Indanylidenes. 2. Design and synthesis of (E)-2-(4-chloro-6-fluoro-1-indanylidene)-N-methylacetamide, a potent antiinflammatory and analgesic agent without centrally acting muscle relaxant activity

Article abstract of DOI:10.1021/jm020068k

Extension of the structure-activity relationship studies that led to the discovery of the nonsedating potent muscle relaxant, antiinflammatory, and analgesic agent (E)-2-(4,6-difluoro-1-indanylidene)acetamide, 1, has given rise to (E)-2-(4-chloro-6-fluoro

Full text of DOI:10.1021/jm020068k

J . Med. Chem. 2003, 46, 409-416
409
In d a n ylid en es. 2. Design a n d Syn th esis of
(E)-2-(4-Ch lor o-6-flu or o-1-in d a n ylid en e)-N-m eth yla ceta m id e, a P oten t
An tiin fla m m a tor y a n d An a lgesic Agen t w ith ou t Cen tr a lly Actin g Mu scle
Rela xa n t Activity
David L. Musso,* G. Faye Orr,† Felicia R. Cochran, J ames L. Kelley,‡ J effrey L. Selph,§ Greg C. Rigdon,|
Barrett R. Cooper, and Michael L. J ones#
GlaxoSmithKline Research and Development, Five Moore Drive, Research Triangle Park, North Carolina 27709
Received February 11, 2002
Extension of the structure-activity relationship studies that led to the discovery of the
nonsedating potent muscle relaxant, antiinflammatory, and analgesic agent (E)-2-(4,6-difluoro-
1-indanylidene)acetamide, 1, has given rise to (E)-2-(4-chloro-6-fluoro-1-indanylidene)-N-
methylacetamide, 2. Compound 2 is a potent antiinflammatory and analgesic agent without
centrally acting muscle relaxant activity.
In tr od u ction
mercially available 2-chloro-4-fluorobenzaldehyde in the
Knoevenagel3 reaction to give the corresponding (E)-
cinnamic acid 20. Cinnamic acid 20 was reduced to the
dihydrocinnamic acid 21 with platinum oxide and
hydrogen. Method B employed the N-bromosuccinimide
bromination of 2-bromo-4-fluorotoluene to give the cor-
responding R-bromotoluene 27. Reaction of the benzyl
bromide 27 with diethyl malonate in the presence of
sodium hydride followed by hydrolysis with potassium
hydroxide gave the desired dihydrocinnamic acid 29.
This was converted to 4-bromo-6-fluoro-1-indanone 30.
In method C, we used Heck4 reaction conditions to
convert 2-bromo-5-fluorotoluene to the corresponding
(E)-ethyl 3-(4-fluoro-2-methylphenyl)acrylate 35. The
ethyl acrylate 35 was reduced with platinum oxide and
hydrogen and was hydrolyzed to the corresponding
dihydrocinnamic acid 37. Cyclization afforded 6-fluoro-
4-methyl-1-indanone 38. For the 6-chloro-4-fluoro-1-
indanone 47, the commercially available phenol was
used. In method D, the phenol was converted to the
trifluoromethane sulfonate 43. The sulfonate 43 was
converted to (E)-ethyl 3-(4-chloro-2-fluorophenyl)acry-
late 44 with bis(triphenylphosphine)palladium(II) chlo-
ride and ethyl acrylate.5 Reduction followed by hydrol-
ysis gave the corresponding dihydrocinnamic acid 46.
Once the dihydrocinnamic acids were obtained, they
were converted to the corresponding indanones 22, 30,
38, and 47 via Friedel-Crafts6 acylation reaction condi-
tions as shown in Scheme 2. The indanones were reacted
with lithioethyl acetate to give the indanyl hydroxy
esters 23, 31, 39, and 48. Hydrolysis of the esters
followed immediately by dehydration with trifluoroace-
tic acid gave the corresponding (E)-indanylidene acetic
acids 25, 33, 41, and 50. Often the dehydrated product
contained minor amounts of the endo isomer. Generally
the endo isomers were carried through to the final
amide products and separated at that stage. If the scale
of reaction were appropriate, the endo isomers were
isolated and evaluated in our biological screens. During
the course of this study, we found that if the intermedi-
ate indanylhydroxy acids are allowed to stand at room
temperature, they spontaneously dehydrate to the
Part 1 of this series describes the structure-activity
relationship studies leading to the discovery of the
nonsedating potent muscle relaxant, antiinflammatory,
and analgesic agent 1,1 (E)-2-(4,6-difluoro-1-indanyli-
dene)acetamide. We were interested in identifying an
antiinflammatory/analgesic agent that lacked the muscle
relaxant activity. This manuscript describes the struc-
ture-activity relationship studies that led to the dis-
covery of 2,2 (E)-2-(4-chloro-6-fluoro-1-indanylidene)-N-
methylacetamide, a potent antiinflammatory/analgesic
agent. Compound 2 shows little or no activity in animal
models designed to assess the muscle relaxant potential
of a drug.
Ch em istr y
Preparation of the (E)-indanylidene acetamides uti-
lized the corresponding indanone as the key intermedi-
ate. The requisite dihydrocinnamic acids for the prepa-
ration of the indanone intermediates were prepared via
several methods. Method A (Scheme 1) for the synthesis
of 4-chloro-6-fluoro-1-indanone 22 utilized the com-
* To whom correspondence should be addressed. Phone: 919-483-
6290. Fax: 919-315-0430. E-mail: dm12907@gsk.com.
† Present Address: 394 Rock Hill Drive, Chapel Hill, NC 27517.
‡ Present Address: 10928 Raven Rock Drive, Raleigh, NC 27614.
§ E-mail: jeff_selph@trelionpharma.com.
| Present Address: Icagen Inc., P.O .Box 14487, Research Triangle
Park, NC 27709.
Present Address: Lineberry Research Associates, P.O. Box 14626,
Research Triangle Park, NC 27709.
#
Present Address: Eli Lilly and Company, Sphinx Laboratories,
P.O. Box 13951, 20 T. W. Alexander Drive, Research Triangle Park,
NC 27709.
10.1021/jm020068k CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/31/2002

410 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 3
Musso et al.
Sch em e 1a
a
(a ) Malonic acid, pyridine, piperidine, ∆; (b) H2, PtO2, 95% EtOH; (c) NBS, benzoyl peroxide, hν, CCl4, ∆; (d ) diethyl malonate, NaH,
DME; (e) KOH, H2O, ∆; (f) ethyl acrylate, PdIIOAc, (o-tolyl)3P, Et3N, CH3CN, ∆; (g) NaOH, H2O, EtOH; (h ) (CF3SO2)2O, pyridine, CH2Cl2;
(i) ethyl acrylate, (Ph3P)2Pd(II)Cl, Et3N, DMF, ∆.
evaluated in the morphine-induced Straub tail8 assay
in rats. This assay is indicative of potential muscle
Sch em e 2. Reaction Sequence from Propionic Acids to
Target Moleculesa
relaxant activity in man. The rotorod9 assay was used
to determine their potential to produce sedation. For the
Straub tail and rotorod assays, compounds were gener-
ally evaluated at a minimum of three doses with N ) 6
animals per dose group. The variability was approxi-
mately 15%. The ratio of the rotorod (RR) ED50 to the
Straub tail (ST) ED50 gives a measure of the sedative
potential of the compounds. Compounds that gave a
greater than 50% inhibition in the Straub tail assay at
100 mg/kg intraperitoneally (ip) were evaluated orally
(po) in both the Straub tail and rotorod assays. In
general, compounds that gave 50% or less inhibition in
the Straub tail assay ip were not evaluated in the
rotorod assay because their propensity to produce seda-
tion is greatly diminished. Initial profiling of compounds
for antiinflammatory and analgesic activity was deter-
mined in the 3 h carrageenan pleurisy10 (CP) assay and
the trypsin hyperalgesia11 (THA) assay, respectively.
a
(a ) (a) ClCOCOCl, CH2Cl2, (b) AlCl3, CH2Cl2; (b) EtOAc, LDA,
THF; (c) 1
ClCOCOCl, CH2Cl2, DMF, (b) NH2R1, CH2Cl2.
N NaOH, EtOH; (d ) CF3CO2H, CH2Cl2; (e) (a)
Table 2 gives the assay results for the indanylidene
acetamides. For the carragenaan pleurisy and trypsin
hyperalgesia assays, compounds were tested two or
three times. An average variation of approximately 10%
was observed in the carragenaan pleurisy assay and
approximately 5% in the trypsin hyperalgesia assay.
undesired endo isomer. Conversion of the (E)-indanyli-
dene acetic acids to the corresponding acid chlorides
with oxalyl chloride followed by amination with amines
gave the (E)-indanylidene acetamides 2, 4, 7, 6, and 15.
Table 1 gives the melting points and the overall yields
for the indanylidene acetamides 2-18 starting from the
appropriate commercially available starting material.
Compound 1 was potent in the Straub tail assay and
had a RR/ST ratio of 2. Compound 1 would not be
expected to produce sedation. Compound 1 had ED50
values of 19 and 15 mg/kg po in cells and edema,
respectively, in the CP assay. It also possessed potent
mild analgesia activity with an ED50 of 4.0 mg/kg po in
the THA assay. Examination of the corresponding 4,6-
dichloro analogue 8 found it to be inactive as a muscle
relaxant in the Straub tail assay, had moderate anti-
inflammatory activity in the CP assay, and had an ED50
of 4.1 mg/kg po as a mild analgesic in the THA assay.
Compound 6, the 6-chloro-4-fluoro derivative showed no
SAR Discu ssion s
The indanylidene, (E)-2-(4,6-difluoro-1-indanylidene)-
acetamide, 1, was reported to be a potent muscle
relaxant, antiinflammatory, and analgesic agent with
little propensity to produce sedation.7 We were inter-
ested in investigating the possibility of finding a potent
antiinflammatory/analgesic agent that did not possess
muscle relaxant or sedative activity. Compounds were

Indanylidenes, Part 2
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 3 411
Ta ble 1. Physicochemical Properties and Methods of Synthesis
method
of synthesis
compd
isomer
Y
R1
R2
mp, °C
% yielda
formula
analysis
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
4-Cl, 6-F
4-Cl, 6-F
4-Br, 6-F
4-Cl, 6-Me
6-Cl, 4-F
6-F, 4-Me
4,6-Cl2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
Me
Me
Me
Me
c-C3H5
c-C3H5
c-C3H5
c-C3H5
H
173-175
182-184
183-185
213-215
171-173
178-180
210-212
204-205
179-181
202-204
184-187
225-227
194-198
147-149
188-190
156-158
153-155
168-169
A
A
B
D
D
C
19
19
5
C
C
C
C
C
C
12H11ClFNO
11H9ClFNO
11H9BrFNO
12H12ClNO
11H9ClFNO
12H12FNO
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
9
13
18
14
15
25
15
25
12
11
12
13
19
20
6e
Ab
A
A
C
C11H9Cl2NO
C11H9Cl2NO
C
C
C12H11ClFNO
C12H11Cl2NO
C12H11Cl2NO
C14H13ClFNO
C14H13ClFNO
C15H16FNO
5,7-Cl2
5-Cl, 6-F
6-F, 4-Me
5-Cl, 6-F
4,6-Cl2
11H9ClFNO
13H14FNO
Ac
A
A
A
D
C
5,7-Cl2
d
4-Cl, 6-F
6-Cl, 4-F
6-F, 4-Me
5-Cl, 6-F
4-Cl, 6-F
E
endo
A
A
C14H13ClFNO
C11H9ClFNO
a
% yield represents overall yield beginning with the corresponding benzaldehyde, cinnamic acid, benzylbromide, phenol, or indanone,
depending on the method of synthesis. Method A beginning with commercially available cinnamic acid. c The cyclization step to prepare
b
the indanone gave both the 5-chloro-6-fluoroindanone (major product) and 6-fluoro-7-chloroindanone (minor product). Both were carried
d
through the synthesis until the final amide. Column chromatography afforded the pure 5-chloro-6-fluoroindanylidenes. c-C3H5 means
cyclopropyl. e The endo isomer 19 was separated from the exo isomer 3 by column chromatography.
Ta ble 2. Antiinflammatory/Analgesic Activitya
muscle relaxant profile,
mouse, ED50, mg/kg
mild analgesia activity,
trypsin hyperalgesia, rat
antiinflammatory activity,
3 h carragenaan pleurisy, rat
% I @20 mg/kg po or [ED50, mg/kg po]
Straub Straub RR,
% I @
ED50,
compd
Y
isomer
R
tail, ip tail, po po RR/ST
cells
edema
20 mg/kg po mg/kg po
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
4,6-F2
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
H
Me
H
H
H
H
H
H
H
[100%]b
[50%]
[0%]
-
68.7
-
138
-
2
[19]
[8]
[11]
[>20]
[>25]
34
11
[25]
5
[15]
[5]
[11]
[>20]
[>25]
36
24
[20]
34
-
40
-
13
100
100
79
-
4
1.4
4
-
-
4-Cl, 6-F
4-Cl, 6-F
4-Br, 6-F
4-Cl, 6-Me
4-F, 6-Cl
4-Me, 6-F
4,6-Cl2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
[33%]
[0%]
[0%]
-
-
-
92
-
>10
10
4.1
>10
-
-
-
-
-
5,7-Cl2
[100%] <100
55
56
-
79
19
77
22
12
22
75
31
97
27
70
5-Cl, 6-F
4-Me, 6-F
5-Cl, 6-F
4,6-Cl2
H
[100%]
[67%]
[17%]
[83%]
[50%]
50
-
-
1.1
-
-
Me
Me
Me
Me
15
-
-
-
-
-
>100
-
-
-
9
0
-
5,7-Cl2
-
-
34
-
4-Cl, 6-F
4-F, 6-Cl
4-Me, 6-F
5-Cl, 6-F
4-Cl, 6-F
c-C3H5 [100%]
c-C3H5 [33%]
c-C3H5 [67%]
c-C3H5
H
44
-
44
-
1
-
-
0.9
-
-
-
-
E
E
endo
-
-
-
5
7
-
-
[83]
-
-
-
-
-
-
-
-
73
96
1.3
7
a
b
Dashes mean that activity was not determined. Values in brackets are the % effect at 100 mg/kg ip.
activity as a muscle relaxant or antiinflammatory/
analgesic agent. A fluoro group at the 6 position of the
bicyclo ring seems to give rise to some of the most potent
antiinflammatory and/or analgesic compounds. Exami-
nation of compound 3 confirmed this observation. Com-
pound 3, the 4-chloro-6-fluoro derivative, was inactive
in the ST assay but was slightly more potent than 1 in
the CP assay in both cells and edema. It was also
equipotent with 1 in the THA assay. If one adds a
substituent next to the 6-fluoro moiety as in compound
10, i.e., the 5-chloro-6-fluoro analogue, muscle relaxant
activity is retained; however, the antiinflammatory/

412 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 3
Musso et al.
300, and Unity 400 instruments and are recorded in δ values
with deuteriochloroform or dimethyl sulfoxide-d6 as the sol-
vent. The NMR spectra of all compounds are consistent with
the proposed structures. Preparative flash chromatography
was performed on silica gel 60 (40-63 µM, E. Merck, no. 9385)
using the method of Still et al.12 Elemental analyses were
performed by Atlantic Microlab, Inc. For all compounds where
elemental analysis is indicated by the symbols for the ele-
ments, the found values are within 0.4% of the theoretical
values unless otherwise indicated.
The following describes the methods used to prepare the
corresponding propanoic acids shown in Scheme 1. In each
method, the conversion of the propanoic acid to a desired target
molecule is described below and illustrated in Scheme 2. The
remainder of the target molecules is listed in Table 1, and their
method of preparation is reported.
Meth od A. P r ep a r a tion of (E)-2-(4-Ch lor o-6-flu or o-1-
in d a n ylid en e)-N-m eth yla ceta m id e (2). (a ) P r ep a r a tion
of 2-Ch lor o-4-flu or ocin n a m ic Acid (20).13 To a mixture of
2-chloro-4-fluorobenzaldehyde (20.0 g, 0.13 mol, Aldrich) and
malonic acid (26.2 g, 0.25 mol, Aldrich) in pyridine (100 mL)
at 50 °C was added dropwise piperidine (10 mL). After 18 h
at 70 °C, the mixture was poured into an ice cold solution of
concentrated HCl (120 mL) and water (1.5 L). The resulting
solid was filtered and washed repeatedly with water to give
24.4 g (96%) of 20 as a white solid. Recrystallization of 1.5 g
from acetone/water mixtures gave 1.1 g of 2-chloro-4-fluoro-
cinnamic acid as a white solid: mp 243-245 °C (lit. mp 253-
255 °C13). Anal. Calcd for C9H6ClFO2 (MW ) 200.60): C, 53.88;
H, 3.02. Found: C, 53.91; H, 3.03.
(b ) P r ep a r a t ion of 3-(2-Ch lor o-4-flu or op h en yl)p r o-
p a n oic Acid (21). A mixture of 20 (22.9 g, 0.11 mol) and
platinum oxide (0.5 g, EM Scientific) in 95% ethanol (140 mL)
was placed in a Parr hydrogenation apparatus. After the
appropriate amount of hydrogen was taken up, the catalyst
was filtered and the mixture was concentrated in vacuo to give
22.6 g (98%) of 21 as a purple solid. This material was used
without further purification. A 1.0 g sample was recrystallized
several times from hot hexanes and dichloromethane/pentane
mixtures. Finally the sample was purified by column chroma-
tography on silica gel using hexanes/ethanol (8:2) as eluent to
give, after triturating with pentane, 0.24 g of 21 as a white
solid: mp 100-102 °C; NMR (DMSO-d6) δ 12.3 (Br, 1H,
COOH), 7.39 (m, 2H, Ar), 7.15 (m, 2H, Ar), 2.88 (t, 2H, CH2),
2.49 (t, 2H, CH2). Anal. (C9H8ClFO2) C, H.
(c) P r ep a r a tion of 4-Ch lor o-6-flu or o-1-in d a n on e (22).
To a mixture of 21 (21.6 g, 0.11 mol) and dichloromethane (20
mL) at room temperature was added dropwise oxalyl chloride
(19.2 mL). The mixture was stirred at room temperature until
gas evolution ceased. The excess oxalyl chloride was removed
by distillation to give 3-(2-chloro-4-fluorophenyl)propionyl
chloride. A solution of the 3-(2-chloro-4-fluorophenyl)propionyl
chloride in dichloromethane (100 mL) was added dropwise to
a mixture of aluminum chloride (17.3 g, 0.13 mol) in dichlo-
romethane (100 mL) at room temperature. After the addition
was completed, the mixture was refluxed for 2.5 h. The
reaction mixture was poured into ice/water (1.5 L). The two
phases were separated and the dichloromethane phase was
washed with 0.1 N aqueous sodium hydroxide, dried (Na2SO4),
and concentrated to give crude 22. Chromatography on silica
gel with hexane/dichloromethane (1:1) as eluent afforded 11.1
g (55%) of 22 as a white solid: mp 94-96 °C; NMR (DMSO-
d6) δ 7.82 (m, 1H, Ar), 7.42 (m, 1H, Ar), 3.16 (m, 2H, CH2),
2.73 (m, 2H, CH2). Anal. (C9H6ClFO) C, H.
(d ) P r ep a r a tion of Eth yl 2-(4-Ch lor o-6-flu or o-1-h y-
d r oxy-1-in d a n yl)a ceta te (23). Ethyl acetate (5.9 g, 0.07 mol)
was added dropwise to a stirred, chilled (dry ice-acetone bath)
solution of lithium diisopropylamide (prepared by dropwise
addition of a 2.5M solution of n-butyllithium (26.8 mL, 0.07
mol) in hexane to a chilled (dry ice/acetone bath) solution of
diisopropylamine (6.8 g, 0.07 mol) in tetrahydrofuran (35 mL).
After 30 min, a solution of 22 (12.4 g, 0.07 mol) in tetrahy-
drofuran (100 mL) was added dropwise, and the mixture was
stirred for 1 h (dry ice/acetone bath). A solution of ammonium
analgesic activity is lost. Compound 10 with an RR/ST
ratio of 1.1 would be expected to produce sedation. The
4-methyl-6-fluoro derivative 7 does not have muscle
relaxant or antiinflammatory activity but is a potent
mild analgesic. All of the above information seemed to
indicate that a combination of a substituent larger than
fluoro at position 4 and a fluoro substituent at position
6 is required to diminish the muscle relaxant activity
while maintaining potent antiinflammatory/analgesic
activity. However, if the substituent at position 4 is too
large as in 4, the 4-bromo-6-fluoro analogue, loss of
antiinflammatory activity is realized. Comparison of
compounds 8 (the 4,6-dichloro derivative) and 5 (the
4-chloro-6-methyl analogue) confirms the idea that a
halogen at position 6 is needed for antiinflammatory/
analgesic activity. Replacement of the 6-Cl group in 8
with a methyl group as in 5 affords a compound that is
less active in the CP screen.
N-alkylation can have a positive effect on antiinflam-
matory and analgesic activity. Comparison of com-
pounds 2 and 3 indicates that methylation of the amide
nitrogen as in 2 gives an analogue that is still considered
inactive as a muscle relaxant, is equipotent as an
antiinflammatory agent, but is almost 3 times more
potent as an analgesic agent than the unsubstituted
amide. However, if the alkyl substituent on the amide
nitrogen is cyclopropyl as in 15, muscle relaxant activity
is restored while the potent mild analgesia is retained
(this compound has a RR/ST ratio of 1 and would likely
produce some sedation). Compound 2 was the most
potent compound in the antiinflammatory CP assay
with ED50 values of 8 and 5 mg/kg po in cells and edema,
respectively. This compares favorably with ibuprofen,
which in our assay had ED50 values of 34 and 8 mg/kg
po in cells and edema, respectively. It was also one of
the more potent mild analgesics with an ED50 of 1.4 mg/
kg po in the THA assay. For comparison, ibuprofen and
naproxen in our assay had ED50 values of 25 and 14
mg/kg po, respectively. Only 15 was more potent as a
mild analgesic. However, 15 possessed muscle relaxant
activity. Since 2 was considered inactive in the ST
screen for muscle relaxation, it was chosen for further
evaluation. In the phalanges algesia assay (see ref 1 for
description of assay) indicative of strong analgesic
activity, compound 2 had an ED50 of 60 mg/kg po. In
comparison, compound 1 had an ED50 of 20 mg/kg po
and codeine in our assay had an ED50 of 27 mg/kg po.
Con clu sion
Structure-activity relationship studies of a series of
disubstituted indanylidenes has resulted in the discov-
ery of 2, (E)-2-(4-chloro-6-fluoro-1-indanylidene)-N-me-
thylacetamide. Compound 2 has the desired balance of
little or no muscle relaxant activity and potent antiin-
flammatory and analgesic activity. Compound 2 also
possesses some strong analgesic activity. As reported
earlier for 1,1 the mechanism of action for the antiin-
flammatory and analgesic activity of 2 is unknown.
Further studies to elucidate the mechanism of action
are underway.
Exp er im en ta l Section
Melting points were taken in capillary tubes with a Thomas-
Hoover melting point apparatus and are uncorrected. The
NMR spectra were recorded on Varian XL-200, Varian XL-

Indanylidenes, Part 2
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 3 413
chloride (10.6, 0.20 mol) in water (80 mL) was added dropwise,
and the mixture was allowed to come to ambient temperature.
The aqueous phase was separated and extracted with diethyl
ether. The combined organic phase was dried (sodium sulfate),
filtered, and concentrated in vacuo to give 19.5 g of crude 23.
Chromatography on silica gel using hexanes/ethyl acetate (8:
2) as eluent gave 15.2 g (83%) of 23 as a yellow oil: NMR
(DMSO-d6) δ 7.26 (m, 1H, Ar), 7.15 (m, 1H, Ar), 5.55 (br s,
1H, OH), 3.97 (q, 2H, CH2CH3), 2.79 (m, 4H, CH2), 2.50 (m,
mol) in dimethoxyethane (10 mL) was added dropwise to a
suspension of sodium hydride (6.0 g of a 60% dispersion in
mineral oil, 0.15 mol, Aldrich) in dimethoxyethane (25 mL) at
ambient temperature. After 1 h, a solution of 27 (40.8 g, 0.15
mol) in dimethoxyethane (125 mL) was added dropwise and
the mixture was refluxed for 1.5 h. The reaction mixture was
cooled to ambient temperature and concentrated in vacuo. The
residue was partitioned between dichloromethane and water.
The dichloromethane extracts were dried (sodium sulfate) and
concentrated in vacuo to give 63.4 g of a yellow oil. Chroma-
tography on silical gel with dichloromethane/hexanes (3:2)
gave 21.3 g (40%) of 28 as a colorless oil. (A second fraction,
11.5 g, containing a minor impurity was obtained and could
be used without further purification.) NMR (CDCl3) δ 7.21-
7.31 (m, 2H, Ar), 6.90-6.97 (m, 1H, Ar), 4.11-4.21 (m, 4H, 2
× CH2), 3.77 (t, 1H, CH), 3.30 (d, 2H, CH2), 1.22 (t, 6H, 2 ×
CH3). Anal. (C14H16BrFO4) C, H.
(c) P r ep a r a tion of 3-(2-Br om o-4-flu or op h en yl)p r op i-
on ic Acid (29). A mixture of 28 (31.8 g, 0.09 mol) and
potassium hydroxide (10.3 g, 0.18 mol) in water (200 mL) was
refluxed for 4.5 h. The mixture was concentrated in vacuo to
remove the ethanol. To the resulting solution was added
concentrated sulfuric acid (15.7 mL, 0.29 mol), and the mixture
was refluxed for 18 h. The reaction mixture was chilled in an
ice bath, and the resulting solid was filtered, washed with
water, and air-dried to give 20.6 g (91%) of crude 29. This
material was used without further purification.
(d ) P r ep a r a tion of 4-Br om o-6-flu or o-1-in d a n on e (30).
To a solution of 29 (19.6 g, 0.08 mol) in dichloromethane (200
mL) at ambient temperature was added dropwise oxalyl
chloride (14.5 mL, 0.17 mol, Aldrich). The mixture was stirred
at ambient temperature for 18 h, and the excess oxalyl chloride
was removed in vacuo to give 3-(2-bromo-4-fluorophenyl)-
propionyl chloride. A solution of the 3-(2-bromo-4-fluorophe-
nyl)propionyl chloride in dichloromethane (100 mL) was added
dropwise to a suspension of aluminum chloride (13.3 g, 0.10
mol, Aldrich) in dichloromethane (200 mL) at ambient tem-
perature. After the addition was completed, the mixture was
refluxed for 2 h and allowed to come to ambient temperature.
The reaction mixture was poured into ice/water (1600 mL),
the two phases were separated, and the aqueous phase was
extracted with dichloromethane. The combined organic phase
was washed successively with 0.1 N aqueous sodium hydroxide
and water, dried over sodium sulfate, and concentrated in
vacuo to give 15.3 g of crude 30. Recrystallization of an 0.8 g
sample from hexanes gave 0.54 g of 30 as a white solid: mp
129-131 °C; NMR (CDCl3) δ 7.54 (dd, 1H, Ar), 7.38 (dd, 1H,
Ar), 3.05 (m, 2H, CH2), 2.78 (m, 2H, CH2). Anal. (C9H6BrFO)
C, H.
(e) P r ep a r a tion of Eth yl 2-(4-Br om o-6-flu or o-1-h y-
d r oxy-1-in d a n yl)a ceta te (31). A solution of 2.5 M n-butyl-
lithium in hexanes (25.2 mL, 0.06 mol, Aldrich) was added
dropwise under a nitrogen atmosphere to a solution of diiso-
propylamine (6.4 g, 0.06 mol, Aldrich) in tetrahydrofuran (50
mL) at -78 °C. After 15 min, a solution of ethyl acetate (5.6
g, 0.06 mol, EM Science) in tetrahydrofuran (10 mL) was added
dropwise and the mixture was stirred at -78 °C for 0.5 h. A
solution of 30 in tetrahydrofuran (125 mL) was added drop-
wise, and the mixture was stirred at -78 °C for 1 h. The
reaction was quenched with a solution of ammonium chloride
(10.1 g, 0.19 mol, Mallinckrodt) in water (100 mL), and the
reaction mixture was allowed to come to ambient temperature
overnight. The phases were separated, and the aqueous phase
was extracted with diethyl ether. The combined organic phase
was dried (sodium sulfate), filtered, and concentrated in vacuo
to give 19.2 g of crude 31. Chromatography on silica gel using
hexanes/ethyl acetate (4:1) gave 14.1 g (70%) of 31 as a pale-
yellow oil: NMR (CDCl3) δ 6.98-7.19 (m, 2H, Ar), 4.21 (q, 2H,
CH2CH3), 3.04 (m, 1H, CH2), 2.74 (m, 3H, CH2′s), 2.31 (m, 2H,
CH2), 1.28 (t, 3H, CH3). Anal. (C13H14BrFO3) C, H.
1H, CH2), 2.11 (m, 1H, CH2), 1.08 (t, 3H, CH3). Anal. (C13H14
ClFO3) C, H.
-
(e) P r ep a r a tion of 2-(4-Ch lor o-6-flu or o-1-h yd r oxy-1-
in d a n yl)a cetic Acid (24). A mixture of 23 (14.5 g, 0.05 mol),
1 N sodium hydroxide (52 mL), and absolute ethanol (100 mL)
was stirred for 18 h at room temperature. The mixture was
concentrated in vacuo, diluted with H2O, and extracted with
diethyl ether. The aqueous phase was neutralized with 1.0 N
hydrochloric acid (52 mL) and extracted with diethyl ether.
The diethyl ether extracts were dried over sodium sulfate,
filtered, and concentrated in vacuo to give 12.5 g (96%) of crude
24. This material was used immediately without further
purification.
(f) P r epar ation of (E)-2-(4-Ch lor o-6-flu or o-1-in dan ylide-
n e)a cetic Acid (25). Trifluoroacetic acid (27.4 mL) was added
to a stirred, chilled (ice/methanol bath) solution of 24 (12.5 g,
0.05 mol) in dichloromethane (200 mL). After 1.5 h, the
mixture was concentrated in vacuo. Dichloromethane was
added to the residue, and the mixture was concentrated in
vacuo to give 10.6 g of crude 25. Chromatography of a 1.0 g
sample on silica gel with ethyl acetate/hexanes (1:1) as eluent
gave 0.32 g of 25 as a white solid: mp 229-230 °C; NMR
(DMSO-d6) δ 12.20 (br, 1H, COOH), 7.75 (m, 1H, Ar), 7.45 (m,
1H, Ar), 6.42 (s, 1H, dCH), 3.21 (m, 2H, CH2), 2.97 (m, 2H,
CH2); steady-state nuclear Overhauser effect (NOE), irradia-
tion at δ 6.42, observed 15.4% NOE at δ 7.75. Anal. (C11H8-
ClFO2) C, H.
(g) P r ep a r a t ion of (E)-2-(4-Ch lor o-6-flu or o-1-in d a -
n ylid en e)a cetyl Ch lor id e (26). A suspension of 25 (9.6 g,
0.04mol) in dichloromethane (100 mL) was treated with oxalyl
chloride (10.7 g, 0.08 mol) and allowed to stir at room
temperature for 3 h. The resulting solution was concentrated
in vacuo, and the residual 26 was used without further
purification.
(h ) P r ep a r a t ion of (E)-2-(4-Ch lor o-6-flu or o-1-in d a -
n ylid en e)-N-m eth yla ceta m id e (2). A solution of 26 (4.0 g,
0.015 mol) in dichloromethane (36 mL) was added dropwise
to an ice-cold mixture of 40% aqueous methylamine (2.6 mL,
0.03 mol) and dichloromethane (100 mL), and the mixture was
stirred at ambient temperature for 18 h. The mixture was
concentrated in vacuo, and the residue was partitioned be-
tween 5% aqueous sodium bicarbonate and ethyl acetate. The
ethyl acetate solution was dried (Na2SO4), filtered, and con-
centrated in vacuo. The residue was purified by column
chromatography on silica gel with ethyl acetate/hexanes (1:1)
as eluent to give 1.59 g (44%) of 2 as a white solid: mp 173-
175 °C; NMR (CDCl3) δ 7.10-7.30 (m, 2H, Ar), 6.16 (s, 1H,
dCH), 5.64 (br, 1H, NH), 3.42-3.48 (m, 2H, CH2), 3.01-3.07
(m, 2H, CH2), 2.95 (s, 3H, CH3), 0.62-0.72. Anal. (C12H11
ClFNO) C, H, N.
-
Meth od B. P r ep a r a tion of (E)-2-(4-Br om o-6-flu or o-1-
in d a n ylid en e)a ceta m id e (4). (a ) P r ep a r a tion of 2-Br om o-
1-(br om om eth yl)-4-flu or oben zen e (27).14 A mixture of
2-Bromo-4-fluorotoluene (46.6 g, 0.25 mol, Aldrich), N-bromo-
succinimide (46.3 g, 0.26 mol, Aldrich), and benzoyl peroxide
(0.5 g, 0.002 mol, Aldrich) in carbon tetrachloride (500 mL)
was refluxed and illuminated (250 W, infrared lamp) for 18 h.
After the mixture was cooled to room temperature, the
succinimide was filtered and the filtrate was concentrated in
vacuo. Chromatography on silica gel with hexanes as eluent
gave 41.8 g (62%) of 27 as a white solid: mp 47-49 °C (lit.,14
no physical data reported); NMR (CDCl3) δ 6.99-7.46 (m, 3H,
Ar), 4.57 (s, 2H, CH2). Anal. (C7H5Br2F) C, H.
(f) P r ep a r a t ion of 2-(4-Br om o-6-flu or o-1-h yd r oxyl-
in d a n yl)a cetic Acid (32). A mixture of 31 (13.6 g, 0.05 mol)
and 1.0 N sodium hydroxide (46 mL, 0.05 mol, Universal
Scientific Supply Co.) in ethanol (100 mL) was stirred for 18
(b) P r ep a r a tion of Dieth yl 2-(2-Br om o-4-flu or oben zyl)-
m a lon a te (28). A solution of diethyl malonate (25.9 g, 0.16

414 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 3
Musso et al.
h at ambient temperature. The reaction mixture was concen-
trated in vacuo, diluted with water, and extracted with diethyl
ether. The aqueous phase was neutralized with 1.0 N hydro-
chloric acid (47 mL, 0.05 mol, Universal Scientific Supply Co.)
and extracted with diethyl ether. The diethyl ether layer was
dried over sodium sulfate, filtered, and concentrated in vacuo
to give 13.6 g (quantitative yield) of crude 32. This material
was used immediately without further purification.
(g) P r ep a r a t ion of (E)-2-(4-Br om o-6-flu or o-1-in d a n -
ylid en e)a cetic Acid (33). Trifluoroacetic acid (34.2 g, 0.30
mol) was added dropwise to a stirred, chilled (ice/methanol
bath) mixture of 32 (13.6 g, 0.05 mol) in dichloromethane (250
mL). After being stirred at -20 °C for 2 h, the mixture was
concentrated in vacuo. Dichloromethane was added to the
residue, and the mixture was concentrated in vacuo. This
procedure was repeated two times, and the resulting solid was
triturated with water. The solid was filtered, washed with
water, and air-dried to give 9.1 g of crude 33. This material
was used without further purification.
(h ) P r ep a r a t ion of (E)-2-(4-Br om o-6-flu or o-1-in d a n -
ylid en e)a cetyl Ch lor id e (34). A suspension of 33 (8.5 g,
0.03mol) in dichloromethane (100 mL) was treated with oxalyl
chloride (7.9 g, 0.06 mol, Aldrich) and allowed to stir at
ambient temperature for 4 h. The resulting solution was
concentrated in vacuo, and the residual 34 was used without
further purification.
(i) P r ep a r a tion of (E)-2-(4-Br om o-6-flu or o-1-in d a n yli-
d en e)a ceta m id e (4). A solution of 34 (3.25 g, 0.011 mol) in
dichloromethane (36 mL) was added dropwise to a stirred,
chilled (ice bath) mixture of 30% aqueous ammonium hydrox-
ide solution (1.4 mL, 0.022 mol) and dichloromethane (50 mL).
After being stirred at ambient temperature for 18 h, the
mixture was concentrated in vacuo and the residue was
partitioned between 5% aqueous sodium bicarbonate solution
and ethyl acetate. The ethyl acetate solution was dried over
sodium sulfate, filtered, and concentrated in vacuo. Chroma-
tography on silica gel with ethyl acetate/hexanes (7:3) as eluent
and trituration of the resulting solid with pentane gave 1.4 g
(47%) of 4 as a white solid: mp 183-185 °C; NMR (DMSO-d6)
δ 7.54 (dd, 1H, Ar), 7.37 (m, 2H, Ar and NH2), 6.98 (br s, 1H,
NH2), 6.39 (t, 1H, dCH), 3.17-3.22, 2.86-3.00 (2m’s, 4H, 2 ×
CH2); steady-state NOE, irradiation at δ 6.39, observed 27.2%
NOE at δ 7.37. Anal. (C11H9BrFNO) C, H, N.
Meth od C. P r ep a r a tion of (E)-2-(6-F lu or o-4-m eth yl-1-
in d a n ylid en e)a ceta m id e (7). (a ) P r ep a r a tion of (E)-Eth yl
3-(4-flu or o-2-m eth ylp h en yl)a cr yla te (35). A mixture of
2-bromo-5-fluorotoluene (17.6 g, 0.09 mol, Aldrich), ethyl
acrylate (9.3 g, 0.09 mol), triethylamine (9.4 g, 0.09 mol),
palladium(II) acetate (2.7 g, 0.01 mol), and tri-o-tolylphosphine
(7.3 g, 0.02 mol) in acetonitrile (60 mL) was placed in a Parr
bomb and heated at 110 °C for 12 h. After cooling to room
temperature, the mixture was diluted with diethyl ether and
filtered. The filtrate was concentrated in vacuo to give 33.0 g
of an orange oil. Chromatography on silica gel using initially
hexanes/dichloromethane (8:2) and subsequently hexanes/
dichloromethane (6:4) as eluent gave 18.0 g (93%) of 35 as a
pale-yellow oil: NMR (DMSO-d6) δ 7.78 (d, 1H, CHd, J ) 16
Hz), 7.78 (m, 1H, ArH), 7.02-7.15 (m, 2H, Ar), 6.48 (d, 1H,
CHd, J ) 16 Hz), 4.17 (q, 2H, CH2), 2.38 (s, 3H, CH3), 1.24 (t,
3H, CH3). Anal. (C12H13FO2) C, H.
(b) P r ep a r a tion of Eth yl 3-(4-F lu or o-3-m eth ylp h en yl)-
p r op ion a te(36). A mixture of 35 (32.9 g, 0.16 mol) and
platinum oxide hydrate (0.5 g, EM Scientific) in 95% ethanol
(125 mL) was placed in a Parr apparatus. After the appropriate
amount of hydrogen was taken up, the catalyst was filtered
and the filtrate was concentrated in vacuo to give 33.7 g of
36. A 1.0 g sample was purified by chromatography on silica
gel with hexanes/dichloromethane as eluent to give 0.92 g of
36 as a colorless oil: NMR (CDCl3) δ 6.78-7.26 (m, 3H, Ar),
4.13 (q, 2H, CH2), 2.90 (t, 2H, CH2), 2.54 (t, 2H, CH2), 2.31 (s,
3H, CH3), 1.24 (t, 3H CH3). Anal. (C12H15FO2) C, H.
portion 1.0 N sodium hydroxide (156 mL) solution, and the
mixture was stirred for 18 h at room temperature. The mixture
was concentrated in vacuo, the residue was dissolved in water,
and the aqueous phase was washed with diethyl ether. The
aqueous phase was chilled in an ice bath and made acidic by
addition of 1.0 N hydrogen chloride (160 mL) solution. Filtra-
tion of the resulting solid gave 25.8 g (91%) of 37. A 0.5 g
sample was recrystallized from water to give 0.26 g of 37 as a
white solid: mp 112-113 °C; NMR (CDCl3) δ 6.79-7.15 (m,
3H, Ar), 2.92 (t, 2H, CH2), 2.64 (t, 2H, CH2), 2.31 (s, 3H CH3).
Anal. (C10H11FO2) C, H.
(d ) P r ep a r a tion of 6-F lu or o-4-m eth yl-1-in d a n on e (38).
To a suspension of 37 (25.3 g, 0.14 mol) in dichloromethane
(50 mL) at ambient temperature was added dropwise oxalyl
chloride (24.3 mL, 0.28 mol, Aldrich). The mixture was stirred
at ambient temperature for 18 h, and the excess oxalyl chloride
was removed in vacuo to give 3-(4-fluoro-2-methylphenyl)-
propionyl chloride. A solution of the 3-(4-fluoro-2-methyl-
phenyl)propionyl chloride in dichloromethane (75 mL) was
added dropwise to a mixture of aluminum chloride (22.0 g, 0.17
mol, Aldrich) in dichloromethane (200 mL) at ice bath tem-
perature. After the addition was completed, the mixture was
refluxed for 2.5 h and allowed to come to ambient temperature
overnight. The reaction mixture was poured into ice/water
(1500 mL), the two phases were separated, and the aqueous
phase was extracted with dichloromethane. The combined
organic phase was washed successively with 0.1 N aqueous
sodium hydroxide and water, dried over sodium sulfate, and
concentrated in vacuo to give 22.3 g of crude 38. Chromatog-
raphy on silica gel with hexanes/methylene chloride (1:1) as
eluent gave 11.9 g (52%) of 38 as a white solid: mp 90-92 °C;
NMR (CDCl3) δ 7.11-7.34 (m, 2H, Ar), 3.04 (m, 2H, CH2), 2.80
(m, 2H, CH2), 2.35 (s, 3H, CH3). Anal. (C10H9FO) C, H.
(e) P r ep a r a t ion of E t h yl 2-(6-F lu or o-1-h yd r oxy-4-
m eth yl-1-in d a n yl)a ceta te (39). A solution of 2.5 M n-
butyllithium in hexanes (54.4 mL, 0.14 mol, Aldrich) was
added dropwise under a nitrogen atmosphere to a solution of
diisopropylamine (13.8 g, 0.14 mol) in tetrahydrofuran (60 mL)
at -78 °C. After 15 min, a solution of ethyl acetate (12.0 g,
0.14 mol) in tetrahydrofuran (10 mL) was added dropwise and
the mixture was stirred at -78 °C for 0.5 h. A solution of 38
in tetrahydrofuran (150 mL) was added dropwise, and the
mixture was stirred at -78 °C for 1 h. The reaction was
quenched with a solution of ammonium chloride (21.8 g, 0.42
mol) in water (120 mL), and the reaction mixture was allowed
to come to ambient temperature overnight. The phases were
separated, and the aqueous phase was extracted with diethyl
ether. The combined organic phase was dried (sodium sulfate),
filtered, and concentrated in vacuo to give 34.0 g of crude 39.
Chromatography on silica gel using hexanes/ethyl acetate (8:
2) followed by rechromatography on silica gel using hexanes/
ethyl acetate (95:5) gave 27.9 g (81%) of 39 as a pale-yellow
oil: NMR (CDCl3) δ 6.76-6.88 (m, 2H, Ar), 4.22 (q, 2H, CH2-
CH3), 2.79 (2m’s, 4H, CH2’s), 2.30 (m, 2H, CH2), 2.24 (s, 3H,
CH3), 1.28 (t, 3H, CH3). Anal. (C14H17FO3) C, H.
(f) P r ep a r a tion of 2-(6-F lu or o-1-h yd r oxy-4-m eth yl-1-
in d a n yl)a cetic Acid (40). A mixture of 39 (27.4 g, 0.11 mol)
and 1.0 N sodium hydroxide (108 mL, 0.108 mol, Universal
Scientific Supply Co.) in ethanol (150 mL) was stirred for 18
h at ambient temperature. The reaction mixture was concen-
trated in vacuo, diluted with water, and extracted with diethyl
ether. The aqueous phase was neutralized with 1.0 N hydro-
chloric acid (108 mL, 0.108 mol, Universal Scientific Supply
Co.) and extracted with diethyl ether. The diethyl ether layer
was dried over sodium sulfate, filtered, and concentrated in
vacuo to give 15.5 g of crude 40. The original diethyl ether
extracts were extracted with 0.1 N NaOH. The aqueous base
was neutralized with 0.1 N HCl and extracted with diethyl
ether to get an additional 1.6 g of crude 40. The total yield of
crude 40 was 17.1 g (70%). This material was used im-
mediately without further purification.
(c) P r ep a r a tion of 3-(4-F lu or o-2-m eth ylp h en yl)p r op i-
on ic Acid (37). To a mixture of 36 (32.7 g, 0.16 mol) in ethanol
(150 mL) chilled to ice bath temperature was added in one
(g) P r ep a r a t ion of (E)-2-(6-F lu or o-4-m et h yl-1-in d a n -
ylid en e)a cetic Acid (41). Trifluoroacetic acid (54.7 g, 0.48
mol) was added dropwise to a stirred, chilled (ice/methanol

Indanylidenes, Part 2
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 3 415
bath) mixture of 40 (17.1 g, 0.08 mol) in dichloromethane (200
mL). After 1.5 h, the mixture was concentrated in vacuo.
Dichloromethane was added to the residue, and the mixture
was concentrated in vacuo. This procedure was repeated four
times to give 11.7 g of crude 41. Recrystallization of 0.5 g from
2-propanol gave 0.23 g of 41 as a white solid: mp 243-246
°C; NMR (DMSO-d6) δ 12.03 (br, 1H, COOH), 7.43 (m, 1H,
Ar), 7.05 (m, 1H, Ar), 6.33 (t, 1H, dCH), 3.15-3.20, 2.84-2.87
(2m’s, 4H, 2 × CH2), 2.23 (s, 3H, CH3); steady-state NOE,
irradiation at δ 6.33, observed 22.7% NOE at δ 7.43. Anal.
(C12H11FO2) C, H.
(h ) P r ep a r a tion of (E)-2-(6-F lu or o-4-m eth yl-1-in d a n -
ylid en e)a cetyl Ch lor id e (42). A suspension of 41 (11.2 g,
0.054 mol) in dichloromethane (100 mL) was treated with
oxalyl chloride (17.3 g, 0.14 mol, Aldrich) and allowed to stir
at ambient temperature for 4 h. The resulting solution was
concentrated in vacuo, and the residual 42 was used without
further purification.
(i) P r ep a r a t ion of (E)-2-(6-F lu or o-4-m et h yl-1-in d a n -
ylid en e)a ceta m id e (7). A solution of 42 (4.0 g, 0.018 mol) in
dichloromethane (40 mL) was added dropwise to a stirred,
chilled (ice bath) mixture of 30% aqueous ammonium hydrox-
ide solution (2.3 mL, 0.036 mol) and dichloromethane (50 mL).
After being stirred at ambient temperature for 18 h, the
mixture was concentrated in vacuo and the residue was
partitioned between 5% aqueous sodium bicarbonate solution
and ethyl acetate. The ethyl acetate solution was dried over
sodium sulfate, filtered, and concentrated in vacuo. Chroma-
tography on silica gel with ethyl acetate/hexanes (6:4) as eluent
and trituration of the resulting solid with pentane gave 1.8 g
(49%) of 7 as an off-white solid: mp 178-180 °C; NMR (DMSO-
d6) δ 7.25 (br s, 1H, NH2), 7.07-7.11 (m, 1H, Ar), 6.99-7.03
(m, 1H, Ar), 6.84 (br s, 1H, NH2), 6.34 (t, 1H, dCH), 3.15-
3.20, 2.80-2.84 (2m’s, 4H, 2 × CH2), 2.22 (s, 3H, CH3); steady-
state NOE, irradiation at δ 6.34, observed 23.2% NOE at δ
and the filtrate was concentrated in vacuo to give 38.3 g of
45. A 1.0 g sample was purified by chromatography on silica
gel with hexanes/ethyl acetate (98:2) as eluent to give 0.38 g
of 45 as a colorless oil: NMR (CDCl3) δ 7.03-7.18 (m, 3H, Ar),
4.13 (q, 2H, CH2), 2.93 (t, 2H, CH2), 2.60 (t, 2H, CH2), 1.23 (t,
3H CH3). Anal. (C11H12ClFO2) C, H.
(d ) P r ep a r a tion of 3-(4-Ch lor o-2-flu or op h en yl)p r op i-
on ic Acid (46). To a mixture of 45 (14.3 g, 0.06 mol) in ethanol
(100 mL) chilled to ice bath temperature was added in one
portion 1.0 N sodium hydroxide solution (60 mL, 0.06 mol),
and the mixture was stirred for 6 h at ambient temperature.
The mixture was concentrated in vacuo, the residue was
dissolved in water, and the aqueous phase was washed with
diethyl ether. The aqueous phase was chilled in an ice bath
and made acidic by addition of 1.0 N hydrogen chloride (70
mL, 0.07 mol) solution. Filtration of the resulting solid gave
8.9 g (73%) of crude 46. A 0.5 g sample was recrystallized from
water to give 0.18 g of 46 as a white solid: mp 83-85 °C; NMR
(CDCl3) δ 7.05-7.19 (m, 3H, Ar), 2.94 (t, 2H, CH2), 2.70 (t,
2H, CH2). Anal. (C9H8ClFO2) C, H.
(e) P r ep a r a tion of 6-Ch lor o-4-flu or o-1-in d a n on e (47).
To a solution of 46 (8.4 g, 0.04 mol) in dichloromethane (50
mL) at ambient temperature was added dropwise oxalyl
chloride (7.2 mL, 0.08 mol, Aldrich). The mixture was stirred
at ambient temperature for 4 h and the excess oxalyl chloride
was removed in vacuo to give 3-(4-chloro-2-fluorophenyl)-
propionyl chloride. A solution of the 3-(4-chloro-2-fluoro-
phenyl)propionyl chloride in dichloromethane (50 mL) was
added dropwise to a mixture of aluminum chloride (6.5 g, 0.05
mol, Aldrich) in dichloromethane (50 mL) at ice bath temper-
ature. After the addition was completed, the mixture was
refluxed for 2 h, allowed to come to ambient temperature, and
poured into ice/water (1.0 L). After the mixture was stirred at
ambient temperature for 18 h, the two phases were separated
and the aqueous phase was extracted with dichloromethane.
The combined organic phase was washed successively with 0.1
N aqueous sodium hydroxide and water, dried over sodium
sulfate, and concentrated in vacuo to give 7.9 g of crude 47.
Chromatography on silica gel with hexanes/methylene chloride
(7:3) as eluent gave 4.1 g (54%) of 47 as a white solid: mp
105-107 °C; NMR (DMSO-d6) δ 7.73 (dd, 1H, Ar), 7.50 (d, 1H,
Ar), 3.07 (m, 2H, CH2), 2.71 (m, 2H, CH2). Anal. (C9H6ClFO)
C, H.
(f) P r ep a r a tion of Eth yl 2-(6-Ch lor o-4-flu or o-1-h y-
d r oxy-1-in d a n yl)a ceta te (48). A solution of ethyl acetate (8.3
g, 0.09 mol) in tetrahydrofuran (10 mL) was added dropwise
to a solution of lithium diisopropylamide (62.7 mL of a 1.5 M
solution in cyclohexane, 10.1 g, 0.09 mol, Aldrich) in tetrahy-
drofuran (100 mL) at -78 °C under a nitrogen atmosphere.
After 30 min, a solution of 47 in tetrahydrofuran (175 mL)
was added dropwise, and the mixture was stirred at -78 °C
for 70 min. The reaction was quenched with a solution of
ammonium chloride (15.1 g, 0.27 mol) in water (100 mL), and
the reaction mixture was allowed to come to ambient temper-
ature overnight. The phases were separated, and the aqueous
phase was extracted with diethyl ether. The combined organic
phase was dried (sodium sulfate), filtered, and concentrated
in vacuo to give 24.4 g of crude 48. Chromatography on silica
gel using hexanes/ethyl acetate (9:1) as eluent gave 14.7 g
(57%) of 48 as a yellow oil. Rechromatography of a 0.5 g sample
on silica gel with dichloromethane as eluent gave 0.27 g of 48
as a colorless oil: NMR (CDCl3) δ 6.96-7.12 (m, 2H, Ar), 4.35
(br s, 1H, OH), 4.22 (q, 2H, CH2CH3), 3.04 (m, 1H, CH2), 2.75
(2m’s, 3H, CH2’s), 2.32 (m, 2H, CH2), 1.28 (t, 3H, CH3). Anal.
(C13H14ClFO3) C, H.
7.09 and NOEs of 3.4% at δ 7.25 and δ 6.84. Anal. (C12H12
FNO) C, H, N.
-
Meth od D. P r ep a r a tion of (E)-2-(6-Ch lor o-4-flu or o-1-
in d a n ylid en e)a ceta m id e (6). (a ) P r ep a r a tion of 4-Ch lor o-
2-flu or op h en yl Tr iflu or om eth a n esu lfon a te (43).15 A mix-
ture of 4-chloro-2-fluorophenol (25.0 g, 0.17 mol, Aldrich) and
pyridine (13.5 g, 0.17 mol, Aldrich) in dichloromethane (120
mL) was added dropwise to a solution of trifluoromethane-
sulfonic anhydride (50.0 g, 0.18 mol, Aldrich) in dichlo-
romethane (120 mL) at ice bath temperature. After being
stirred at ambient temperature for 60 h, the reaction mixture
was washed with water and dried over sodium sulfate, filtered,
and concentrated in vacuo to give 45 g of crude 43. Chroma-
tography on silica gel with hexanes as eluent gave 32.2 g (68%)
of 43 as a colorless oil (lit.,15 no physical data reported); NMR
(CDCl3) δ 7.20-7.33 (m, 3H, Ar). Anal. (C7H3ClF4O3S) C, H.
(b ) P r ep a r a t ion of (E)-E t h yl 3-(4-Ch lor o-2-flu or o-
p h en yl)a cr yla te (44). A mixture of 43 (5.0 g, 0.02 mol), ethyl
acrylate (1.8 g, 0.02 mol, Aldrich), triethylamine (1.8 g 0.02
mol), and bis(triphenylphosphine)palladium(II) chloride (1.4
g, 0.002 mol, Aldrich) in dimethylformamide (20 mL) was
placed in a Parr bomb and heated at 110 °C for 12 h. After
cooling to ambient temperature, the mixture was diluted with
diethyl ether and filtered. The filtrate was washed with water,
filtered, and concentrated in vacuo to give 6.6 g of an orange
oil. Chromatography on silica gel using initially hexanes/
dichloromethane (7:3) as eluent gave (A) 1.57 g of pure 44 as
a green oil that solidified on standing and (B) 0.93 g of 44
containing a minor impurity. Recrystallization of (A) from
acetone/water mixtures gave 0.82 g of 44 as a white solid: mp
38-40 °C; NMR (CDCl3) δ 7.73 (d, 1H, CHd, J ) 16.1 Hz),
7.47 (m, 1H, ArH), 7.12-7.18 (m, 2H, Ar), 6.51 (d, 1H, CHd,
(g) P r ep a r a tion of 2-(6-Ch lor o-4-flu or o-1-h yd r oxy-1-
in d a n yl)a cetic Acid (49). A mixture of 48 (16.0 g, 0.06 mol)
and 1.0 N sodium hydroxide (58 mL, 0.058 mol, Universal
Scientific Supply Co.) in ethanol (150 mL) was stirred for 18
h at ambient temperature. The reaction mixture was concen-
trated in vacuo, diluted with water, and extracted with diethyl
ether. The diethyl ether was extracted with 0.1 N aqueous
NaOH (110 mL). The combined aqueous phase was neutralized
with 1.0 N hydrochloric acid (68 mL, 0.068 mol, Universal
J ) 16.4 Hz), 4.27 (q, 2H, CH2), 1.34 (t, 3H, CH3). Anal. (C11H10
ClFO2) C, H.
-
(c) P r ep a r a tion of Eth yl 3-(4-Ch lor o-2-flu or op h en yl)-
p r op ion a te (45). A mixture of 44 (37.9 g, 0.17 mol) and
platinum oxide hydrate (0.5 g, EM Scientific) in 95% ethanol
(150 mL) was placed in a Parr apparatus. After the appropriate
amount of hydrogen was taken up, the catalyst was filtered,

416 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 3
Musso et al.
Scientific Supply Co.) and extracted with diethyl ether. The
diethyl ether solution was dried over sodium sulfate, filtered,
and concentrated in vacuo to give 15.2 g of crude 49. This
material was used immediately without further purification.
(h ) P r ep a r a t ion of (E)-2-(6-Ch lor o-4-flu or o-1-in d a n -
ylid en e)a cetic Acid (50). Trifluoroacetic acid (43.3 g, 0.38
mol) was added dropwise to a stirred, chilled (ice/methanol
bath) mixture of 49 (14.7 g, 0.06 mol) in dichloromethane (150
mL). After being stirred for 1.5 h, the mixture was concen-
trated in vacuo. Dichloromethane was added to the residue,
and the mixture was concentrated in vacuo. This procedure
was repeated four times to give 11.7 g of crude 50. A 1.0 g
sample was purified by column chromatography on silica gel
with hexanes/ethyl acetate (1:1) as eluent followed by recrys-
tallization with 2-propanol to give 0.21 g of 50 as a white
solid: mp 254-256 °C; NMR (DMSO-d6) δ 12.23 (br, 1H,
COOH), 7.80 (d, 1H, Ar), 7.40 (dd, 1H, Ar), 6.47 (t, 1H, dCH),
3.18-3.22, 2.96-3.00 (2m’s, 4H, 2 × CH2); steady-state NOE,
irradiation at δ 6.47, observed 28.9% NOE at δ 7.80. Anal.
(C11H8ClFO2) C, H.
and 5% aqueous sodium bicarbonate solution. The ethyl
acetate phase was dried (sodium sulfate), filtered, and con-
centrated in vacuo to give crude 15. Chromatography on silica
gel using hexanes/ethyl acetate (3:1) followed by recrystalli-
zation from ethyl acetate/pentane mixtures gave 0.78 g (27%)
of 15 as a white solid: mp 147-149 °C; NMR (DMSO-d6) δ
8.06 (d, 1H, NH), 7.41 (m, 1H, Ar), 7.27 (m, 1H, Ar), 6.31 (s,
1H, dCH), 3.24 (m, 2H, CH2), 2.92 (m, 2H, CH2), 2.70 (m, 1H,
CH), 0.64 (m, 2H, CH2), 0.41 (m, 2H, CH2); steady-state NOE
(CDCl3), irradiation at δ 6.31, observed 23% NOE at δ 7.27
and 16% NOE at δ 8.06. Anal. (C14H13ClFNO) C, H, N.
Refer en ces
(1) Kelley, J . L.; Rigdon, G. C.; Cooper, B. R.; McLean, E. W.; Musso,
D. L.; Orr, G. F.; Selph, J . L.; Styles, V. L. Bicyclic Amide
Derivatives and Their Use as Muscle Relaxants. U.S. Patent 5,-
872,118, 1999.
(2) Kelley, J . L.; Musso, D. L. Amide Derivatives and Their
Therapeutic Use. U.S. Patent 5,708,033, 1998.
(3) Rabjohn, N., Ed. Org. Synth. (Collective) 1963, 4, 327-329.
(4) Heck, R. F. Palladium-Catalyzed Vinylation of Organic Halides.
In Organic Reactions; Dauben, W. G., Ed.; J ohn Wiley and
Sons: New York, 1982; Vol. 27, Chapter 2, pp 345-390.
(5) Ritter, K. Synthetic Transformations of Vinyl and Aryl Triflates.
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(6) J ohnson, W. S. The Formation of Cyclic Ketones by Intramo-
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177.
(i) P r ep a r a tion of (E)-2-(6-Ch lor o-4-flu or o-1-in d a n yli-
d en e)a cetyl Ch lor id e (51). A suspension of 50 (10.7 g,
0.047mol) in dichloromethane (100 mL) was treated with
oxalyl chloride (11.9 g, 0.094 mol, Aldrich) and allowed to stir
at ambient temperature for 4 h. The resulting solution was
concentrated in vacuo, and the residual 51 was used without
further purification.
(j) P r ep a r a tion of (E)-2-(6-Ch lor o-4-flu or o-1-in d a n yli-
d en e)a ceta m id e (6). A solution of 51 (3.9 g, 0.016 mol) in
dichloromethane (35 mL) was added dropwise to a stirred,
chilled (ice bath) mixture of 30% aqueous ammonium hydrox-
ide solution (2.0 mL, 0.032 mol, Mallinckrodt) and dichlo-
romethane (150 mL). After being stirred at ambient temper-
ature for 18 h, the mixture was concentrated in vacuo and the
residue was partitioned between 5% aqueous sodium bicarbon-
ate solution and ethyl acetate. The ethyl acetate solution was
dried over sodium sulfate, filtered, and concentrated in vacuo.
Chromatography on silica gel with ethyl acetate/hexanes (7:
3) as eluent and trituration of the resulting solid with pentane
gave 1.77 g (49%) of 6 as a white solid: mp 171-173 °C; NMR
(DMSO-d6) δ 7.43 (d, 1H, Ar), 7.37 (dd, 1H, Ar), 7.31 (br s,
1H, NH2), 6.99 (br s, 1H, NH2), 6.46 (t, 1H, dCH), 3.17-3.22,
2.92-2.97 (2m’s, 4H, 2 × CH2); steady-state NOE, irradiation
at δ 6.46, observed 29.8% NOE at δ 7.43 and NOEs of 3.3% at
δ 7.31 and 1.8% at δ 6.99. Anal. (C11H9ClFNO) C, H, N.
Meth od E. P r ep a r a tion of (E)-2-(4-Ch lor o-6-flu or o-1-
in d a n ylid en e)-N-cyclop r op yla ceta m id e (15). A solution of
cyclopropylamine (1.3 g, 0.022 mol) in dichloromethane (25
mL) was added dropwise to an ice cold solution of 26 (3.0 g,
0.011 mol) in dichloromethane (25 mL). After being stirred at
ambient temperature for 18 h, the mixture was concentrated
in vacuo and the residue was partitioned between ethyl acetate
(7) Musso, D. L.; Cochran, F. R.; Kelley, J . L.; McLean, E. W.; Selph,
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(9) Kinnard, W. J .; Carr, C. J . A Preliminary Procedure for the
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J M020068K