Discovery of +(2-{4-[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy]phenyl}-cyclopropyl)acetic acid as potent and selective αvβ3 inhibitor: Design, synthesis, and optimization

Article abstract of DOI:10.1016/j.bmc.2007.03.020

The integrin α_vβ₃ is expressed in a number of cell types and is thought to play a major role in several pathological conditions. Various small molecules that inhibit the integrin have been shown to suppress tumor growth and retinal a

Full text of DOI:10.1016/j.bmc.2007.03.020

Bioorganic & Medicinal Chemistry 15 (2007) 3390–3412
Discovery of +(2-{4-[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-
yl)ethoxy]phenyl}-cyclopropyl)acetic acid as potent and selective
avb3 inhibitor: Design, synthesis, and optimization
Srinivasan R. Nagarajan,a,* Hwang-Fun Lu,a Alan F. Gasiecki,b Ish K. Khanna,b
Mihir D. Parikh,a Bipinchandra N. Desai,b Thomas E. Rogers,a Michael Clare,b
Barbara B. Chen,b Mark A. Russell,b Jeffery L. Keene,a Tiffany Duffin,a
V. Wayne Engleman,a Mary B. Finn,a Sandra K. Freeman,a Jon A. Klover,a
G. Alan Nickols,a Maureen A. Nickols,a Kristen E. Shannon,a Christina A. Steininger,a
William F. Westlin,a Marisa M. Westlina and Melanie L. Williamsa
aPfizer Global Research and Development, St. Louis Laboratories, Pfizer, Inc., 700 Chesterfield Parkway West,
Chesterfield, MO 63017, USA
bPfizer Global Research and Development, Pfizer, Inc., 4901 Searle Parkway, Skokie, IL 60077, USA
Received 21 December 2006; revised 26 February 2007; accepted 8 March 2007
Available online 13 March 2007
Abstract—The integrin avb3 is expressed in a number of cell types and is thought to play a major role in several pathological con-
ditions. Various small molecules that inhibit the integrin have been shown to suppress tumor growth and retinal angiogenesis. The
tripeptide Arg-Gly-Asp (RGD), a common binding motif in several ligands that bind to avb3, has been depeptidized and optimized
in our efforts toward discovering a small molecule inhibitor. We recently disclosed the synthesis and biological activity of several
small molecules that did not contain any peptide bond and mimic the tripeptide RGD. The phenethyl group in one of the lead com-
pounds was successfully replaced with a cyclopropyl moiety. The new lead compound was optimized for potency, selectivity, and for
its ADME properties. We describe herein the discovery, synthesis, and optimization of cyclopropyl containing analogs that are
potent and selective inhibitors of avb3.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
aggregation of activated platelets. The integrin avb3 is
promiscuous, recognizing several extracellular matrix
proteins such as vitronectin and osteopontin that con-
tain RGD. It is expressed on several cell types, including
osteoclasts, smooth muscle cells, and endothelial cells,
and mediates several biological processes, including
adherence to bone matrix, angiogenesis, and the migra-
tion of endothelial cells, vascular smooth muscle cells,
and tumor cells through the extracellular matrix.2–9
Integrins are thought to play a role in several patholog-
ical conditions, including cancer, arthritis, and patho-
logic thrombotic events.10–14 Several anti-integrin
drugs are currently being evaluated clinically.15–18
Integrins are heterodimeric trans-membrane receptors,
having a and b subunits, classified broadly according
to ligand specificity.1 The tripeptide sequence Arg-Gly-
Asp (RGD), found in extracellular matrix and cell sur-
face proteins such as vitronectin, fibronectin, fibrinogen,
thrombospondin, von Willebrand factor, and osteopon-
tin, is recognized by the av integrins (b1, b3, b5, b6, b8),
the platelet glycoprotein receptor (GPIIb/IIIa, aIIbb3),
and the b1 integrins, aVb1 and aVIIIb1. These integrins
function in bone remodeling, angiogenesis, and the
We disclosed the discovery of 1 as potent inhibitors of
the integrin avb3, which showed excellent anti-angio-
genic properties including its suppression of tumor
growth in animal models, through depeptidization and
Keywords: Integrin receptors; Avb3; Angiogenesis; RGD mimics;
Antagonists; Cyclopropyl.
*
Corresponding author. Tel.: +1 636 247 7305; fax: +1 636 247
1045; e-mail: Srinivasan.Nagarajan@Pfizer.com
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.03.020

S. R. Nagarajan et al. / Bioorg. Med. Chem. 15 (2007) 3390–3412
3391
optimization of the peptide RGD.19–21 We have also re-
cently reported22 the discovery of 3 as potent inhibitors
of the integrin avb3 (12 nM in Solid Phase Receptor
Assay, SPRA) from the modification of 1 via the key
compounds 2a (254 nM) and 2b (38 nM) as part of a
research program to discover new lead molecules that
lacked amide bonds while other groups23 have utilized
a different approach in the identification of the lead
compound. Our efforts resulted in the determination
that the amide bonds and other functionalities could
be successfully removed from 1, the substitutions on
the phenyl group of the b-amino acid could be deleted,
and that the amino acid glycine could be displaced by
a phenyl group. Several recent publications from our
laboratories have described the results on replacing the
oxyphenyl group in 3 by oxadiazole, thiazole, isoxazole,
and pyrazoles, and other heterocycles.24 The goals of the
project have been to improve upon the potency, selectiv-
ity against various integrins, and improved absorption,
distribution, metabolism, and elimination (ADME)
characteristics of 3. We disclose herein our successful
efforts in replacing the phenethyl group in 3 by cyclo-
propyl moiety as exemplified in 7 which showed
improvement in all the desirable properties (Scheme 1).
groups to explore spatial and electronic requirements.
The pyridyl analog of 3 was targeted toward this goal
as shown in Scheme 2. Condensation of methyl nicoti-
noate (8) with p-methoxyphenyl acetonitrile (9) using
sodium methoxide gave the a-cyanoketone 10a. At-
tempted hydrolysis of the cyanoketone 10a with 48%
HBr also deprotected the methoxy group to give
p-hydroxybenzyl 3-pyridyl ketone (10b). Wittig reaction
of the O-acetyl derivative 10c with (carbethoxymethyl-
ene) triphenylphosphorane yielded the olefin as a mix-
ture of isomers. The mixture, without further
purification, upon reduction, followed by acidic work
up, afforded the phenol 11. Mitsunobu coupling of the
phenol 11 with 14,23a followed by the reduction of the
N-oxide and saponification, gave 4. The compound
was found to be a potent inhibitor of avb3 [0.5 nM in
solid phase receptor assay (SPRA) vs 8 nM for 3].
However, the half-life (1.7 h in mice) and plasma
concentration (AUC) of the compound in mice were
low (see Table 2) and we looked to other substitutions
for this position. We explored numerous aromatic
substitutions for this position (not reported here) and
found them to be unsatisfactory.
We investigated the synthesis of several alkyl substituted
analogs of the compound 3. The 3-methyl compound
was chosen as the initial target and was obtained as
shown in Scheme 2 by starting from p-methoxyphenyl
acetone (12) and using published procedures.23 The
methyl analog 5 (21 nM in avb3 SPRA) was less potent
than the parent compound and the plasma levels in mice
(Table 2, for 20 mpk dose) relatively higher than either
of the compounds 3 or 4. We explored other alkyl sub-
stitutions for this position. Simple variations like ethyl
and isopropyl moieties resulted in loss of potency. We
therefore looked for moieties to replace the methyl
group that would mimic its size, but would afford
2. Results and discussion
We initiated a research program to optimize and under-
stand the scope of structure-activity relationships
around 3. Structure based drug design approach was
not used as no X-ray crystal structure of the receptor
was available during the course of this research. Tradi-
tional medicinal chemistry efforts were successfully em-
ployed to achieve our goals. Our initial attempts were
directed at replacing the phenyl group with different
aromatic moieties including heterocycles and alkyl
O
COOH
COOH
H
N
H
N
H
H
H
H
N
N
N
N
N
H
N
O
OH
Cl
N
O
OH
Cl
HO
OH
Br
Br
2a
1
OH
OH
N
R
O
Ph
O
N
N
O
N
H
N
H
O
H
2b
3, R = Ph; 4, R = 3-Pyridyl; 5, R = Me
OH
OH
O
O
N
N
H
O
N
N
O
H
7
6
Scheme 1.

3392
S. R. Nagarajan et al. / Bioorg. Med. Chem. 15 (2007) 3390–3412
N
N
N
O
CN
OEt
a
d, e, f
+
OMe
O
O
R1
O
8
9
RO
HO
11
10a, R1 = CN, R = Me
10b, R1 = H, R = H
10c, R1 = H, R = Ac
b
c
O
OEt
d, e, g
O
O
HO
12
13
-
O
H
N
H
+
N
OH
N
N
O
h, i, j
R
O
OH
14
4, R = 3-Pyridyl
5, R = Me
Scheme 2. Reagents and conditions: (a) NaOMe, HCl; (b) 48% HBr, reflux, 18 h; (c) Ac2O, NEt3; (d) Ph3P = CHCOOEt; (e) Pd/C, H2; (f) HCl;
(g) BBr3; (h) PPh3/DEAD, 11 or 13; (i) Pd/C, cyclohexene; (j) base, HCl.
Table 1. Potencies of compounds in avb3 solid phase receptor assay and cell assays
Compound
avb3/SPRA (nM)
avb1 293 cells (nM)
avb3 293 cells (nM)
avb5 293 cells (nM)
avb6 HT-29 cells (nM)
3
8
96
28
29
2
20
19,800
25,000
4360
4
0.5
21
5
102
234
64
51
42
3
33
6
19
5
7
4.4
1.4
33
(+)7
(À)7
28
0.6
16
6
297
0.6
16
7
2568
10,000
20,000
3531
7.4
0.5
2
62
63
11
11
10
0.9
3
3
10,000
9800
10,000
64
67
1
1900
472
1000
776
954
1.3
0.4
42
69
70
156
71
72
205
525
1.5
0.4
9600
83
10,000
1787
10,000
(+)83
(À)83
84
4
12
92
93
1.6
3.3
2700
36
1.5
1.7
4500
4330
20
100
104
Assay data (IC50) for the solid phase receptor assay and cell data for select compounds. Potencies are average of three determinations.
compounds with enhanced potency and pharmacoki-
netic (PK) properties. We envisioned that the molecules
containing cyclopropyl moiety might afford properties
similar to those of 5 in both size and polarity. The
synthesis of the cyclopropyl compound 6 is shown in
Scheme 3.
In general, the cyclopropanation has been achieved
using Simmons–Smith reaction with a carbene on an
unsaturated alcohol or an amide.25–31 The starting
b,c-unsaturated acid 16 was synthesized from p-anisal-
dehyde (15) and 2-carboxyethylenetriphenylphosphora-
ne.32,33 The Weinreb amide (17) of the acid was then

S. R. Nagarajan et al. / Bioorg. Med. Chem. 15 (2007) 3390–3412
3393
Table 2. Mouse pharmacokinetic data for selected compounds
Compound AUC AUC Dose BA Half-life
(po, lg h/mL) (iv, lg h/mL) (mpk)
generated by the reaction of sodium hydride and tri-
methylsulfoxonium iodide.34 The Weinreb amide of
cyclopropyl analog 24 was then reduced with diisobutyl-
aluminum hydride to give the corresponding aldehyde
25. This aldehyde requires one carbon homologation
to get to the acid 19. Homologation of the aldehyde
was accomplished by reacting it with methoxymethyltri-
phenyl-phosphorane followed by hydrolysis of the enol
ether intermediate to give the aldehyde 26. The aldehyde
26 was oxidized using Tollens reagent to give 19.
Although the overall yield of this reaction sequence is
good, the scalability of the reaction described in Scheme
3 is better. The methoxy group in 19 was converted to
the ester 20 and was deprotected using BBr3 to give
the key phenolic intermediate, ethyl 1-(p-hydroxyphe-
nyl)cyclo-propaneacetate (21). Mitsunobu reaction of
21 with N-(2-pyridyl-N-oxide)-3-aminopropanol23a (14)
followed by the reduction of the N-oxide and saponifica-
tion gave the cyclopropyl compound 6. The compound 6
was shown to be a potent inhibitor of avb3 (19 nM in
SPRA) compared to 5, and its PK properties were
equally good as measured by the plasma concentration
(AUC, Table 2) for both iv and po administration in
mice.
(h)
3
4
5
6
7
2.8
0.3
2.3
0.2
2
100 4.4
100 1.7
92 4.1
79 2.3
62 1.6
2
195
18.3
398
106
14.2
378
20
2
2
reacted with Simmons–Smith reagent to give the corre-
sponding cyclopropyl compound 18. The solvent used
for Simmons–Smith cyclopropanation, dichlorometh-
ane, was found to be unsuitable for the larger scale reac-
tions as a vigorous exotherm was observed during the
addition of diethyl zinc to a solution of iodochlorome-
thane. Even on a smaller scale (ꢀ1 mmol), a sudden in-
crease in temperature and pressure was noted that had
led to expulsion of the rubber septa of the reaction flask
and on one occasion, shattering of the reaction vessel.
However, addition of dimethoxyethane to the reaction
mixture slows down the reaction considerably with no
exotherms as also the use of dichloroethane as the
solvent for the reaction. Larger scale cyclopropanations
have been conducted in our laboratories without any
incidents using the earlier modification. The amide 18
was hydrolyzed to the acid 19, which was esterified to
afford 20.
We were encouraged by the potency and the pharmaco-
kinetic properties of 6 and we proceeded to optimize
each of the regions of the molecule while keeping the
other sites constant. We divided the molecule into sev-
eral regions, the aminopyridine, central phenyl ring,
and apical carbon of the cyclopropyl and other carbon
atoms of the cyclopropyl moiety for optimization.
An alternative method for the synthesis of 19 is de-
scribed in Scheme 4. The Weinreb amide (23) of p-meth-
oxycinnamic acid (22) was reacted with the sulfur ylide
N
O
CHO
a
COOH
b, c
O
O
O
O
17, 39%
16
92%
15
N
OH
O
e
f
d
O
O
O
O
18, 98%
19, 88%
OEt
OEt
h, i, j
g
O
O
HO
O
21, 89%
20, 82%
OH
O
N
N
O
H
6, 41%
Scheme 3. Reagents: (a) Ph3P = CHCH2COOH; (b) EDC/OBt; (c) N,O-dimethylhydroxylamine HCl/NEt3; (d) iodochloromethane/Et2Zn/CH2Cl2,
(CH2OCH3)2; (e) NaOH, HCl; (f) EtOH/HCl; (g) BBr3; (h) PPh3/DEAD and 14; (i) Pd/C, cyclohexene; (j) base, HCl.

3394
S. R. Nagarajan et al. / Bioorg. Med. Chem. 15 (2007) 3390–3412
O
O
O
O
O
OH
a
N
N
b
MeO
MeO
MeO
22
24, 71%
23, 100%
O
COOH
f
c
d, e
H
CHO
MeO
MeO
MeO
25, 100%
26, 79%
19, 92%
Scheme 4. Reagents: (a) EDC/HOBt/N,O-dimethylhydroxylamine hydrochloride/NEt3; (b) Me3SOI, NaH; (c) DIBAH; (d) Ph3P = CHOMe; (e)
HCl; (f) AgNO3/NaOH.
Table 3. Rat pharmacokinetic data for selected compounds
3. Modification of the amino pyridine
Compound BA Half-life Cmax
(%) (h)
CL
(lg/mL) (mL/min/kg) (mL/kg)
Vz
The relatively low half-life and AUC for 6 in mice may
be attributed to the in vivo N-dealkylation of the amino-
pyridine moiety. To counter this potential metabolic
pathway, we switched the point of attachment of the
propyloxy group to the pyridine ring from nitrogen to
carbon to give 3-(6-aminomethyl-2-pyridyl)propyl moi-
ety. The chain length was shortened to keep both the
nitrogens of aminomethylpyridine in the same general
position relative to the phenyl group as in 6. The synthe-
sis was accomplished by the coupling of 21 with 6-ami-
nomethyl-2-hydroxyethylpyridine (27) under Mitsunobu
conditions as shown in Scheme 5. The product 28 was
shown to be very potent (7.4 nM in the avb3 SPRA).
7
62 1.6
4
24.5
14.8
15
31
6.2
221
915
864
419
276
493
(+)7
62
100
100 3.7
100 3.5
100 5.1
5.8
1.8
0.9
2.2
83
(+)83
92
23.5
33
100
4
17.4
and rat PK, see Table 3). The product obtained was a
mixture of two enantiomers and they were separated
at the ester stage (conditions for chiral chromatography
are provided in the experimental). Saponification of the
separated esters gave the enantiomerically pure isomers.
The absolute configuration of the products could not be
assigned based on the available data. The designation of
the products is based on the sign of the observed optical
rotation. The product with the positive rotation (+)7
was found to be the most potent, (+)7 [a]D +34.3 (c
0.04, methanol), 0.6 nM and (À)7 [a]D À34.0 (c 0.07,
methanol), 16 nM in the avb3 assay. The rat pharmaco-
kinetic data indicated a high volume of distribution and
low clearance with a half-life of 4 h. Numerous other
heterocyclic moieties were synthesized in order to opti-
Replacement of the aminopyridine with tetra-
hydronaphthyridine was then considered. The tetra-
hydronaphthyridine23,35–38
29
was
synthesized
according to literature procedures starting from
2-aminonicotinaldehyde. The Mitsunobu reaction of 2-
(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-1-ethanol (29)
with the phenol 21 (Scheme 6) followed by saponifica-
tion afforded 7 with improved potency compared to 6
(5 nM in avb3 SPRA, 3 nM in 293-b3 cell assay) and
with excellent PK properties (mouse PK, see Table 2
COOH
a, b
N
N
OH
H
N
N
O
H
27
28, 15%
Scheme 5. Reagents: (a) 21, PPh3P/DEAD; (b) LiOH, H+.
COOH
a, b
COOEt
+
N
N
OH
N
N
O
HO
H
H
7, 36%
21
29
Scheme 6. Reagents: (a) PPh3P/DEAD; (b) LiOH, H+.

S. R. Nagarajan et al. / Bioorg. Med. Chem. 15 (2007) 3390–3412
3395
O
c
OH
OH
H
d
g, h
46
R1
R1
R1
34, R1 = OMe; R2 = F
R2
R2
R2
36, R1 = OMe; R2 = F
35, R1 = OMe; R2 = F
a, b
O
O
O
OH
N
f
e
R1
R3
R1
R3
R2
R2
30, R1 = OMe; R2 = F; R3 = H
31, R1 =OMe, R2, R3 = F
32, R1 = H; R2 = OMe; R3 = H
33, R1,R2 = OMe; R3 =H
37, R1 =OMe, R2, R3 = F
38, R1 = H; R2 = OMe; R3 = H
39, R1,R2 = OMe; R3 =H
O
O
b
O
g, h
CHO
H
N
R1
R3
R1
R3
R1
R3
R2
R2
R2
46, R1 = OMe; R2 = F; R3 = H
47, R1 = H; R2 = OMe; R3 = H
48, R1 =OMe, R2, R3 = F
49, R1,R2 = OMe; R3 =H
43, R1 = H; R2 = OMe; R3 = H
44, R1 =OMe, R2, R3 = F
45, R1,R2 = OMe; R3 =H
40, R1 = H; R2 = OMe; R3 = H
41, R1 =OMe, R2, R3 = F
42, R1,R2 = OMe; R3 =H
COOH
i
COOEt
j
R1
R3
R1
R3
R2
R2
50, R1 = OMe; R2 = F; R3 = H
51, R1 = H; R2 = OMe; R3 = H
52, R1 =OMe, R2, R3 = F
53, R1,R2 = OMe; R3 =H
54, R1 = OMe; R2 = F; R3 = H
55, R1 = H; R2 = OMe; R3 = H
56, R1 =OMe, R2, R3 = F
57, R1,R2 = OMe; R3 =H
k
COOEt
COOH
l, m
R1
R3
R3
N
N
O
R2
H
R2
58, R1 = OH; R2 = F; R3 = H
59, R1 = H; R2 = OH; R3 = H
60, R1 =OH, R2, R3 = F
62, R2 = F; R3 = H
63, R2, R3 = F
64, R2 = OH; R3 =H
61, R1,R2 = OH; R3 =H
Scheme 7. Reagents: (a) EtOH, HCl; (b) DIBAL; (c) Et2Zn/iodochloromethane; (d) PCC; (e) EDC/HOBt/N,O-dimethylhydroxylamine
hydrochloride/NEt3; (f) Me3SOI, NaH; (g) Ph3P = CHOMe; (h) HCl; (i) AgNO3/NaOH; (j) EtOH/HCl; (k) BBr3; (l) 29/PPh3P/DEAD; (m)
LiOH, H+.
mize the guanidine surrogate. Some of these heterocy-
cles have been presented in other publications from
our laboratories in the context of replacement for the
central phenyl ring.24 Tetrahydronaphthyridine moiety
was chosen as an ideal guanidine surrogate in the cyclo-
propyl containing compounds based on its ease of
synthesis.
compounds was accomplished as shown in Scheme 7.
The methodology described in Scheme 7 is similar to
the one depicted for the alternate synthesis of 19
(Scheme 4). The monofluoro compound 62 was synthe-
sized by starting from 3-fluoro-4-methoxycinnamic acid
30. The ethyl ester of 30 was reduced to the allylic alco-
hol 34 with DIBAL. Cyclopropanation of the allylic
alcohol with Simmons–Smith reagent afforded 35.
Homologation of the alcohol was accomplished using
the following sequence. The alcohol 35 was oxidized to
the aldehyde 36 using pyridinium chlorochromate
(PCC). The aldehyde was reacted with methoxymethyl-
triphenylphosphorane to give the enol ether which was
4. Modifications of the central phenyl ring
We considered several substitutions on the aromatic ring.
The synthesis of fluoro, hydroxyl, difluoro substituted

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S. R. Nagarajan et al. / Bioorg. Med. Chem. 15 (2007) 3390–3412
hydrolyzed with dilute hydrochloric acid to give the
homologated aldehyde 46. The aldehyde was oxidized
with Tollens reagent to the acid 50. The ethyl ester 54
of the acid was treated with BBr3 to give the phenol
58, which was converted to 62 using the Mitsunobu con-
ditions described earlier Scheme 5.
dine-2-ethanol (29) gave the desired product 67 in very
low yield (Scheme 8). The potency of the product in
the avb3 solid phase receptor assay (>100 nM, Table 1)
was poor and we did not pursue any other heterocycle
replacements in the context of the cyclopropyl contain-
ing compounds.
The difluoro (63) and the hydroxyl (64) analogs were
synthesized by starting from the corresponding difluoro-
methoxy (31) or dimethoxycinnamic acid (33) as shown
in Scheme 7. We did not attempt to differentiate the two
methoxy groups in 33, so the p-methoxy moiety could be
selectively exposed at a latter stage for the Mitsunobu
reaction. After considering several possible ways, we
chose to start with dimethoxycinnamic acid (33) and
hoped to separate the two isomeric products by HPLC
at the end of the reaction. The dimethoxycinnamic acid
(33) was converted to ethyl 2-(3,4-dimethoxy-
phenyl)cyclopropaneacetate (57) using the procedure
described above. Deprotection of the dimethoxy com-
pound using BBr3 gave ethyl 2-(3,4-dihydroxyphe-
nyl)cyclopropaneacetate (61). Mitsunobu reaction of
the dihydroxy compound 61 with tetrahydronaphthyri-
dine-2-ethanol (29) afforded a mixture of products from
which 64 was isolated in very low yield. The structure
was confirmed by NMR experiments. All the compounds
synthesized have been shown to be very potent inhibitors
of avb3 (62, 0.5 nM; 63, 2 nM; 64, 1 nM in the solid phase
receptor assay, Table 1). The PK properties of 62 (Table
3) were examined in rat and were found to be very similar
to those of (+)7. Since the unsubstituted central phenyl
ring is easier to synthesize and to scale-up, based on
the potency and PK data available, further substitutions
on the central phenyl ring were not pursued.
5. Relative distances between key recognition elements
The importance of the relative positions of naphthyri-
dine nitrogens, the phenyl group, and the carboxylic
acid moiety in 7 was examined by synthesizing com-
pounds 69 and 70. The synthesis of these compounds
starting from 25 is shown in Scheme 9. Reaction of
the aldehyde 25 (see Scheme 4 for the synthesis) with
carbethoxymethylenetriphenylphosphorane gave the
unsaturated ester. Catalytic reduction of the double
bond followed by treatment with BBr3 afforded the phe-
nolic intermediate 68. Mitsunobu reaction of 68 with
either tetrahydronaphthyridine-2-ethanol (29) or tetra-
hydronaphthyridine-2-methanol39 (73) followed by
saponification gave the products 69 and 70. Both com-
pounds were found to be less potent inhibitors of the
integrin avb3 (470 nM and 1000 nM in the SPRA,
respectively). The synthesis of meta analog of 7 was also
targeted. The ethyl 2-(3-hydroxyphenyl)cyclopropyl-
acetate (59) was synthesized starting from m-methoxy-
cinnamic acid (32) as shown in Scheme 7 using the
Weinreb amide route. Since the meta substitution re-
duces the overall distance between the nitrogens in tetra-
hydronaphthyridine and the carboxylic acid, a higher
homolog of 71 was also synthesized starting from 43
as described for 69. Both the analogs 71 (800 nM) and
72 (>1 lM) were shown to be less potent (Table 1).
We concluded, based on the data shown, that the 1,4
substitution pattern on the central phenyl ring and the
relative distances between the nitrogens, the phenyl ring,
and the carboxyl groups as in 7 are crucial for the avb3
potency.
We successfully replaced the central phenyl group in 3
with several heterocycles (thiazoles, oxadiaxoles, pyraz-
oles, oxazoles, isoxazoles, etc.) with superior potency
and pharmacokinetic properties (low clearance, high
volume of distribution and half-life).24 Similar replace-
ments were explored in the cyclopropyl series of com-
pounds. We initiated our optimization efforts starting
from replacement by pyridine. The starting material,
ethyl 3-(6-methoxypyridyl)acrylate (65), was synthesized
as reported in the literature.39 Synthesis of 66 from this
intermediate was accomplished in a similar fashion to
examples in Scheme 7. Mitsunobu reaction of the
deprotected compound 66 with tetrahydro-naphthyri-
6. Substitutions on the apical carbon of the cyclopropyl
moiety
We considered several substitutions on the apical car-
bon. In order to reduce the number of optical isomers,
we chose to synthesize gem di-substituted analogs.
COOEt
COOEt
a, b
O
N
N
HO
see scheme 7
66
65
COOH
N
N
N
O
H
67
Scheme 8. Reagents: (a) 29/PPh3P/DEAD; (b) LiOH, H+.

S. R. Nagarajan et al. / Bioorg. Med. Chem. 15 (2007) 3390–3412
3397
O
COOEt
a, b, c
H
O
HO
25
68
d, e
f, e
COOH
COOH
H
N
N
N
H
N
O
O
70
69
d, e
COOEt
COOH
HO
N
N
O
H
59
71
COOH
a,b,c,d,e
O
CHO
N
N
O
H
43
72
g, b, h, i
CHO
NH2
OH
N
N
N
H
73
Scheme 9. Reagents: (a) Ph3P = CHCOOEt; (b) Pd/C, H2; (c) BBr3; (d) 29/PPh3P/DEAD; (e) LiOH, H+; (f) 73/PPh3P/DEAD; (g) pyruvaldehyde; (h)
HCl; (i) NaBH4.
gem-Dimethyl, dichloro, and dibromo analogs were tar-
geted for synthesis. The syntheses of gem-dimethyl
cyclopropyl compounds are well known in the litera-
ture.40–46 Synthesis of the ester of compound 76 as re-
ported by Ahmad et al.,45 although successful, suffered
from low yields and was not amenable for scale up.
Tandem Michael addition followed by cyclization for
the synthesis of the dimethyl cyclopropyl compound as
reported by Babler and Spina43 was considered next
(Scheme 10). Condensation of p-anisaldehyde and
diethyl malonate with piperidine as base afforded the
unsaturated diester.47 Reaction of this with 2-nitropro-
pane and two equivalents of potassium tert-butoxide
gave cyclopropyl diester 74. Removal of the one of the
carboxyl groups from the malonyl derivatives has been
well documented. The Krapcho conditions48 using lith-
ium, sodium or potassium chloride and water in DMSO
resulted mainly in the opening of the cyclopropyl ring
although the desired product was obtained in small
amounts. However, heating of the diester 74 in DMSO
with several equivalents of potassium cyanide resulted
in a mixture of products in which the ester of the
trans-cyclopropylcarboxylic acid 75 was the major
product. The major product was easily purified by
chromatography.
A minor fraction obtained during the purification was
a 1:1 mixture of the esters of trans (75) and cis (76)
products and they were not separable by chromatogra-
phy. However, we were surprised to find that even with
excess base, at room temperature, only the ester of the
trans isomer was rapidly hydrolyzed to the correspond-
ing acid while it took a long reaction time (24 h) for
saponification of the ester of the cis isomer. We were
able to get quantities of the cis isomer by taking
advantage of the different rates of saponification. Both
the trans (75) and cis (76) isomers were carried to the
desired final products using standard one carbon
homologation, followed by esterification, deprotection,
and Mitsunobu reactions as shown in Scheme 10. The
structures of both the cis and trans analogs 84 and 83
were established using NMR experiments. The trans
isomer (1.3 nM vs avb3) was found to be a potent
inhibitor, while the cis isomer (12 nM) was less active.
Again, the racemic mixture 83 was separated into its
pure enantiomers (+)83 (0.4 nM) and (À)83 (42 nM,

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S. R. Nagarajan et al. / Bioorg. Med. Chem. 15 (2007) 3390–3412
COOH
O
e
75, 51%
CHO
c, d
COOEt
COOEt
a, b
O
O
74, 66%
15
COOH
O
76, 2%
j, k
COOEt
f, g, h, i
CH2COOH
CH2OH
O
HO
O
77, trans
78, cis
81 trans
82, cis
79, trans
80, cis
l, m
N
COOH
COOH
N
O
N
N
O
H
H
84
83
Scheme 10. Reagents and conditions: (a) diethyl malonate, HOAc, toluene, reflux; (b) 2-nitropropane, pot. tert-butoxide, DMSO; (c) KCN, DMSO,
160 ꢁC, 48 h; (d) NaOH, H+; (e) BH3, THF (f) swern oxidation; (g) Ph3P = CHOMe; (h) HCl; (i) AgNO3/NaOH; (j) EtOH, HCl; (k) BBr3;
(l) 29/PPh3P/DEAD; (m) LiOH, H+.
both in the avb3 solid phase receptor assay). Both the
racemic mixture and the active isomer were examined
in the rat for PK properties (Table 3). Although the
volume of distribution was lower compared to (+)7,
the compound was cleared slowly resulting in better
half-life for the molecule.
The dichloro and the dibromo compounds were synthe-
sized starting from 4-phenyl-3-butenoic acid (16) as
shown in Scheme 11. The acid was reduced with LAH
to the alcohol and the alcohol was protected as its
tert-butyldimethylsilyl ether 85. The protected unsatu-
rated compound was reacted with a dihalocarbene
O
a, b
OH
c, d
Si
O
O
O
85
75%
16
X
X
X
X
OH
f, g
e
OH
O
O
O
88, X = Cl
89, X = Br
86, X = Cl
87, X = Br
X
X
X
X
OH
h, i
O
O
N
H
N
O
O
HO
92, X = Cl
93, X = Br
90, X = Cl
91, X = Br
Scheme 11. Reagents: (a) LAH; (b) TBDMS–Cl, imidazole/DMAP; (c) haloform, NaOH; (d) TBAF; (e) Jones reagent; (f) EtOH/HCl; (g) BBr3;
(h) 29/PPh3P/DEAD; (i) LiOH, H+.

S. R. Nagarajan et al. / Bioorg. Med. Chem. 15 (2007) 3390–3412
3399
generated by treatment of the haloform with base under
phase transfer conditions.49 The dihalocyclopropana-
tion proceeded in very good yield. The silyl ether protec-
tive group was removed using TBAF and the resulting
alcohols 86 and 87 were oxidized to the acid 88 and 89
with Jone’s reagent. The acid was esterified and the
methoxy group was deprotected with BBr3. Mitsunobu
reaction of 90 and 91 with the tetrahydronaphthyri-
dine-2-ethanol (29) followed by hydrolysis afforded the
desired products 92 and 93. Both 92 (2.3 nM) and 93
(3.3 nM) are very potent inhibitors of the integrin avb3
in the solid phase receptor assay (Table 1). The results
from these efforts lead us to conclude that the apical po-
sition of the cyclopropyl moiety would tolerate substitu-
tions of various sizes.
very slow and use of excess iodobenzene was required
to improve the yield of 4-(p-methoxyphenyl)-3-phenyl-
but-3-en-1-ol (97) (Scheme 12).
Other aryl halides required much higher temperatures
for the completion of the reaction and 3-iodopyridine
did not give the desired product. Cyclopropanation of
the unsaturated alcohol 97 was accomplished using
modified Simmons–Smith reaction. Jones oxidation of
the alcohol 98 to the corresponding carboxylic acid in
one step led to mostly decomposition and recovery of
some of the starting material. However, stepwise oxida-
tion of the alcohol with pyridiniumchloro chromate to
the aldehyde followed by further oxidation with Tollens
reagent afforded the carboxylic acid. The acid was con-
verted to the ester and the methoxy group was deprotec-
ted using BBr3 to give the phenol 99. Mitsunobu
reaction of the phenol with tetrahydronaphthyridine-2-
ethanol (29) followed by hydrolysis gave the desired
product 100. The product was shown to be less potent
(>1 lM) in the avb3 assay. No further analogs were
made with modifications at the 3-position.
6.1. Other substitutions on the cyclopropyl group
We synthesized compounds with substitutions on the
other two carbons of the cyclopropyl moiety to further
explore this part of the molecule. The 3-phenyl substi-
tuted cyclopropyl compound was chosen as the next
target since the 3-methyl-3-phenyl as well as 3,3-gem-
dimethyl analogs of 5 were reasonably potent.50 Meth-
ods have been developed for the Palladium mediated
cross coupling of vinyl silanes and aryl halides.51–58
The vinyl silanes in turn have been synthesized by intra-
molecular hydrosilylation of silyl ethers. We explored
this route for the synthesis of phenyl substituted cyclo-
propyl analogs as shown in Scheme 11. Palladium cata-
lyzed reaction of iodoanisole (94) with 3-butyn-1-ol
using triethylamine as the solvent afforded 4-(p-meth-
oxyphenyl)-3-butyn-1-ol (95) in very good yield.59,60
Reaction of the alcohol with chlorodiisopropylsilane
gave the silyl ether 96. The intramolecular hydrosilyla-
tion with Pt(0)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane
[Pt(DVDS)] proceeded smoothly to give the cyclic silox-
ane. The crude cyclic siloxane without further purifica-
tion was treated with tetrabutylammonium fluoride to
give the vinyl silane, which was reacted in the same
pot with iodobenzene and Pd2(dba)3. The reaction was
The 4-methyl analog was synthesized as shown in
Scheme 13. Reduction of the acid 101, prepared using
literature procedure,61 with LAH gave the alcohol.
Cyclopropanation of the alcohol using Simmons–Smith
reagent afforded the 102. Oxidation of the alcohol to the
carboxylic acid has been shown to be very difficult, often
resulting in decomposition. Use of NaClO2/NaOCl/
TEMPO gave the desired acid. Esterification and depro-
tection of the methoxyl group to 103 followed by Mits-
unobu coupling with 29 gave 104. This modification also
resulted in the loss of potency.
7. Conclusions
The initial cyclopropyl lead compound 6 was divided
into several regions and each was optimized for potency
against the integrin avb3, selectivity against various
O
H
OH
Si
I
a
b
O
O
O
94
96, 90%
95, 80%
OH
OH
f
c,d, e
Ph
O
Ph
O
97, 58%
98, 59%
OH
g, h, i, j
O
k, l
Ph
100, 18%
O
N
N
O
Ph
O
H
HO
99, 16%
Scheme 12. Reagents: (a) 3-butyn-1-ol, Pd(PPh3)2Cl2, NEt3; (b) chlorodiisopropylsilane/NEt3; (c) Pt(DVDS); (d) TBAF; (e) Pd2(dba)3/iodobenzene;
(f) Et2Zn/iodochloromethane; (g) PCC; (h) AgNO3/NaOH; (i) EtOH, HCl; (j) BBr3; (k) 29/DEAD/PPh3P; (l) LiOH, H+.

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S. R. Nagarajan et al. / Bioorg. Med. Chem. 15 (2007) 3390–3412
OH
c, d, e
OH
a, b
O
O
O
101
102
OH
O
f, g
O
O
N
H
N
O
HO
103
104
Scheme 13. Reagents: (a) LAH; (b) Et2Zn/iodochloromethane; (c) NaClO2/NaOCl/TEMPO; (d) EtOH/HCl; (e) BBr3; (f) 29/DEAD/PPh3P;
(g) LiOH, H+.
integrins, and their PK properties. The overall distance
between the nitrogens of the naphthyridines and the cen-
tral phenyl ring as well as the distance between the nitro-
gens and carboxylic acid moiety has been shown to be
crucial. Even though we have shown that the central
phenyl ring in 3 could be replaced by other heterocycles
with improvements in potency and PK properties, a sim-
ilar change in cyclopropyl analogs is not tolerated. The
tetrahydronaphthyridine has been shown to be a very
good guanidine surrogate by others23 and us. The cyclo-
propyl moiety has been shown to be an ideal replace-
ment for the methyl group in this class of compounds.
The absolute configuration of 7 has not been deter-
mined. The compounds have very good selectivity for
avb3 over avb6. The selectivity versus the integrin avb6
is crucial due to the physiological effects observed in
the b6 knockout mouse.62 Most of the compounds
tested showed very good selectivity (at least 200·) over
avb6. Some of the compounds have been tested for bind-
ing to 293 cell lines that express avb1, avb3, and avb5.63
In general, good selectivity over avb1 cell lines was ob-
served. The (+)7 analog has been scaled up and exten-
sive in vivo studies have been performed and the
results will be reported elsewhere.
Association for Assessment and Accreditaion of Labo-
ratory Animal Care, International. Male Swiss-Webster
mice and Sprague–Dawley rats were obtained from
Charles River Laboratories (Wilmingotn, MA). All
Simmons–Smith reactions were conducted behind a
blast shield in the hood.
9. Materials and methods
Human vitronectin receptor avb3 was purified from hu-
man placenta64 and from fresh frozen plasma65 as previ-
ously described. Biotinylated human vitronectin was
prepared by coupling NHS-biotin from Pierce Chemical
Company (Rockford, IL) to purified vitronectin.66 As-
say buffer, OPD substrate tablets, and RIA grade BSA
were obtained from Sigma (St. Louis, MO). Anti-biotin
antibody was obtained from Sigma (St. Luois, MO).
Nalge Nunc-Immuno microtiter plates were obtained
from Nalge Company (Rochester, NY). Optical rota-
tions were determined on a Rudolph Autopol III Auto-
matic polarimeter with 1 dm cell in methanol.
9.1. Solid phase receptor assays67
The purified human vitronectin receptor avb3 was di-
luted from stock solutions to 1.0 lg/mL in Tris-buffered
saline containing 1.0 mM Ca2+, Mg2+, and Mn2+, pH
7.4 (TBS3+). The diluted receptors were immediately
transferred to Nalge Nunc-Immuno microtiter plates
at 100 lL/well (100 ng receptor/well). The plates were
sealed and incubated overnight at 4 ꢁC to allow the
receptors to bind to the wells. All remaining steps were
at room temperature. The assay plates were emptied
8. General
Nuclear magnetic resonance spectra were recorded on a
Varian XL-400 spectrometer and chemical shifts are re-
ported in ppm relative to TMS as internal standard. Pre-
parative HPLC was performed on a Waters Prep LC
2000 System using a UV detector (Waters 2487 Dual k
absorbance detector) on a Waters Delta pak C18-100A
(5 cm · 30 cm column) at a flow rate of 80 mL/min using
acetonitrile/water gradient containing 0.01% TFA. All
final compounds were analyzed by analytical HPLC
(gradient 5–100% acetonitrile in water containing
0.01% TFA) and peaks were monitored at 210 and
254 nM for purity. Mass spectral data were acquired
on a Waters ZQ model single quadrupole instrument
with an electro spray probe. High resolution data were
acquired on a Perception Biosystems Mariner Time of
Flight instrument with an electro spray probe. All
animal studies were approved by the Pharmacia
Institutional Animal Care and Use Committee. Animals
were housed in Pharmacia facilities accredited by the
and 200 lL of 1% RIA grade BSA in TBS3+ (TBS3+
/
BSA) was added to block exposed plastic surfaces. Fol-
lowing 2-h incubation, the assay plates were washed
with TBS3+ using a 96-well plate washer. Logarithmic
serial dilution of the test compound and controls was
made starting at a stock concentration of 2 mM and
using 2 nM biotinylated vitronectin in TBS3+/BSA as
the diluent. This premixing of labeled ligand with test
(or control) ligand, and subsequent transfer of 50 lL ali-
quots to the assay plate, was carried out with a CETUS
Propette robot; the final concentration of the labeled
ligand was 1 nM and the highest concentration of test
compound was 1.0 · 10À4 M. The competition occurred

S. R. Nagarajan et al. / Bioorg. Med. Chem. 15 (2007) 3390–3412
3401
for 2 h after which all wells were washed with a plate
washer as before. Affinity-purified horseradish peroxi-
dase labeled goat anti-biotin antibody was diluted
1:2000 in TBS3+/BSA and 125 lL was added to each
well. After 45 min, the plates were washed and incu-
bated with OPD/H2O2 substrate in 100 mM/L citrate
buffer, pH 5.0. The plate was read with a microtiter plate
reader at a wavelength of 450 nM and when the maxi-
mum-binding control wells reached an absorbance of
about 1.0, the final A450 were recorded for analysis.
The data were analyzed using a macro written for use
with the EXCEL spreadsheet program. The mean, stan-
dard deviation, and %CV were determined for duplicate
concentrations. The mean A450 values were normalized
to the mean of four maximum-binding controls (no
competitor added) (B-MAX). The normalized values
were subjected to a four-parameter curve fit algorithm,
plotted on a semi-log scale, and the computed concen-
tration corresponding to inhibition of 50% of the maxi-
mum binding of biotinylated vitronectin (IC50) and
corresponding R2 were reported for those compounds
exhibiting greater than 50% inhibition at the highest
concentration tested; otherwise the IC50 is reported as
being greater than the highest concentration tested.
b-[[2-[[5-[(aminoiminomethyl)amino]-1-oxopentyl]amino]-
1-oxoethyl]amino]-3-pyridinepropanoic acid which is a
potent avb3 antagonist (IC50 in the range 3–10 nM) was
included on each plate as a positive control.
peptide (LAP) was mediated by the avb6, as determined
by a panel of integrin-specific, neutralizing monoclonal
antibodies. Briefly, cells were incubated with inhibitor
in the presence of 200 lM Mn2+, allowed to adhere to
immobilized LAP, washed, and adherent cells are de-
tected by quantifying endogenous alkaline phosphatase
using para-nitrophenyl phosphate. An 8-point dose–re-
sponse curve using either 10- or 3-fold dilutions of com-
pound was evaluated by fitting a four-parameter
logistic, nonlinear model (using SAS).
9.3. Mouse pharmacokinetics
Test compounds were administered orally (po) or intra-
venously (iv) as solutions. For iv dosing the compounds
were dissolved in normal saline. Compounds for po
administration were suspended in 0.5% (w/v) methylcel-
lulose and 0.025% (w/v) polyethylene sorbitan mono-
oleate (Tween 80). Blood samples were collected by
cardiac puncture following CO2 euthanasia, citrated to
prevent clotting, and the plasma immediately separated
by centrifugation. Plasma samples were stored at
À20 ꢁC until assayed for avb3 inhibitory activity using
a solid-phase competitive displacement assay. Pharma-
cokinetic parameters were calculated using WinNonLin
software (Pharsight Corp., Mountain View, CA).
9.4. Rat pharmacokinetic studies
9.2. Cell assays for potency and selectivity
Under isoflurane anesthesia, the femoral artery (all 6
rats) and femoral vein (only 3 of 6 rats) were isolated
and cannulated with PE50 tubing and secured with 3.0
silk sutures. The procedure required two catheters, with
the venous line being used for infusion of compound (in
the group of rats that received compound iv), and the
arterial line being used for collection of blood samples.
The rats were then placed in restraining cages, which
allow minimal movement and allowed to recover from
anesthesia for approximately 30 min. At time 0, blood
samples (400 lL) were collected from arterial cannula.
While the b3 subunit of avb3 is only known to complex
with av or aIIb, the av subunit complexes with multiple
b subunits. The three av integrins most homologous with
avb3 are avb1, avb5, and avb6, with 43%, 56%, and 47%
amino acid identity in the b subunits, respectively. To
evaluate the selectivity of compounds between the inte-
grins avb3 and avb6, cell-based assays were established
using the 293 human embryonic kidney cell line. Two
hundred and ninety three cells express avb1, but little
to no detectable avb3 or avb6. cDNAs for b3 and b6 were
transfected separately into 293 cells to generate 293-b3
and 293-b6 cells, respectively. High surface expression
of avb3 and avb6 was confirmed by flow cytometry. Con-
ditions were established for each cell line in which cell
adhesion to immobilized human vitronectin was medi-
ated by the appropriate integrin, as determined by a pa-
nel of integrin-specific, neutralizing monoclonal
antibodies. Briefly, cells were incubated with inhibitor
in the presence of 200 lM Mn2+, allowed to adhere to
immobilized vitronectin, washed, and adherent cells
are detected by quantifying endogenous alkaline phos-
phatase and para-nitrophenyl phosphate. An 8-point
dose–response curve using either 10- or 3-fold dilutions
of compound was evaluated by fitting a four-parameter
logistic, nonlinear model (using SAS).
One group of rats (three rats per group) received com-
pound via the oral route (18G, 3 in. curved gavage nee-
dle) at a dose of 10 mpk (10 mg/mL, dissolved in
PEG200: 40%, EtOH: 10%, and saline: 40%), while the
other group of rats received compound via the intrave-
nous cannula, at a dose of 2 mpk (10 mg/mL, dissolved
in PEG200: 40%, EtOH: 10%, and saline: 40%). The
blood samples were collected from the arterial cannula
at 10, 30, 60, 120, 240, and 360, 480, 960, and
1440 min with an additional 5 min sample being col-
lected from iv group. After each sample, the cannulas
were flushed with PBS containing 10-U/ml heparin.
After 24 h, the animals were terminated with excess of
anesthesia or by CO2 asphyxiation. The plasma was ob-
tained by immediate centrifugation and kept frozen
(À20 ꢁC) until analyzed. Plasma proteins were precipi-
tated with acetonitrile and subjected to centrifugation.
The supernatant containing compound was evaporated
under nitrogen and reconstituted in DMSO. To ensure
complete extraction, a standard compound at various
concentrations was mixed with control rat plasma and
extracted (spiked standard curve). The concentration
To evaluate compound potency for membrane-bound
avb6, a cell-based adhesion assay was established using
the HT-29 human colon carcinoma cell line. High sur-
face expression of avb6 on HT-29 cells was confirmed
by flow cytometry. Conditions were established in which
cell adhesion to immobilized human latency associated

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S. R. Nagarajan et al. / Bioorg. Med. Chem. 15 (2007) 3390–3412
of the inhibitor present in the plasma was determined
using the SPRA (assay described above).
9.4.3. 4-[3-(2-N-Pyridyl)amino]-1-propyloxyphenyl-3-(3-
pyridyl)butyric acid (4). A solution of DEAD (12.90 g,
74.06 mmol) and N-(2-pyridyl-N-oxide)-3-aminopropa-
nol23 (14, 12.44 g, 74.06 mmol) in DMF (150 mL) was
added to a solution of ethyl 3-(3-pyridyl)-4-(p-hydroxy-
phenyl)butyrate (13, 10.0 g, 37.03 mmol) and triphenyl-
phosphine (20.39 g, 74.06mmol) in DMF (150 mL) over
a period of 20 min and the reaction mixture was stirred
for 24 h. DMF was removed in vacuo and the residue
was purified by HPLC (reverse phase C18, 10–100% gra-
dient of acetonitrile in water containing 0.05% TFA) to
give 10.8 g of the product as oil. A mixture of the prod-
uct (10.6 g, 24.37 mmol), palladium/C (3.0 g), and cyclo-
hexene (20 mL) in ethanol (200 mL) was heated at reflux
over 24 h. The reaction mixture was filtered, and the res-
idue was washed with additional amount of ethanol
(100 mL). The combined filtrates were concentrated.
The residue was added ethanol (5 mL) and sodium
hydroxide (5 mL, 2.5 N) and stirred for 8 h. The reac-
tion mixture was concentrated and the residue was dis-
solved in water (5 mL) and the pH was adjusted to 2
by the addition of TFA. This was purified by HPLC (re-
verse phase C18, 10–100% gradient of acetonitrile in
water containing 0.05% TFA) and 6.8 g (36%) of the
product was obtained as its TFA salt. 1H NMR
(CD3OD) d 8.72 (m, 2H), 8.58 (m, 1H), 8.04 (t, 1H,
J = 5.8 Hz), 7.8–7.87 (m, 2H), 7.0–7.18 (m, 3H), 6.8–
6.91 (m, 3H), 4.08–4.12 (m, 2H), 3.58–3.73 (m, 3H),
3.05–3.2 (m, 1H), 2.87–3.08 (m, 3H), 2.16–2.24 (m,
2H). HRMS (ES, m/z) Calcd for C23H25N3O3:
392.1969 (M+H). Found: 392.1990 (M+H).
9.4.1. 1-(3-Pyridyl)-2-(p-acetoxyphenyl)-ethan-1-one (10).
A mixture of p-methoxybenzonitrile (9, 73.0 g, 0.5 mol)
and methyl nicotinoate (68.5 g, 0.5 mmol) in ethanol
(400 mL) was added sodium methoxide (270 mL,
25%) at 0 ꢁC and was stirred for 10 min. The reaction
mixture was heated at reflux for 2.5 h, then was poured
into ice-water mixture (2 L), neutralized with concen-
trated HCl. The deep yellow solid was filtered, washed
with water, and dried to yield 95 g (80%) of the desired
product. Hydrobromic acid (48%, 400 mL) was added
to the deep yellow product and was heated at reflux
for 18 h. Vigorous foaming occurs in the beginning of
the reaction. The reaction mixture was poured into ice.
The aqueous mixture was neutralized with ammonium
hydroxide to afford a precipitate. The precipitate was
filtered and dried to give 1-(3-pyridyl)-2-(p-hydroxy-
phenyl)ethan-1-one as
a
white solid. 1H NMR
(CD3OD) d 9.11 (s, 1H), 8.67 (m, 1H), 8.37 (m, 1H),
7.52 (m, 1H), 7.06 (d, 2H, J = 8.0 Hz), 6.72 (m, 2H),
4.25 (s, 2H). HRMS (ES, m/z) Calcd for C13H11NO2:
Mol. wt, 214.0863 (M+H). Found: 214.0836 (M+H).
A mixture of 1-(3-pyridyl)-2-(p-hydroxyphenyl)ethan-
1-one (19.9 g, 0.1 mol), acetic anhydride (10.2 g,
0.1 mol), DMAP (0.20 g), and methylene chloride
(250 mL) was heated at reflux for 18 h. The cooled
reaction mixture was washed with sodium bicarbonate
(100 mL), brine, dried, and concentrated to afford the
product as oil (17.4 g, 72%), which solidified upon
1
standing. H NMR (CD3OD) d 9.17 (s, 1H), 8.72 (m,
1H), 8.23–8.26 (m, 1H), 7.39–7.42 (m, 1H), 7.23 (d,
2H, J = 8.2 Hz), 7.02 (d, 2H, J = 8.2 Hz), 4.26 (s,
2H), 2.0 (s, 3H). HRMS (ES, m/z) Calcd for
C15H13NO3: 256.0968 (M+H). Found: 256.0939
(M+H).
9.4.4. 4-(p-Methoxyphenyl)-but-3-enoic acid (16). A mix-
ture of 3-carboxypropyl-triphenylphosphonium bromide
(210 g, 506 mmol) and p-anisaldehyde (62.1 mL) in
dimethylsulfoxide (600 mL) was added slowly to a sus-
pension of sodium hydride 41 g (60% suspension in min-
eral oil) in tetrahydrofuran (300 mL). The reaction
mixture was stirred mechanically for 18 h, quenched with
water (1 L) followed by addition of sodium hydroxide
(100 mL, 2.5 M), and extracted with ether. The aqueous
layer was acidified to afford oil. The oil was extracted with
ethyl acetate (2 L), dried (MgSO4), and concentrated. The
residue was added hexane and ethyl acetate and was
cooled. The desired product precipitated and filtered
and was washed with hexane to yield 90 g (92%) as a yel-
low crystalline solid. 1H NMR (CD3OD) d 7.29 (m, 2H),
6.83 (m, 2H), 6.42 (d, 1H, J = 15.8 Hz), 6.11–6.18 (m, 1H),
3.76 (s, 3H), 3.17 (m, 2H). HRMS (ES, m/z) Calcd for
C11H12O3: 192.0786. Found: 192.1176.
9.4.2. Ethyl 3-(3-pyridyl)-4-(p-hydroxyphenyl)butyrate (11).
(Carbethoxymethylene)-triphenylphosphorane
(30.2 g,
86.63 mmol) was added to the ketone (10c, 22.18 g,
86.63 mmol), heated at reflux in toluene (300 mL) for
40 h, and concentrated. Ethyl acetate (200 mL) was
added to the residue and was allowed to stand. The
precipitate formed was filtered off and the filtrate was
concentrated and the residue was purified by chromatog-
raphy (silica gel, 75% EA in hexane) to yield 16.8 g of the
desired product as a complex mixture of three isomers
and was subjected to hydrogenation (50 psi) for 4 h.
The catalyst was filtered, and the filtrate was concen-
trated to give a residue. The residue was stirred in
saturated ethanol/HCl (200 mL) for 3h and was concen-
trated. The residue was partitioned between ethyl acetate
(400 mL) and sodium bicarbonate (200 mL) and the or-
ganic layer was dried (MgSO4). The organic layer was
concentrated to afford 12.27 g (84%) of the product as
oil. 1H NMR (CD3OD) d 8.68 (d, 1H, J = 5.5 Hz),
8.63 (S, 1H), 8.52 (d, 1H, J = 7.8 Hz), 7.80 (t, 1H,
J = 6.3 Hz), 6.87 (d, 2H, J = 8.2 Hz), 6.63 (d, 2H,
J = 8.2 Hz), 3.95–4.01 (m, 2H), 3.58-3.63 (m, 1H), 2.81–
3.17 (m, 4H), 1.11 (t, 3H,J = 7 Hz). HRMS (ES, m/z)
Calcd for C17H19NO3: 286.1438 (M+H). Found:
286.1439 (M+H).
9.4.5. (N-Methoxy-N-methyl)-4-(p-Methoxyphenyl)-but-
3-enamide (17). A mixture of 4-(p-methoxyphenyl)-but-
3-enoic acid (81.51 g, 0.425 mol), HOBt (57.6 g,
0.425 mol), and EDC (81.4 g, 0.425 mol) in dimethyl-
formamide (1.5 L) was stirred mechanically. N-Methyl-
O-methylhydroxylamine
hydrochloride
(41.5 g,
0.425 mol) was added followed by triethylamine
(120 mL) to the reaction mixture and stirring continued
for 18 h. The solvent was removed in vacuo and the res-
idue was partitioned between ethyl acetate (1 L) and so-
dium bicarbonate (saturated solution, 0.75 L). The
organic layer was washed with water (1 L), brine (1 L),

S. R. Nagarajan et al. / Bioorg. Med. Chem. 15 (2007) 3390–3412
3403
dried (MgSO4), and concentrated to give a residue. A
solution of the residue was passed through a thick pad
of silica gel (40% ethyl acetate in hexane) to yield
40.8 g (39%) of the product. 1H NMR (CD3OD) d
7.29 (m, 2H), 6.83 (m, 2H), 6.44 (d, 1H, J = 15.8 Hz),
6.11–6.18 (m, 1H), 3.75 (s, 3H), 3.74 (s, 3H), 3.35 (m,
2H), 3.19 (s, 3H). HRMS (ES, m/z) Calcd for
C13H17NO3: 235.1208. Found: 236.1255 (M+H).
84 mmol) in dry DMF (100 mL), 4-methylmorpholine
(11 g, 92 mmol) was added at À5 ꢁC and stirred for
25 min at À5 ꢁC. iso-Butylchloroformate (12.6 g,
92 mmol) was added to the above solution and stirred
for 10 min at À5 ꢁC followed by the addition of solid
N, O-dimethylhydroxyamine HCl (9 g, 92 mmol) and
4-methylmorpholine (11 g, 108 mmol). The reaction
mixture was stirred for 6 h at room temperature. The
reaction mixture was quenched with HCl (0.5 N,
200 mL) at 4 ꢁC and was extracted with CH2Cl2 (3·
250 mL). The combined organic solution was washed
with NaOH (0.5 N, 2· 200 mL), brine (1· 200 mL)
and was concentrated. The residue was dissolved in
ether (600 mL) and washed with brine, dried over
Na2SO4, concentrated, and dried to give 19 g oil (quan-
titative). The crude material was used in the next reac-
9.4.6. N-Methoxy-N-methyl-1-(p-Methoxyphenyl)-2-cyclo-
propane-acetamide (18). Iodochloromethane (247 g,
102 mL, 1.4 mol) was added to a solution of dimethoxye-
thane (73 mL) in dichloromethane (1 L) at À15 ꢁC. A solu-
tion of diethyl zinc (704 mL, 1 M in hexane) was slowly
added maintaining the internal temperature at À15 ꢁC.
The reaction mixture was stirred for 20 min and (N-meth-
oxy-N-methyl)-4-(p-methoxyphenyl)-but-3-enamide (17,
82.06 g, 0.349 mol) in dichloromethane (500 mL) was
added. The reaction mixture was allowed to warm up to
room temperature and stirred for 18 h. It was quenched
with hydrochloric acid (1 N, 1 L). The organic layer was
washed with water (1 L), brine (1 L), dried (MgSO4), and
concentrated. The residue was passed through a pad of sil-
ica gel (30% ethyl acetate in hexane) to yield 89 g (98%) of
1
tion without further purification. H NMR (CDCl3) d
7.65 (d, 1H, J = 15.7 Hz), 7.5 (m, 2H), 6.9 (m, 3H), 3.8
(s, 3H), 3.75 (s, 3H), 3.3 (s, 3H). HRMS (ES, m/z) Calcd
for C12H15NO3 (M+H): 222.1125. Found: 222.1143.
9.4.10. N-Methoxy-2-(4-methoxyphenyl)-N-methylcyclo-
propanecarboxamide (24). Sodium hydride (60% in min-
eral oil, 7 g, 170 mmol) was added portionwise over
20 min to a solution of trimethylsulfoxonium iodide
(38 g, 173 mmol) in DMSO (100 mL) in a water bath.
The suspension was stirred for 1 h. A solution of the ole-
fin amide (19 g, 86 mmol) in DMSO (100 mL) was
added to the reaction mixture and stirred for 6 h. The
reaction mixture was poured into a saturated solution
of ammonium chloride (500 mL) and was extracted with
CH2Cl2 (3·300 mL). The combined organic layer was
washed with brine, dried over Na2SO4, filtered, and con-
centrated. The concentrated residue was purified by
chromatography on silica gel (30% ethyl acetate in hex-
ane) to give 14.3 g oil (71%). 1H NMR (CDCl3) d 7.1 (m,
2H), 6.8 (m, 2H), 3.8 (s, 3H), 3.7 (s, 3H), 3.2 (s, 3H), 2.4–
2.5 (m, 1H), 2.3–2.4 (m, 1H), 1.5–1.6 (m, 1H), 1.2–1.3
(m, 1H). HRMS (ES, m/z) Calcd for C13H17NO3
(M+H): 236.1281. Found: 236.1287.
1
the product as oil. H NMR (CD3OD) d 7.03 (d, 2H,
J = 8.7 Hz), 6.78 (d, 2H, J = 8.6 Hz), 3.75 (s, 3H), 3.66 (s,
3H), 3.18 (s, 3H), 2.40–2.61 (m, 2H), 1.7–1.73 (m, 1H),
1.32–1.37 (m, 1H), 0.88–0.94 (m, 1H), 0.78–0.83 (m, 1H).
HRMS (ES, m/z) Calcd for C14H19NO3: 249.1365. Found:
250.1405 (M+H).
9.4.7. 1-(p-Methoxyphenyl)cyclopropane-2-acetic acid (19).
Sodium hydroxide (100 mL, 2.5 M) was added to a
solution of N-methoxy-N-methyl-1-(p-methoxyphenyl)-2-
cyclopropaneacetamide (89 g) in ethanol (300 mL) and
was stirred for 24 h at rt. The solvent was removed in vacuo
and the residue was partitioned between ether (400 mL)
and water (1 L). The aqueous layer was acidified to afford
1
65 g (88%) of the product as a crystalline powder. H
NMR (CD3OD) d 7.02 (d, 2H, J = 8.6 Hz), 6.79 (d, 2H,
J = 8.6 Hz), 3.76 (s, 3H), 2.39–2.50 (m, 2H), 1.7–1.76
(m, 1H), 1.29–1.41 (m, 1H), 0.92–0.97 (m, 1H), 0.80–0.84
(m, 1H). HRMS (ES, m/z) Calcd for C12H14O3: 206.0943.
Found: 206.0901.
9.4.11. 2-(4-Methoxyphenyl)cyclopropanecarbaldehyde
(25). To the cyclopropyl amide (24, 15.6 g, 66 mmol)
in dry THF (100 mL) under nitrogen at À78 ꢁC, DI-
BAL (1 M in hexane, 100 mmol) was added. The reac-
tion was complete in 1 h. Reaction mixture was poured
into a saturated potassium sodium tartarate (250 mL)
and stirred for 1 h and was extracted with ethyl acetate
(3· 250 mL). The combined organic solution was
washed with brine and dried over Na2SO4, concen-
trated, and dried to give 12 g (quantitative) of white so-
lid. 1H NMR (CDCl3) d 9.3 (d, 1H, J = 4.7 Hz), 7.0 (m,
2H), 6.8 (m, 2H), 3.8 (s, 3H), 2.6 (m, 1H), 2.1 (m, 1H),
1.7 (m, 1H), 1.4 (m, 1H). HRMS (ES, m/z) Calcd for
C11H12O2: Mol. wt, 176.0837. Found: 176.0840.
9.4.8. Ethyl 1-(p-methoxyphenyl)cyclopropane-2-acetate
(20). A mixture of 1-(p-methoxyphenyl)cyclopropane-2-
acetic acid (65 g, 301 mmol), ethanol (500 mL), and
hydrochloric acid (10 mL) was heated at reflux for
18 h. The solvent was removed in vacuo and the residue
in ether (500 mL) was washed with saturated bicarbon-
ate (200 mL), dried, and concentrated to afford 60 g
1
(82%) of the product as oil. H NMR (CD3OD) d 7.02
(d, 2H, J = 8.5 Hz), 6.79 (d, 2H, J = 8.5 Hz), 4.14 (q,
2H, J = 7.2 Hz), 3.76 (s, 3H), 2.30–2.40 (m, 2H), 1.69–
1.73 (m, 1H), 1.23–1.31 (m, 4H), 0.89–0.94 (m, 1H),
0.76–0.81 (m, 1H). HRMS (ES, m/z) Calcd for
C14H18O3: 234.1256. Found: 252.1582 (M+NH4).
9.4.12. [2-(4-Methoxyphenyl)cyclopropyl]acetaldehyde (26).
To a solution of (methoxymethyl)triphenylphosphonium
chloride (24.5 g, 0.071 mol) in dry THF (50 mL) at 4 ꢁC
was added lithium bis(trimethylsilyl)amide (1 M in THF,
72 mL). The reaction mixture was stirred for 20 min at
9.4.9. Alternative preparation of ethyl 1-(p-methoxyphe-
nyl)cyclopropane-2-acetate (20): (2E)-N-Methoxy-3-(4-
methoxyphenyl)-N-methylprop-2-enamide (23). To
solution of trans 4-methoxycinnamic acid (15 g,
a
4 ꢁC and a solution of the aldehyde 25 (8.4 g,
0.0477 mol) in THF (100 mL) was added. Ice bath was

3404
S. R. Nagarajan et al. / Bioorg. Med. Chem. 15 (2007) 3390–3412
removed 30 min later and reaction mixture was stirred for
1 h at room temperature. The reaction mixture was
poured into water (350 mL), extracted with ether (3·
200 mL), washed with brine, dried over Na2SO4, and con-
centrated. The residue was purified by chromatography
on silica gel (5% ethyl acetate in hexane) to remove the po-
lar spot. Fractions containing top two spots (very close to-
gether) were combined, dried to give 9.5 g of the olefin.
The resulting methoxy olefin in THF (50 mL) was added
HCl (1.5 N, 50 mL) and refluxed for 2 h. The reaction
mixture was cooled to room temperature and was neutral-
ized by adding saturated NaHCO3 and extracted with
ether. The combined organic solution was concentrated
and purified by chromatography on silica gel (20% ethyl
acetate in hexane) to give 7.1 g (79%) oil. 1H NMR
(CDCl3) d 9.8 (t, 1H, J = 1.9 Hz), 7.0 (m, 2H), 6.8 (m,
2H), 3.85 (s, 3H), 2.5 (m, 2H), 1.7 (m, 1H), 1.25 (m,
1H), 1.0 (m, 1H), 0.8 (m, 1H). HRMS (ES, m/z) Calcd
for C12H14O2: 190.0994. Found: 190.0990.
(14), and following the procedure described for 3, the
desired product was obtained. 1H NMR (CD3OD) d
7.82–7.87 (m, 1H), 7.7 (d, 1H, J = 5.9 Hz), 7.02 (d,
1H, J = 9.1 Hz), 6.99 and 6.77 (AB, 4H, J = 8.7 Hz),
6.83 (t, 1H, J = 6.4 Hz), 4.06 (t, 2H, J = 5.9 Hz), 3.55
(t, 2H, J = 6.9 Hz), 2.34 (m, 2H), 2.13 (m, 2H), 1.65–
1.71 (m, 1H), 1.16–1.24 (m, 1H), 0.74–0.88 (m, 2H).
Anal. Calcd for C19H22N2O3. TFA C, 57.27; H, 5.26;
N, 6.36; Mol. wt, 327.1703 (M+H). Found: C, 57.99;
H, 5.44; N, 6.27; Mol. wt, 327.1708 (M+H. HRMS).
9.4.16. [2-(4-{2-[6-(Methylamino)pyridin-2-yl]ethoxy}phenyl)-
cyclopropyl]acetic acid trifluoroacetate (28). To a solu-
tion of 2-[6-(methylamino)pyridin-2-yl]ethanol (27,
1 g, 6.6 mmol) and polymer bound PPh3 (1.4 g,
9.9 mmol) in dry THF (50 mL) was added ethyl
[2-(4-hydroxyphenyl)cyclopropyl]acetate (21, 1.4 g,
6.6 mmol) followed by diisopropyl azodicarboxylate
(1.5 mL, 7.7 mmol). The reaction mixture was stirred
at room temperature. After 18 h, the polymer was fil-
tered through Celite and was washed with excess
THF. The filtrate was concentrated and the residue
was dissolved in 1:1 acetonitrile/water (40 mL) and
was treated with LiOH (1 g). The reaction mixture
was heated for 2 h at 55 ꢁC, then cooled to room tem-
perature and was purified on reverse phase HPLC to
give 0.45 g (15%) of title compound. 1H NMR
(CD3OD) d 7.8 (m, 1H), 7.0 (d, 2H, J = 8.6 Hz),
6.9–6.6 (m, 4H), 4.26 (t, 2H, J = 6 Hz), 3.21 (t, 2H,
J = 6 Hz), 3.0 (s, 3H), 2.35–2.33 (m, 2H), 1.71–1.67
(m, 1H), 1.21–1.18 (m, 1H), 0.89–0.76 (m, 2H).
HRMS (ES, m/z) Calcd for C19H22N2O3 (M+H):
327.1703. Found: 327.1677.
9.4.13. [2-(4-Methoxyphenyl)cyclopropyl]acetic acid (19).
The aldehyde (26, 15.5 g, 0.08 mol) in ethanol (100 mL)
was cooled in ice bath and silver nitrate was added
(27.4 g in 36 mL of distilled water) followed by NaOH
(12.8 g in 36 mL of distilled water). Ice bath was re-
moved 20 min later. The reaction mixture was stirred
for 30 min at room temperature. The solid was filtered
through Celite and was washed with water (200 mL).
The filtrate was concentrated to remove ethanol. The
aqueous solution was washed with ether (3· 100 mL)
and was acidified (concentrated HCl). The acidified
aqueous solution was extracted with CH2Cl2. The com-
bined organic extracts were washed with brine, dried
over Na2SO4, and concentrated to give 15.5 g (92%)
yellow solid. 1H NMR (CD3OD) d 7.0 (m, 2H), 6.8
(m, 2H), 3.7 (s, 3H), 2.3 (m, 2H), 1.7 (m, 1H), 1.2
(m, 1H), 0.9 (m, 1H), 0.7 (m, 1H). HRMS (ES, m/z)
Calcd for C12H14O3 (MÀH): 205.0859. Found:
205.0858.
9.4.17. (2-{4-[2-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-
yl)ethoxy]phenyl}-cyclopropyl)acetic acid, trifluoroace-
tate (7). Starting from 2-(5,6,7,8-tetrahydro-1,8-naph-
thyridin-2-yl)-1-ethanol (29, 3.9 g, 22 mmol) and the
phenol 21, and following the procedure described for
28, the ethyl ester of the product was obtained. Yield:
1
9.4.14. Ethyl 1-(p-hydroxyphenyl)cyclopropane-2-acetate
(21). Boron tribromide (246 mL, 1 M) in dichlorometh-
ane was added slowly to a solution of ethyl 1-(p-meth-
oxyphenyl)cyclopropane-2-acetate (20, 60 g, 246 mmol)
in dichloromethane (1L) at 0 ꢁC and the reaction mix-
ture was stirred at room temperature for 18 h. It was
cooled to 0 ꢁC and was quenched with excess ethanol.
The reaction mixture was concentrated and the residue
in ethyl acetate (1 L) was washed with saturated sodium
bicarbonate (500 mL), washed with brine (500 mL),
dried, and concentrated. The residue was purified by
passing through a thick pad of silica and eluting with
20% ethyl acetate in hexane to give 50.2 g (89%) of the
54%. H NMR (CD3OD) d 7.11 (d, 1H, J = 7.2 Hz),
6.98–6.95 (m, 2H), 6.75 (m, 2H), 6.43 (d, 1H,
J = 7.4 Hz), 4.17–4.09 (m, 4H), 3.35 (t, 2H,
J = 5.5 Hz), 2.91 (t, 2H, J = 6.8 Hz), 2.68 (t, 2H,
J = 6.2 Hz), 2.42–2.29 (m, 2H), 1.88–1.82 (m, 2H),
1.71–1.66 (m, 1H), 1.24–1.13 (m, 4H), 0.88-0.84 (m,
1H), 0.78–0.74 (m, 1H). HRMS (ES, m/z) Calcd for
C23H28N2O3 (M+H): 381.2173. Found: 381.2193.
The ethyl ester of (3.7 g, 9.8 mmol) was dissolved in
40 mL of 50% acetonitrile in water and LiOH (1.64 g,
39 mmol) was added. The reaction mixture was heated
at 50 ꢁC for 2 h, then acidified by adding TFA. The res-
idue was purified on reverse phase HPLC to give 3 g
product. 1H NMR (CD3OD)
d
6.93 (d, 2H,
1
J = 8.6 Hz), 6.71 (d, 2H, J = 8.6 Hz), 4.15 (q, 2H,
J = 7.1 Hz), 2.37 (d, 2H, J = 7.2 Hz), 1.66–1.71 (m,
1H), 1.23–1.28 (m, 4H), 0.87–0.91 (m, 1H), 0.75–0.79
(m, 1H). HRMS (ES, m/z) Calcd for C13H16O3:
220.1099. Found: 238.1410 (M+NH4).
(66%) clear oil. H NMR (400 MHz, CD3OD) d 7.57
(d, 1H, J = 7.4 Hz), 7.01–6.98 (m, 2H), 6.79–6.76 (m,
2H), 6.70 (d, 1H, J = 7.4 Hz), 4.22 (t, 2H, J = 6.0 Hz),
3.48 (t, 2H, J = 5.71 Hz), 3.10 (t, 2H, J = 5.98 Hz),
2.80 (t, 2H, J = 6.24 Hz), 2.88–2.40 (m, 2H), 1.96–1.90
(m, 2H), 1.71–1.68 (m, 1H), 1.24–1.20 (m, 1H), 0.88–
0.85 (m, 1H), 0.76–0.84 (m, 1H). HRMS (ES, m/z) Calcd
for C21H24N2O3 (M+H): 353.1865. Found: 353.1876
(M+H).
9.4.15. 2-[4-[3-(2-Pyridinylamino)propoxy]phenyl]cyclo-
propaneacetic acid, trifluoroacetate (6). Starting from
21 and 2-[(3-hydroxy-1-propyl)amino]pyridine-N-oxide

S. R. Nagarajan et al. / Bioorg. Med. Chem. 15 (2007) 3390–3412
3405
Separation of diastereomers of ethyl (2-{4-[2-(5,6,7,8-tet-
rahydro-1,8-naphthyridin-2-yl)ethoxy]-phenyl}cyclopro-
pyl)acetate: the isomeric mixture of ethyl (2-{4-[2-
(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy]phenyl}-
cyclopropyl)acetate (48 g) was separated on ChiralPak AS
column (flow rate: 50 mL/min; room temperature, isopro-
pylalcohol/heptane/diethylamine/-30:70:0.1) to give 21 g
ethyl ester of isomer A and 20 g ethyl ester of isomer B.
(m, 1H), 1.33 (m, 1H),1.02 (m, 1H), 0.92 (m, 1H). Calcd
for C21H22N2O3F2. 1TFA, 0.5H2O: C, 54.01; H, 4.73; N,
5.48. Found: C, 53.99; H, 4.61; N, 5.21.
9.4.20. (2-{3-Hydroxy-4-[2-(5,6,7,8-tetrahydro-1,8-naph-
thyridin-2-yl)ethoxy]phenyl}-cyclopropyl)acetic acid (64).
Mitsunobu reaction of 2-(5,6,7,8-tetrahydro-1,8-naph-
thyridin-2-yl)-1-ethanol (29) and ethyl [2-(3,4-dihydr-
oxyphenyl)cyclopropyl]-acetate (61), followed by
saponification and purification by HPLC, afforded the
product (<1% yield). Two-dimensional NMR confirmed
The ethyl ester of isomer A (10 g, 26 mmol) was dis-
solved in 50% acetonitrile in water (100 mL) and then
treated with lithium hydroxide (4.4 g, 104 mmol). The
solution was heated at 55 ꢁC for 3 h. The solution was
then cooled to room temperature and was acidified by
adding TFA. The crude material was purified on reverse
phase HPLC to give 11 g TFA salt of isomer A of 7. The
TFA salt was passed through Bio-Rad AG 2-X8 (200–
400 Mesh, chloride form, 100 g) column and was eluted
with 50% acetonitrile in water to give 9.5 g (94%) HCl
1
the structure. H NMR (400 MHz, D2O) d 7.3 (d, 1H,
J = 7.2 Hz), 6.7 (d, 2H, J = 8.7 Hz), 6.4 (m, 3H), 4.2 (t,
2H, J = 6.0 Hz), 3.2 (t, 2H, J = 5.5 Hz), 2.9 (t, 2H,
J = 5.7 Hz), 2.5 (t, 2H, J = 5.5 Hz), 2.2 (m, 2H), 1.7
(m, 2H), 1.5 (m, 1H), 1.1 (m, 1H), 0.7 (m, 2H). HRMS
(ES, m/z) Calcd for C21H24N2O3 (M+H): 369.1814.
Found: 369.1781.
1
salt of isomer A of 7 H NMR (400 MHz, CD3OD) d
9.4.21.
(2-{6-[2-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-
7.57 (d, 1H, J = 7.4 Hz), 7.0 (d, 2H, J = 8.6 Hz), 6.8
(d, 2H, J = 8.6 Hz), 6.71 (d, 1H, J = 7.4 Hz), 4.22 (t,
2H, J = 6.0 Hz), 3.48 (t, 2H, J = 5.6 Hz), 3.10 (t, 2H,
J = 5.9 Hz), 2.80 (t, 2H, J = 6.2 Hz), 2.40–2.28 (m,
2H), 1.96–1.90 (m, 2H), 1.71–1.67 (m, 1H), 1.22–1.18
(m, 1H), 0.88–0.84 (m, 1H), 0.76–0.80 (m, 1H). [a]D
+34.3 (c 0.04, MeOH). HRMS (ES, m/z) Calcd for
C21H24N2O3 (M+H): 353.1860. Found: 353.1864.
yl)ethoxy]pyridin-3-yl}cyclopropyl)acetic acid (67). Mits-
unobu reaction of 2-(5,6,7,8-tetrahydro-1,8-naphthyri-
din-2-yl)-1-ethanol (29) and ethyl [2-(6-hydroxypyridin-3-
yl)cyclopropyl]acetate (66, prepared from 2-methoxy-5-
[(1E)-prop-1-enyl]pyridine39) and using the procedure
described for 28, followed by purification, gave the prod-
1
uct. H NMR (400 MHz, CD3OD) d 7.92 (m, 1H), 7.65
(m, 1H), 7.42 (m, 1H), 6.79 (m, 2H), 4.1 (q, 2H), 3.45 (t,
2H), 3.12 (t, 2H), 2.91 (t, 2H), 2.2–2.4 (m, 1H), 2.5–2.6
(m, 1H), 1.93 (m, 2H), 1.62–1.8 (m, 1H), 0.95 (m, 1H),
0.84 (m, 1H). HRMS (ES, m/z) Calcd for C20H23N3O3:
353.42. Found: 354.1971 (M+H).
The ethyl ester of isomer B (10 g, 26 mmol) was hydro-
lyzed and converted to 9.1 g of (89%) HCl salt by using
the procedure described above. 1H NMR (400 MHz,
CD3OD) d 7.59 (d, 1H, J = 7.4 Hz), 7.0 (d, 2H,
J = 8.6 Hz), 6.8 (m, 2H), 6.71 (d, 1H, J = 7.4 Hz), 4.22
(t, 2H, J = 6.0 Hz), 3.48 (t, 2H, J = 5.6 Hz), 3.11 (t, 2
H, J = 5.9 Hz), 2.80 (t, 2H, J = 6.2 Hz), 2.40–2.28 (m,
2H), 1.96–1.90 (m, 2H), 1.71–1.67 (m, 1H), 1.22–1.18
(m, 1H), 0.88–0.84 (m, 1H), 0.76-0.80 (m, 1H). [a]D
À34.0 (c 0.07, MeOH). HRMS (ES, m/z) Calcd for
C21H24N2O3 (M+H): 353.1860. Found: 353.1862.
9.4.22. Ethyl 3-[2-(4-hydroxyphenyl)cyclopropyl]propio-
nate (68). To the solution of 2-(4-methoxyphenyl)cyclo-
propanecarbaldehyde (25) (5 g, 28 mmol) in toluene
(100 mL), (carbethoxymethylene)triphenylphosphorane
(12.8 g, 37 mmol) was added. The reaction mixture
was refluxed overnight. The reaction mixture was con-
centrated and the residue was purified by passing
through a pad of silica gel eluting with 20% ethyl acetate
in hexane to yield 7.6 g of ethyl (2E)-3-[2-(4-methoxyphe-
nyl)cyclopropyl]prop-2-enoate. 1H NMR (400 MHz,
CDCl3) d 6.9 (m, 2H), 6.8 (m, 2H), 6.6 (m, 1H), 5.9 (d,
1H), 4.2 (m, 2H), 3.8 (s, 3H), 2.1 (m, 1H), 1.7 (m, 1H),
1.2 (m, 5H). HRMS (ES, m/z) Calcd for C15H18O3:
246.3061. Found: 246.1256. The product was dissolved
in ethyl acetate (100 mL) followed by addition of Rho-
dium/aluminum powder (1.1 g). The reaction mixture
was stirred under H2(g) (50 psi) overnight. The catalyst
was filtered through Celite and was washed with excess
ethyl acetate. The filtrate was concentrated and dried to
afford 3.5 g oil. The crude reduction product was used
9.4.18. (2-{3-Fluoro-4-[3-(5,6,7,8-tetrahydro-1,8-naphthyri-
din-2-ylamino)propoxy]-phenyl}cyclopropyl)acetic acid (62).
Mitsunobu reaction of 5,6,7,8-tetrahydro-1,8-naphthyri-
din-2-ethanol (29) with the phenol 58 followed by
1
saponification and purification gave 62 (30% yield). H
NMR (400 MHz, CDCl3) d 15.34 (1H, br s), 10.02
(1H, s), 7.33 (1H, d), 6.90 (1H, t), 6.80 (1H, d), 6.78
(1H, d), 6.60 (1H, br s), 6.54 (1H, d), 4.31 (2H, t),
3.49 (2H, t), 3.16 (2H, t), 2.74 (2H, t), 2.45 (1H, dd),
2.39 (1H, dd), 1.92 (2H, p), 1.71 (1H, dt), 1.28 (1H,
m), 0.93 (1H, dt), 0.84 (1H, dt). Anal Calcd for:
C21H23N2O3F plus 1.75 TFA. C, 51.63; H, 4.38; N,
4.91. Found: C, 52.01; H, 4.27; N, 4.92.
1
for the next reaction without further purification. H
NMR (400 MHz, CDCl3) d 6.9 (m, 2H), 6.8 (m, 2H), 4.1
(m, 2H), 3.7 (s, 3H), 2.4 (t, 2H, J = 7.4 Hz), 1.7 (m, 2H),
1.6 (m, 1H), 1.2 (m, 3H), 1.0 (m, 1H), 0.9 (m, 1H), 0.85
(m, 1H). HRMS (ES, m/z) Calcd for C15H20O3: 248.3220.
Found: 248.1412. To a solution of ethyl 3-[2-(4-methoxy-
phenyl)cyclopropyl]-propionate (2 g, 8.1 mmol) in
CH2Cl2 (20 mL) at 0 ꢁC was added BBr3 (1 M in CH2Cl2,
8 mL). The temperature was kept under 2 ꢁC during the
addition. The reaction mixture was slowly warmed up
9.4.19. (2-{2,3-Difluoro-4-[2-(5,6,7,8-tetrahydro-1,8-naph-
thyridin-2-yl)ethoxy]-phenyl}cyclopropyl)acetic acid trifluo-
roacetate (63). Mitsunobu reaction of 5,6,7,8-tetrahydro-
1,8-naphthyridin-2-ethanol (29) with the phenol 60
followed by saponification and purification afforded 63
(30% yield). HNMR (400 MHz, CD3OD): d 7.65 (d,
1H), 6.88 (m, 1H), 6.75 (m, 2H), 4.38 (t, 2H), 3.52 (t, 2H),
3.2 (t, 2H), 2.85 (t, 2H), 2.42 (m, 2H), 2.05 (m, 2H), 1.85
1

3406
S. R. Nagarajan et al. / Bioorg. Med. Chem. 15 (2007) 3390–3412
to room temperature and stirred for 18 h at room
temperature. The reaction mixture was quenched with
ethanol (10 mL) very slowly and stirred for 1 h at
room temperature. The reaction mixture was concen-
trated and purified by passing through a pad of silica
gel eluting with 20% ethyl acetate in hexane to afford
1.0 g oil (55%). 1H NMR (400 MHz, CDCl3) d 6.91
(m, 2H), 6.70 (m, 2H), 4.11 (m, 2H), 2.42 (t, 2H,
J = 7.4 Hz), 1.65 (m, 2H), 1.57 (m, 2H), 1.22 (t, 3H,
J = 7.1 Hz), 0.97 (m, 1H), 0.80 (m, 1H), 0.70 (m,
1H). HRMS (ES, m/z) Calcd for C14H18O3:
234.2960. Found: 234.1256.
9.4.26. 3-(2-{3-[2-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-
yl)ethoxy]phenyl}-cyclopropyl)propionic acid (72). Start-
ing from the aldehyde 41, and following the reaction se-
quence described for the synthesis of 69, 81% of the
desired product was obtained. 1H NMR (400 MHz,
CD3OD) d 7.6 (d, 1H, J = 7.4 Hz), 7.1 (t, 1H,
J = 7.9 Hz), 6.7 (d, 2H, J = 7.4), 6.6 (m, 2H), 6.57 (m,
1H), 4.2 (t, 2H, J = 5.9 Hz), 3.5 (t, 2H, J = 5.6 Hz),
3.10 (t, 2H, J = 5.9 Hz), 2.80 (t, 2H, J = 6.2 Hz), 2.40
(t, 2H, J = 7.3 Hz), 1.90 (m, 2H), 1.7 (m, 3H), 1.05 (m,
1H), 0.9 (m, 1H), 0.8 (m, 1H). HRMS (ES, m/z) Calcd
for C22H26N2O3 (M+H): 367.2027. Found: 367.2013.
9.4.23. 3-{2-[4-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-
ylmethoxy)phenyl]-cyclopropyl}propionic acid (70). To a
solution of NaBH4 (0.46 g, 12 mmol) in THF (10 mL)
was added 5,6,7,8-tetrahydro-1,8-naphthyridine-2-carb-
aldehyde (2 g, 12 mmol) at 0 ꢁC. The reaction mixture
was stirred for 1 h at 0 ꢁC, quenched with water at
0 ꢁC. The mixture was extracted with ethyl acetate (3·
50 mL). The combined organic solution was dried and
concentrated under vacuum to give 1.75 g (87%) of the
desired alcohol (73) as oil. Mitsunobu reaction of
5,6,7,8-tetrahydro-1,8-naphthyridin-2-ylmethanol with
9.4.27. Diethyl 2,2-dimethyl-3-(p-methoxyphenyl)cyclo-
propane-1,1-dicarboxylate (74). A mixture of anisalde-
hyde (340 g, 2.5 mol), diethylmalonate (400 g, 2.5 mol),
acetic acid (150 g), and piperidine (40 g) in dry toluene
(2 L) was heated at reflux for 24 h. The solvent was re-
moved in vacuo and the residue was dried to afford
690 g of the product. This was dissolved in dry DMSO
(2.5 L) and was added 2-nitropropane (500 mL) and
potassium tert-butoxide (600 g), and the reaction mix-
ture was stirred using a mechanical stirrer and was
heated to 100 ꢁC for 36 h. The pink reaction mixture
was poured into ice-water (10 L) and was extracted with
ether (10 L overall). The ether layer was washed with
brine, dried (MgSO4), and concentrated. The residue
was passed through a pad of silica (2.5 kg, 30 cm thick)
and was eluted with hexane (10 L). Appropriate frac-
tions of hexane eluents were combined and concentrated
ethyl
3-[2-(4-hydroxyphenyl)-cyclopropyl]propionate
(68) followed by saponification and purification afforded
47% of the desired product. 1H NMR (400 MHz,
CD3OD) d 7.6 (d, 1H, J = 7.4 Hz), 7.0 (m, 2H), 6.9
(m, 2H), 6.8 (m, 1H), 5.0 (s, 2H), 3.5 (t, 2H,
J = 5.7 Hz), 2.80 (t, 2H, J = 6.2 Hz), 2.40 (t, 2H,
J = 7.3 Hz), 2.0 (m, 2H), 1.7 (m, 3H), 1.0 (m, 1H), 0.9
(m, 1H), 0.85 (m, 1H). HRMS (ES, m/z) Calcd for
C21H24N2O3 (M+H): 353.1860. Found: 353.1889.
1
to yield 523 g (66%) of the product as oil. H NMR
(400 MHz, CD3OD) d 7.08 (m, 2H), 6.80 (d, 2H,
J = 8.7 Hz), 4.04–4.27 (m, 4H), 3.74 (s, 3H), 2.88 (s,
1H), 1.36 (s, 3H), 1.26 (s, 3H), 1.16 (t, 3H,
J = 7.2 Hz). HRMS (ES, m/z) Calcd for C18H24O5:
320.1624. Found: 320.1616.
9.4.24. 3-(2-{4-[2-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-
yl)ethoxy]phenyl}-cyclopropyl)-propionicacid(69). Mitsun-
obu reaction of 2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-
yl)-1-ethanol (29) with ethyl 3-[2-(4-hydroxyphenyl)cyclo-
propyl]-propionate (68) followed by saponification and
9.4.28. Ethyl 2,2-dimethyl-3-(p-methoxyphenyl)cyclopro-
pane-1-carboxylate (trans-isomer) (75). A mixture of the
diester (74, 425 g, 1.33 mol), potassium cyanide (392 g,
6 mol) in dry dimethylsulfoxide (1.5 L) was heated at
160 ꢁC for 48 h. The reaction mixture was cooled and
was poured into ice-water (6 L) and was extracted with
several portions of ether (8 L overall). The ether layer
was dried and was concentrated to afford a residue.
Chromatography of the residue with 2% hexane in ethyl
acetate gave 168 g (51%) of the product as oil. 1H NMR
(400 MHz, CD3OD) d 7.07 (dd, 2H, J = 2.8, 11.1 Hz),
6.82 (m, 2H), 4.15 (q, 2H, J = 7.2 Hz), 3.75 (s, 3H),
2.53 (d, 1H, J = 5.8 Hz), 1.91 (d, 1H, J = 5.8 Hz), 1.32
(s, 3H), 1.27 (t, 3H, J = 7.1 Hz), 0.88 (s, 3H). HRMS
(ES, m/z) Calcd for C15H20O3: 248.1412. Found:
248.1415.
1
purification gave 20% of the desired product. H NMR
(400 MHz, CD3OD) d 7.57 (d, 1H, J = 7.4 Hz), 6.94 (d,
2H, J = 8.7 Hz), 6.75 (d, 2H, J = 8.7 Hz), 6.70 (d, 1H,
J = 7.4 Hz), 4.21 (t, 2H, J = 5.9 Hz), 3.48 (t, 2H, J =
5.6 Hz), 3.11 (t, 2H, J = 5.9 Hz), 2.80 (t, 2H, J = 6.3 Hz),
2.40 (t, 2H, J = 7.25 Hz), 1.9 (m, 2H), 1.6 (m, 3H), 0.9
(m, 1H), 0.8 (m, 1H), 0.7 (m, 1H). HRMS (ES, m/z) Calcd
for C22H26N2O3 (M+H): 367.2016. Found: 367.2017.
9.4.25. (2-{3-[2-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-
yl)ethoxy]phenyl}-cyclo-propyl)acetic acid (71). Mitsun-
obu reaction of 2-(5,6,7,8-tetrahydro-1,8-naphthyridin-
2-yl)-1-ethanol (29) and ethyl [2-(3-hydroxyphe-
nyl)cyclopropyl]-acetate(59), prepared as described for
the p-isomer, followed by saponification and purifica-
tion afforded 63% of the desired product. 1H NMR
(400 MHz, CD3OD) d 7.60 (d, 1H, J = 7.4 Hz), 7.11 (t,
1H, J = 7.8 Hz), 6.74–6.63 (m, 4H), 4.26 (t, 2H,
J = 5.8 Hz), 3.49 (t, 2H, J = 5.6 Hz), 3.13 (t, 2H,
J = 5.8 Hz), 2.82 (t, 2H, J = 6.2 Hz), 2.38–2.35 (m,
2H), 1.98–1.91 (m, 2H), 1.76–1.70 (m, 1H), 1.31–1.25
(m, 1H), 0.97–0.90 (m, 1H), 0.88–0.81 (m, 1H). HRMS
(ES, m/z) Calcd for C21H24N2O3 (M+H): 353.1860.
Found: 353.1853.
9.4.29. 2,2-Dimethyl-3-(p-methoxyphenyl)cyclopropane-
1-carboxylic acid (cis-isomer) (76). A minor fraction
(more polar fraction) obtained from the above was
found to be a 1:1 mixture of the cis and trans isomers.
The mixture in ethanol (50 mL) was stirred at rt with ex-
cess sodium hydroxide (10%, 20 mL). Monitoring by
HPLC indicated the disappearance of the trans isomer
in about 3 h. The reaction mixture was diluted with
water and was extracted with ether. The ether layer

S. R. Nagarajan et al. / Bioorg. Med. Chem. 15 (2007) 3390–3412
3407
was dried and was concentrated to yield a residue. The
ester was hydrolyzed with ethanol (200 mL), sodium
hydroxide (10%, 50 mL) overnight. The reaction mix-
ture was poured into water and was acidified to afford
6.8 g of the product as white solid. 1H NMR
(400 MHz, CD3OD) d 7.04 (m, 2H), 6.82 (m, 2H),
3.73 (s, 3H), 2.39 (d, 1H, J = 9.1 Hz), 1.79 (d, 1H,
J = 9.1 Hz), 1.31 (s, 3H), 1.23 (s, 3H). HRMS (ES, m/
z) Calcd for C13H16O3: 220.1099. Found: 219.1016
(MÀH).
(100 mL), extracted with ethyl acetate (100 mL), and
discarded. The aqueous layer was acidified and then ex-
tracted with ether (200 mL), dried, and concentrated to
afford 1.40 g (62% overall) of [3-(4-methoxyphenyl)-2,2-
dimethylcyclopropyl]acetic acid as oil. 1H NMR
(400 MHz, CD3OD) d 7.04 (m, 2H), 6.81 (m, 2H),
3.74 (s, 3H), 1.97–2.04 and 2.30–2.36 (m, 2H), 1.84 (d,
1H, J = 9 Hz), 1.24 (s, 3H), 1.21 (m, 1H), 0.91 (s, 3H).
HRMS (ES, m/z) Calcd for C14H18O3: 234.1256. Found:
233.1154 (MÀH).
9.4.30. [(cis)-3-(4-Methoxyphenyl)-2,2-dimethylcyclopro-
pyl]methanol (78). BoraneÆTHF (40 mL, 40 mmol) was
added to a solution of 2,2-dimethyl-(cis)-3-(p-methoxy-
phenyl)-cyclopropane-1-carboxylic acid (76, 4.0 g,
18 mmol) in THF (40 mL). After 3-h stirring at rt, the
reaction mixture was quenched with hydrochloric acid
(40 mL, 1 N), diluted with water (200 mL), and extracted
with ether (2· 100 mL). The organic layer was washed
with water, dried, and concentrated to afford 3.7 g
(100%) of the product as oil. 1H NMR (400 MHz,
CD3OD) d 7.08 (m, 2H), 6.79 (m, 2H), 3.73 (s, 3H), 3.68
(m, 1H), 3.33 (m, 1H), 1.89 (d, 1H, J = 9.0 Hz), 1.24 (s,
3H), 1.12 (m, 1H), 0.94 (s, 3H). HRMS (ES, m/z) Calcd
for C13H18O2: 206.1307. Found: 206.1316.
9.4.32. Ethyl (cis)2,2-dimethyl-3-(p-hydroxyphenyl)cyclo-
propaneacetate (82). A solution of [3-(4-methoxyphe-
nyl)-2,2-dimethylcyclopropyl]acetic acid (80, 1.40 g)
was heated at reflux with ethanol (100 mL) and hydro-
chloric acid (1 mL) for 3 h. The reaction mixture was
concentrated and the residue was dissolved in ether
(200 mL). The ether layer was washed with water, dried,
1
and concentrated to afford 1.2 g of the ester. H NMR
(400 MHz, CD3OD) d 7.03 (m, 2H), 6.80 (m, 2H),
4.08–4.16 (m, 2H), 3.74 (s, 3H), 1.99–2.05 and 2.34–
2.40 (m, 2H), 1.85 (d, 1H, J = 9 Hz), 1.23 (s, 3H), 1.23
(m, 3H), 1.18 (m, 1H), 0.90 (s, 3H). HRMS (ES, m/z)
Calcd for C16H22O3: 262.1569. Found: 262.1569.
Boron tribromide (1 N, 8 mL) was added to a solution
of ethyl (cis)2,2-dimethyl-3-(p-methoxyphenyl)cyclo-
propaneacetate (described above, 1.03 g, 3.93 mmol) in
dichloromethane (20 mL) at 0 ꢁC and was stirred for
3 h. The reaction mixture was quenched with ethanol
(10 mL) and was stirred at rt for 18 h. Diluted with
dichloromethane (100 mL) it was washed with sodium
bicarbonate (saturated), dried, and concentrated. The
residue was purified on silica gel (flash, 40%ethyl acetate
in hexane) to yield 0.58 g (39%) of the phenol. 1H NMR
(400 MHz, CD3OD) d 6.94 (m, 2H), 6.67 (m, 2H), 4.07–
4.06 (m, 2H), 1.99–2.05 and 2.34–2.39 (m, 2H), 1.82 (d,
1H, J = 9 Hz), 1.22 (s, 3H), 1.22 (m, 3H), 1.17 (m, 1H),
0.90 (s, 3H). HRMS (ES, m/z) Calcd for C15H20O3:
248.1412. Found: 248.1415.
9.4.31. [(cis)-3-(4-Methoxyphenyl)-2,2-dimethylcyclopro-
pyl]acetic acid (80). Oxalyl chloride (19.3 mL, 1 M,
19.3 mmol) was added to a solution of DMSO (1.51 g,
38.64 mmol) in dichloromethane (20 mL) at À78 ꢁC.
After 15 min, a solution of the alcohol (78, 2.0 g,
9.66 mmol) in dichloromethane (5 mL) was added. After
30 min, triethylamine (10 mL) was added to the reaction
mixture and was warmed up to ambient temperature.
Water (100 mL) was added followed by additional
dichloromethane (100 mL). The organic layer was dried
and concentrated to give the crude aldehyde. The above
crude aldehyde in THF (10 mL) was added to the Wittig
reagent [prepared by adding lithium hexamethyldisilaz-
ane (21.3 mL, 21.3 mmol) to methoxymethyltriphenyl-
phosphonium chloride (6.62 g, 21.3 mmol) in
tetrahydrofuran (40 mL) at 0 ꢁC. After 6h, the reaction
mixture was diluted with water (200 mL), extracted with
ether (200 mL), dried, and concentrated to afford 2.0 g
9.4.33. 2,2-Dimethyl-3-(cis)-{4-[2-(5,6,7,8-tetrahydro-1,8-
naphthyridin-2-yl)ethoxy]phenyl}-cyclopropylacetic acid
trifluoroacetate (84). Mitsunobu reaction of 2-(5,6,7,8-
tetrahydro-1,8-naphthyridyl)-amino ethanol (29) and
ethyl (cis)2,2-dimethyl-3-(p-hydroxyphenyl)cyclopropa-
neacetate (82) followed by saponification and purifica-
tion by HPLC gave 23% of the desired product. 1H
NMR (400 MHz, CD3OD) d 7.58 (d, 1H, J = 7.4 Hz),
7.06 (m, 2H), 6.80 (m, 2H), 6.70 (d, 1H, J = 7.3 Hz),
4.24 (t, 2H, J = 5.9 Hz), 3.48 (m, 2H), 3.13 (t, 2H,
J = 5.9 Hz), 2.8 (m, 2H), 1.99–2.02 and 2.27–2.33 (m,
2H), 1.93 (m, 2H), 1.83 (d, 1H, J = 9 Hz), 1.23 (s,
3H), 1.18 (m, 1H), 0.89 (s, 3H). HRMS (ES, m/z)
Calcd for C23H28N2O3: 380.2100. Found: 379.2036
(MÀH).
1
of the product as a mixture of E- and Z-isomers. H
NMR (400 MHz, CD3OD) d 7.31–7.33 (m, 1H), 7.06–
7.09 (m, 2H), 6.76–6.81 (m, 2H), 6.38–6.41 and 6.02–
6.04 (m, 1H), 3.37 and 3.60 (2s, 3H), 3.73 and 3.74
(2s, 3H), 1.9 (m, 1H), 1.2 and 1.21 (2s, 3H), 0.88 and
0.86 (2s, 3H). HRMS (ES, m/z) Calcd for C13H18O2:
232.1463. Found: 232.1466.
A mixture of the crude 1-methoxy-4-{3-[2-methoxyethe-
nyl]-2,2-dimethylcyclo-propyl}benzene
(2.0 g)
was
heated at reflux in THF (50 mL) and hydrochloric acid
(1 N, 5 mL) for 4 h. The reaction mixture was diluted
with water, extracted with ether (200 mL), dried, and
concentrated to give the aldehyde mixed with triphenyl-
phosphine oxide. The aldehyde in ethanol (100 mL) was
added to an aqueous solution of silver nitrate (2.48 g) in
water (20 mL) followed by sodium hydroxide (12.4 mL,
1 N) at 0 ꢁC. After 3 h, the reaction mixture was filtered
through Celite. The filtrate was diluted with water
9.4.34. (2,2-dimethyl-3-{4-[2-(5,6,7,8-tetrahydro-1,8-naph-
thyridin-2-yl)ethoxy]-phenyl}cyclopropyl)acetic acid (83).
Mitsunobu reaction of 2-(5,6,7,8-tetrahydro-1,8-napthyri-
din-2-yl)-1-ethanol (29) and the cyclopropyl phenol (81),
prepared from the acid as described for the cis ester, fol-
lowed by saponification and purification by HPLC, gave

3408
S. R. Nagarajan et al. / Bioorg. Med. Chem. 15 (2007) 3390–3412
1
the title compound as yellow solid in a similar yield. H
NMR (400 MHz, CD3OD) d 7.57 (d, 1H), 7.09 (d, 2H),
6.79 (d, 2H), 6.71 (d, 1H), 4.23 (t, 2H), 3.48 (t, 2H),
3.11 (t, 2H), 2.80 (t, 2H), 2.47 (m, 4H), 1.93 (m, 2H),
1.57 (m, 1H), 1.18 (s, 3H), 0.81 (s, 3H). HRMS (ES,
m/z) Calcd for C23H28N2O3: 380.2100. Found: 381.2192
(M+H).
To the solution of (3E)-4-(4-methoxyphenyl)but-3-en-1-
ol (7.3 g, 41 mmol) in DMF (40 mL), tert-butyldimeth-
ylsilyl chloride (1 M in dichloromethane, 62 mL) and
imidazole (5.5 g, 80.1 mmol) were added followed by
DMAP (cat.). The reaction mixture was stirred for
18 h at room temperature and was diluted with ether
(500 mL). The organic solution was washed with water
(2· 200 mL), brine (1· 200 mL), dried over MgSO4,
1
9.4.35. Separation of diastereomers of ethyl (2,2-
dimethyl-3-{4-[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-
yl)ethoxy]phenyl}cyclopropyl)acetate (83). The isomeric
mixture of ethyl (2,2-dimethyl-3-{4-[2-(5,6,7,8-tetrahy-
dro-1,8-naphthyridin-2-yl)ethoxy]phenyl}cyclopropyl)-
acetate (83, 6 g) was separated on ChiralPak AS
column (isopropylalcohol/heptane/diethylamine/20:80:0.1,
flow rate: 50 mL/min at room temperature) to give
2.5 g ethyl ester of isomer A and 1.5 g ethyl ester of
isomer B.
and concentrated to yield 9 g (75%) of oil. H NMR
(400 MHz, CDCl3) d 7.26 (m, 2H), 6.8 (m, 2H), 6.35
(d, 1H, J = 15.8 Hz), 6.05 (m, 1H), 3.8 (s, 3H), 3.7 (t,
2H, J = 6.7 Hz), 2.4 (m, 2H), 0.9 (s, 9H), 0.05 (s, 6H).
HRMS (ES, m/z) Calcd for C17H28O2Si: 292.1859.
Found: 292.1851.
9.4.37.
pyl]ethanol (86). To a solution of tert-butyl{[(3E)-4-(4-
methoxyphenyl)but-3-enyl]oxy}dimethylsilane (85,
2-[2,2-Dichloro-3-(4-methoxyphenyl)cyclopro-
7.2 g, 24.6 mmol) in chloroform (60 mL), 50% NaOH
(30 mL) and benzyltriethylammonium chloride (0.3 g)
were added. The reaction mixture was stirred for 4 h
at room temperature. Water (100 mL) was added and
the reaction mixture was extracted with dichlorometh-
ane (2· 250 mL). The organic solution was washed with
water (2· 150 mL), brine (1· 150 mL), dried over
MgSO4, and concentrated to afford 4.9 g (53%) of
brown oil. 1H NMR (400 MHz, CDCl3) d 7.17–7.14
(m, 2H), 6.87–6.84 (m, 2H), 3.83–3.77 (m, 5H), 2.4 (m,
1H), 2.05–1.96 (m, 2H), 1.84–1.79 (m, 1H), 0.89 (s,
9H), 0.06 (s, 6H). To a solution of tert-butyl{2-[2,2-
dichloro-3-(4-methoxyphenyl)cyclopropyl]ethoxy}dimeth-
ylsilane (4.9 g, 13 mmol) in THF (50 mL), tetrabutylam-
monium flouride (1 M in THF, 69 mL) was added
followed by water (2 mL). The reaction mixture was stir-
red for 3 h at room temperature. Water was added
(100 mL). The aqueous solution was extracted with
dichloromethane (2· 200 mL). The combined organic
solution was washed with water, brine, dried (MgSO4),
and concentrated. The concentrated residue was purified
by passing through a thick pad of silica gel and eluting
with 30% ethyl acetate in hexane to yield 3 g (88%) of
The ethyl ester of isomer A (2.5 g, 6.12 mmol) was dis-
solved in ethanol (10 mL), water (2 mL) and treated
with lithium hydroxide (0.56 g, 13.46 mmol). The solu-
tion was heated at 55 ꢁC for 2 h, solvent concentrated,
residue dissolved in (10 mL) acetonitrile/water, and
acidified by adding TFA. The crude material was
purified on reverse phase HPLC to give 1.3 g TFA
salt of isomer A of (83). The TFA salt was passed
through Bio-Rad AG 2-X8 (200–400 Mesh, Chloride
form, 13 g) column and was eluted with 50% acetoni-
trile in water to give 1.02 g (93%) HCl salt of isomer
A of (83). 1H NMR (400 MHz, CD3OD) d 7.57 (d,
1H), 7.09 (d, 2H), 6.79 (d, 2H), 6.71 (d, 1H), 4.23
(t, 2H), 3.48 (t, 2H), 3.11 (t, 2H), 2.80 (t, 2H), 2.47
(m, 4H), 1.93 (m, 2H), 1.57 (m, 1H), 1.18 (s, 3H),
0.81 (s, 3H). [a]D 12.3 (c 0.3, methanol). HRMS
(ES, m/z) Calcd for C23H28N2O3: 380.2100. Found:
381.2192 (M+H).
The ethyl ester of isomer B (1.5 g, 3.6 mmol) was hydro-
lyzed and converted to 1.0 g (92%) HCl salt by using the
1
above procedure. H NMR (400 MHz, CD3OD) d 7.57
1
(d, 1H), 7.09 (d, 2H), 6.79 (d, 2H), 6.71 (d, 1H), 4.23 (t,
2H), 3.48 (t, 2H), 3.11 (t, 2H), 2.80 (t, 2H), 2.47 (m,
4H), 1.93 (m, 2H), 1.57 (m, 1H), 1.18 (s, 3H), 0.81 (s,
3H). [a]D À11.7 (c 0.3, methanol). HRMS (ES, m/z) Calcd
for C23H28N2O3: 380.2100. Found: 381.2192 (M+H).
the product. H NMR (400 MHz, CDCl3) d 7.18–7.15
(m, 2H), 6.88–6.85 (m, 2H), 3.90–3.84 (m, 2H), 3.79 (s,
3H), 2.44 (d, 1H, J = 8.2 Hz), 2.12–2.0 (m, 2H), 1.99–
1.85 (m, 1H). HRMS (ES, m/z) Calcd for C12H14O2Cl2:
260.0371. Found: 260.0369.
9.4.36. tert-Butyl{[(3E)-4-(4-methoxyphenyl)but-3-enyl]oxy}-
dimethylsilane (85). Lithium aluminum hydride (1 M in
THF, 4.8 mL) was added slowly to a solution of (3E)-4-
(4-methoxyphenyl)-but-3-enoic acid (16, 14.6 g, 70 mmol)
in ether (300 mL) at room temperature. The reaction mix-
ture was stirred for 3 h at room temperature, then
quenched slowly with water. The organic layer was sepa-
rated and water layer was extracted with ether (1·
200 mL). Combined organic layer was washed with brine,
dried over MgSO4, concentrated, and dried to afford
7.3 g (58%) of product as solid. The material was used
for the next reaction without further purification. 1H
NMR (400 MHz, CDCl3) d 7.3 (m, 2H), 6.8 (m, 2H),
6.42 (d, 1H, J = 15.8 Hz), 6.0 (m, 1H), 3.8 (s, 3H), 3.7 (t,
2H, J = 6.2 Hz), 2.4 (m, 2H). HRMS (ES, m/z) Calcd for
C11H14O2: 178.2310. Found: 178.0994.
9.4.38. [2,2-Dichloro-3-(4-methoxyphenyl)cyclopropyl]ace-
tic acid (88). To a solution of 2-[2,2-dichloro-3-(4-meth-
oxyphenyl)cyclopropyl]ethanol (86, 0.21 g, 0.8 mmol) in
acetone (4 mL), Jone’s reagent (2 mL) was added at
0 ꢁC. The reaction mixture was warmed up to room tem-
perature and stirred for 1.5 h. The reaction mixture was
quenched with isopropyl alcohol (4 mL), filtered through
Celite, and the filtrate was concentrated. Saturated NaH-
CO3 (20 mL) was added to the concentrated residue and
was washed with ether (2· 20 mL). The aqueous solution
was acidified and was extracted with ether (3· 20 mL).
The combined ether layer was washed with brine, dried
(MgSO4), and concentrated to afford 0.09 g (41%) of
1
the product. H NMR (400 MHz, CDCl3) d 7.30–7.22
(m, 2H), 6.94–6.81 (m, 2H), 3.79 (s, 3H), 3.01–2.68 (m,
2H), 2.53 (d, 1H, J = 8.3 Hz), 2.25–2.16 (m, 1H). HRMS

S. R. Nagarajan et al. / Bioorg. Med. Chem. 15 (2007) 3390–3412
3409
(ES, m/z) Calcd for C12H12O3Cl2: 274.0163. Found:
274.0155.
2.71–2.59 (m, 2H), 2.25–2.19 (m, 1H), 1.97–1.90 (m,
2H). HRMS (ES, m/z) Calcd for C21H22N2O3 (M+H):
421.1080, Found: 421.1069 (M+H).
9.4.39. Ethyl [2,2-dichloro-3-(4-hydroxyphenyl)cyclopro-
pyl]acetate (90). [2,2-Dichloro-3-(4-methoxyphenyl)cyclo-
propyl]acetic acid (88, 0.1 g, 0.36 mmol) in ethanol
(1 mL) was added 4 N HCl (0.5 mL) and the reaction
mixture was stirred for 3 h at room temperature and con-
9.4.42. 4-(p-Methoxyphenyl)-3-butyn-1-ol (95). A solu-
tion of 4-iodoanisole (200 g, 0.8547 mol) and 3-butyn-
1-ol (64 mL) in triethylamine (1 L) was degassed and
stirred using mechanical stirrer under nitrogen. A
mixture of dichlorobis-(triphenylphosphine)palladium
(4.80 g) and cuprous iodide (2.46 g) was added to the
mixture. The reaction mixture slowly warmed up due
to the exotherm and reached the boiling point of trieth-
ylamine in 45 min. The reaction mixture was cooled
down to room temperature in 90 min and was poured
into water (1 L) and ethyl acetate (1.5 L). The organic
layer was washed with water (1 L), brine (1 L), dried,
and concentrated. The residue was purified using a thick
pad of silica gel (30% ethyl acetate in hexane) to afford
120 g (80%) of the product as a crystalline solid. 1H
NMR (400 MHz, CD3OD) d 7.28 (d, 2H, J = 8.7 Hz),
6.82 (d, 2H, J = 8.7 Hz), 3.76 (s, 3H), 3.68 (t, 2H,
J = 6.7 Hz), 2.56 (t, 2H, J = 6.8 Hz). HRMS (ES, m/z)
Calcd for C11H12O2: 176.0837. Found: 176.0839.
1
centrated to give 0.1 g (91%) of the product. H NMR
(400 MHz, CDCl3) d 7.25 (d, 2H, J = 8.7 Hz), 6.9 (d,
2H, J = 8.7 Hz), 4.23 (q, 2H, J = 7.1 Hz), 3.83 (s, 3H),
2.96–2.53 (m, 3H), 2.33–2.22 (m, 1H), 1.31 (t, 3H,
J = 7.1 Hz). HRMS (ES, m/z) Calcd for C14H16O3Cl2:
302.0476. Found: 302.0469. Borontribromide (1 M in
CH2Cl2, 1 mL) was added to a solution of ethyl [2,2-
dichloro-3-(4-methoxyphenyl)cyclopropyl]acetate (0.36 g,
1.2 mmol) in dichloromethane (10 mL). The reaction mix-
ture was stirred for 18 h at room temperature and was
concentrated. The concentrated residue was purified by
passing through a thick pad of silica to afford 0.18 g
1
(53%) of the product. H NMR (400 MHz, CDCl3) d
7.21–7.15 (m, 2H), 6.82–6.75 (m, 2H), 4.20 (q, 2H,
J = 7.1 Hz), 2.92–2.86 (m, 1H), 2.65–2.59 (m, 1H), 2.51–
2.49 (m, 1H), 2.23–2.17 (m, 1H), 1.29–1.24 (m, 3H).
HRMS (ES, m/z) Calcd for C13H14O3Cl2: 288.0320.
Found: 288.0336 (HRMS).
9.4.43. Diisopropyl-[4-(4-methoxyphenyl)-3-butynyloxy]silane
(96). Triethylamine (9.1 mL, 64.55 mmol) was added to a
solution of 4-(p-methoxyphenyl)-3-butyn-1-ol (95, 11.25 g,
63.9 mmol) and diisopropylchlorosilane (10.0 g, 64.55
mmol) and DMAP (0.80 g) in dry dichloromethane
(100 mL) at 0 ꢁC. After 4h, the reaction mixture was filtered
through silica gel (100 g) and the filtrate concentrated to yield
9.4.40. (2,2-Dichloro-3-{4-[2-(5,6,7,8-tetrahydro-1,8-naph-
thyridin-2-yl)ethoxy]phenyl}-cyclopropyl)acetic acid (92).
To a solution of 2-(5,6,7,8-tetrahydro-1,8-naphthyridin-
2-yl)-1-ethanol (29, 0.16 g, 0.9 mmol) and polymer bound
PPh3 (0.3 g, 0.9 mmol) in dry THF (6 mL), ethyl [2,2-
dichloro-3-(4-hydroxyphenyl)-cyclopropyl]-acetate (90,
0.18 g, 0.6 mmol) was added followed by diisopropyl azo-
dicarboxylate (0.2 mL, 1 mmol). The reaction mixture
was stirred at room temperature. After 18 h, the reaction
mixture was filtered through Celite to remove the polymer
and washed with excess THF and the filtrate was concen-
trated. The residue in 50% acetonitrile in water (4 mL)
was added LiOH (0.1 g). The reaction mixture was stirred
for 3 h at room temperature. The reaction mixture was
acidified with TFA and purified by reverse phase HPLC
to afford 0.12 g (36%) of the product. 1H NMR
(400 MHz, CD3OD) d 7.64 (d, 1H, J = 8 Hz), 7.26 (d,
2H, J = 8.4 Hz), 6.93 (d, 2H, J = 8.8 Hz), 6.77 (d, 1H,
J = 7.6 Hz), 4.32 (t, 2H, J = 6 Hz), 3.53 (t, 2H,
J = 5.6 Hz), 3.19 (t, 2H, J = 6 Hz), 2.87–2.59 (m, 5H),
2.32–2.26 (m, 1H), 2.01–1.95 (m, 2H). HRMS (ES, m/z)
Calcd for C21H22N2O3 (M+H): 421.1080, Found:
421.1069.
1
16.9 g (90%) of the product as oil. H NMR (400 MHz,
CD3OD) d 7.31 (d, 2H, J = 8.7 Hz), 6.79 (d, 2H,
J = 8.7 Hz), 4.18 (s, 1H), 3.87 (t, 2H, J = 7 Hz), 3.78 (s,
3H), 2.63 (t, 2H, J = 6.8 Hz) 1.00–1.08 (m, 14H). HRMS
(ES, m/z) Calcd for C17H26O2Si: 290.1702. Found: 290.1715.
9.4.44. 4-(p-Methoxyphenyl)-3-phenyl-3-butene-1-ol (97).
A xylene solution (5 mL) of Pt(DVDS) was added to
diisopropyl-(4-phenyl-3-butynyloxy)silane (96, 20.0 g,
67.91 mmol) in THF (200 mL). A mild exotherm re-
sulted and the reaction mixture was stirred for 2 h. To
this tetrabutylammonium fluoride (150 mL, 1 M) in
THF was added followed by iodobenzene (8 mL) and
Pd2(dba)3 (6.2 g) was added. Additional amount of iod-
obenzene (8 mL) was added after 6 h and the reaction
mixture was stirred for 18 h at room temperature. The
reaction mixture was concentrated and the residue was
partitioned between ether (500 mL) and water
(500 mL). The organic layer was washed with brine
and dried and was concentrated to afford a residue. This
was purified on a pad of silica (15% EA in hexane) to
yield 10.0 g (58%) of the product as crystalline solid.
1H NMR (400 MHz, CD3OD) d 7.43–7.46 (m, 2H),
7.33–7.38 (m, 4H), 7.27–7.30 (m, 1H), 6.88–6.92 (m,
2H), 6.79 (s, 1H), 3.82 (s, 3H), 3.71 (t, 2H, J = 7 Hz),
3.03 (t, 2H, J = 7 Hz). HRMS (ES, m/z) Calcd for
C17H18O2: 254.1307. Found: 254.1321.
9.4.41. (2,2-Dibromo-3-{4-[2-(5,6,7,8-tetrahydro-1,8-naph-
thyridin-2-yl)ethoxy]phenyl}-cyclopropyl)acetic acid (93).
Mitsunobu reaction of 2-(5,6,7,8-tetrahydro-1,8-naph-
thyridin-2-yl)-1-ethanol (29) and ethyl [2,2-dibromo-3-
(4-hydroxyphenyl)-cyclopropyl]acetate (91), prepared as
described for the dichloro compound but starting from
bromoform, followed by saponification and purification
afforded the desired product in 2% overall yield. 1H
NMR (400 MHz, CD3OD) d 7.59 (d, 1H, J = 7.4 Hz),
7.21 (d, 2H, J = 8.6 Hz), 6.88 (d, 2H, J = 8.7 Hz), 6.73
(d, 1H, J = 7.2 Hz), 4.27 (t, 2H, J = 6.0 Hz), 3.49 (t, 2H,
J = 5.9 Hz), 3.14 (t, 2H, J = 5.9 Hz), 2.82–2.78 (m, 3H),
9.4.45. 2-(p-Methoxyphenyl)-1-phenyl-1-(2-hydroxyeth-
yl)cyclopropane (98). Diethyl zinc (95 mL, 95 mmol)
was added to a solution of iodochloromethane
(13.87 mL, 190 mmol) in dichloroethane (300 mL) over

3410
S. R. Nagarajan et al. / Bioorg. Med. Chem. 15 (2007) 3390–3412
30 min at À20 ꢁC. After 20 min, dichloroethane
(100 mL) solution of 4-(p-methoxyphenyl)-3-phenyl-3-
butene-1-ol (97, 8.50 g, 33.45 mmol) was added. It was
warmed over to rt over 2 h and was stirred for 18 h.
The reaction mixture was quenched with hydrochloric
acid (200 mL, 1 N). The organic layer was washed with
brine (200 mL), dried, and concentrated. The residue
was purified by chromatography (20% hexane in ethyl
6.75 (m, 2H), 3.86–3.91 (m, 2H), 2.44–2.48 (m, 1H),
2.27–2.31 (m, 1H), 1.99–2.04 (m, 1H), 1.39–1.47 (m,
2H), 1.01–1.05 (m, 3H). HRMS (ES, m/z) Calcd for
C19H20O3: 296.1412. Found: 296.1361.
9.4.47.
1-Phenyl-2-{4-[2-(5,6,7,8-tetrahydro-1,8-naph-
thyridin-2-yl)ethoxy]phenyl}-cyclopropylacetic acid (100).
Mitsunobu reaction of 2-(5,6,7,8-tetrahydro-1,8-naph-
thyridyl)amino ethanol (29) and ethyl 2-(p-hydroxyphe-
nyl)-1-phenylcyclo-propaneacetate (99) followed by
saponification and purification gave the product as its
1
acetate) to give 4.8 g (54%) of the product as oil. H
NMR (400 MHz, CD3OD) d 7.37–7.40 (m, 2H), 7.23–
7.29 (m, 4H), 7.15–7.20 (m, 1H), 6.88–6.90 (m, 2H),
3.77 (s, 3H), 3.30–3.38 (m, 2H), 2.20–2.22 (m, 1H),
1.69–1.76 (m, 1H), 1.20–1.39 (m, 2H). HRMS (ES, m/
z) Calcd for C18H20O2: 268.1463. Found: 268.1464.
1
TFA salt. Yield: 18%. H NMR (400 MHz, CD3OD) d
7.58 (d, 1H, J = 7.4 Hz), 7.39 (m, 2H), 7.28 (t, 2H,
J = 7.4 Hz), 7.22 (d, 2H, J = 8.2 Hz), 7.16 (t, 1H,
J = 7.0 Hz), 6.88 (d, 2H, J = 8.2 Hz), 6.72 (d, 1H,
J = 7.4 Hz), 4.27 (t, 2H, J = 5.9 Hz), 3.49 (t, 2H,
J = 5.6 Hz), 3.14 (t, 2H, J = 5.9 Hz), 2.81 (t, 2H,
J = 6.3 Hz), 2.44 and 1.93 (AB q, 2H, J = 16.1 Hz),
2.30 (t, 1H, J = 8.3 Hz), 1.91–1.94 (m, 2H), 1.42–1.54
(m, 2H). HRMS (ES, m/z) Calcd for C27H28N2O3:
428.2100. Found: 429.2184 (M+H).
9.4.46. Ethyl 2-(p-hydroxyphenyl)-1-phenylcyclopropa-
neacetate (99). PCC (5.35 g, 24.80 mmol) was added to
a suspension of molecular sieves (4A, 10 g) and 2-(p-
methoxyphenyl)-1-phenyl-1-(2-hydroxyethyl)cyclopro-
pane (98, 4.20 g, 16.54 mmol) in dichloromethane
(200 mL) and the mixture was stirred for 3 h. The reac-
tion mixture was filtered through Celite and the filtrate
was concentrated. The residue in ethyl acetate was then
passed through a pad of silica gel. The filtrate was con-
centrated to provide the aldehyde. An aqueous solu-
tion of silver nitrate (5.6 g) was added to a solution
of the aldehyde in ethanol (200 mL) followed by so-
dium hydroxide (28 mL, 2.5 M). The dark reaction
mixture was stirred for 2 h at rt and then was filtered
through Celite. The solid was washed with ethanol.
The filtrate was combined and concentrated. The resi-
due was partitioned between water and ether. The
aqueous layer was acidified and was extracted with
ether (300 mL). The ether layer was dried and was con-
centrated to afford 4.0 g of the product. 1H NMR
(400 MHz, CD3OD) d 7.39–7.41 (m, 2H), 7.23–7.32
(m, 4H), 7.14–7.21 (m, 1H), 6.87–6.89 (m, 2H), 3.77
(s, 3H), 2.46–2.50 (m, 1H), 2.29–2.33 (m, 1H), 1.97–
1.98 (m, 1H), 1.52–1.54 (m, 1H), 1.44–1.47 (m, 1H),
1.14–1.17 (m, 1H). HRMS (ES, m/z) Calcd for
C18H18O3: 282.1256. Found: 282.1218.
9.4.48. 2-[2-(4-Methoxyphenyl)-2-methylcyclopropyl]eth-
anol (102). To a solution of LiAlH4 (1 M in THF,
6.17 mL, 6.17 mmol) in THF (20 mL) at 0 ꢁC, a solution
of (3E)-4-(4-methoxyphenyl)pent-3-enoic acid61 (101,
1.0 g, 4.1 mmol) in THF (20 mL) was slowly added.
The reaction mixture was stirred for 3h at room temper-
ature, cooled to 0 ꢁC, and quenched by dropwise addi-
tion of 2.5 N NaOH. The solution was stirred at room
temperature for few minutes, the solid complex filtered
and washed with excess THF. The organic layer washed
with sat. NH4Cl, dried over MgSO4, and concentrated
to give white solid in quantitative yield. 1H NMR
(400 MHz, CDCl3) d 7.28 (m, 2H), 6.88 (m, 2H), 5.72
(m, 1H), 3.8 (s, 3H), 3.7 (t, 2H), 2.29 (m, 2H), 2.02
(m, 3H). To a solution of iodochloromethane (1 mL,
13.52 mmol) in 1,2-dichloroethane (20 mL) at 0 ꢁC, a
solution of diethyl zinc (1.0 M in hexane, 6.76 mL,
6.76 mmol) was added dropwise over 10–15 min. A solu-
tion of the alcohol (1.0 g, 5.2 mmol) in 1,2-dichloroeth-
ane (30 mL) was added dropwise at 0 ꢁC. The solution
was then stirred at room temperature for few minutes,
heated at 40 ꢁC for 1 h, and stirred at room temperature
for 2 days. The solution was cooled at 0 ꢁC and
quenched by addition of 1.5 N HCl. The aqueous layer
was extracted several times with ethyl acetate, the com-
bined organic layer washed with water, brine, dried over
A mixture of 2-(p-methoxyphenyl)-1-phenylcyclopro-
paneacetic acid (4.0 g), ethanol (200 mL), and hydro-
chloric acid (2 mL) was heated at reflux for 6 h. The
reaction mixture was concentrated. The residue was par-
titioned between ether and water. The ether layer was
dried and was concentrated to afford 4.0 g of ethyl
2-(p-methoxy-phenyl)-1-phenyl-cyclopropaneacetate. 1H
NMR (400 MHz, CD3OD) d 7.39–7.40 (m, 2H), 7.14–
7.31 (m, 5H), 6.85–6.87 (m, 2H), 3.85–3.90 (m, 2H),
3.75 (s, 3H), 2.42–2.48 (m, 1H), 2.29–2.33 (m, 1H),
1.99–2.04 (m, 1H), 1.32–1.49 (m, 2H), 1.00–1.04 (m,
3H). HRMS (ES, m/z) Calcd for C20H22O3: 311.1642
(M+H). Found: 311.1546 (M+H). Borontribromide
(10 mL) was added to a solution of ethyl 2-(p-methoxy-
phenyl)-1-phenylcyclopropaneacetate (1.43 g, 4.6 mmol)
in dry dichloromethane and stirred for 18 h. The
reaction mixture was quenched with ethanol and was
concentrated. The residue was purified by chromatogra-
phy to afford 0.270 g (16% overall) of the product as
1
MgSO4, and concentrated to give oil. Yield: 25%. H
NMR (400 MHz, CDCl3) d 7.2 (m, 2H), 6.8 (m, 2H),
3.8 (s, 3H), 3.7 (t, 2H), 2.26 (m, 2H), 1.62 (m, 3H),
0.89 (m, 2H), 0.62 (m, 1H). HRMS (ES, m/z) Calcd
for C13H18O2: 206.1307. Found: 206.1287 (M+H).
9.4.49. Ethyl [2-(4-hydroxyphenyl)-2-methylcyclopro-
pyl]acetate (103). A solution of alcohol (102, 0.25 g,
1.2 mmol), Tempo (0.012 g, 0.08 mmol), and phosphate
buffer (4.55 mL, 22.33 mmol) was stirred at room tem-
perature.
A solution of NaClO2 (80%, 0.273 g,
2.4 mmol) in water (1 mL) and NaOCl (10–13% chlo-
rine, 0.2 mL, 0.3 mmol, 30 mol%) were added. The solu-
tion was heated at 35 ꢁC for 6 h, cooled to room
temperature, and adjusted to pH 8 using water and
1
brown oil. H NMR (400 MHz, CD3OD) d 7.36–7.38
(m, 2H), 7.25–7.28 (m, 2H), 7.11–7.17 (m, 3H), 6.73–

S. R. Nagarajan et al. / Bioorg. Med. Chem. 15 (2007) 3390–3412
3411
11. Brooks, P. C.; Clark, R. A. F.; Cheresh, D. A. Science
1994, 264, 569–571.
12. Carron, C. P.; Meyer, D. M.; Pegg, J. A.; Engleman, V.
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NaOH. A solution of Na2S2O3 in water was added and
reaction mixture was stirred for 30 min. Ethyl acetate
was added and the solution was acidified using 1.5 N
HCl. The aqueous layer was extracted three times with
ethyl acetate and the combined organic layer was
washed with brine, dried over Na2SO4, and concen-
13. Kumar, C. C.; Malkowski, M. Cancer Res. 2001, 61,
2232–2238.
1
trated to give oil. H NMR (400 MHz, CDCl3) d 7.24
(m, 2H), 6.82 (m, 2H), 3.82 (s, 3H), 3.7 (t, 2H), 2.3–
2.7 (m, 2H), 1.92 (m, 1H), 1.02 (m, 1H), 0.82 (m, 1H).
To a solution of the acid in ethanol (10 mL), 4 N HCl
in dioxane (1 mL) was added. The reaction mixture
was stirred for 3 h at room temperature and then con-
centrated in vacuo. The residue was dissolved in ethyl
acetate, washed with NaHCO3, brine, dried over
Na2SO4, and concentrated to give yellow oil. The crude
material was stirred in CH2Cl2 (20 mL) at 0 ꢁC and BBr3
(1.0 M in CH2Cl2, 1.6 mL) was added dropwise. The
reaction mixture was stirred for 1 h at 0 ꢁC, quenched
by addition of ethanol, and stirred for 1 h at room tem-
perature. The solvent was concentrated to remove etha-
nol. The residue was dissolved in ethyl acetate, washed
with satd NaHCO3, brine, and dried over Na2SO4 to
give brown oil. The crude material was used without fur-
ther purification in the next step. HRMS (ES, m/z)
Calcd for C15H20O3: 266.1751 (M+NH4). Found:
266.1732 (HRMS, M+NH4).
14. Kerr, J. S.; Slee, A. M.; Mousa, S. A. Drugs 2002, 11,
1765–1774.
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Colson, P. J.; Awasthi, A. K.; Nagarajan, S. R; Devadas,
B; Malecha, J. W.; Chandrakumar, N. S.; Nickols, G. A;
Westlin, W. F.; Meyer, D. M.; Keene, J. L.; Settle, S. L.;
Carron, C. P.; Engleman, V. W.; Freeman, S. K.;
Shannon, K. E.; Knoerzer, D. L.; Westlin, M. M.;
Nickols, M. A. Abstracts of Papers 221st ACS National
Meeting SanDiego, CA, 2001, MEDI-225.
20. Ruminski, P. G.; Rogers, T. E.; Rico, J. G.; Nickols, G. A;
Westlin, W. F.; Engleman, V. W; Settle, S. L.; Keene, J.
L.; Freeman, S. K.; Carron, C. P.; Meyer, D. M. Book of
Abstracts, 219th ACS National Meeting, San Francisco,
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9.4.50.
(2-Methyl-2-{4-[2-(5,6,7,8-tetrahydro-1,8-naph-
thyridin-2-yl)ethoxy]-phenyl}cyclopropyl)acetic acid (104).
Mitsunobu reaction of 2-(5,6,7,8-tetrahydro-1,8-naph-
thyridin-2-yl)-1-ethanol (29) and 103 followed by sapon-
ification and purification afforded the desired product.
Yield: 15% 1H NMR (400 MHz, CD3OD) d 7.58 (d,
1H), 7.25 (m, 2H), 6.83 (m, 2H), 6.77 (d, 1H), 4.23 (m,
2H), 3.48 (m, 2H), 3.12 (m, 2H), 2.84 (m, 2H), 2.7–2.32
(m, 2H), 2.01–1.90 (m, 2H), 1.3 (m, 3H), 1.05 (m, 1H),
0.8–0.72 (m, 2H). HRMS (ES, m/z) Calcd for
C22H26N2O3 (M+H): 367.2016. Found: 367.2015.
21. Ruminski, P. G.; Rogers, T. E.; Rico, J. G.; Nickols, G. A;
Westlin, W. F.; Engleman, V. W; Settle, S. L.; Keene, J.
L.; Freeman, S. K.; Carron, C. P.; Meyer, D. M. Book of
Abstracts, 218th ACS National Meeting, New Orleans,
LA, 1999, MEDI-169.
Acknowledgment
22. Nagarajan, S. R.; Meyer, J. M.; Miyashiro, J. M.;
Engleman, V. W.; Freeman, S. k.; Griggs, D. W.; Klover,
J. A.; Nickols, G. A. Chem. Biol. Drug Des. 2006, 67,
177–181.
The authors thank Professor Scott E. Denmark of the
University of Illinois at Urbana-Champaign for many
helpful discussions and valuable suggestions.
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