PROCESS FOR THE PREPARATrON OF CPLA2 INHIBITORS
Field of the Invention
This invention relates to processes for the preparation of inhibitors of the
enzyme cytosolic phospholipase A2 (cPLAj). and to certain novel intermediates
useful in such processes.
Background Of The Invention
Compounds which inhibit cytosolic phospholipase A2 and a process for
making those compounds have been disclosed in U.S. Publication No.
2003-0144282 A1 filed November 22,2002. These compounds are useful for a
variety of purposes, including the relief of pain and inflammation. In order to bring a
drug to market, it is necessary to have an economically feasible process for making
the compound. Often, a process that works in the laboratory Is not practical from a
commercial standpoint. It would be desirable to have a relatively inexpensive and
efficient method for making at least some of the aforesaid compounds.
Appleton, et al., in Tetrahedron Lett. 1993. 34,1529, teach reductive C-3
alkylation of 3-unsubstituted indoles to produce C-3 functionalized indoles, especially
3-(arylmethyl)indoleis and 3-(heteroarylmethyl)indoles. In the reference reaction, the
initial indole is reacted with an aldehyde or ketone using triethylsilane and
trifluoroacetic acid.
A solid-phase synthesis of indoles using palladium-catalyzed coupling of
alkynes with iodoaniiine derivatives is described by Fagnola, et al.. Tetrahedron
Letters. 38(13). 2307-2310 (1997).
wherein:
n is an integer in the range of 0-10;
R, represents a straight or branched C1-C10alkyi group or -CHz-phenyl wherein the
phenyl ring is either unsubstituted or has up to two substituents independently
selected from the group consisting of C1-C4alkyl, C1-C4alkoxy, halogen, and nitrite,
each alkyl and alkoxy being either unsubstituted or substituted by from one to the
maximum number of halogen atoms;
Rz and R3 are each independently selected from the group consisting of H, halogen,
nitrile, CrC4aikyl, and C1-C4alkoxy; and
R4 represents a straight or branched C1-C10alkyf group,

The process comprises reacting the compwnd HCsC-{CH2)i,-NH2 w^re n is
as defined above, or a salt fomi (hereof, preferably an HCI salt thereof, under mildly
aJkafCne conditions, preferably in a solution of potassium cartxjnate. with the
compound R^-SOzCI wherein R, is as defined above to produce the intennedJate
compound of formula (I!)

and then reacting the compound of formula (I!) with tfie compound of formula

preferably in the presence of a catalyst
The compound of formula (I) may be cyclized by heating, preferably in NMP
in the presence of a catalytic amount of Cul, to form a compound of fomiula (111)

The compound of formula (III) may be reacted with a compound of fomiula 0=CH-R5
in the presence of a reducing agent under acidic conditions, where R5 is -(CH2)m-X-
phenyl-C(0)0R6, m is an integer in the range of 1-4, X is O or CH2, and Re is C1-C4
afkyi, to form a compound of formula (IV)

The compound of formula (IV) may be reacted with LiOH in THF, methanol
and water to convert Rs to R7, where R7 is -(CH2)m-X-phenyl-C(0)0H, wherein m and
X are as defined above.
The present invention further comprises compounds of formulae (I) and (II).
Various advantages and objects of the present invention will be apparent to
those skilled in the art from the description below and from the appended claims.
These cPLAa inhibitors include, for example, 4-[3-[5-chloro-2-[2-[[[(3,4-
dichlorophenyl)-methyll-sulfonyi]amino]ethyl]-1-(diphenylmethyl)-1H-indoI-3-yl]propy(]
benzoic acid and 4-[2-[5-chloro-2-[2-[I[(3,4-dichiorophenyl)methyi]-
sulfonyilamlnolethyl]-1-(diphenylmethyl)-1H-indol-3-yi]ethoxy] benzoic acid, as well
as many other compounds. They are useful for relieving pain and inflammation
associated with a variety of conditions or disease states.
In the process of this invention, n may be an integer in the range of 0-10, but
/ is preferably 0-4 and most preferably is 1, 2. or 3. Ri is preferably -CHa-phenyl,
wherein the phenyl ring is either unsubstituted or has up to two substituents independently
selected from the group consisting of C1-C4alkyl, C1-C4alkoxy, halogen, and nitrite, each alkyl
and alkoxy being either unsubstituted or substituted by from one to a maximum number of
halogen atoms. More preferably, the substituents are halogen, alkyl or perfluoroalkyl.
Especially prefen^ed Ri groups Include 3.4-dichlorophenyImefhyl, 2,6-dimethylphenyi-
metfiyl and 2-(trTfluoromethyl)phenylmethyl. Rz and R3 are preferably H, F, CI, or Br.
R4 is preferably a benzhydryl group, especially an unsubstituted l)en2hydryl group.
Prderably, Re Is methyl or ethyl and m is Z Examples of highly preferred R5 groups
include -(CH2)rO-(p-)phenyl-C(0)OCH3 and -(CH2)3-0>)phenyf-C(O)OC2Hs.
In the reaction of the aikynylamlne and the sulfonyichioride to forni a
compound of formula (II), it is highly preferred to use a solution of K2CO3 in THF and
water. However, other suitable bases or solvents may be used. Those skilled in the
artwflll readily be able to determine which solutions are suitable in carrying out this
reaction.
In reacting the compound of fomiula (II) with the substituted 2-
iodophenylamine compound, a suitable catalyst is preferably employed. Preferably,
the catalyst is Cul and/or dichlorobis(triphenyIphosphine)palIadium (II). It is
preferable to carry out the reaction in a solvent such as THF, or the like.
fn one preferred aspect of the invention, the compound of formula (I) may be
converted to a compound of formula (111) by heating, preferably in the presence of a
catalyst such as Cul In a solvent such as N-methylpyn-olidinone. Other suitable
catalysts and/or solvents known to those skilled in the art may also be employed.
The compound of fonnuia (I) suitably may be heated to approximately 100-140°C,
preferably to about 120°C, until the conversion to an indole compound is completed.
In a further aspect of the invention, the compound of fonmula (III) is reacted
with an aldehyde of formula R5CHO In the presence of a reducing agent to make a
compound of formula (IV). Preferably, this reaction takes place in an acidic solvent
system. Suitable solvent systems include mixtures of a halogenated acid such as
chloroacetic acid, di or trichloroacetic acid, trifluoroacetic acid and/or a Lewis acid
such as boron trifluoride and dichloromethane, preferably with trifluoroacetic acid.
Suitable reducing agents Include triethylsilane, or the like. Those skilled in the art will
readily be able to identify other suitable solvent systems and reducing agents to use
in the practice of this invention.
The compound of formula (IV) may be converted from an ester to an acid by
any means known in the art A preferred method is to react the ester with LiOH in
THF, methanol and water to produce a compound of fomiula (V)

This invention provides a method for making a wide variety of C-2 and C-3
substituted indole compounds, such as compounds of fonmulae (III), (IV) and (V),
shown above. Scheme 1 illustrates various preferred aspects of this invention. In
Scheme 1 below, the terms n, Ri, Rj R3, R4. R5 and R7 have the definitions set forth
above, THF refers to tefrahydrofuran, NMP refers to N-methy/pyrroKdinone and TFA
refers to trifluoroacetic acid.
Scheme 2 Illustrates a highly preferred embodiment of the present invention,
providing a relatively short synthesis for 4-[3-[5-chloro-2-[2-m(3,4-dich!orophenyl)-
methyl]-sulfonyl]amino]ethyl]-1-(diphenylmethyl)-1 H-indol-S-yHpropyi] benzoic acid
(2)and4-[2-[5-chIoro-2-[2-[[[{3,4-dichlorophenyl)methyI]suIfonyl]-amino]ethyl]-1-
(diphenylmethyl)-1H-mdol-3-yl]ethoxy] benzoic acid (3).
In Scheme 2, the first intermediate (6) is coupled with benzhydryl-(4-chloro-2-
iodophenyl)amine (7) with a catalytic amount of dichlorobis(triphenylphosphine)
palladium (II) to give an arylalkyne derivative. Cyclization of this arylalkyne is
perfomied in N-methyl-pynrolidinone with catalytic amount of Cul to give
corresponding indole (9) in two steps. These coupling and cyclization reactions are
known as Sonogashira and Castro reactions and are mediated by catalytic palladium
and copper salts. The indole (9) can be alkylated with the aldehyde (10) using the
reagent combination triethylsilane and trifluoroacetic acid in dichloromethane to yield
the ester (13). Compound (12) is produced when the indole (9) is alkylated with the
aldehyde (11) under the same conditions, but the yield typically is smaller.
Hydrolysis of the ester (13) under common basic conditions produces the compound
(2), and the ester (12) may be hydrolyzed to produce the compound (3).
Other highly preferred embodiments of the present invention include a
process comprising the reactions illustrated in Scheme 2 wherein in compounds 8,
10-13, and 2-3 in place of the 3,4-dichlorophenyl group is a 2,6-dimethylphenyl or 2-
(trifluoromethyl)phenyl group.
The present invention provides a variety of new compounds. Examples of
these new compounds include:
N-But-3-ynyl-1-(3,4-dichlorophenyl)methanesulfonamide,
N-{4-[2-(benzhydrylamino)-5-chtorophenyl]but-3-ynyl}-1-(3,4-dichlorophenyl)-
methanesulfonamide,
N-[2-(1-benzhydryl-5-chIoro-1H-indol-2-yl)ethyl]-1-(3,4-dichlorophenyl)methane-
sutfonamide, and
ethyl 4-{3-[1 -benzhydryI-5-chloro-2-(2-{[(3,4-dichlorobenryl)sulfonyl]amino}ethyl)-1 H-
indol-3-yl]propyl}benzoate.
Other examples include:
N-But-3-ynyl-1-(2,6-dimethylphenyl)methanesulfonamide,
N-{4-[2-(benzhydrylamino)-5-chlorophenyl]but-3-ynyl}-1-(2,6-dimethylphenyl)-
methanesutfonamide,
N-[2-(1-benzhydryl-5-chloro-1H-indol-2-yl)ethy!]-1-(2,6-dimethylphenyl)methane-
sulfonamide,
ethyl 4-{3-[1-benzhydryl-5-chIoro-2-(2-{[(2,6-dimethyIben2yl)sulfonyl]amino}ethyl)-1H-
indol-3-yripropyl}benzoate,
N-But-3-ynyl-1-(2-(trifluoromethyl)phenyl)methanesutfonamide,
N-{4-[2-(benzhydrylamino)-5-chlorophenyl]but-3-ynyl}-1-(2-(trifluoromethyl)phenyl)-
methanesulfonamide,
N-[2-(1-benzhydryl-5-chioro-1H-indol-2-yl)ethyl]-1-(2-(trifluoromethyl)phenyl)-
methane-sulfonamide, and
ethyl 4-{3-[1 -benzhydryI-5-chtoro-2-{2-{[(2-(trifIuoromethyl)benzyl)sulfonyI]am ino}-
ethyi)-1H-indol-3-yl]propyl}benzoate.
Unless the context dictates otherwise, the following terms have the meanings
set forth below wherever they appear in this specification or the appended claims.
Halogen and halo- refer to F, CI. Br and I. Alkyl refers to a saturated
hydrocarbon substituent or group containing from one to twenty carbon atoms and
having straight or branched chains. Alkenyl refers to a hydrocarbon substituent or
group containing from one to twenty carbon atoms, at least one carbon-carbon
double bond, and having straight or branched chains. Alkynyl refers to a
hydrocarbon substituent or group containing from one to twenty carbon atoms, at
least one carbon-carbon triple bond, and having straight or branched chains. Alkoxy
refers to an alkyl group bonded to an oxygen atom by a single oxygen-cart>on bond.
Aryl refers to an unsaturated hydrocarbon ring system containing from one to three
fused rings, in which each ring is composed of 5-7 atoms and has conjugated double
bonds. Heteroaryi refers to an unsaturated ring system which differs form aryl in that
at least one ring atom is nitrogen, oxygen or sulfur.
Phamiaceutically acceptable salts can be fomied from organic and inorganic
acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic,
malonic, mandelic, malic, phthalfc, hydrochtoric, hydrobromic, phosphoric, nitric,
sulfuric, methanesulfonic, naphthatenesulfonic, benzenesulfonic, toluenesulfonic,
cannphorsulfonic, and similariy known acceptable acids when a compound of this
invention contains a basic moiety. Salts may also be fomried from organic and
inorganic bases, preferably alkali metal salts, for example, sodium, lithium, or
potassium, when a compound of this invention contains an acidic moiety.
Pharmaceutlcally acceptable esters can be fonmed from reaction with an
alcohol, for example, a Ci-Csalkanol, when a compound of this invention contains an
acidic moiety.
The following examples are presented to illustrate certain embodiments of the
present invention, but should not be construed as limiting the scope of this invention.
Example 1
N-But-3-vnvl-1-(3.4-dichlorophenvnmethanesulfonamide
To a mixture of potassium carbonate (40.2 g, 296 mmol) in water (50 mL) and
THF (50 mL) at 15-20 "C was added but-3-ynylamine hydrogen chloride (10.4 g, 98.5
mmol). Then. (3,4-dichlorophenyl) methanesulfonyl chloride (5,30.7 g, 118 mmol)
was added in portions during of a period of 30 min. The mixture was stirred for 4 h at
rt. THF is evaporated. The mixture is extracted with EtOAc (2x200 mL). The
combined organic extracts were dried over Na2S04. The solvent is evaporated to
give a white solid (20.5 g. 71%). ^H NMR (CDCI3): 57.53 (d, 1H, J = 2.0 Hz), 7.47 (d.
1H. J = 4.2 Hz). 7.27 (m, 1H), 4.52 (t, 1H. J = 6.2 Hz). 4.22 (s, 2H). 3.17 (dd, 2H, J =
6.2 Hz, 12.5 Hz), 2.41 (m, 2H), 2.07 (m, 1H)
Example 2
N-f4-r2-(benzhvdrvlamlno)-5-chlorophenvnbut-3-vnvl>-1-(3.4-dichloroDhenvl>-
methanesulfonamlde
To a mixture of benzhydryl-(4-ch!oro-2-iodophenyl)amine (2.0 g, 4.76 mmol).
dichlorobis(triphenyiphosphine)palladium (II) (66.8 mg, 0.0952 mmol), copper (I)
iodide (18.0 mg, 0.0952 mmol), and triethylamine (0.72 g, 7.14 mmol) was added N-
but-3-ynyl-1-(3,4-dichlorophenyl)methanesulfonamide_(1.67 g, 5.71 mmol). The
mixture was stirred for 18 h at rt. Then, N-but-3-ynyl-1-(3,4-
dichlorophenyl)methanesulfonamide_(0.42 g) was added. The mixture was stirred for
3 hours. The solvent was evaporated. The residue was purified by column
chromatography, using a mixture of heptane and EtOAc (3:1) as elute to give a white
solid (2.20 g. 81%). ^H NMR (CDCI3): 57.2-7.6 (m. Ph. CHPhj), 6.98 (m, 1H), 6.30 (d,
1H, J = 8.9 Hz), 5.49 (d. 1H. J = 4.6 Hz). 5.06 (d. 1H. J = 4.5 Hz). 4.38 (t, 1H. J =
6.24 Hz), 4.14 (s, 2H), 3.14 (dd, 2H, J = 6.4,12.6 Hz). 2.61 (t, 2H. J = 6.3 Hz).
Example 3
N-r2-f 1 >benzhvdrvl-5-chloro-1 H-indol-2-vl)ethvlM -(3.4-dichlorophenvnmethane-
sulfonamfde
A mixture of N-{4-[2-(benzhydrylamino)-5-chlorophenyl]but-3-ynyl}-l-(3,4-
dichlorophenyl)-methanesulfonamide (1.0 g, 1.71 mmol) and copper (I) iodide (0.30
g, 1.58 mmol) was heated to 120 °C and stin-ed for 7 li, and then cooled to room
temperature. Water (50 mL) was added. The mixture was extracted with EtOAc
(2x50 mL). The combined organic extracts were dried over Na2S04. The solvent
was evaporated. The residue was purified by column chromatography, using a
mixture of heptane and EtOAc (2:1) as elute to give a white solid (0.76 g, 76%). ^H
NMR (CDCI3): 56.7-7.6 (m, Ph. CHPhz). 6.58 (d, 1H. J = 8.9 Hz). 4.20 (m. 1H). 3.99
(s, 2H). 3.10 (dd, 2H, J = 6.9.13.3 Hz), 2.94 (t. 2H. J = 6.7 Hz).
Example 4
Ethyl 4-f3-ri -benzhvdrvl-5-chloro-2-f2-f r(3.4-
dichlorobenzvl)sulfonvnamlno>ethvl)-1H-indol-3-vnpropvl>benzoate
To a solution N-[2-(1-benzhydryl-5-chloro-1H-indol-2-yl)ethyl]-1-(3,4-
dichlorophenyl)-methanesulfonamlde (3.0 g, 5.14 mmol), triethylsllane (1.79 g, 15.4
mmol), and 4-(3-oxopropyl) benzoic acid ethyl ester (1.26 g, 6.16 mmol) in
dichloromethane (30 mL) at -20 to -25 °C was added trifioroacetic acid (2.93 g, 25.7
mmol) during a period of 1 min. The mixture was warmed to -10 °C and stirred for 4
h. Saturated aqueous NaHCOs (20 mL) was added. The mixture was extracted with
EtOAc (150 mL). The organic extract was dried over Na2S04. The solvent is
evaporated. The residue is purified by column chromatography, using a mixture of
heptane and EtOAc (4:1) as elute to give a white solid (2.25 g, 56%). ^H NMR
(CDCI3): 56.9-7.6 (m, Ph, CHPhz), 7.97 (d, 1H, J= 1.6 Hz), 7.41 (d, 1H, J= 1.9 Hz),
6.50 (d. 1H, J = 8.9 Hz). 4.35 (dd, 2H. J= 7.1. 14.3 Hz), 4.13 (m, 1H). 3.92 (s, 2H).
2.95 (m. 2H), 2.71 (m, 6 H), 1.96 (m, 2H), 1.38 (t, 3H, J = 7.1 Hz).
Example 5
4-r3-f5-chloro-2-r2-rrrf3.4'dichlorophenvl)-methvn-su»fonvnamino1ethvn-1-
(diphenvlmethvl>-1H-indoi-3-vnpropvil benzoic acid
A solution of ethyl 4-{3-[1-benzhydryi-5-chloro-2-(2-{[(3.4-
dichlorobenzyl)sulfonyI]-amino}ethyl)-1H-indol-3-yl]propyl}benzoate (0.50 g, 0.65
mmol), LiOH (0.24 g, 10.0 mmol), methanol (5 mL), THF (5 mL) and water (5 mL)
was stinred for 18 h at rt, then diluted with water (200 mL). 1 N HCI (10 mL) was
added. The reaction mixture was extracted with EtOAc (2x50 mL). The organic
extracts were dried over Na2S04. The solvent is evaporated to give a white solid
(0.46 g. 96%). 'H NMR (DMSO.d6): 512.80 (br.s, 1H). 7.89 (d. 2H, J=2Hz), 7.59 (d,
1H, J=1.5Hz), 7.53 (d.lH, J=6Hz), 7.48 (d. 1H, J=1.5Hz), 7.38 (m. 9H). 7.20 (m, 5H).
6.77 (dd. 1H, J=6.9 & 1.5Hz). 6.46 (d. 1H, J=6.9Hz), 4.36 (s, 2H). 3.18 (m.2H), 2.96
(m,2H). 2.76 (m. 4H), 1.90(m. 2H).
Many variations of the present invention not illustrated herein will occur to
those skilled in the art. The present invention is not limited to the embodiments
illustrated and described herein, but encompasses all the subject matter within the
scope of the appended claims.
wherein:
n is an integer in the range of 0-10;
Ri represents a straight or branched C1-C10ali