.2,
77.0, 76.8, 74.3, 73.5, 73.2, 71.1, 70.0, 67.7, 65.4, 63.5, 62.4, 49.4, 45.2,
42.4, 41.4, 36.5, 35.3, 27.2, 26.7, 22.0, 21.4, 21.2, 21.1, 17.9, 16.2, 15.0,
11.2, 9.4, 7.6; MS (ESI) m/z calcd. for C46H79N3O13 882.1; found
(M þ Hþ) 883.0; Anal. calcd (%) for C46H79N3O13: C 62.63, H 9.03, N
4.76. Found: C 62.68, H 9.09, N 4.70.
6.3.3. 400-O-(4-Fluorobenzyl-carbamoyl)azithromycin (4c)
6.3.6. 400-O-(Phenethyl-carbamoyl)azithromycin (4f)
20
20
White solid, yield 68.4%, mp 140–143 ꢀC, [
a
]
¼ ꢂ38.4 (c 0.6,
White solid, yield 70.1%, mp 134–136 ꢀC, [
a]
¼ ꢂ52.5 (c 0.6,
D
D
EtOH), TLC Rf ¼ 0.31 (dichloromethane/methanol, 5:1); IR (KBr):
EtOH), TLC Rf ¼ 0.32 (dichloromethane/methanol, 5:1); IR (KBr):
3457, 2972, 2937, 2830, 1727, 1605, 1511, 1456, 1380, 1338, 1256,
3446, 2972, 2936, 2877, 1728, 1506, 1455, 1378, 1345, 1255, 1170,
1223, 1170, 1110, 1094, 1073, 1046, 1014 cmꢂ1
;
1H NMR (600 MHz,
1109, 1050, 1014 cmꢂ1 1H NMR (600 MHz, CDCl3):
; d 7.32–7.29
CDCl3):
d
7.27–7.25 (m, 2H), 7.03–7.01 (m, 2H), 5.13 (d, J ¼ 4.5 Hz,
(m, 2H), 7.25–7.19 (m, 3H), 5.13 (d, J ¼ 4.7 Hz, 1H), 4.70 (d,
J ¼ 9.5 Hz, 1H), 4.55–4.49 (m, 2H), 4.43–4.32 (m, 3H), 4.29 (m, 1H),
3.70–3.60 (m, 3H), 3.57–3.43 (m, 2H), 3.31(s, 3H), 2.85–2.79 (m,
3H), 2.53 (d, J ¼ 10.8 Hz, 1H), 2.40 (d, J ¼ 15.2 Hz, 1H), 2.34 (s, 3H),
2.33 (s, 6H), 2.13 (m, 1H), 2.01 (m, 2H), 1.91 (m, 2H), 1.79 (d,
J ¼ 14.7 Hz, 1H), 1.65 (dd, J ¼ 15.0 Hz, J ¼ 5.0 Hz, 1H), 1.48 (m, 1H),
1.31 (s, 3H), 1.28 (m, 1H), 1.25 (m, 2H), 1.22–1.19 (m, 6H), 1.15 (s,
3H), 1.11–1.09 (m, 9H), 1.06 (d, J ¼ 5.8 Hz, 3H), 0.92–0.90 (m, 6H);
MS (ESI) m/z calcd. for C47H81N3O13 896.2; found (M þ Hþ) 897.2;
Anal. calcd (%) for C47H81N3O13: C 62.99, H 9.11, N 4.69. Found: C
62.90, H 9.07, N 4.64.
1H), 4.72 (d, J ¼ 9.1 Hz, 1H), 4.60–4.55 (m, 2H), 4.41–4.45 (m, 3H),
4.28 (m, 1H), 3.72 (m, 1H), 3.69 (s, 1H), 3.64 (d, J ¼ 6.6 Hz, 1H), 3.30
(s, 3H), 2.85–2.72 (m, 3H), 2.54 (d, J ¼ 10.8 Hz, 1H), 2.45 (s, 6H), 2.41
(d, J ¼ 15.1 Hz, 1H), 2.35 (s, 3H), 2.09 (m, 1H), 2.07 (m, 2H), 1.90
(m, 2H), 1.76 (d, J ¼ 14.6 Hz, 1H), 1.67 (dd, J ¼ 15.0 Hz, J ¼ 5.0 Hz, 1H),
1.48 (m, 1H), 1.31 (s, 3H), 1.29 (m, 1H), 1.24–1.21 (m, 8H), 1.18 (s, 3H),
1.14 (d, J ¼ 6.0 Hz, 3H), 1.11 (d, J ¼ 6.7 Hz, 3H), 1.09 (s, 3H), 1.05
(d, J ¼ 7.4 Hz, 3H), 0.93–0.90 (m, 6H); 13C NMR (600 MHz, CDCl3):
d
178.5, 163.0, 156.4, 134.4, 129.1, 115.6, 102.1, 95.0, 79.4, 78.2, 77.2,
77.0, 76.8, 74.3, 73.5, 73.2, 71.1, 70.0, 67.7, 65.4, 63.5, 62.4, 49.4, 45.1,
44.5, 42.4, 41.4, 36.4, 35.2, 26.7, 22.0, 21.4, 21.2, 21.1, 17.9, 16.2, 15.0,
11.2, 9.4, 7.6; MS (ESI) m/z calcd. for C46H78FN3O13 900.1; found
(M þ Hþ) 901.2; Anal. calcd (%) for C46H78FN3O13: C 61.38, H 8.73, F
2.11, N 4.67. Found: C 61.47, H 8.78, F 2.14, N 4.59.
6.3.7. 400-O-(3,4-Methylenedioxyphenethyl-carbamoyl)
azithromycin (4g)
20
White solid, yield 74.0%, mp 161–163 ꢀC, [
a
]
¼ ꢂ40.7 (c 0.7,
D
EtOH), TLC Rf ¼ 0.32 (dichloromethane/methanol, 5:1); IR (KBr):
6.3.4. 400-O-(2-Chlorophenethyl-carbamoyl)azithromycin (4d)
3443, 2972, 2937, 2878, 1727, 1616, 1504, 1491, 1456, 1378, 1248,
20
White solid, yield 69.0%, mp 135–137 ꢀC, [
a
]
¼ ꢂ41.0 (c 0.5,
1170, 1109, 1038, 1014 cmꢂ1 1H NMR (600 MHz, CDCl3):
; d 6.75
D
EtOH), TLC Rf ¼ 0.31 (dichloromethane/methanol, 5:1); IR (KBr):
3475, 2972, 2937, 2877, 2830, 2788, 1727, 1632, 1507, 1457, 1378,
1344, 1255, 1170, 1109, 1094, 1073, 1050, 1036, 1014 cmꢂ1; 1H NMR
(d, J ¼ 7.9 Hz, 1H), 6.68 (s, 1H), 6.64 (d, J ¼ 7.9 Hz, 1H), 5.94 (m, 2H),
5.11 (d, J ¼ 4.6 Hz, 1H), 4.70 (d, J ¼ 8.8 Hz, 1H), 4.55–4.52 (m, 2H),
4.35–4.29 (m, 4H), 3.70 (m, 1H), 3.66–3.65 (m, 2H), 3.53–3.37 (m,
2H), 3.33 (s, 3H), 2.79–2.71 (m, 3H), 2.52 (d, J ¼ 10.3 Hz, 1H), 2.32 (s,
3H), 2.24–2.28 (m, 6H), 2.05 (m, 1H), 2.02 (m, 3H), 1.90 (m, 1H), 1.76
(m, 1H), 1.66 (dd, J ¼ 15.0 Hz, J ¼ 5.0 Hz, 1H), 1.49 (m, 1H), 1.31–1.27
(s, 6H), 1.22–1.19 (m, 6H), 1.16 (s, 3H), 1.11–1.06 (m, 12H), 0.93–0.90
(m, 6H); MS (ESI) m/z calcd. for C48H81N3O15 940.2; found (M þ Hþ)
941.3; Anal. calcd (%) for C48H81N3O15: C 61.32, H 8.68, N 4.47.
Found: C 61.22, H 8.689, N 4.44.
(600 MHz, CDCl3):
d 7.36 (m, 1H), 7.23–7.18 (m, 3H), 5.15
(d, J ¼ 4.7 Hz, 1H), 4.71 (d, J ¼ 9.8 Hz, 1H), 4.59 (m, 1H), 4.54–4.90
(m, 2H), 4.51 (m, 2H), 4.27 (m, 1H), 3.70–3.64 (m, 3H), 3.59–3.46
(m 2H), 3.31 (s, 3H), 2.87 (m, 1H), 2.79 (m, 1H), 2.71 (m, 1H), 2.54
(d, J ¼ 10.8 Hz, 1H), 2.40 (m, 3H), 2.33 (s, 6H), 2.18 (s, 1H), 2.07
(m, 1H), 2.00 (m, 2H), 1.90 (m, 2H), 1.79 (d, J ¼ 14.6 Hz, 1H), 1.66
(d, J ¼ 5.1 Hz, 1H), 1.63 (d, J ¼ 5.0 Hz, 1H), 1.48 (m, 1H), 1.31 (s, 3H),
1.28 (m, 1H), 1.21 (m, 2H), 1.20–1.19 (m, 6H), 1.15 (s, 3H), 1.11–1.09
(m, 9H), 1.06 (d, J ¼ 7.5 Hz, 3H), 0.92–0.89 (m, 6H); 13C NMR
6.3.8. 400-O-(Propyl-carbamoyl)azithromycin (4h)
20
(600 MHz, CDCl3):
d
178.7, 156.3, 136.2, 134.1, 131.1, 129.6, 128.1,
White solid, yield 70.4%, mp 138–140 ꢀC, [
a
]
¼ ꢂ39.1 (c 0.7,
D
126.9, 102.4, 95.0, 83.1, 79.3, 77.2, 77.0, 76.8, 74.3, 74.0, 73.5, 73.1,
71.0, 68.7, 65.4, 63.2, 49.4, 45.0, 42.4, 41.6, 40.6, 36.4, 35.1, 33.8,
27.4, 26.8, 21.9, 21.6, 21.2, 21.1, 17.8, 16.2, 14.9, 11.3, 9.3, 7.5; MS
(ESI) m/z calcd. for C47H80ClN3O13 930.6; found (M þ Hþ) 931.1;
Anal. calcd (%) for C47H80ClN3O13: C 60.66, H 8.66, Cl 3.81, N 4.52.
Found: C 60.54, H 8.60, Cl 3.77, N 4.54.
EtOH), TLC Rf ¼ 0.34 (dichloromethane/methanol, 5:1); IR (KBr):
3427, 2969, 2935, 2875, 1727, 1509, 1459, 1378, 1259, 1170, 1109,
1074, 1050, 1014 cmꢂ1
; d 5.13
1H NMR (600 MHz, CDCl3):
(d, J ¼ 4.6 Hz, 1H), 4.78 (m, 1H), 4.71 (m, J ¼ 8.0 Hz, 1H), 4.54
(m, 2H), 4.34 (m, 1H), 4.26 (m, 1H), 4.09 (d, J ¼ 6.7 Hz, 1H), 3.76
(m, 1H), 3.69 (s, 1H), 3.65 (d, J ¼ 6.7 Hz, 1H), 3.33 (s, 3H), 3.19
(m, 1H), 3.14 (m, 1H), 2.76 (m, 2H), 2.71 (d, J ¼ 6.7 Hz, 1H), 2.52 (d,
J ¼ 10.8 Hz, 1H), 2.45 (s, 6H), 2.38 (d, J ¼ 15.2 Hz, 2H), 2.33 (s, 3H),
2.02 (m, 4H), 1.89 (m, 2H), 1.75 (d, J ¼ 14.5 Hz, 1H), 1.64 (dd,
J ¼ 15.0 Hz, J ¼ 5.0 Hz, 1H), 1.51 (m, 2H), 1.46 (m, 1H), 1.30–1.28 (m,
4H), 1.25 (m, 2H), 1.21–1.19 (m, 9H), 1.16 (s, 3H), 1.11 (m, 3H), 1.08
(s, 3H), 1.04 (d, J ¼ 7.6 Hz, 3H), 0.99 (d, J ¼ 6.7 Hz, 3H), 0.93–0.88
(m, 9H); MS (ESI) m/z calcd. for C42H79N3O13 834.1; found
(M þ Hþ) 835.3; Anal. calcd (%) for C42H79N3O13: C 60.48, H 9.55, N
5.04. Found: C 60.59, H 9.51, N 5.11.
6.3.5. 400-O-(Benzyl-carbamoyl)azithromycin (4e)
20
White solid, yield 73.8%, mp 136–139 ꢀC, [
a
]
¼ ꢂ45.0 (c 0.6,
D
EtOH), TLC Rf ¼ 0.31 (dichloromethane/methanol, 5:1); IR (KBr):
3427, 2972, 2936, 2877, 1721, 1642, 1506, 1455, 1380, 1344, 1256,
1170, 1109, 1075, 1046, 1015 cmꢂ1 1H NMR (600 MHz, CDCl3):
;
d
7.34–7.31 (m, 2H), 7.28–7.25 (m, 3H), 5.11 (d, J ¼ 4.6 Hz, 1H), 4.70
(d, J ¼ 9.6 Hz, 1H), 4.59 (d, J ¼ 9.7 Hz, 1H), 4.54 (d, J ¼ 6.6 Hz, 1H),
4.43–4.36 (m, 3H), 4.27 (m, 1H), 3.73 (m, 1H), 3.69 (s, 1H), 3.65
(d, J ¼ 6.6 Hz, 1H), 3.30 (s, 3H), 2.80–2.70 (m, 3H), 2.52 (d,
J ¼ 10.2 Hz,1H), 2.42 (s, 6H), 2.37 (d, J ¼ 7.9 Hz,1H), 2.31 (s, 3H), 2.10
(m, 1H), 2.00 (m, 2H), 1.89 (m, 2H), 1.74 (d, J ¼ 14.4 Hz, 1H), 1.65
(dd, J ¼ 15.0 Hz, J ¼ 5.0 Hz, 1H), 1.46 (m, 1H), 1.30 (s, 3H), 1.28 (m,
1H), 1.25 (m, 2H), 1.23 (d, J ¼ 6.2 Hz, 3H), 1.21 (d, J ¼ 7.4 Hz, 3H), 1.18
(s, 3H), 1.13 (d, J ¼ 6.0 Hz, 3H), 1.11 (d, J ¼ 6.6 Hz, 3H), 1.07 (s, 3H),
6.3.9. 400-O-(Propenyl-carbamoyl)azithromycin (4i)
20
White solid, yield 72.7%, mp 142–145 ꢀC, [
a]
¼ ꢂ41.5 (c 0.7,
D
EtOH), TLC Rf ¼ 0.32 (dichloromethane/methanol, 5:1); IR (KBr):
3458, 3083, 2972, 2937, 2877, 2830, 1728, 1644, 1505, 1456, 1423,
1379, 1335, 1256, 1170, 1108, 1094, 1073, 047, 1015 cmꢂ1 1H NMR
;

4016
S. Ma et al. / European Journal of Medicinal Chemistry 44 (2009) 4010–4020
(600 MHz, CDCl3):
d
5.87 (m, 1H), 5.21–5.14 (m, 3H), 4.78 (m, 1H),
(m, 1H), 3.64 (m, 1H) 3.31 (s, 3H), 2.96 (s, 1H), 2.89 (s, 1H), 2.84
(m, 1H), 2.77 (m, 1H), 2.72 (m, 1H), 2.54 (m, 3H), 2.40 (s, 1H), 2.37
(s, 1H), 2.32 (s, 6H), 2.03–2.00 (m, 3H), 1.91–1.89 (m, 2H), 1.71–1.62
(m, 3H), 1.47 (m, 1H), 1.35–1.29 (m, 5H), 1.26–1.21 (m, 9H), 1.13
(s, 3H), 1.11 (m, 3H), 1.08 (s, 3H),1.03 (m, 3H), 0.93–0.89 (m, 6H); MS
(ESI) m/z calcd. for C45H83N3O13 874.2; found (M þ Hþ) 875.2; Anal.
calcd (%) for C45H83N3O13: C 61.83, H 9.57, N 4.81. Found: C 61.74, H
9.54, N 4.78.
4.71 (d, J ¼ 8.9 Hz, 1H), 4.55 (m, 2H), 4.47 (m, 1H), 4.39 (m, 1H), 4.29
(m, 1H), 3.85 (m, 1H), 3.70 (m, 2H), 3.70 (s, 1H), 3.66 (d, J ¼ 6.8 Hz,
1H), 3.33 (s, 3H), 3.28 (m, 1H), 3.27 (m, 1H), 2.73 (m, 1H), 2.52
(d, J ¼ 10.9 Hz, 1H), 2.41–2.39 (m, 2H), 2.35–2.34 (m, 9H), 2.08–2.00
(m, 4H), 1.91 (m, 2H), 1.79 (d, J ¼ 14.7 Hz, 1H), 1.66 (dd, J ¼ 15.0 Hz,
J ¼ 5.0 Hz, 1H), 1.49 (m, 1H), 1.32–1.28 (m, 4H), 1.25 (m, 2H), 1.23–
1.21 (m, 9H), 1.18 (s, 3H), 1.11 (m, 3H), 1.09 (s, 3H), 1.07 (d, J ¼ 7.5 Hz,
3H), 0.93–0.89 (m, 6H); MS (ESI) m/z calcd. for C42H77N3O13 832.1;
found (M þ Hþ) 833.8; Anal. calcd (%) for C42H77N3O13: C 60.63, H
9.33, N 5.05. Found: C 60.53, H 9.38, N 5.06.
6.4. 20-O-Acetyl-400-O-acylimidazolyl azithromycin 11,12-cyclic
carbonate (5)
6.3.10. 400-O-(Butyl-carbamoyl)azithromycin (4j)
To a solution of 2 (1.5 g, 1.90 mmol) in toluene (20 mL) was
added Et3N (0.68 mL, 4.33 mmol, 2.3 equiv) and CDI (1.23 g,
7.60 mmol, 4.0 equiv.). The resulting solution was heated to 75 ꢀC
and stirred at the same temperature for 24 h. The reaction was
quenched with saturated NaHCO3 (40 mL) and the aqueous layer
was extracted with toluene (3 ꢁ 10 mL). The combined organic
layers were dried over anhydrous Na2SO4, filtered, and concen-
trated in vacuo. The residue was purified by flash chromatography
(dichloromethane/methanol, 20:1) to afford 1.61 g (93%) of 5 as
a white solid: mp 117–120 ꢀC; Rf ¼ 0.61 (dichloromethane/meth-
anol, 10:1); MS (ESI) m/z calcd. for C45H74N4O15 911.1; found
(M þ Hþ) 912.4.
20
White solid, yield 76.5%, mp 145–148 ꢀC, [
a
]
¼ ꢂ39.5 (c 0.6,
D
EtOH), TLC Rf ¼ 0.33 (dichloromethane/methanol, 5:1); IR (KBr):
3457, 2970, 2936, 2874, 1727, 1632, 1509, 1459, 1378, 1255, 1170,
1108,1094,1073,1052,1014 cmꢂ1; 1H NMR (600 MHz, CDCl3):
d 5.12
(d, J ¼ 6.7 Hz,1H), 4.71–4.70 (m, 2H), 4.54 (m, 2H), 4.40 (m,1H), 4.29
(m, 1H), 3.75 (m, 1H), 3.70 (m, 1H), 3.67 (s, 1H), 3.66 (d, J ¼ 6.8 Hz,
1H), 3.33 (s, 3H), 3.25 (m, 1H), 3.18 (m, 1H), 2.81 (m, 2H), 2.72
(d, J ¼ 4.9 Hz, 1H), 2.54 (d, J ¼ 10.2 Hz, 2H), 2.49–2.38 (m, 8H), 2.09
(s, 3H), 1.91 (m, 2H), 1.76 (d, J ¼ 14.4 Hz, 1H), 1.64 (dd, J ¼ 15.0 Hz,
J ¼ 5.0 Hz, 1H), 1.52–1.48 (m, 4H), 1.37 (m, 1H), 1.30–1.28 (m, 4H),
1.25 (m, 2H), 1.24–1.21 (m, 9H), 1.18 (s, 3H), 1.12 (m, 3H), 1.09 (s, 3H),
1.06 (d, J ¼ 7.5 Hz, 3H), 0.95–0.90 (m, 9H); MS (ESI) m/z calcd. for
C43H81N3O13 848.1; found (M þ Hþ) 849.1; Anal. calcd (%) for
C43H81N3O13: C 60.90, H 9.63, N 4.95. Found: C 60.83, H 9.60, N 4.99.
6.5. General methods for 400-O-arylalkylcarbamoyl azithromycin
11,12 -cyclic carbonates (6a–m)
6.3.11. 400-O-(Pentyl-carbamoyl)azithromycin (4k)
To a solution of 5 (1.5 g, 1.65 mmol) in DMF (15 mL) at 0 ꢀC was
added DBU (0.33 mL, 2.25 mmol, 1.4 equiv) and corresponding
amine (2.25 mmol, 1.4 equiv). The resulting solution was raised to
room temperature and stirred for 12 h at the same temperature.
The reaction was quenched with water (30 mL) and the aqueous
layer was extracted with ethyl acetate (3 ꢁ15 mL). The combined
organic layers were washed with brine, and dried over anhydrous
Na2SO4, filtered. The filtrate was concentrated in vacuo to afford
a crude product.
A solution of the above crude product in methanol (15 mL) was
heated to 55 ꢀC and stirred for 20 h at the same temperature. After
concentrating the reaction solution in vacuo, the residue was
purified by flash chromatography (dichloromethane/methanol,
5:1) to afford products 6a–m.
20
White solid, yield 77.8%, mp 144–146 ꢀC, [
a
]
¼ ꢂ41.2 (c 0.6,
D
EtOH), TLC Rf ¼ 0.33 (dichloromethane/methanol, 5:1); IR (KBr):
3438, 2970, 2935, 2873, 2830, 1726, 1638, 1509, 1458, 1378, 1346,
1277, 1255, 1170, 1108, 1046, 1014 cmꢂ1; 1H NMR (600 MHz, CDCl3):
d
5.11 (d, J ¼ 4.6 Hz, 1H), 4.70 (d, J ¼ 8.8 Hz, 1H), 4.36 (m, 1H), 4.30
(m, 2H), 4.17 (m, 2H), 3.73–3.68 (m, 4H), 3.34 (s, 3H), 3.22 (m, 1H),
3.19 (m, 1H), 2.82 (m, 2H), 2.71 (m, 1H), 2.52 (d, J ¼ 10.3 Hz, 1H),
2.41–2.28 (m, 11H), 1.90 (m, 2H), 1.79 (d, J ¼ 14.0 Hz, 1H), 1.66 (dd,
J ¼ 15.0 Hz, J ¼ 5.0 Hz, 1H), 1.53–1.48 (m, 3H), 1.36–1.28 (m, 10H),
1.23–1.21 (m, 9H), 1.18 (s, 3H), 1.11–1.07 (m, 9H), 0.93–0.89 (m, 9H);
MS (ESI) m/z calcd. for C44H83N3O13 862.1; found (M þ Hþ) 863.3;
Anal. calcd (%) for C44H83N3O13: C 61.30, H 9.70, N 4.87. Found: C
61.38, H 9.66, N 4.82.
6.3.12. 400-O-(Isopropyl-carbamoyl)azithromycin (4l)
6.5.1. 400-O-(4-Hydroxyphenethyl-carbamoyl)azithromycin
20
White solid, yield 62.1%, mp 144–146 ꢀC, [
a]
D
¼ ꢂ49.6 (c 0.6,
11,12-cyclic carbonate (6a)
20
EtOH), TLC Rf ¼ 0.34 (dichloromethane/methanol, 5:1); IR (KBr):
White solid, yield 73%, mp 152–155 ꢀC, [
a
]
¼ ꢂ42.4 (c 0.6,
D
3450, 2972, 2937, 2877, 2830,1727,1632,1500,1457,1379,1343,1257,
EtOH), TLC Rf ¼ 0.60 (dichloromethane/methanol, 5:1); IR (KBr):
3427, 2972, 2936, 2880, 1812, 1727, 1615, 1516, 1456, 1380, 1353,
1238, 1168, 1109, 1074, 1046, 1015 cmꢂ1; 1H NMR (600 MHz, CDCl3):
1170, 1108, 1076, 1050, 1015 cmꢂ1; 1H NMR (600 MHz, CDCl3):
d 5.17
(d, J ¼ 4.5 Hz, 1H), 4.70 (d, J ¼ 9.8 Hz, 1H), 4.58–4.52 (m, 3H), 4.34 (m,
1H), 4.28 (s, 1H), 3.85 (m, 1H), 3.74 (m, 1H), 3.64 (d, J ¼ 6.8 Hz, 1H),
3.30 (s, 3H), 3.27 (m, 1H), 2.93 (s, 1H), 2.54 (d, J ¼ 10.4 Hz, 1H), 2.41–
2.38 (m, 2H), 2.27 (s, 6H), 1.99 (m, 3H),1.78 (m,1H), 1.75 (m, 1H),1.63
(dd, J ¼ 15.0 Hz, J ¼ 5.0 Hz, 2H),1.45 (m, 2H),1.30 (s, 6H),1.23–1.21 (m,
8H),1.18–1.14 (m, 9H),1.10–1.09 (m, 6H),1.05 (d, J ¼ 7.6 Hz, 3H), 0.91–
0.88 (m, 6H); MS (ESI) m/z calcd. for C42H79N3O13 834.1; found
(M þ Hþ) 835.2; Anal. calcd (%) for C42H79N3O13: C 60.48, H 9.55, N
5.04. Found: C 60.59, H 9.50, N 5.07.
d
7.10 (m, 2H), 6.99 (m, 2H), 5.05 (m, 1H), 4.87 (m, 1H), 4.56–4.55
(m, 2H), 4.42 (s, 1H), 4.35 (m, 2H), 4.19 (m, 1H), 3.60 (d, J ¼ 6.7 Hz,
1H), 3.56–3.50 (m, 2H), 3.45–3.43 (m, 2H), 3.33 (s, 3H), 2.85 (m, 2H),
2.79 (m, 6H), 2.47 (m, 1H), 2.34 (m, 1H) 2.22 (s, 3H), 2.02 (m, 2H),
1.92 (m, 2H), 1.85 (m, 2H), 1.68–1.60 (m, 4H), 1.45 (s, 3H), 1.27–1.21
(m, 6H), 1.18 (s, 3H), 1.16 (m, 6H), 1.09 (m, 6H), 0.95–0.88 (m, 6H);
MS (ESI) m/z calcd. for C48H79N3O15 938.2; found (M þ Hþ) 939.1;
Anal. calcd (%) for C48H79N3O15: C 61.45, H 8.49, N 4.48. Found: C
61.38, H 8.41, N 4.53.
6.3.13. 400-O-(Cyclohexyl-carbamoyl)azithromycin (4m)
20
White solid, yield 59.9%, mp 135–137 ꢀC, [
a
]
¼ ꢂ45.9 (c 0.7,
6.5.2. 400-O-(4-Methoxybenzyl-carbamoyl)azithromycin 11,
D
EtOH), TLC Rf ¼ 0.34 (dichloromethane/methanol, 5:1); IR (KBr):
12-cyclic carbonate (6b)
20
3449, 2972, 2935, 2877, 2832, 1727, 1654, 1631, 1499, 1455, 1379,
White solid, yield 78%, mp 138–142 ꢀC, [
a
]
¼ ꢂ33.7 (c 0.5,
D
1336, 1266, 1170, 1108, 1073, 1048, 1014 cmꢂ1
;
1H NMR (600 MHz,
EtOH), TLC Rf ¼ 0.66 (dichloromethane/methanol, 5:1); IR (KBr):
3434, 2973, 2937, 2880, 2834, 2788, 1814, 1727, 1613, 1586, 1513,
1457, 1380, 1352, 1337, 1302, 1240, 1169, 1109, 1073, 1045,
CDCl3):
d 5.10 (m, 1H), 4.70 (m, 1H), 4.69–4.63 (m, 2H), 4.59–4.55
(m, 1H), 4.53 (d, J ¼ 9.8 Hz, 1H), 4.29–4.26 (m, 2H), 3.80 (s, 1H), 3.6

S. Ma et al. / European Journal of Medicinal Chemistry 44 (2009) 4010–4020
4017
1015 cmꢂ1
;
1H NMR (600 MHz, CDCl3):
d
7.20 (m, J ¼ 8.5 Hz, 2H),
calcd. for C47H77N3O14 908.1; found (M þ Hþ) 909.1; Anal. calcd (%)
for C47H77N3O14: C 62.16, H 8.55, N 4.63. Found: C 62.10, H 8.52, N
4.68.
6.84 (m, J ¼ 8.6 Hz, 2H), 5.07 (m, 1H), 4.89 (dd, J ¼ 9.3 Hz,
J ¼ 3.2 Hz, 1H), 4.60 (d, J ¼ 9.8 Hz, 1H), 4.44 (m, 1H), 4.39–4.36 (m,
3H), 4.30 (m, 1H), 3.80 (s, 3H), 3.63–3.60 (m, 3H), 3.30 (s, 3H), 2.84
(m, 3H), 2.41 (d, J ¼ 10.4 Hz, 2H), 2.30 (s, 6H), 2.19 (s, 3H), 2.06–
2.00 (m, 4H), 1.90 (m, 1H), 1.82 (m, 1H), 1.65 (dd, J ¼ 15.0 Hz,
J ¼ 5.0 Hz, 1H), 1.58 (m, 1H), 1.44 (s, 3H), 1.28 (s, 3H), 1.26–1.20 (m,
6H), 1.18–1.16 (m, 6H), 1.07–1.05 (m, 9H), 0.93–0.91 (m, 6H); MS
(ESI) m/z calcd. for C48H79N3O15 938.1; found (M þ Hþ) 939.1;
Anal. calcd (%) for C48H79N3O15: C 61.45, H 8.49, N 4.48. Found: C
61.56, H 8.47, N 4.43.
6.5.6. 400-O-(Phenethyl-carbamoyl)azithromycin 11,12-cyclic
carbonate (6f)
20
White solid, yield 76.5%, mp 138–141 ꢀC, [
a
]
¼ ꢂ48.4 (c 0.6,
D
EtOH), TLC Rf ¼ 0.65 (dichloromethane/methanol, 5:1); IR (KBr):
3442, 2973, 2938, 2881, 2830, 1815, 1728, 1634, 1506, 1455, 1380,
1353, 1336, 1238, 1167, 1111, 1046, 1014 cmꢂ1 1H NMR (600 MHz,
;
CDCl3): d 7.32–7.29 (m, 2H), 7.27–7.19 (m, 3H), 5.06 (m, 1H), 4.90 (d,
J ¼ 8.9 Hz, 1H), 4.57–4.56 (m, 2H), 4.39–4.32 (m, 3H), 4.29 (m, 1H),
3.61–3.54 (m, 3H), 3.46 (m, 2H) 3.30 (s, 3H), 2.87–2.84 (m, 4H), 2.45
(d, J ¼ 10.2 Hz,1H), 2.38 (m,1H), 2.20 (s, 3H), 2.05–2.02 (m, 2H),1.92
(m, 1H), 1.91 (m, 1H), 1.67 (dd, J ¼ 15.0 Hz, J ¼ 5.0 Hz, 1H), 1.64 (m,
1H), 1.61 (s, 7H), 1.27 (s, 3H), 1.26 (m, 1H), 1.25 (m, 2H), 1.23 (m, 3H),
1.16 (s, 3H), 1.09 (m, 6H), 1.09 (d, J ¼ 6.6 Hz, 3H), 1.06 (m, 3H), 0.95–
0.92 (m, 6H); MS (ESI) m/z calcd. for C48H79N3O14 922.1; found
(M þ Hþ) 923.1; Anal. calcd (%) for C48H79N3O14: C 62.52, H 8.63, N
4.56. Found: C 62.43, H 8.61, N 4.49.
6.5.3. 400-O-(4-Fluorobenzyl-carbamoyl)azithromycin 11,12-cyclic
carbonate (6c)
20
White solid, yield 76%, mp 140–142 ꢀC, [
a
]
¼ ꢂ36.6 (c 0.7,
D
EtOH), TLC Rf ¼ 0.62 (dichloromethane/methanol, 5:1); IR (KBr):
3427, 2973, 2937, 2880, 2830, 1813, 1727, 1605, 1510, 1456, 1381,
1353, 1337, 1223, 1111, 1093, 1073, 1046, 1015 cmꢂ1 1H NMR
;
(600 MHz, CDCl3): d 7.25 (m, 2H), 7.02 (m, 2H), 5.20 (d, 1H), 5.09 (d,
J ¼ 4.4 Hz, 1H), 4.90 (dd, J ¼ 9.3 Hz, J ¼ 3.2 Hz, 1H), 4.61 (d,
J ¼ 9.7 Hz, 1H), 4.47 (m, 1H), 4.43–4.33 (m, 6H), 3.64 (m, 1H), 3.61
(d, J ¼ 5.6 Hz, 1H), 3.32 (s, 3H), 2.86 (m, 2H), 2.41 (m, 6H), 2.36 (d,
1H), 2.21 (s, 3H), 2.18 (m, 1H), 2.05 (m, 2H), 1.95 (m, 1H), 1.93 (m,
1H), 1.83 (m, 2H), 1.64 (m, 2H), 1.60 (m, 2H), 1.45 (s, 3H), 1.29 (s,
3H), 1.22 (m, 6H), 1.18 (m, 6H), 1.07 (m, 6H), 0.93 (m, 6H); 13C NMR
6.5.7. 400-O-(3,4-Methylenedioxyphenethyl-carbamoyl)
azithromycin 11,12-cyclic carbonate (6g)
20
White solid, yield 78.6%, mp 153–156 ꢀC, [
a
]
¼ ꢂ37.6 (c 0.5,
D
EtOH), TLC Rf ¼ 0.62 (dichloromethane/methanol, 5:1); IR (KBr):
(600 MHz, CDCl3):
d
176.8, 163.0, 156.4, 153.3, 134.3, 129.5, 115.6,
3434, 2972, 2936, 2881, 1813, 1727, 1632, 1504, 1491, 1456, 1379,
102.9, 95.6, 79.4, 78.2, 77.2, 77.0, 76.8, 76.3, 73.3, 70.7, 68.3, 67.4,
65.2, 63.4, 61.1, 49.6, 45.3, 44.5, 43.9, 41.7, 35.4, 34.3, 26.7, 26.2,
22.1, 21.9, 21.2, 21.0, 17.7, 15.0, 14.4, 11.2, 10.4; MS (ESI) m/z calcd. for
C47H76FN3O14 926.1; found (M þ Hþ) 927.1; Anal. calcd (%) for
C47H76FN3O14: C 60.95, H 8.27, F 2.05, N 4.54. Found: C 60.86, H
8.23, F 2.09, N 4.48.
1353, 1247, 1167, 1110, 1074, 1044, 1015 cmꢂ1 1H NMR (600 MHz,
;
CDCl3):
d
6.73 (d, J ¼ 7.8 Hz, 1H), 6.67 (s, 1H), 6.63 (d, J ¼ 7.8 Hz, 1H),
5.07 (m, 1H), 4.88 (dd, J ¼ 9.2 Hz, J ¼ 3.2 Hz, 1H), 4.57 (d, J ¼ 9.8 Hz,
2H), 4.44–4.33 (m, 4H), 3.61 (m, 1H), 3.51–3.48 (m, 2H), 3.39 (m,
2H), 3.31(s, 3H), 2.87 (m, 1H), 2.75 (m, 2H), 2.44 (m, 1H), 2.38–2.32
(m, 3H), 2.20 (s, 3H), 2.05–1.83 (m, 6H), 1.80 (m, 1H), 1.63 (m, 7H),
1.46 (s, 3H),1.29 (s, 3H),1.19 (m, 6H),1.17–1.13 (m, 6H),1.09–1.05 (m,
6H), 0.94–0.89 (m, 6H); MS (ESI) m/z calcd. for C49H79N3O16 966.2;
found (M þ Hþ) 967.2; Anal. calcd (%) for C49H79N3O16: C 60.91, H
8.24, N 4.35. Found: C 60.98, H 8.20, N 4.31.
6.5.4. 400-O-(2-Chlorobenethyl-carbamoyl)azithromycin 11,
12-cyclic carbonate (6d)
20
White solid, yield 80%, mp 130–133 ꢀC, [
a
]
¼ ꢂ34.1 (c 0.7,
D
EtOH), TLC Rf ¼ 0.64 (dichloromethane/methanol, 5:1); IR (KBr):
3443, 2973, 2938, 2883, 2830, 1815, 1728, 1634, 1058, 1457, 1379,
6.5.8. 400-O-(Propyl-carbamoyl)azithromycin 11,12-cyclic carbonate (6h)
20
1534, 1237, 1167, 1110, 1073, 1047, 1015 cmꢂ1
;
1H NMR (600 MHz,
White solid, yield 77.6%, mp 202–205 ꢀC, [
a]
D
¼ ꢂ37.6 (c 0.7,
CDCl3):
d
7.36 (m, 1H), 7.23–7.16 (m, 3H), 5.09 (d, J ¼ 4.5 Hz, 1H),
EtOH), TLC Rf ¼ 0.64 (dichloromethane/methanol, 5:1); IR (KBr):
4.89 (dd, J ¼ 9.3 Hz, J ¼ 3.2 Hz, 1H), 4.83 (m, 1H), 4.56 (d, J ¼ 9.8 Hz,
1H), 4.43–4.33 (m, 5H), 3.61–3.60 (m, 2H), 3.59–3.49 (m, 2H), 3.31
(s, 3H), 2.98 (m, 2H), 2.87 (m, 2H), 2.44 (d, J ¼ 10.7 Hz, 1H), 2.34 (m,
6H), 2.22 (s, 3H), 2.18 (m, 1H), 2.09–1.98 (m, 2H), 1.93 (m, 1H), 1.84
(m, 1H), 1.65 (m, 2H), 1.63–1.57 (m, 2H), 1.50 (m, 2H), 1.44 (s, 3H),
1.30 (s, 3H), 1.20 (m, 6H), 1.16 (m, 6H), 1.07 (m, 6H), 0.93 (m, 6H); 13C
3435, 2971, 2935, 2875, 2830,1815,1730,1631,1508,1458,1379,1354,
1260, 1166, 1110, 1047, 1015 cmꢂ1; 1H NMR (600 MHz, CDCl3):
d 5.05
(s,1H), 4.88 (d, J ¼ 6.6 Hz,1H), 4.83 (m,1H), 4.56 (m, 2H), 4.45 (m,1H),
4.38 (m, 2H), 3.65 (m,1H), 3.62 (d, J ¼ 4.5 Hz,1H), 3.32 (s, 3H), 3.16 (m,
3H), 2.80 (m, 2H), 2.44 (d, J ¼ 10.0 Hz, 1H), 2.38 (d, J ¼ 15.1 Hz, 1H),
2.19 (s, 6H), 2.05–2.02 (m, 2H),1.82 (s, 3H),1.66 (m, 2H),1.60 (m, 1H),
1.57 (m, 1H), 1.28–1.25 (m, 7H), 1.22–1.20 (m, 8H), 1.17 (s, 6H), 1.07–
1.06 (m, 6H), 0.93–0.84 (m,12H); MS (ESI) m/z calcd. for C43H77N3O14
860.1; found (M þ Hþ) 861.1; Anal. calcd (%) for C43H77N3O14: C 60.05,
H 9.02, N 4.89. Found: C 60.13, H 9.07, N 4.85.
NMR (600 MHz, CDCl3):
d 176.9, 156.3, 153.4, 136.3, 134.2, 131.1,
129.6, 128.0, 126.9, 103.3, 95.6, 85.3, 79.3, 77.2, 77.0, 76.8, 76.1, 73.5,
73.4, 70.7, 68.5, 65.2, 63.3, 61.0, 49.6, 45.0, 42.4, 41.7, 40.6, 35.5, 34.2,
33.8, 26.7, 26.3, 22.0, 21.9, 21.4, 21.0, 17.7, 14.9, 14.4, 11.4, 10.4, 5.8;
MS (ESI) m/z calcd. for C48H78ClN3O14 956.6; found (M þ Hþ) 957.1;
Anal. calcd (%) for C48H78ClN3O14: C 60.27, H 8.22, Cl 3.71, N 4.39.
Found: C 60.29, H 8.18, Cl 3.74, N 4.33.
6.5.9. 400-O-(Propenyl-carbamoyl)azithromycin 11,12-cyclic
carbonate (6i)
White solid, yield 77.6%, mp 151–154 ꢀC, TLC Rf ¼ 0.63
(dichloromethane/methanol, 5:1); IR (KBr): 3431, 3084, 2973,
2936, 2879, 2830, 2788, 1814, 1728, 1643, 1507, 1457, 1425, 1380,
6.5.5. 400-O-(Benzyl-carbamoyl)azithromycin 11,12-cyclic carbonate (6e)
20
White solid, yield 78.5%, mp 155–158 ꢀC, [
a
]
¼ ꢂ39.4 (c 0.7,
D
EtOH), TLC Rf ¼ 0.63 (dichloromethane/methanol, 5:1); IR (KBr):
3435, 2973, 2936, 2880, 2830, 2788, 1818, 1731, 1634, 1506, 1455,
1380, 1352, 1337, 1300, 1236, 1166, 1110, 1075, 1046, 1015 cmꢂ1; 1H
1353, 1335, 1237, 1167, 1110, 1074, 1046, 1015 cmꢂ1 1H NMR
;
(600 MHz, CDCl3):
d 5.85 (m, 1H), 5.22–5.12 (m, 2H), 5.07 (m, 1H),
4.89 (m, 1H), 4.88 (m, 1H), 4.58 (m, 2H), 4.45 (m, 1H), 4.39 (m, 1H),
3.82 (m, 3H), 3.65 (s, 1H), 3.61 (d, J ¼ 5.2 Hz, 1H), 3.31 (s, 3H), 2.95
(m, 1H), 2.85 (m, 2H), 2.43 (d, J ¼ 10.7 Hz, 1H), 2.38–2.35 (m, 2H),
2.30 (m, 6H), 2.19 (s, 6H), 2.07–2.00 (m, 2H), 1.91 (m, 1H), 1.82 (m,
1H), 1.71–1.52 (m, 7H), 1.43 (s, 3H), 1.28 (s, 3H), 1.25 (m, 3H), 1.21
(m, 6H), 1.17 (s, 3H), 1.06 (d, J ¼ 6.5 Hz, 3H), 0.92–0.86 (m, 6H); MS
(ESI) m/z calcd. for C43H75N3O14 858.1; found (M þ Hþ) 859.0; Anal.
NMR (600 MHz, CDCl3):
d 7.34 (m, 2H), 7.28 (m, 3H), 5.15 (m, 1H),
5.09 (m, 1H), 4.90 (m, 1H), 4.61 (d, J ¼ 9.8 Hz, 1H), 4.48–4.35 (m,
6H), 3.61–3.60 (m, 2H), 3.32 (s, 3H), 2.88 (m, 2H), 2.44–2.33
(m, 7H), 2.20 (s, 3H), 2.18 (m, 1H), 2.02 (m, 2H), 1.92 (m, 2H), 1.83
(m, 2H), 1.67 (m, 2H), 1.62 (m, 2H), 1.45 (s, 3H), 1.32 (s, 3H), 1.24
(m, 6H), 1.18 (m, 6H), 1.08 (m, 6H), 0.93 (m, 6H); MS (ESI) m/z

4018
S. Ma et al. / European Journal of Medicinal Chemistry 44 (2009) 4010–4020
calcd (%) for C43H75N3O14: C 60.19, H 8.81, N 4.90. Found: C 60.11, H
8.88, N 4.85.
6.6. General methods for 11,400-di-O-arylalkylcarbamoyl
derivatives of azithromycin (7a–k)
6.5.10. 400-O-(Butyl-carbamoyl)azithromycin 11,12-cyclic
Method 1 To a solution of 6 (1.50 mmol) in corresponding amine
(5 mL) at room temperature was added pyridine hydrochloride
(0.34 g, 3.00 mmol). The resulting solution was allowed to stir for
2–5 days at the same temperature. The reaction was quenched with
water (30 mL) and the aqueous layer was extracted with
dichloromethane (3 ꢁ 15 mL). The combined organic layers were
washed with brine and dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by flash chroma-
tography (dichloromethane–methanol, 10:1) to afford products 7.
Method 2 To a solution of 6 (1.50 mmol) in 1-methyl-1H-
imidazole (15 mL) at room temperature was added corresponding
amine (3.00 mmol). The resulting solution was allowed to stir for
2–5 days at the same temperature. The reaction was quenched
with water (30 mL) and the aqueous layer was extracted with
dichloromethane (3 ꢁ15 mL). The combined organic layers were
washed with brine and dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by flash chro-
matography (dichloromethane–methanol, 10:1) to afford products
7.
carbonate (6j)
20
White solid, yield 76.9%, mp 99–102 ꢀC, [
a
]
¼ ꢂ39.3 (c 0.7,
D
EtOH), TLC Rf ¼ 0.64 (dichloromethane/methanol, 5:1); IR (KBr):
3427, 2970, 2938, 2873, 2830, 1815, 1724, 1511, 1458, 1379, 1357,
1244, 1167, 1110, 1047, 1014 cmꢂ1 1H NMR (600 MHz, CDCl3):
;
d
5.09 (m, 1H), 4.91 (d, J ¼ 9.0 Hz, 1H), 4.81 (m, 1H), 4.71 (d,
J ¼ 9.7 Hz, 1H), 4.57 (m, 1H), 4.45–4.36 (m, 4H), 3.67 (m, 1H), 3.62
(d, J ¼ 5.5 Hz, 1H), 3.30 (s, 3H), 2.87 (m, 2H), 2.44–2.34 (m, 7H),
2.20 (s, 3H), 2.07 (m, 1H), 2.02 (m, 2H), 1.92 (m, 1H), 1.84 (m, 1H),
1.70 (m, 2H), 1.64 (m, 2H), 1.50 (m, 2H), 1.46 (s, 3H), 1.28 (s, 3H),
1.22 (m, 6H), 1.17 (s, 6H), 1.08 (m, 6H), 0.93 (m, 6H); MS (ESI) m/z
calcd. for C44H79N3O14 874.1; found (M þ Hþ) 875.1; Anal. calcd (%)
for C44H79N3O14: C 60.46, H 9.11, N 4.81. Found: C 60.53, H 9.07, N
4.84.
6.5.11. 400-O-(Pentyl-carbamoyl)azithromycin 11,12-cyclic
carbonate (6k)
20
White solid, yield 74.9%, mp 105–110 ꢀC, [
a]
¼ ꢂ33.3 (c 0.7,
D
EtOH), TLC Rf ¼ 0.64 (dichloromethane/methanol, 5:1); IR (KBr):
3419, 2969, 2935, 2872, 2830, 1815, 1724, 1670, 1510, 1457, 1379,
1353, 1336, 1256, 1238, 1167, 1109, 1093, 1073, 1045, 1014 cmꢂ1; 1H
6.6.1. 11-O-(Butyl-carbamoyl)-400-O-(4-hydroxyphenethyl-carbamoyl)
azithromycin (7a)
20
NMR (600 MHz, CDCl3):
d
5.07 (m, 1H), 4.89 (d, J ¼ 9.1 Hz, 1H), 4.69
White solid, yield 79.1%, mp 104–107 ꢀC, [
a
]
¼ ꢂ34.8 (c 0.7,
D
(m, 1H), 4.55 (m, 2H), 4.36 (m, 2H), 3.69–3.60 (m, 4H), 3.30 (s, 3H),
3.21 (m, 1H), 3.16 (m, 1H), 2.86 (m, 2H), 2.58 (m, 1H), 2.43 (m, 1H),
2.35–2.29 (m, 3H), 2.19 (m, 2H), 1.90 (s, 6H), 1.64 (m, 2H), 1.63 (m,
1H), 1.50–1.47 (m, 4H), 1.44 (s, 3H), 1.33–1.29 (m, 7H), 1.26 (s, 3H),
1.23–1.21 (m, 9H), 1.17 (s, 3H), 1.09–1.06 (m, 6H), 0.93–0.88 (m, 9H);
MS (ESI) m/z calcd. for C45H81N3O14 888.1; found (M þ Hþ) 889.3;
Anal. calcd (%) for C45H81N3O14: C 60.86, H 9.19, N 4.73. Found: C
60.80, H 9.14, N 4.78.
EtOH), TLC Rf ¼ 0.44 (dichloromethane/methanol, 5:1); IR (KBr):
3419, 2974, 2934, 2874, 1724, 1615, 1516, 1459, 1382, 1301, 1251,
1170,1118,1072,1049, 016 cmꢂ1; 1H NMR (600 MHz, CDCl3)
d (ppm)
7.02–7.01(m, 4H), 5.05 (m, 1H), 4.98 (d, J ¼ 9.8 Hz, 1H), 4.50–4.46
(m, 3H), 4.36 (m, 1H), 4.26 (m, 2H), 3.57–3.50 (m, 3H), 3.48 (m, 2H),
3.32 (m, 2H), 3.29 (s, 3H), 3.15–3.13 (m, 3H), 2.97 (m, 1H), 2.74 (m,
7H), 2.22 (s, 3H), 2.10 (m, 1H), 2.01 (m, 2H), 1.90 (m, 1H), 1.74 (m,
2H), 1.65 (m, 1H), 1.36 (m, 6H), 1.26 (s, 3H), 1.22 (m, 2H), 1.20–1.17
(m, 6H), 1.14 (d, J ¼ 6.1 Hz, 3H), 0.99–0.95 (m, 12H), 0.92–0.89 (m,
9H); MS (ESI) m/z calcd. for C52H90N4O15 1011.3; found (M þ Hþ)
1012.0; Anal. calcd (%) for C52H90N4O15: C 61.76, H 8.97, N 5.54.
Found: C 61.70, H 8.94, N 5.59.
6.5.12. 400-O-(Isopropyl-carbamoyl)azithromycin 11,12-cyclic
carbonate (6l)
White solid, yield 65.1%, mp 140–143 ꢀC, TLC Rf ¼ 0.64
(dichloromethane/methanol, 5:1); IR (KBr): 3442, 2920, 2850,1814,
1741, 1644, 1499, 1462, 1378, 1354, 1336, 1296, 1238, 1168, 1112,
6.6.2. 11-O-(2-Chlorobenethyl-carbamoyl)-400-O-(4-hydroxyphenethyl-
1075, 1045, 1014 cmꢂ1
;
1H NMR (600 MHz, CDCl3):
d
5.07
carbamoyl)azithromycin (7b)
20
(d, J ¼ 4.5 Hz, 1H), 4.89 (d, J ¼ 9.1 Hz, 1H), 4.68 (m, 1H), 4.50–4.45
(m, 2H), 4.42–4.36 (m, 2H), 3.80 (m, 2H), 3.71 (m, 1H), 3.61 (d,
J ¼ 7.4 Hz, 1H), 3.30 (s, 3H), 2.85 (m, 3H), 2.44 (m, 8H), 2.19 (s, 3H),
2.07–2.02 (m, 2H), 1.65–1.64 (m, 2H), 1.62–1.58 (m, 2H), 1.58 (s, 5H),
1.28 (s, 6H), 1.25–1.23 (m, 6H), 1.20–1.19 (m, 6H), 1.10–1.04 (m, 6H),
0.93–0.86 (m, 9H); MS (ESI) m/z calcd. for C43H77N3O14 860.1; found
(M þ Hþ) 861.1; Anal. calcd (%) for C43H77N3O14: C 60.05, H 9.02, N
4.89. Found: C 60.07, H 9.07, N 4.83.
White solid, yield 76.3%, mp 110–113 ꢀC, [
a]
¼ ꢂ36.9 (c 0.7,
D
EtOH), TLC Rf ¼ 0.45 (dichloromethane/methanol, 5:1); IR (KBr):
3426, 2974, 2937, 2877, 2830, 1708, 1614, 1516, 1457, 1382, 1344,
1253, 1170, 1111, 1093, 1073, 1046, 1037, 1015 cmꢂ1 1H NMR
;
(600 MHz, CDCl3)
d (ppm) 7.37 (m, 1H), 7.20–7.02 (m, 3H), 7.01 (m,
4H), 5.05 (m, 1H), 4.99 (d, J ¼ 9.0 Hz, 1H), 4.50–4.44 (m, 3H), 4.42
(m, 1H), 4.29–4.26 (m, 3H), 3.59–3.56 (m, 4H), 3.55 (m, 4H), 3.30 (s,
3H), 3.00 (m, 3H), 2.74 (m, 6H), 2.65 (m,1H), 2.22–2.20 (m, 4H), 2.10
(m, 5H), 1.74–1.71 (m, 2H), 1.65–1.59 (m, 3H), 1.26 (s, 3H), 1.20 (m,
2H), 1.18–1.17 (m, 6H), 1.11 (d, J ¼ 6.1 Hz, 3H), 1.04–1.01 (m, 9H),
0.97–0.88 (m, 9H); MS (ESI) m/z calcd. for C56H89ClN4O15 1093.7;
found (M þ Hþ) 1094.0; Anal. calcd (%) for C56H89ClN4O15: C 61.49,
H 8.20, Cl 3.24, N 5.12. Found: C 61.58, H 8.21, Cl 3.21, N 5.15.
6.5.13. 400-O-(Cyclohexyl-carbamoyl)azithromycin 11,12-cyclic
carbonate (6m)
20
White solid, yield 66.7%, mp 140–142 ꢀC, [
a
]
¼ ꢂ32.6 (c 0.6,
D
EtOH), TLC Rf ¼ 0.65 (dichloromethane/methanol, 5:1); IR (KBr):
3387, 2973, 2936, 2879, 1814, 1742, 1719, 1456, 1380, 1353, 1330,
1269, 1236, 1167, 1110, 1087, 1061, 1046, 1014 cmꢂ1
;
1H NMR
6.6.3. 11-O-(Benzyl-carbamoyl)-400-O-(4-hydroxyphenethyl-carbamoyl)
(600 MHz, CDCl3):
d
5.08 (m, 1H), 4.89 (d, J ¼ 9.0 Hz, 1H), 4.74 (m,
azithromycin (7c)
20
2H), 4.54 (m, 1H), 4.42–4.35 (m, 3H), 3.80 (s, 1H), 3.62 (m, 1H), 3.50
(m, 1H) 3.32 (s, 3H), 3.30 (s, 1H), 2.96 (s, 1H), 2.87 (m, 1H), 2.85
(m, 2H), 2.41 (s, 3H), 2.32 (s, 6H), 2.21 (s, 1H), 2.19 (s, 1H), 2.04–2.02
(m, 3H), 1.93 (m, 2H), 1.71–1.68 (m, 3H), 1.60 (m, 1H), 1.44 (d, 5H),
1.36 (m, 3H), 1.29 (s, 3H), 1.26–1.21 (m, 12H), 1.16 (s, 3H), 1.08 (m,
6H), 0.93–0.91 (m, 6H); MS (ESI) m/z calcd. for C46H81N3O14 900.1;
found (M þ Hþ) 901.3; Anal. calcd (%) for C46H81N3O14: C 61.38, H
9.07, N 4.67. Found: C 61.44, H 9.05, N 4.64.
White solid, yield 78.6%, mp 118–120 ꢀC, [
a
]
¼ ꢂ38.2 (c 0.7,
D
EtOH), TLC Rf ¼ 0.41 (dichloromethane/methanol, 5:1); IR (KBr):
3423, 2975, 2937, 2874, 1728, 1615, 1516, 1456, 1379, 1301, 1253,
1170, 1111, 1073, 1047, 1034, 1016 cmꢂ1 1H NMR (600 MHz, CDCl3)
;
d
(ppm) 7.36 (m, 2H), 7.30 (m, 3H), 7.21 (m, 3H), 7.03 (m, J ¼ 8.3 Hz,
2H), 5.00 (d, J ¼ 9.8 Hz, 1H), 4.98 (m, 1H), 4.46–4.36 (m, 4H), 4.26
(m, 2H), 3.62 (m, 1H), 3.57 (m, 2H), 3.50 (m, 2H), 3.45 (m, 1H), 3.27
(s, 3H), 3.00 (m, 2H), 2.62 (m, 2H), 2.50 (m, 6H), 2.32 (m, 2H), 2.25

S. Ma et al. / European Journal of Medicinal Chemistry 44 (2009) 4010–4020
4019
(s, 3H), 2.10 (m, 1H), 2.02 (m, 2H), 1.90 (m, 2H), 1.74 (m, 3H), 1.45
(m, 2H), 1.26–1.24 (m, 9H), 1.23–1.21 (m, 3H), 1.13 (m, 9H), 1.07 (m,
6H), 1.01 (d, J ¼ 6.5 Hz, 3H), 0.89–0.88 (m, 3H); MS (ESI) m/z calcd.
for C55H88N4O15 1045.3; found (M þ Hþ) 1045.9; Anal. calcd (%) for
C55H88N4O15: C 63.20, H 8.49, N 5.36. Found: C 63.21, H 8.42, N 5.33.
(s, 3H), 2.20 (m,1H), 2.05 (m, 2H),1.95 (m, 2H),1.81 (m, 2H),1.64 (m,
2H), 1.50 (m, 2H), 1.26 (s, 3H), 1.26–1.22 (m, 12H), 1.20–1.10 (m, 6H),
1.03 (d, J ¼ 6.5 Hz, 3H), 0.90–0.88 (m, 6H); MS (ESI) m/z calcd. for
C55H86ClFN4O14 1081.7; found (M þ Hþ) 1082.0; Anal. calcd (%) for
C55H86ClFN4O14: C 61.78, H 7.84, Cl 3.28, F 1.76, N 5.19. Found: C
61.72, H 7.81, Cl 3.31, F 1.77, N 5.24.
6.6.4. 11-O-(Pentyl-carbamoyl)-400-O-(4-methoxybenzyl-
carbamoyl)azithromycin (7d)
6.6.8. 11-O-(Pentyl-carbamoyl)-400-O-(2-chlorophenethyl-
20
White solid, yield 69.4%, mp 115–117 ꢀC, [
a
]
¼ ꢂ41.1 (c 0.6,
carbamoyl)azithromycin (7h)
D
20
EtOH), TLC Rf ¼ 0.50 (dichloromethane/methanol, 5:1); IR (KBr):
White solid, yield 67%, mp 98–101 ꢀC, [
a
]
¼ ꢂ37.8 (c 0.7, EtOH),
D
3427, 2974, 2934, 2873, 1728, 1613, 1514, 1489, 1379, 248, 1173, 1109,
TLC Rf ¼ 0.53 (dichloromethane/methanol, 5:1); IR (KBr): 3435,
1093, 1072, 1049, 1034, 1015 cmꢂ1
;
1H NMR (600 MHz, CDCl3)
2974, 2935, 2872,1727,1515,1457,1379,1344,1254,1169,1110,1092,
d
(ppm) 7.21 (d, J ¼ 8.4 Hz, 2H), 6.86 (d, J ¼ 8.6 Hz, 2H), 5.05 (m, 1H),
1073,1046,1036,1015 cmꢂ1; 1H NMR (600 MHz, CDCl3)
d (ppm) 7.36
5.00 (d, J ¼ 9.9 Hz, 1H), 4.61 (m, 2H), 4.44 (m, 1H), 4.34 (m, 2H), 3.85
(m, 1H), 3.81 (s, 3H), 3.63–3.60 (m, 3H), 3.33 (s, 3H), 3.17 (m, 2H),
2.68 (m, 2H), 2.42–2.39 (m, 3H), 2.30 (s, 6H), 2.23 (s, 3H), 2.10–2.01
(m, 3H), 1.90 (m, 2H), 1.65 (m, 2H), 1.51 (m, 4H), 1.37 (m, 6H), 1.26 (s,
3H), 1.25–1.23 (m, 6H), 1.19 (m, 6H), 0.99–0.96 (m, 9H), 0.92–0.89
(m, 9H); MS (ESI) m/z calcd. for C53H92N4O15 1025.3; found
(M þ Hþ) 1026.1; Anal. calcd (%) for C53H92N4O15: C 62.09, H 9.04, N
5.46. Found: C 62.00, H 9.04, N 5.49.
(m, 1H), 7.26–7.18 (m, 3H), 5.03 (m, 2H), 4.53 (d, J ¼ 9.8 Hz, 1H), 4.41
(t, 1H), 4.29 (m, 2H), 3.63–3.50 (m, 5H), 3.32 (m, 2H), 3.31 (s, 3H),
3.15 (m, 2H), 2.98 (m, 2H), 2.68 (m, 2H), 2.44 (m, 1H), 2.38 (m, 6H),
2.24 (s, 3H), 2.18 (m, 1H), 2.09–1.98 (m, 2H), 1.89 (m, 2H), 1.61 (m,
1H), 1.50–1.47 (m, 4H), 1.44 (s, 3H), 1.33–1.29 (m, 7H), 1.25–1.19 (m,
12H), 1.15 (s, 3H), 1.10 (s, 3H), 1.08 (d, J ¼ 6.4 Hz, 3H), 1.06 (d,
J ¼ 6.5 Hz, 3H), 0.91 (m, 9H); MS (ESI) m/z calcd. for C53H91ClN4O14
1043.7; found (M þ Hþ) 1043.9; Anal. calcd (%) for C53H91ClN4O14: C
60.99, H 8.79, Cl 3.40, N 5.37. Found: C 60.87, H 8.74, Cl 3.43, N 5.33.
6.6.5. 11-O-(Butyl-carbamoyl)-400-O-(4-methoxybenzyl-
carbamoyl)azithromycin (7e)
6.6.9. 11-O-(Benzyl-carbamoyl)-400-O-(2-Chlorophenethyl-
20
White solid, yield 64%, mp 106–109 ꢀC, [
a
]
¼ ꢂ47.3 (c 0.6,
carbamoyl)azithromycin (7i)
D
20
EtOH), TLC Rf ¼ 0.50 (dichloromethane/methanol, 5:1); IR (KBr):
White solid, yield 66%, mp 115–117 ꢀC, [
a
]
¼ ꢂ43.7 (c 0.7,
D
3419, 2974, 2935, 2854, 1726, 1610, 1513, 1460, 1379, 1301, 1248,
EtOH), TLC Rf ¼ 0.48 (dichloromethane/methanol, 5:1); IR (KBr):
1173, 1109, 1092, 1073, 1049, 1033, 1015 cmꢂ1
;
1H NMR (600 MHz,
3439, 2974, 2936, 2877, 1728, 1634, 1510, 1455, 1379, 1344, 1253,
CDCl3)
d
(ppm) 7.20 (d, J ¼ 8.5 Hz, 2H), 6.87 (d, J ¼ 8.6 Hz, 2H), 5.04
1170, 1111, 1093, 1073, 1046, 1037, 1015 cmꢂ1 1H NMR (600 MHz,
;
(m, 1H), 4.97 (d, J ¼ 9.9 Hz, 1H), 4.61 (m, 2H), 4.44 (m, 1H), 4.34 (m,
2H), 3.85 (m, 1H), 3.81 (s, 3H), 3.63–3.60 (m, 3H), 3.33 (s, 3H), 3.17
(m, 2H), 2.68 (m, 2H), 2.42–2.39 (m, 3H), 2.30 (s, 6H), 2.23 (s, 3H),
2.10–2.01 (m, 3H), 1.90 (m, 2H), 1.65 (m, 2H), 1.37 (m, 6H), 1.26 (s,
3H), 1.22 (m, 2H), 1.25–1.23 (m, 6H), 1.19 (m, 6H), 0.99–0.96 (m, 9H),
0.95–0.89 (m, 9H); MS (ESI) m/z calcd. for C52H90N4O15 1011.2;
found (M þ Hþ) 1012.0; Anal. calcd (%) for C52H90N4O15: C 61.76, H
8.97, N 5.54. Found: C 61.65, H 8.89, N 5.58.
CDCl3) d (ppm) 7.38 (m, 1H), 7.35 (m, 2H), 7.33 (m, 3H), 7.20 (m, 3H),
5.02 (d, J ¼ 9.1 Hz, 1H), 4.95 (m, 1H), 4.46–4.41 (m, 4H), 4.33–4.31
(m, 2H), 3.62 (m, 1H), 3.56 (m, 2H), 3.51 (m, 2H), 3.49 (m, 1H), 3.28
(s, 3H), 2.99 (m, 2H), 2.62 (m, 2H), 2.36 (m, 6H), 2.29 (m, 2H), 2.26
(s, 3H), 2.10 (m, 1H), 2.02 (m, 2H), 1.90 (m, 2H), 1.74 (m, 3H), 1.45
(m, 2H), 1.26–1.24 (m, 8H), 1.18 (d, J ¼ 5.7 Hz, 3H), 1.13 (m, 9H), 1.07
(m, 6H), 1.02 (d, J ¼ 6.5 Hz, 3H), 0.90–0.89 (m, 3H); MS (ESI) m/z
calcd. for C55H87ClN4O14 1063.7; found (M þ Hþ) 1064.1; Anal. calcd
(%) for C55H87ClN4O14: C 62.10, H 8.24, Cl 3.33, N 5.27. Found: C
62.13, H 8.29, Cl 3.30, N 5.21.
6.6.6. 11-O-(Phenethyl-carbamoyl)-400-O-(4-fluorobenzyl-
carbamoyl)azithromycin (7f)
20
White solid, yield 65%, mp 105–108 ꢀC, [
a]
¼ ꢂ28.2 (c 0.5,
6.6.10. 11-O-(4-Fluorobenzyl-carbamoyl)-400-O-(2-chlorophene
D
EtOH), TLC Rf ¼ 0.50 (dichloromethane/methanol, 5:1); IR (KBr):
thyl-carbamoyl)azithromycin (7j)
20
3435, 2974, 2935, 2854, 1727, 1604, 1511, 1455, 1379, 1339, 1254,
White solid, yield 79%, mp 119–121 ꢀC, [
a]
¼ ꢂ42.8 (c 0.8,
D
1169, 1112, 1093, 1073, 1047 cmꢂ1
;
1H NMR (600 MHz, CDCl3)
EtOH), TLC Rf ¼ 0.43 (dichloromethane/methanol, 5:1); IR (KBr):
d
(ppm) 7.31 (m, 2H), 7.24 (m, 5H), 7.02 (m, 2H), 5.01 (m, 2H), 4.70
3445, 2975, 2938, 2854, 1727, 1605, 1511, 1456, 1380, 1344, 1254,
(m, 1H), 4.58 (m, 1H), 4.47 (m, 2H), 4.40 (m, 2H), 4.25–4.20 (m, 3H),
3.54 (m, 1H), 3.45 (m, 2H), 3.32 (s, 3H), 3.19 (m, 1H), 2.86 (m, 2H),
2.63 (m, 2H), 2 .37 (m, 1H), 2.32 (m, 6H), 2.23 (s, 3H), 2.20 (m, 1H),
2.05(m, 2H),1.95(m, 2H),1.81 (m, 2H),1.64 (m, 2H),1.50 (m, 2H),1.26
(s, 3H), 1.25–1.21 (m, 15H), 1.10 (d, J ¼ 6.5 Hz, 3H), 1.03 (d, J ¼ 6.4 Hz,
3H), 0.98 (d, J ¼ 6.4 Hz, 3H), 0.88 (m, 3H); MS (ESI) m/z calcd. for
C55H87FN4O14 1047.3; found (M þ Hþ) 1048.0; Anal. calcd (%) for
C55H87FN4O14: C 63.08, H 8.37, F 1.81, N 5.35. Found: C 63.01, H 8.39,
F 1.84, N 5.39.
1169, 1111, 1093, 1073, 1049, 1037, 1015 cmꢂ1 1H NMR (600 MHz,
;
CDCl3) d (ppm) 7.36 (m, 1H), 7.35 (m, 2H), 7.21 (m, 3H), 7.02 (m, 2H),
4.96 (d, 1H), 4.95 (d, 1H), 4.46–4.41 (m, 4H), 4.33–4.31 (m, 2H), 3.62
(m, 1H), 3.56 (m, 2H), 3.51 (m, 2H), 3.49 (m, 1H), 3.27 (s, 3H), 2.99
(m, 2H), 2.62 (m, 2H), 2.36 (m, 6H), 2.29 (m, 2H), 2.25 (s, 3H), 2.10
(m, 1H), 2.02 (m, 2H), 1.91 (m, 2H), 1.60–1.59 (m, 3H), 1.48 (m, 2H),
1.26–1.24 (m, 8H), 1.18 (d, J ¼ 5.8 Hz, 3H), 1.13 (m, 9H), 1.07 (m, 6H),
1.01 (d, J ¼ 6.5 Hz, 3H), 0.91–0.89 (m, 3H); MS (ESI) m/z calcd. for
C55H86ClFN4O14 1081.7; found (M þ Hþ) 1082.0; Anal. calcd (%) for
C55H86ClFN4O14: C 61.07, H 8.01, Cl 3.28, F 1.76, N 5.18. Found: C
61.01, H 8.07, Cl 3.25, F 1.77, N 5.12.
6.6.7. 11-O-(2-Chlorophenethyl-carbamoyl)-400-O-(4-fluorobenzyl-
carbamoyl)azithromycin (7g)
20
White solid, yield 67%, mp 104–106 ꢀC, [
a
]
D
¼ ꢂ40.3 (c 0.6,
6.6.11. 11-O-(4-Hydroxyphenethyl-carbamoyl)-400-O-
EtOH), TLC Rf ¼ 0.50 (dichloromethane/methanol, 5:1); IR (KBr):
(2-chlorophenethyl-carbamoyl)azithromycin (7k)
20
3428, 2974, 2928, 2854, 1727, 1605, 1511, 1456, 1380, 1344, 1254,
White solid, yield 65%, mp 121–124 ꢀC, [
a
]
¼ ꢂ42.6 (c 0.6,
D
1169, 1111, 1093, 1073, 1049, 1036, 1015 cmꢂ1
;
1H NMR (600 MHz,
EtOH), TLC Rf ¼ 0.49 (dichloromethane/methanol, 5:1); IR (KBr):
CDCl3)
d
(ppm) 7.36 (m, 1H), 7.25 (m, 2H), 7.24 (m, 3H), 7.02 (m, 2H),
3429, 2974, 2935, 2854, 1728, 1614, 1594, 1515, 1457, 1376, 1344,
5.01 (m, 2H), 4.70 (m, 1H), 4.59 (m, 1H), 4.41–4.40 (m, 2H), 4.38 (m,
2H), 4.30–4.27 (m, 2H), 4.19 (m, 1H), 3.55 (m, 1H), 3.48 (m, 2H), 3.32
(s, 3H), 2.99 (m, 3H), 2.70 (m, 2H), 2 .38 (m, 1H), 2.33 (m, 6H), 2.23
1245, 1170, 1111, 1093, 1073, 1050, 1036, 1015 cmꢂ1 1H NMR
;
(600 MHz, CDCl3)
d (ppm) 7.28 (m, 1H), 7.21 (m, 3H), 7.09 (m, 2H),
6.84 (m, 2H), 5.00–4.95 (m, 2H), 4.56 (m, 2H), 4.40 (m, 1H), 4.42 (m,

4020
S. Ma et al. / European Journal of Medicinal Chemistry 44 (2009) 4010–4020
[4] G.G. Zhanel, M. Dueck, D.J. Hoban, L.M. Vercaigne, J.M. Embil, A.S. Gin,
J.A. Karlowsky, Drugs 61 (2001) 443–498.
1H), 4.29–4.26 (m, 3H), 3.59–3.56 (m, 4H), 3.55 (m, 4H), 3.30 (s, 3H),
3.00 (m, 3H), 2.74 (m, 6H), 2.60 (m, 1H), 2.37 (d, J ¼ 14.8 Hz, 1H),
2.23 (s, 3H), 2.10 (m, 1H), 2.01 (m, 2H), 1.90 (m, 2H), 1.70–1.62 (m,
1H), 1.47 (m, 2H), 1.26 (s, 3H), 1.20 (m, 2H), 1.25–1.13 (m, 18H), 1.02
(m, 6H), 0.89 (m, 3H); MS (ESI) m/z calcd. for C56H89ClN4O15 1093.7;
found (M þ Hþ) 1094.0; Anal. calcd (%) for C56H89ClN4O15: C 61.49,
H 8.20, Cl 3.24, N 5.12. Found: C 61.58, H 8.22, Cl 3.21, N 5.16.
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Acknowledgments
This research was supported by the National Natural Science
Foundation of China (20872081), Natural Science Foundation of
Shandong (Y2006C31) and Shandong Science and Technology
Promotion Project (2005GG3202098).
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