Note: Descriptions are shown in the official language in which they were submitted.
l~asss6
-1- 64680-307D
This is a divisional application of Serial Number 473,576
filed February 5, 1985 and is directed to intermediates of formulae
(II) and (IV) described hereinafter and useful for the production
of novel compounds of the parent application.
The parent application relates to new chemical compounds
which are of value as new medicinal agents. More particularly
the new chemical compounds are derivatives of 2-oxindole-1-
carboxamide, and they are further substituted at the 3-position
and on the carboxamide nitrogen by an acyl group. These new
chemical compounds are inhibitors of boththe cyclooxygenase (CO)
and lipoxygenase (LO) enzymes.
The compounds of the parent application possess analgesic
activity in mammals, particularly man, and they are useful there-
fore for acute administration for ameliorating or eliminating
pain, such as the pain experienced by patients recovering from
surgery or trauma.
In addition to their usefulness for acute administration
to combat pain, the compounds of the parent application are useful
for chronic administration to mammals, particularly man, to
alleviate the symptoms of chronic diseases, such as the inflam-
mation and pain associated with rheumatoid arthritis and osteo-
arthritis.
In the specification hereinafter, the expression "this
invention" includes both the subject matter of the parent applica-
tion and that of this divisional application.
89556
. _
This invention provides novel 2-oxindole compounds
of the formula
X ~ ,c
y ~ N ~ 0
ODC-NH-~--R
o
and the pharmaceutically-acceptable base salts thereof;
s wherein
X i8 selected from the group consisting of hydrogen,
fluoro, chloro, bromo, alkyl having 1 to 4 carbons,
cycloalkyl having 3 to 7 carbon~, alkoxy having 1 to 4
carbons, alkylthio having 1 to 4 carbons, trifluoro-
methyl, alkylsulfinyl having 1 to 4 carbons, alkyl-
sulfonyl having 1 to 4 carbons, nitro, phenyl, alkanoyl
having 2 to 4 carbons, benzoyl, thenoyl, alkanamido
having 2 to 4 carbons, benzamido and N,N-dialkylsulfamoyl
having 1 to 3 carbons in each of said alkylst and Y i~
- lS selected from the group consisting of hydrogen, fluoro,
chloro, bromo, alkyl having 1 to 4 carbons, cycloalkyl
having 3 to 7 carbons, alkoxy having 1 to 4 carbons,
alkylthio having 1 to 4 carbons and trifluoromethyl;
or X and Y when taken together are a 4,5-, 5,6-
or 6,7-methylenedioxy group or a 4,5-, 5,6- or 6,7-
ethylenedioxy group;
or X and Y when taken together and when attached
to adjacent carbon atoms, form a divalent radical Z,
wherein Z is selected from the group consi~ting of
~ ` ~ 1;~89556
-3-
C ' C ' ~ '
- zl z2 z3
~W_ W_
and
\ \
z4 zS
wherein W is oxygen or sulfur;
Rl i~ selected from the group consisting of alkyl
having l to 6 carbons, cycloalkyl having 3 to 7 carbons,
phenyl, substituted phenyl, phenylalkyl having l to 3
carbons in said alkyl, (substituted phenyl)alkyl
having l to 3 carbons in said alkyl, phenoxyalkyl
having l to 3 carbons in said alkyl, (substituted
- phenoxy)alkyl having l to 3 carbons in said alkyl,
naphthyl and -lCH2)n-Q-R ;
wherein the substituent on said substituted
phenyl, said (substituted phenyl)alkyl and said
(substituted phenoxy)alkyl is selected from the group
consisting of fluoro, chloro, alkyl having 1 to 3
carbons, alkoxy having l to 3 carbons and trifluoro-
methyl; n 18 zero, l or 27 Q is a divalent radical
derived from a compound selected from the group
consisting of furan, thiophene, pyrrole, thiazole,
isothiazole, oxazole, isoxazole, 1,2,3-thiadiazole,
l,2,5-thiadiazole, tetrahydrofuran, tetrahydrothiophene,
pyridine, pyrimidine, pyrazine, benzolblfuran and
benzolb]thiophene; and R is hydrogen or alkyl having
l to 3 carbons;
'~ s~ --
and R2 is selected from the group consisting of
alkyl having 1 to 6 carbons, cycloalkyl having 3 to 7
carbons, phenoxymethyl, furyl, thienyl, pyridyl and
R3
~ R4
wherein R3 and R4 are each selected from the group
consisting of hydrogen, fluoro, chloro, alkyl having 1
to 4 carbons, alkoxy having 1 to 4 carbons and tri-
fluoromethyl.
Said compounds of formula I are active as analgesic
agents, and a~ agents for treating inflammatory diseases,
such as the arthritides. Accordingly this invention
also provides a method of eliciting an analgesic response
in a mammalian subject, especially man a method of
treating an inflammatory disease in a mammalian subject,
especially man; and pharmaceutical compositions comprising
a compound of formula I and a pharmaceutically-acceptable
carrier.
A first preferred group of compounds of this
invention consists of the compounds of formula I,
wherein X and Y are each hydrogen and Rl is selected
from the group consisting of 2-furyl, 2-thienyl and (2-
thienyl)methyl. Among this first preferred group,
particularly preferred compounds are those wherein R
is phenyl.
A second preferred group of compounds of this
invention consists of the compounds of formula I,
wherein X is 5-chloro, Y is hydrogen and Rl i9 selected
from the group consisting of 2-furyl, 2-thienyl and
(2-thienyl)methyl. Among thi8 second preferred group,
particularly preferred compounds are tho8e wherein R2
is cyclohexyl.
Especially preferred individual compounds of the
invention are:
N-benzoyl-3-(2-furoyl)-2-oxindole-1-carboxamide
(I:X is hydrogen Y is hydrogen; Rl is 2-furyl; R2 is
phenyl) and
N-cyclohexylcarbonyl-5-chloro-3-(2-thenoyl)-2-
~10 oxindole-l-carboxamide (I:X is 5-chloro; Y is hydrogen;
Rl is 2-thienyl; R2 is cyclohexyl).
Yet further thi8 invention provides novel com-
pounds Of the formula
X ~ N ~ O ---(II)
OzC-NH-C-R
wherein X, Y and R2 are as defined previously. The
compounds of formula II are useful as intermediates to
the compounds of formula I.
Also useful as intermediates to the compounds of
the formula I are the compounds of the formula
~ ~0 ---(IV)
556
-5a-
and the base salts thereof, wherein X, Y and Rl are
as defined previously. A preferred sub-group of
compounds of the formula IV consists of those compounds
in which X is hydrogen, 5-fluoro or 5-chloro; Y is
hydrogen, 6-fluoro or 6-chloro; and Rl is benzyl,
furyl, thienyl or thienylmethyl; provided that when X
and Y are both hydrogen, Rl is not benzyl. The
compounds of formula IV in said latter preferred sub-
group are novel, and as such they form part of this
invention.
The analgesic and antiinflammatory compounds of
this invention are the compounds of formula I, wherein
X, Y, Rl and R2 are as defined previously. Thus, the
compounds of this invention are derivatives of 2-
oxindole, the bicyclic amide of the formula
895~fi
--6--
More particularly, the analgesic and antiinflammatory
agents of this invention have an N-acylcarboxamido
substituent, -C(=O)-NH-C(=O)-~2, at the l-position and
an acyl substituent, -C(=O)-Rl, at the 3-position of
2-oxindole, and the benzo ring can be further substi-
tuted by X and Y groups. X and Y can be certain
monovalent substituents as defined previously, or X
and Y when on adjacent carbon atoms on the benzo ring
can represent a methylenedioxy group, -OCH2O-, or
ethylenedioxy group, -OCH2CH2O-. Yet further, X and
Y, when they are attached to adjacent carbon atoms of
the benzo ring of the 2-oxindole, can form a divalent
unit, Z, such that when Z is taken with the carbon
atoms to which it is attached it forms a fused carbo-
lS cyclic or heterocyclic ring. Certain divalent groupsfor Z (i.e. zl_Z5) have been listed earlier. Thus,
when Z is zl, X and Y when taken with the carbons to
which they are attached represent a fused cyclopentene
ring; and when Z is Z5, X and Y when taken with the
carbons to which they are attached represent a fused
furan or thiophene ring. Moreover, it is to be
understood that when Z is Z4 or Z5, the Z group can be
_ attached in either of two possible ways. Thus, for
example, when X and Y are at C-5 and c-6 and they are
Z , the formula I embraces both of the following
formulae:
01
~-R
O=C-NH-C-R
o
~89556
Rl
O-C-NH-Il-R
.
Additionally, as will be appreciated by one
skilled in the art, the analgesic and anti-inflammatory
compounds of this invention of formula I, wherein X, Y,
Rl and R2 are defined previously, are capable of
enolization, and therefore they can exist in one or
more tautomeric (enolic) forms. All such tautomeric
(enolic) forms of the compounds of formula I are
considered to be within the scope of this invention.
The compounds of formula I are prepared from the
appropriate 2-oxindole compound of the formula
K ~ 1 o ---(III)
H
wherein X and Y are as defined previously. This is
accomplished by attaching the substituent -C(sO)-
NH-C(=O)-R2 to the l-position and the substituent
-C(~O)-Rl to the 3-position. These substituents can be
attached in either order, and~this leads to two vari-
ations in the method for making the compounds of
formula I, as ~hown in the Scheme.
1~895~6
., --8--
SCHEME
X~,_,
y ~N~)
~ III )
/
IE y ~ O
OnC--NH-C-R2
( IV ) ( I I )
~C--Rl
O~C-NH-~-R2
. (I)
Thus the first variation involves the sequence:
compound III to compound IV to compound I, while the
second varlation involves the qequence: compound III
S to compound II to compound I.
~ 895S~i --
~ he -Cl=0)-NH-C(~0)-R2 group is attached by
reacting a compound of the formula III or a compound
of the formula IV with an acyl isocyanate of the
formula R2-C(50)-N=C-O. Most commonly, the reaction
5 i8 carried out by contacting substantially equimolar
quantities of the reactants in an inert solvent at a
temperature in the range from 50 to 150C., and
preferably from 100 to 130C. In this context an
inert solvent is one which will dissolve at least one
of the reactants, and which does not adversely interact
with either of the reactants or the product. Typical
solvents which can be used include aliphatic hydro-
carbons, such as octane, nonane, decane and decalin:
aromatic hydrocarbons, such as benzene, chlorobenzene,
lS toluene, xylenes and tetralin; chlorinated hydrocarbons,
such as 1,2-dichloroethane; ethers, such as tetra-
hydrofuran, dioxane, 1,2-dimethoxyethane and di(2-
methoxyethyl)ether; and polar, aprotic solvents such
ag N,N-dimethylformamide, N,N-dimethylacetamide, N-
methylpyrrolidone and dimethyl sulfoxide. The reactiontime varies according to the reaction temperature, but
at a temperature from 100 to 130C , reaction times of
- a few hourc, e.g., 5 to 10 hours are commonly used.
When a relatively non-polar reaction solvent is
used for the reaction of a compound of formula III or
IV with an acyl isocyanate of formula R2-C(=0)-N-C~0,
the product (I or II) i8 usually out of solution at
the end of the reaction when the reaction mixture is
cooled to room temperture. Under these circumstances
the product is usually recovered by filtration.
~owever, if relatively polar solvents are used and the
product is not out of solution at the end of the
reaction, the product can be recovered by solvent
evaporation or, in the case of water-miscible solvents,
~895~
--10--
by dilution of the reaction medium with water. This
causes the product to precipitate and again it can
be recovered by filtrat$on. The reaction product (I
or II) can be purified by standard methods, e.g.,
S recrystallization.
The reaction between a compound of formula ~V
and an acyl isocyanate of formula R2-C( 80 )-N-CSO can
be speeded up by the addition of a base, such as a
tertiary amine, e.g., trimethylamine, triethylamine,
tributylamine, N-methylpiperidine, N-methylmorpholine
or N,N-dimethylaniline. From about one to about four
equivalents of the basic agent is usually added, and
this permits the use of reaction temperature from 20
to 50C. At the end of the reaction, the reaction
medium must be neutralized (or made acidic) and then
the product is isolated as described earlier.
The -C(-O)-Rl side-chain can be attached to a
compound of the formula II by reaction with an activated
derivative of a carboxylic acid of the formula Rl-
C(~OlOH. The reaction is carried out by treating saidcompound of formula II in an inert solvent with one
molar equivalent, or a slight exce~s, of an activated
~ derivative of a compound of formula Rl-C(-O)OH, in the
presence of from one to four equivalents of a basic
agent. An inert solvent is one which will dissolve at
least one of the reactants, and will not adversely
interact with either of the reactants or the product.
However, in practice, a polar, aprotic solvent, such
as N,N-dimethylformamide, N,N-dimethylacetamide, N-
methylpyrrolidone or dimethyl sulfoxide, is commonlyused. Conventional methods for activating the acid of
formula Rl-C~O)OH are used. For example, acid
halides, e.g., acid chlorides; symmetrical acid
1289556
anhydrides, Rl-C~=O)-O-Ct=O)-Rl mixed acid anhydrides
with a hindered low-molecular weight carboxylic acid,
R -C(=o)-o-C~=o)-R5, where R5 is a bul~y lower-al~yl
group such as t-butyl; and mixed carboxylic-carbonic
S anhydrides, Rl-C(=O)-O-C~-O)-OR6, wherein R5 is a
lower-alkyl group, can all be used. In addition, N-
hydroxyimide esters (such as N-hydroxysuccinimide and
N-hydroxyphthalimide esters), 4-nitrophenyl esters,
thiol esters ~such as thiol phenyl esters) and 2,4,5-
trichlorophenyl e~ters, and the like, can be used.
A wide variety of basic agents can be used in thereaction between a compound of formula II and the
activated derivative of the acid of the formula Rl-
C(~O)OH. However, preferred basic agents are tertiary
amines, such as trimethylamine, triethylamine, tri-
butylamine, N-methylmorpholine, N-methylpiperidine and
4-(N,N-dimethylamino)pyridine.
The reaction between a compound of the formula II
and thé activated derivative of the acid of formula
Rl-C(-O)-OH is usually carried out in the temperature
range from -10 to 25C. Reaction times of from ~0
minutes to a few hours are common. At the end of the
~ reaction, the reaction medium is usually diluted with
water and acidified, and then the product can be
recovered by filtration. It can be purified by
standard methods, such as recrystallizatlon.
The -C(~O)-Rl side-chain can be attached to a
compound of the formula III by reaction w-th a derivative
of the appropriate acid of the formula Rl-C(=O)-OH,
in a lower-alkanol solvent (e.g. ethanol), in the
presence of an alkali metal salt of the lower-alkanol
solvent (e.g. sodium ethoxide), according to standard
procedures. Typical derivatives of the acid of the
~ 12~95S6 ~
formula Rl-C(=O)OH which can be used include acid
chlorides, acid anhydrides of the formula Rl-C(=O)-O-
c(=o)-Rl Rl-C(=o)-o-C(=o)-R5 and Rl-c(=o)-o-c(=o)-OR ,
and simple alkyl esters of the formula Rl-C(=O)-OR6,
wherein R5 and R6 are as defined previously. Usually,
a small excess of the derivative of the acid of
formula Rl-C(=O)-OH is used, and the alkoxide salt is
usually present in an amount from one to two molar
equivalents, based on said derivative of the acid of
formula Rl-C(=O)OH. The reaction between the derivative
of the acid of the formula Rl-C(=O)OH and the compound
of formula III is usually started at 0 to 25C., but
it is then usual to heat the reaction mixture at a
temperature in the range from 50 to 130C., and
preferably at about 80C., to complete the reaction.
Under these circumstances, reaction times of a few
hours, e.g. two hours, up to a few days, e.g., two
days, are commonly used. The reaction mixture is then
cooled, diluted with an excess of water, and acidified.
The product of formula IV can then be recovered by
filtration or by the standard procedure of solvent
extraction.
The acyl isocyanates of the formula R2-C(=O)-
N=C=O which are known can be prepared by the published
procedures. Those which are analogs of known compounds
can be prepared by analogous procedures. In general,
the corresponding amide of the formula R2-C(=O)-NH2
reacts with oxalyl chloride, or the acid chloride of
formula R2-C(=O)-Cl reacts with silver cyanate.
Consult: Speziale et al., Journal of Organic Chemistry,
28, 1805 (1963) and 30, 4306 (1965); Ramirez et al.,
Journal of Orqanic Chemistry, 34, 376 (1969); and
1~8~556
-13-
Naito et al., Journal of Antibiotics (Japan), 18, 145
~1965).
The 2-oxindole compounds of formula III are
prepared by known methods, or methods analogous to
known methods. Consult: ~Rodd's Chemistry of Carbon
Compounds,~ Second Edition, S. Coffey editor, Volume
IV Part A, Elsevier Scientific Publishing Company,
1973, pp. 448-450; Gassman et al., Journal of Oraanic
Chemistry, 42, 1340 (1977); Wright et al., Journal of
the American Chemical SocietY, 78, 221 (1956); Beckett
et al., Tetrahedron, 24, 6093 (1968); United States
Patents Nos. 3,882,236, 4,006,161 and 4,160,032;
Walker, Journal of the American Chemical Society, 77,
3844 (1955); Protiva et al., Collection of Czechoslovakian
Chem$cal Communications, 44, 2108 (1979); McEvoy et al.,
Journal of Or~anic Chemistrv, 38, 3350 (1973); Simet,
Journal of Orqanic ChemistrY, 28, 3580 tl963);
Wieland et al., Chemische Berichte, 96, 253 (1963);
and references cited therein.
The compounds of the formula I are acidic and
they form base salts. All such base salts are within
the scope of this invention and they can be prepared
~ by conventional methods. For example, they can be
prepared simply by contacting the acidic and basic
entities, usually in a stoichiometric ratio, in either
an aqueous, non-aqueous or partially aqueous medium,
as appropriate. The salt~ are recovered either by
filtration, by precipitation with a non-solvent
followed by filtration, by evaporation of the solvent,
as appropriate, or, in the case of aqueous solutions,
by lyophilization. Typical salts of the compounds of
formula I which can be prepared are primary, secondary
`~ 8~556
-14-
and tertiary amine salts, alkali metal salts and
alkaline earth metal salts. Especially valuable are
the ethanolamine, diethanolamine and triethanolamine
salts.
~asic agents suitably employed in salt formation
belong to both the organic and inorganic types, and
they include organic amines, al~ali metal hydroxides,
alkali metal carbonates, alkali metal bicarbonates,
al~ali metal hydrides, alkali metal alkoxides, alkaline
earth metal hydroxides, alkaline earth metal carbonates,
alkaline earth metal hydrides and alkaline earth metal
alkoxides. Representative examples of such bases are
primary amines, such as n-propylamine, n-butylamine,
aniline, cyclohexylamine, benzylamine, ~-toluidine,
ethanolamine and glucamine; secondary amines, such as
diethylamine, diethanolamine, N-methylqlucamine, N-
methylaniline, morpholine, pyrrolidine and piperidine;
tertiary amines, such as triethylaminq, triethanol-
amine, N,N-dimethylaniline, N-ethylpiperidine and N-
methylmorpholine; hydroxides, such as sodium hydroxide;
al~oxides, such as sodium ethoxide and potassium
methoxide; hydrides, such as calcium hydride and
sodium hydride; and carbonates, such as potassium
carbonate and sodium carbonate.
The compounds of formula I possess analgesic
activity. This activity has been demonstrated in mice
by showing blockade of the abdominal stretching
induced by administration of 2-phenyl-1,4-benzoquinone
(PBQ). The method used was based on that of Siegmund
et al., Proc. Soc. Exp. Biol. Med., 95: 729-731,
1957, as adapted for high throughput (see further
Milne and Twomey, ents and Actions, 10: 31-37,
1~8955g~
-15-
.,
1980). The mice used in these experiments were
Carworth males, albino CF-l strain, weighing 18-20 g.
All mice were fasted overnight prior to drug adminis-
tration and testing.
The compounds of formula I were dissolved or
suspended in a vehicle consisting of ethanol (5%),
emulphor 620 (a mixture of polyoxyethylene fatty acid
esters, 5%) and saline (90%). This vehicle also
served as control. Doses were on a logarithmic scale
(i.e., ... 0.32, 1.0, 3.2, 10, 32... mg/~g), and were
calculated from weights of the salt when applicable,
and not of the acid. The route of administration was
oral, with concentrations varied to allow a constant
dosage volume of 10 ml/kg of body weight. The afore-
said method of Milne and Twomey was used to determine
efficacy and potency. Mice were treated with com-
pounds orally, and one hour later received PBQ, 2
mg~kg, intraperitoneally. Individual mice were then
lmmediately placed in a warmed ~ucite (transparent
plastic) chamber, and, starting five minutes after
PBQ administration, the number of abdominal constrictions
during the subsequent 5 minutes was recorded. The
~ degree of analgesic protection (% MPE) was calculated
on the basis of suppression of abdominal constriction
relative to counts from concurrent control animals
run on the same day. At least four such determinations
(N > S) provided dose-response data for generation of
an MPE50, the best estimate of the dose that reduces
abdominal constriction to 50% of control levels.
The compounds of formula I also posses~ anti-
inflammatory activity. This activity has been demonstrated
in rats by a method based on the standard carrageenin-
induced rat-foot edema test. (Winter et al., Proc.
Soc. Exp. Biol. Med., 111: 544, 1963).
556
-16-
~ nanesthetized, adult, male, albino rats of 150 g
to 190 g body weight were numbered, weighed, and an
ink mark placed on the right lateral malleolus. Each
paw was immersed in mercury exactly to the ink mark.
The mercury was contained in a glass cylinder, connected
to a Statham Pressure Transducer. The output from the
transducer was fed through a control unit to a micro-
voltameter. The volume of mercury displaced by the
immersed paw was read. Drugs were given by gavage.
One hour after drug administration, edema was induced
by injection of 0.05 ml of 1% solution of carrageenin
into the plantar tissue of the marked paws. Immediately
thereafter, the volume of the injected foot was
measured. The increase in foot volume 3 hours after
the injection of carrageenin constitutes the individual
inflammatory response.
The analgesic activity of the compounds of
formula I makes them useful for acute adm~nistration
to mammals for the control of pain, e.g., post-operative
pain and the pain of trauma. Additionally the compounds
of formula I are useful for chronic administration to
mammals for the alleviation of the symptoms of chronic
diseases, such as the inflammation of rheumatoid
arthritis, and the pain associated with osteoarthritis
and other musculoskeletal disorders.
When a compound of the formula I or a pharma-
ceutically acceptable salt thereof is to be used as
either an analgesic agent or an anti-inflammatory
agent, it can be administered to a mammalian subject
either alone, or, preferably, in combination with
pharmaceutically-acceptable carriers or diluents in a
pharmaceutical composition, according to standard
pharmaceutical practice. A compound can be administered
.
1~8~556
orally or parenterally. Parenteral administration
includes intravenous, intramuscular, intraperitoneal,
subcutaneous and topical administration.
In a pharmaceutical composition comprising a
compound of formula I, or a pharmaceutically-acceptable
salt thereof, the weight ratio of carrier to active
ingredient will normally be in the range from 1:4 to
4:1, and preferably 1:2 to 2:1. However, $n any given
case, the.ratio chosen will depend on such factors as
the solubility of the active component, the dosage
contemplated and the precise route of administration.
For oral use of a compound of formula I of this
$nvention, the compound can be administered, for
example, in the form of tablets or capsules, or as an
aqueous solution or suspension. In the case of
tablets for oral use, carriers which are commonly used
include lactose and corn starch, and lubricating
agents, such as magnesium stearate, are commonly
added. For oral administration in capsule form,
useful diluents are lactose and dried corn starch.
When aqueous suspensions are required for oral use,
the active ingredient is co~bined with emulsifiying
and suspending agents. If desired, certain sweetening
and/or flavoring agents can be added. For intramuscular,
intraperitoneal, subcutaneous and intravenous use,
sterile solutions of the active ingredient are usually
prepared, and the pH of the solutions should be
suitably adjusted and buffered. For intravenous use,
the total concentration of solutes should be controlled
to render the preparation isotonic.
When a compound of formula I or salt thereof is
used in a human subject, the daily dosage will normally
be determined by the prescribing physician. Moreover,
1~89556
-18-
the dosage will vary according to the age, weight and
response of the individual patient, as well as the
severity of the patient's symptoms and the potency of
the particular compound being administered. However,
for acute administration to relieve pain, an effective
analgesic response eliciting dose in most instances
will be 0.1 to 1.0 g as needed (e.g., every four to
six hours). For chronic administration to alleviate
(treat) inflammation and pain, in most instances an
effective dose will be from 0.5 to 3.0 g per day, and
preferably 0.5 to 1.5 g per day, in single or divided
doses. On the other hand, it may be necessary to use
dosages outside these limits in some cases.
The following examples and preparations are being
provided solely for the purpose of further illustration.
1~8955~ --
--19--
EXAMPLE 1
N-Benzoyl-3-~2-furoyl)-2-oxindolc-1-
carboxamide
=~
A mixture of 909 mg ~4.0 mmole) of 3-(2-furoyl)-
2-oxindole and 706 mg (4.8 mmole) of benzoyl iso-
! cyanate in 25 ml of toluene was heated to reflux and
then it was heated at reflux temperature for 7 hours.
The mixture was allowed to stand at room temperature
overnight and then the precipitate which had formed
wa~ removed by filtration, giving 1.3 g of crude
product. The crude product was recrystallized from ca
30 ml of acetic acid, giving 920 mg of the title
compound, mp 184C (dec).
Analvsis: Calcd. for C21H14O5N2: C, 67.37; H, 3.77;
N, 7.49~. Found- C, 66.90; H, 4.02; N, 7.38%.
1;~895~6
-20-
EXAMPLE 2
N-Benzoyl-3-(2-furoyl)-2-oxindole-1-
carboxamide
To 30 ml of N,N-dimethylformamide was added,
with stirring, 2.8 g (10 mmole) of N-benzoyl-2-
oxindole-l-carboxamide, followed by 2.9 g 124 mmole)
of 4-(N,N-dimethylamino)pyridine. The mixture was
cooled in an ~ce-bath and then to it was added,
dropwise, with stirring, during 10 minutes, a solution
of 1.6 g (12 mmole) of 2-furoyl chloride in 10 ml of
N,N-dimethylformamide. Stirring was continued for 30
minutes and then the reaction mixture was poured into
a mixture prepared from 250 ml of water and 8.5 ml of
3N hydrochloric acid. The resulting mixture was
cooled in an ice-bath and the solid was removed by
filtration. The solid was recrystallized from ca. 75
ml of acetic acid to give 2.94 g of the title compound
as yellow-brown crystals, mp 190C.
The ultraviolet spectrum of the title compound
~howed absorptions as follows:
SolventWavelenqth Epsilon
(nanometers)
C~30H 245 6,920
375 2,530
CH OH + 1 drop 249 7,200
0.~N NaOH 372 2,710
C~ OH ~ 1 drop 241 9,070
0.~N HCl
89556
-21-
EXAMPLE 3
N-~enzoyl-3-acetyl-2-oxindole-
l-carboxamide
To a stirred slurry of 841 mg (3.0 mmole) of N-
benzoyl-2-oxindole-1-carboxamide in 5 ml of N,N-
dimethylformamide was added 806 mg (6.6 mmole) of 4-
(N,N-dimethylamino)pyridine. Stirring was continued
for a few minutes, and then the slurry was cooled in
an ice-bath and a solution of 337 mg ~3.3 mmole) of
acetic anhydride in 2 ml of N,N-dimethylformamide was
added dropwise. Stirring was continued for 1 hour,
and then the reaction mixture was poured onto a
mixture of 65-70 ml. of ice-water and 2.2 ml of 3N
hydrochloric acid. The solid which precipitated was
lS recovered by filtration. It was recrystallized from
cthanol to give 385 mg of the title compound as tan
crystals, mp 198C.
Analysis Calcd. for C18H14O4N2:
C, 67.07; H, 4.38; N, 8.69%.
- 20 Found: C, 66.78; H, 4.65; N, 8.62%.
5S6
-22-
EXAMPLE 4
N-Benzoyl-3-l2-thenoyl)-2-oxindole-1-
carboxamide
To a stirred solution of 486 mg ~2.0 mmole) of
3-~2-thenoyl)-2-oxindole and 445 mg (4.4 mmole) of
triethylamine in 5 ml of dimethyl sulfoxide was added
324 mg (2.2 mmole) of benzoyl isocyanate. Stirring
wa~ continued for 1 hour, and then the mixture was
poured into a mixture of 50 ml of water and 1.7 ml of
3N hydrochloric acid. The resulting mixture was
cooled in an ice-bath and the solid was removed by
filtration. The solid was recrystallized from ca. 30
ml of 2:1 ethanol:water to give 190 mg of the title
compound as fluffy, yellow crystals, mp 165-166C.
(dec).
AnalYsi5: Calcd. for C21H1404N2S c~ 64-60; H~
3.615 N, 7.18~. Found: C, 64.53; H, 3.75; N, 7.10~.
EXAMPLE 5
Reaction of the appropriate N-substituted-2-
oxindole-l-carboxamide with the requisite acid
chloride of the formula Rl-CO-Cl, substantially
according to the procedure of Example 2, afforded the
following compounds:
X ~-Rl
O=C-NH-ICl-R2
o
SS6
--23--
_ ._ O
_ ~ ~ U~ ~ ~ _ t` ~ U~ ~
Z . ...
I~
1: Il'~~ _ ~N ~I` ~~:1 0 1`~
~ ~` O~ ~ ~~O ~ ~ ~ CO 0 0
~3: ~
~ ~ ~ o ~ _ I~
Uu~ ~ o
r oa~
.U7
_
~1
~ ~ u~ a~ co1~r~ ~u~ o o
_ o~ ~ ~ O ~ I` U
~¢ Z . . . . . . . . . -
~1 _ ~ O Q~r Oa~ O ~ ~ D
1~ ~ocn ~ o ~ ~ o
_:~ . . . . .
~ ~ ~ r~
O
n~ O1'1 O ~rt O ~ I~ O ~ ~
U
C~
~ _ ~ o ~ r o ~ cn
C ~ O
_ ~ o
~ C ~ _
O o 1~ W ~D O 1'~ 0 ~ ~ 1
O ~ O ~ O ~ O--1 0 _ O _~
. C: C C C C ~1 ~
2: C~ U X U X U X U X U X U X
S C S S S ~ ~
.p~ t) s u s u s u s u s u s
_ ~ _
~1 _I ~1 _
:b C ~ c ~c ~ C
0~C ~ _~ C
~~ S >~)~ ''I S ~ ~ S ~ S :~
,C J~ C :1 C ~ S :~ S J~ S :~ S ~ S
N --6 ~ ~`1 --E ~`1~ --E ~ ~ E
X ~ U C~
u~
1;~8~55~S
--24--
I` o co ~ u~
0~ ~D ~ O O 11-1 N C~
Z . - - - - - - ~U
I~
C ~ u~ C
O ~ ~ o o ~ ~ O
O-~ 11'1
~r ~ ~ ~ ~eo o ~ o~
~ ~ O
11~ ~ o ~ o E
_l ~ O
Il~ t~
:~ _
.
_ ~o ~ _I ~Cr~ ~ ~o o 1` 1`
~: a~
~C Z.. ... .. , .. . .
~` ~`I` t` ~D 'D ~ r~ r' r` r` ~o
~ _ 3
U ~ O ~ o ~ I` ~ ~
~ ,, ~~ ~ ~ u~~ O ~ ~ a
,1 ~ .. . .. . . . . . .
In ~U~ ~ ~ ~ ~r ~~ ~ ~ ~ _
U . E
~1 O O0 01 ~.0 ~r N ~0 O a~
~r w~r u~ 1~1 ~ It~ ~o ~o ~o ~ ~ ~
. . - - - - - C
~ _I N et~ ~0 1~ ~O _I 1~ Y ~ 1~1
~ U~
U~ ~
If~ N ~ t)
~ C -- u~ I E
_~ ~ U N I I I I O
0 0 0 ~ I 0 11
_ o t~ a~ o o 11
N ~ N
a
N _~
~ '' ~ ~ '' ~ ~ 2 ~ ~ ~ 8
N ~ JJ C
~: .a .a .a ~ .q ~ o o o o o o ~n o ~
t) U O
. ~J ~a E
~ O U
_~ ~ C ~ C ~ C ~. C ~
~ ~ c ~ rl c O _ C ~ 3
r1 S ~ rl S ~ 01-~
S ~ S :~ S ~ C ::1 S ~ S ~ S ~J S ~ 3 N O
I ~ ~ ~ I V ~ ~ I ~ ~ ~ I Y C ~ ~ S
I I N Cl I I N ~ I I N O I I N
N t`~ -- E N N -- E N N -- E N N -- E O S _. rl
O~ 1 3
E O J~
~ 0 01 '~1
X U U ~ U ~ U ~ ~1 0
, , o ~ a
~: C ~ ~r
,_1 N ~'7
` - -
1~8~55~
-25-
EXAMPLE 6
N-Benzoyl-3-(2-thenoyl)-2-oxindole-1-carboxamide
was also prepared by reaction of 3-(2-ther.oyl)-2-
oxindole with benzoyl i~ocyanate u~ing the method of
Example 1.
N-Ben.zoyl-3-(2-12-thienyl]acetyl)-2-oxindole-1-
carboxamide was prepared by reaction of 3-(2-[2-
thienyl]acetyl)-2-oxindole with benzoyl isocyanate
u~ing the method of Example 1.
EXAMPLE 7
Following the method of Example 1 (Method A),
Example 2 or 3 (Method B), or Example 4 IMethod C),
the following compounds were made:
X ~-Rl
N
o-C-NH--C--R2
. ~
1~89556
-26-
Method Melting
1 2 of Prepl Poin~
X R R aration ~C)
H methyl phenyl A,B 198-200d
H isopropylphenyl ~ 165d
- ~ cyclohexylphenyl B 181d
S~5-Cl methyl phenyl B 215-217d
~S-Cl isopropyl phenyl B 185.5-
187.5d
5-Cl cyclohexylphenyl B 192-194d
H phenoxymethyl phenyl A 202d
H 3-furyl phenyl C 187d
; S-Cl cyclopropyl phenyl B 213-215d
H cyclopropyl phenyl B 173d
i~opropyl phenyl B 165d
H l-phenylethyl phenyl B 173d
5-Cl benzyl phenyl B 239-240d
lS 5-CH3 2-furyl phenyl B 204-205d
(3-thienyl)-
methyl phenyl B 195-lg7d
6-C1 2-thienylphenyl 8 192-193d
6-F 2-furyl phenyl B 189-190
6-F 2-thienylphenyl B 190-194
20 S-Cl S-ethyl-2-
furyl phenyl B 202-203.5d
H S-ethyl-2-
furyl phenyl B 174-175
5-F 2-furyl phenyl B 172d
5-F (2-thienyl)-
methyl phenyl B 189d
'6-C1 2-furyl phenyl B 199-200
5-F (2-thienyl)-
methyl phenyl B 167d
~-Cl (2-thienyl)-
methyl phenyl B 199-200d
~89556
-27-
Method Melting
, of Prep- Poin~
X R' . . R2 arationl (C)'
H 2-thienyl 4-fluoro- C 163.5-
phenyl 164.5d
2-furyl 4-fluoro- C 164.Sd
phenyl
H . methyl 4-fluoro- A 205-207d
phenyl
~ benzyl 4-fluoro- ~ 207-209d
phenyl
H cyclopropyl 4-fluoro- B 167.5d
phenyl
(2-thienyl)- 4-fluoro-
methyl phenyl A 216-217d
5-CH3 2-thienyl 4-fluoro- B 178-179d
phenyl
S-Cl 2-furyl 4-fluoro- B 197-199d
phenyl
10S-CH3 2-furyl 4-fluoro- B 179-181d
phenyl
5-C1 2-thienyl 4-fluoro- B 191.5-
phenyl 192.5d
H 12-thienyl)- 4-methoxy-
methyl phe4yl A 197-198d
- ~ 2-thienyl 4-methoxy- B 173d
phenyl
2-furyl 4-methoxy- B 146d
phenyl
H cyclopropyl 4-methoxy- B 193d
phenyl
H isopropyl 4-methoxy- B 125d
phenyl
2-furyl 4-chloro- B 180-181d
phenyl
H 2-thienyl 4-chloro- B 170-17ld
phenyl
H isopropyl 4-chloro- B 164-165d
phenyl
H propyl 4-chloro- B 184-185d
2-thienyl 2-methyl- B 173.5d
phenyl
1~8~5~ --
-28-
Method Melting
1 2 of Prepl Poin~
X R R aration (C)
H 2-furyl 2-methyl- B 167-168d
phenyl
R (2-thienyl)- 2-methyl-
methyl phenyl B 179.5d
~ cyclopropyl cyclohexyl B 153-154d
H methyl cyclohexyl B 167-168d
l-phenylethyl cyclohexyl B l9ld
H 5-methyl-2-
furyl cyclohexyl B 163-165d
S-Cl S-methyl-2-
furyl cyclohexyl B 197.Sd
5-Cl methyl cyclohexyl B 214.Sd
S-Cl propyl cyclohexyl B 162-163d
5-Cl isopropyl cyclohexyl B 205-206d
S-CH3 2-furyl cyclohexyl B 170-171
S-CH3 2-thienyl cyclohexyl B 153-154.Sd
H 5-ethyl-2-
. furyl cyclohexyl B 146-147
lS S-CH3 S-ethyl-2-
furyl cyclohexyl B 190-191
5-C~3 (2-th~enyl)-
- methyl cyclohexyl B 158-lS9
5-Cl S-ethyl-2-
furyl cyclohexyl B 210-211d
6-C1 2-furyl cyclohexyl B 183-184
S-F 2-furyl cyclohexyl B 186.5-
187.Sd
S-F 2-thienyl cyclohexyl B 145 5-
S-F (2-thienyl)-
methyl cyclohexyl B 164-165
39556
' -29- .
Method Melting
1 ~of Prep- Poin~
X R R~arationl ~C)~
6-C1 2-thienyl cyclohexyl B 172-173
6-Cl (2-thienyl)-
methyl cyclohexyl B 173-175d
4-C1 2-thienyl cyclohexyl B 189-190
S 4-Cl t2-th$enyl)-
methyl cyclohexyl B 172-173
4-Cl methyl cyclohexyl B 131-132
S-CF3 2-fUrYl cyclohexyl B 194-195d
5-CF3 2-thienyl cyclohexyl B 171-172d
6-F 2-furyl cyclohexyl B 164-166
6-F 2-thienyl cyclohexyl B
5-C~3 2-thienyl t-butyl B 189.5d
S-CH3 Methyl t-butyl B 194d
S-Cl methyl t-butyl B 211.5d
S-CH S-ethyl-2-
3 furyl t-butyl B 214-215
5-C1 5-ethyl-2-
furyl t-butyl 8 224-225
5-F 2-furyl t-butyl B 212.5d
S-F 2-thienyl t-butyl B 183.Sd
- S-F l2-thienyl)-
methyl t-butyl B 161d
6-C1 2-thienyl t-butyl B 191-192
S-C~3 2-thienyl isopropyl B 146-147d
5-C~3 2-furYl isopropyl B 166-167d
5-CH3 phenoxymethyl isopropyl B 184-186
5-Cl phenoxymethyl isopropyl B 186-188d
S-Cl benzyl isopropyl B 184-185
5-Cl cyclohexyl isopropyl B 206-208d
5-CH 5-methyl-2-
3 furyl isopropyl B 194d
5-C~3 methyl isopropyl B 158-159
556
-30-
Method Melting
1 2 of Prep- Poin~
X R R arationl (C)
5-C1 5-methyl-2- isopropyl B 198.5-
furyl 199.5
5-Cl methyl isopropyl B 215-216
~ methyl isopropyl B 170-172
h cyclohexyl isopropyl B 188-189
8 benzyl isopropyl B 145-146
B phenoxymethyl isopropyl B 157-158
S-Cl 5-ethyl-2-
furyl isopropyl 8 20g-211d
5-Cl isopropyl isopropyl B 142-143
6-C1 2-furyl isopropyl B 184-185d
6-Cl. 2-thienyl isopropyl B 174.5-175
6-Cl (2-thienyl)-
methyl isopropyl B 157-158d
8 2-thienyl phenoxy- B 161-162
methyl
S-Cl 2-thienyl phenoxy- B 182-183
. methyl
8 2-furyl phenoxy- ~ 173-175d
methyl
B 12-thienyl)- phenoxy-
_ methyl methyl B 193-194
S-Cl 2-furyl phenoxy- B 194-195.5
methyl
lThe letter A in this column indicates that the compound
was p~epared substantially according to Example 1~ the
letter B indicates that the compound wa~ prepared
substantially according to Example 2 or 3; and the
letter C indicates that the compound was prepared
substant$ally according to Example 4.
2The letter "d" indicates that the compound melted
with decomposition.
-31-
EXAMPLE 8
Ethanolamine Salt of N-Benzoyl-3-(2-furoyl)-
_ _ __ 2-oxindole-1-carboxamide
To a slurry of 562 mg (1.5 mmole) of N-benzoyl-
3-(2-furoyl)-2-oxindole-1-carboxamide in 10 ml of
methanol was added 101 mg (1.65 mmole) of ethanolamine.
The re~ulting mixture was heated to boiling for a few
minutes and then it was allowed to cool. The solid
which precipitated was reco~ered by f~ltration to
give 524 mg of the title salt, mp 165-166C. Yield:
80%.
AnalYsis: Calcd. for C23H21O6N3: C, 63.44; H, 4.86;
N, 9.65%. Found: C, 63.27; H~ 4.95; N, 9.58%.
EXAMPLE 9
The diethanolamine salt of N-benzoyl-3-(2~
furoyl)-2-oxindole-1-carboxamide was prepared by
substituting diethanolamine for ethanolamine in the
procedure of Example 8 . The product melted at 157-
158C. Yield: 74%.
AnalYsis: Calcd. for C25H25O7N3: C, 62.62; H, 5.26;
N, 8.76%. Found: C, 62.53; H, 5.31; N, 8.74%.
EXAMPLE 10
The triethanolamine salt of N-benzoyl-3-(2-
furoyl)-2-oxindole-1-carboxamide was prepared by
substituting triethanolamine for ethanolamine in the
procedure of Example 8 . The product melted at 154-
155C. Yield: 60%.
AnalYsis: Calcd. for C27H29O8N3: C, 61.94; H, 5.58;
N, 8.03~. Found: C, 61.84; H, 5.61; N, 7.99%.
1;~89556
--32--
EXAMPLE 11
N-8enzoyl-2-oxindole-1-carboxamide
. . .
To a stirred slurry of 399 mg (3.0 mmole) of 2-
oxindole in 7 ml of toluene was added 485 mg l3.3
mmole) of benzoyl ~socyanate. The mixture was heated
under reflux for 2.2 hours and then lt was cooled to
room temperature. The 501 id was recovered by fil-
tration and it was then dissolved in ca. 10 ml of hot
acetonitrile. ~he acetonitrile solution was decolorized
using activated carbon and then allowed to cool and
the precipitate was recovered by filtration. Recrystal-
lization of the precipitate from acetonitrile gave 131
mg of the title compound, mp 183.5-184.5C.
Anal~sis: Calcd. for C16H12O3N2:
N, 9.99~. Found: C, 68.37; H, 4.58; N, 10.16%.
1~89556
.. -33-
EXAMPLE 12
Reaction of the appropriate 2-oxindole with the
requi~ite acyl isocyanate, substantially according to
the procedure of Example 11, afforded the following
compounds:
' X~
O~C--NH--IC-R2
2 Melting 1
X R Point(0C) Yield~%)
S-Clphenyl 193-195 43
5-CH3phenyl 202-203 68
6-Clphenyl 206-207 59
6-F phenyl 174-175.5
5-F phenyl 187d 37
H 4-fluorophenyl 177-178d 21
__ S-C~3 4-fluorophenyl 209-211d 78
5-C1 4-fluorophenyl 198-199d 59
R 4-methoxyphenyl 180d 72
H 4-chlorophenyl 186.5-187.5d 53
R 2-methylphenyl 166.5-167.5 59
H cyclohexyl 144.5-145.5 62
5-Cl cyclohexyl 172-174 63
5-CH3 cyclohexyl 140-141.~ 68
6-Cl cyclohexyl 181-182 56
5-F cyclohexyl 163.5-164.5 63
; ~
1~89556
' -34-
Melting
X R2 Point(0C)1 Yield(%~
4-Cl cyclohexyl 173-174 69
5-CF3 cyclohexyl 177.5-178.5d 40
6-F cyclohexyl 203-206 43
S H t-butyl 151-152 35
S-CH3 t-butyl 202.Sd 34
5-Cl t-butyl 176.5-177.5d 43
5-F t-butyl 161.5-162.5d 31
6-Cl t-butyl 146-147 42
~ isopropyl 114-llS 23
S-CH3 isopropyl 169-171 38
5-Cl isopropyl 164-165 77
6-Cl isopropyl 128-129 69
H phenoxymethyl 187-188 78
5-Cl phenoxymethyl 218-219 51
. ..
lThe letter ~d~ in this column indicates that the
material melted with decomposition.
1~8~55~
-35-
PREPARATION 1
3-(2-Furoyl)-2-oxindole
To a stirred solution of 5.5 9 (0.24 moleJ of
sodium in 150 ml of ethanol was added 13.3 9 (0.10
mole) of 2-oxindole at room temperature. The resulting
slurry was cooled to ice-bath temperature, and then
15.7 g (0.12 mole) of 2-furoyl chloride was added,
dropwise, during 10-15 minutes. The ice-bath was
removed, and additional 100 ml of ethanol was added
and then the reaction mixture was heated under reflux
for 7 hours. The reaction mixture was allowed to
stand overnight and then the solid was filtered off.
The solid was added to 400 ml of water and the
resulting mixture was acidified using concentrated
hydrochloric acid. The mixture was cooled with ice
and the ~olid was collected by filtration. The solid
residue was recrystallized from 150 ml of acetic
acid, affording 8.3 9 of yellow crystal~, mp 209-210C.
(dec).
Analvsis: Calcd. for C13~9O3N: C, 68.72; ~, 3.99;
N, 6.17%. Found: C, 68.25; ~, 4.05; N, 6.20%.
PREPARATION 2
Reaction of 2-oxindole with the appropriate acid
chloride, using the method of Preparation 1, gave the
following additional products:
3-(2-thenoyl)-2-oxindole, mp 189-190C, 17%
yield;
3-(2-[2-thienyl]acetyl)-2-oxindole, mp 191-
192.5C, 38% yield;
3-(2-phenoxyacetyl)-2-oxindole, mp ~35-136C,
42% yield; and
5-chloro-3-(2-12-thienyl]acetyl)-2-oxindole,
mp 228-230C., 22% yield.
89S56
-36-
PREPARATION 3
3-(3-Furovl)-2-oxindole
To a stirred solution of 2.8 g (0.12 mole) of
sodium in 200 ml of ethanol was added 13.3 g (0.10
mole) of 2-oxindole, followed by 16.8 g of ethyl 3-
furoate. The mixture was heated under reflux for 47
hours, cooled and then the solvent was removed by
evaporation in vacuo. The residue was triturated
under 200 ml of ether, and the solid was collected by
filtration and discarded. The filtrate was evaporated
in vacuo, and the residue triturated under diisopropyl
ether and recovered by filtration. The solid was
suspended in 250 ml of water, which was then acidified
with concentrated hydrochloric acid. This mixture
was stirred to give a solid, which was recovered by
filtration. This latter solid was recrystallized
from acetic acid followed by acetonitrile to give 705
mg of the title compound, mp 185-186C.
Analvsis: Calcd. for Cl3HgO3N: C, 68.72: H, 3.99;
N, 6.17%. Found: C, 68.72; H, 4.14; N, 6.14%.
PREPARATION 3A
Reaction of the appropriate 2-oxindole with the
ethyl ester of the requisite carboxylic acid, ~ub-
stantially according to the procedure of Preparation
3, gave the following compounds:
5-chloro-3-(2-thenoyl)-2-oxindole, mp 190.5-
192C., 36% yield;
5-chloro-3-(2-furoyl)-2-oxindole, mp 234-235C.,
54% yield;
5-chloro-3-(2-phenylacetyl)-2-oxindole, mp 241-
243C., 61% yield;
8~55~ _
-36a-
PREPARATION 3A (Cont.)
S-fluoro-3-(2-furoyl)-2-oxindole, mp 222-224C.,
51% yield;
5-fluoro-3-(2-thenoyl)-2-oxindole, mp 200-203C.,
26% yield;
6-fluoro-3-(2-furoyl)-2-oxindole, mp 239-242C.,
26~ yield; and
6-chloro-5-fluoro-3-(2-thenoyl)-2-oxindole, mp
212-215C., 20~ yield.
PREPARATION 4
5-Chloro-2-oxindole
To a stirred slurry of 100 g ~0.55 mol) of 5-
chloroisatin in 930 ml of ethanol was added 40 ml
(0.826 molJ of hydrazine hydrate, resulting in a red
solution. The solution was heated under reflux for
3.5 hours, during which time a precipitate appeared.
The reaction mixture was stirred overnight, and then
the precipitate was recovered by filtration to give
5-chloro-3-hydrazono-2-oxindole as a yellow solid,
; ~
~ 395S6
--37--
PREPARATION 4 (Cont. ?
which was dried in a vacuum oven. The dried solid
weighed 105.4 g.
The dried solid was then added portionwise,
during 10 minutes, to a solution of 125.1 g of sodium
methoxide in 900 ml of absolute ethanol. The resultant
solution was heated under reflux for 10 minutes and
then it was concentrated in vacuo to a gummy solid.
The gummy solid was dissolved in 400 ml of water and
the aqueous solution thus obtained was decolorized
with activated carbon and then poured into a mixture
of 1 liter of water and 180 ml of concentrated hydro-
chloric acid containing ice chips. A tan solid
precipitated and it was collected by filtration and
washed thoroughly with water. The solid was dried
and then it was washed with diethyl ether. Finally
it was recrystallized from ethanol to give 48.9 g of
the title compound, mp 193-195C. (dec).
In an analogous fashion, 5-methylisatin was
converted into 5-methyl-2-oxindole by treatment with
hydrazine hydrate followed sodium ethoxide in ethanol.
The product melted at 173-174C.
PREPARATION 5
4,5-Dimethyl-2-oxindole and
5,6-dimethvl-2-oxindole
3,4-Dimethylaniline was converted into 3,4-di-
methyl-isonitrosoacetanilide by reaction with chloral
hydrate and hydroxylamine, using the method described
in ~Organic Syntheses," Collective Volume I, page
327. The 3,4-dimethyl-isonitrosoacetanilide was
cyclized with sulfuric acid, according to the method
of Baker et al., Journal of Orqanic Chemistry, 17,
149 (1952), to give 4,5-dimethylisatin (m.p. 225-226
C.) and 5,6-dimethylisatin (m.p. 217-218 C.).
~ 95S6
-38-
PREPARATION 5 (Cont.)
4,5-Dimethylisatin was converted into 4,5-dimethyl-
2-oxindole, m.p. 245.5-247.5 C., by treatment with
hydrazine hydrate, followed by sodium ethoxide in
ethanol, substantially according to the procedure of
Preparation 4.
In like manner, 5,6-dimethylisatin was converted
into 5,6-dimethyl-2-oxindole, m.p. 196.5-198 C., by
treatment with hydrazine hydrate, followed by sodium
ethoxide in ethanol, substantially according to the
procedure of Preparation 4.
PREPARATION 6
4-Chloro-2-oxindole and 6-chloro-2-oxindole
A. 3-Chloro-isonitrosoacetanilide
To a stirred solution of 113.23 g (0.686 mol) of
chloral hydrate in 2 liters of water was added 419 g
(2.95 mol) of sodium sulfate, followed by a solution
prepared from 89.25 g (0.70 mol) of 3-chloroaniline,
62 ml of concentrated hydrochloric acid and 500 ml of
water. A thick precipitate formed. To the reaction
mixture was then added, with stirring, a solution of
155 g (2.23 mol) of hydroxylamine in 500 ml of water.
Stirring was continued and the reaction mixture was
warmed slowly and it was maintained between 60 and
75C. for approximately 6 hours, during which time an
additional 1 liter of water had been added to facili-
tate stirring. The reaction mixture was then cooled
and the precipitate was recovered by filtration. The
wet solid was dried to give 136.1 g of 3-chloro-
isonitrosoacetanilide.
1~955~
-39-
PREPARATION 6 (Cont.)
B. 4-Chloroisatin and 6-chloroisatin
To 775 ml of concentrated sulfuric acid, preheated
to 70C., was added, with stirring, 136 g of 3-chloro-
isonitrosoacetanilide at such a rate as to maintain
the reaction medium at a temperature between 75 and
85C. When all the solid had been added, the reaction
mixture was heated at 90C. for an additional 30
m$nutes. The reaction mixture wa~ then cooled, and
poured slowly onto ca 2 liters of ice, with stirring.
Additional ice was added as necessary to maintain the
temperature below room temperature. A red-orange
precipitate formed which was recovered by filtration,
washed with water and dried. The resultant solid was
slurried in 2 liters of water, and then it was brought
into solution by the addition of ca 700 ml of 3N
sodium hydroxide. The solution was filtered, and then
pH was adjusted to 8 with concentrated hydrochloric
acid. At this point, 120 ml of a mixture of 80 parts
water and 20 parts concentrated hydrochloric acid was
added. The solid which precipitated was recovered by
filtration, washed with water and dried to give 50 g
of crude 4-chloroisatin. The filtrate from which the
4-chloroisatin had been recovered was further acidified
to pH 0 using concentrated hydrochloric acid, whereupon
a further prec$pitate formed. It was recovered by
filtration, washed with water and dried, to give 43 g
of crude 6-chloroisatin.
The crude 4-chloroisatin was recrystallized from
acetic acid to give 43.3 g of material melting at 258-
259 C .
The crude 6-chloroisatin was recrystallized from
acetic acid to give 36.2 g of material melting at 261-
262C.
1289556
-40-
PREPARATION 6 (Cont.)
C. 4-Chloro-2-oxindole
To a stirred slurry of 43.3 g of 4-chloroisatin in
350 ml of ethanol was added 17.3 ml of hydrazine
S hydrate, and then the reaction mixture was heated under
reflux for 2 hours. The reaction mixture was cooled,
and the precipitate was recovered by filtration to give
43.5 g of 4-chloro-3-hydrazono-2-oxindole, mp 235-
236C.
To a stirred solution of 22 g of sodium in 450 ml
of anhydrous ethanol was added, portionwise, 43.5 g of
4-chloro-3-hydrazono-2-oxindole, and the resulting
solution was heated under reflux for 30 minutes.
The cooled ~olution was then concentrated to a gum,
lS which was dissolved in 400 ml of water and decolorized
using activated carbon. The resulting solution was
poured onto a mixture of 1 liter of water and 45 ml of
concentrated hydrochloric acid. The precipitate which
formed was recovered by filtration, dried and recrystal-
lized from ethanol, giving 22.4 g of 4-chloro-2-oxindole,
mp 216-218C (dec).
D. 6-Chloro-2-oxindole
Reaction of 36.2 g of 6-chloroisatin with hydrazine
hydrate followed by sodium ethoxide in ethanol, sub-
stantially according to C above, afforded 14.2 g of 6-
chloro-2-oxindole, mp 196-198C.
1~8~556
! 41
PREPARATION 7
5,6-Difluoro-2-oxindole
Reaction of 3,4-difluoroaniline with chloral
hydrate and hydroxylamine followed cyclization with
sulfuric acid, in a manner analogous to Parts A and B
of Preparation 6, gave 5,6-difluoroisatin, which was
reacted with hydrazine hydrate followed by sodium
methoxide in ethanol, in a manner analogous to
Preparation 4, to give the title compound, m.p. 187-
190C.
PREPARATION 8
5-Fluoro-2-oxindole
To a stirred solution of 11.1 g (0.1 mol) of 4-
fluoroaniline in 200 ml of dichloromethane, at -60 to
lS -65C, was added, dropwise, a solution of 10.8 g (0.1
mol) of t-butyl hypochlorite in 25 ml of dichloro-
methane. Stirring was continued for 10 minutes at
-60 to -65C, and t~len was added, dropwise, a solution
of 13.4 g (0.1 mol) of ethyl 2-(methylth~o)acetate in
25 ml of dichloromethane. Stirring was continued at
-60C. for 1 hour and then was added, dropwise, at
- -60 to -65C, a solution of 11.1 g (0.11 mol) of
triethylamine in 25 ml of dichloromethane. The
cooling bath was removed, and when the reaction mixture
had warmed to room temperature, lC0 ml of water was
added. The phases were separated, and the organic
phase was washed with saturated sodium chloride
solution, dried (Na2SO4) and evaporated in vacuo. The
residue was dissolved in 350 ml of diethyl ether, to
which was added 40 ml of 2N hydrochloric acid. This
mixture was stirred at room temperature overnight. The
phases were separated and the ether phase was washed
3556
-42-
PREPARATION 8 (Cont.)
with water, followed saturated sodium chloride. The
dried (Na2S041 ether phase was evaporated in vacuo to
give 17 g of an orange-brown solid which was triturated
under isopropyl ether. The solid was then recrystal-
lized form ethanol, to give 5.58 g of 5-fluoro-3-
methylthio-2-oxindole, mp 151.5-152.5C.
Analysis: Calcd for CgH80NFS C, 54.80; ~, 4.09; N,
7.10~. Found: C, 54.74; H, 4.11; N, 7.11%.
A sample of the above 5-fluoro-3-methylthio-2-
oxindole (986 mg, 5.0 mmol) was added to 2 teaspoonsful
of Raney nickel under 50 ml of absolute ethanol, and
then the reaction mixture was heated under reflux for
2 hour~. The catalyst was removed by decantation and
was washed with absolute ethanol. The combined
ethanol solutions were evaporated in vacuo and the
residue was dissolved in dichloromethane. The dichloro-
methane solution was dried (Na2so4) and evaporated in
vacuo to give 475 mg of 5-fluoro-2-oxindole, mp 121-
1~4C.
In analogous fashion, 4-trifluoromethylaniline
- was reacted with t-butyl hypochlorite, ethyl 2-(methyl-
thio)acetate and triethylamine followed by reduction
of the 3-thiomethyl-5-trifluoromethyl-2-oxindole thus
obtained with Raney nickel, to give 5-trifluoromethyl-
2-oxindole, mp 189.5-190.5C.
PREPARATION 9
5-Methoxv-2-oxindole
5-Methoxy-2-oxindole was prepared from 4-methoxy-
aniline in a manner similar to the procedure of
Preparation 8, except that the initial chlorination
step was carried out using a solution of chlorine gas
in dichloromethane in place of t-butyl hypochlorite.
The title product melted at 150.5-151.5 C.
1~8~556
PREPARATION 10
6-Chloro-5-fluoro-2-oxindole
To 130 ml of toluene was added, with stirring,
24.0 g (0.165 mole) of 3-chloro-4-fluoroaniline and
13.5 ml ~0.166 mole) of pyridine. The resulting
solution was cooled to ca 0C. and 13.2 ml (0.166
mole) of 2-chloroacetyl chloride was added. The
reaction mixture was stirred at room temperature for
5 hours and then it was extracted twice with 100 ml of
lN hydrochloric acid, followed by 100 ml of ~aturated
sodium chloride solution. The resulting toluene
solution was dried using magnesium sulfate, and then
it was concentrated in vacuo to give 32.6 g (88~
yield) of N-(2-chloroacetyl)-3-chloro-4-fluoroaniline.
lS A 26.63-g sample of the N-(2-chloroacetyl)-3-
chloro-4-fluoroaniline was thoroughly mixed with 64 g
of anhydrous aluminum chloride, and the mixture was
heated at 210-230C. for 8.5 hours. The reaction
mixture was then poured onto a mixture of ice and lN
hydrochloric acid, with stirring. Stirring was
continued for 30 minutes, and then the solid was
collected by filtration (22.0 g). The solid was
dissolved in 1:1 ethyl acetate-hexane and chroma-
tographed on 800 g of silica gel. Elution of the
column, followed by evaporation of the fractions,
produced 11.7 g of the N-(2-chloroacetyl)-3-chloro-4-
fluoroaniline, followed by 3.0 g of 6-chloro-5-fluoro-
2-oxindole. The latter material was recrystallized
from toluene to give 1.70 g (7~ yield) of the title
compound, mp 196-206C. Analysis by NMR spectroscopy
indicated that the product was contaminated by some 4-
chloro-5-fluoro-2-oxindole. A second crop weighing
0.8 g was obtained.
3955~
-44-
PREPARATION 11
6-Fluoro-5-methvl-2-oxindole
An intimate mixture of 11.62 g (57.6 mmol) of N-
~2-chloroacetyl)-3-fluoro-4-methylaniline and 30.6 g
~229.5 mmol) of anhydrous aluminum chloride was heated
to 210-220C. After 4 hours, the reaction mixture was
cooled and then added to 100 ml of lN hydrochloric acid
and 50 ml of ice. A tan solid formed, which was
collected by filtration and recrystallized from agueous
ethanol. Three crops were obtained, weighing 4.49 g,
2.28 g and 1.0 g, respectively. The crop weighing 1.0
g was further recrystallized from water to give 280 mg
of the title compound, mp 168.5-171C.
PREPARATION 12
lS 6-Bromo-2-oxindole
To 9.4 g of sodium hydr$de was added 195 ml of
dimethyl sulfoxide, followed b~ the dropwi~e addition
of 22.37 ml of dimethyl malonate. At the end of the
addition, the mixture was heated to 100 C. and main-
tained at that temperature for 40 minutes. At thispoint, 25 g of 1,4-dibromo-2-nitrobenzene was added
all at once. The reaction mixture was maintained at
100 C. for 4 hours and then it was added to 1.0 liter
of ~aturated ammonium chloride solution. The resulting
mixture was extracted with ethyl acetate and the
extracts were washed with ammonium chloride solution,
water and saturated sodium chloride. The dried (MgSO4)
solution was evaporated, and the residue was recrystal-
lized from ethyl acetate-hexane to give 22.45 g of
dimethyl 2-(4-bromo-2-nitrophenyl)malonate.
A solution of 17.4 g of dimethyl 2-(4-bromo-2-
nitrophenyl)malonate and 4.6 g of lithium chloride in
150 ml of dimethyl sulfoxide was placed in an oil bath
at 100 C. After 3 hours, the reactlon mixture was
~ ~8~55fi
-45-
PREPARATION 12 (Contd)
cooled to room temperature and then it was poured into
a mixture of 500 ml of ethyl acetate and 500 ml of
saturated sodium chloride solution. The layers were
separated and the aqueous layer was extra~ted with
further ethyl acetate. The combined organic layers
were washed with saturated sodium chloride solution,
dried using sodium sulfate, and then evaporated in vacuo.
The residue was chromatographed using silica gel as
adsorbant and ethyl acetate-hexane mixture as eluant.
This afforded 9.4 g of methyl 2-14-bromo-2-nitrophenyl)-
acetate.
To a solution of 7.4 g of methyl 2-(4-bromo-2-
nitrophenyl)acetate in 75 ml of acetic acid was added
6.1 g of iron powder. The reaction mixture was placed
in an oil bath at 100 C. After 1 hour, the solvent was
removed by evaporation in vacuo, and the ~esidue was
dissolved in 250 ml of ethyl acetate. The solution was
filtered, washed with saturated sodium chloride solution,
dried using sodium sulfate, decolorized using activated
carbon, and evaporated in vacuo. This afforded 5.3 g
of 6-bromo-2-oxindole as a white crystalline solid,
m.p. 213-214 C.
In like manner, starting with 1,4,5-trichloro-2-
nitrobenzene, 5,6-dichloro-2-oxindole was prepared,
m.p. 209-210 C.
~ c
~9556
--46--
PF~EPARATION 1 3
6-PhenYl-2-oxindole
To 3.46 g. (0.072 mole) of sodium hydride was
added 50 ml. of dimethyl sulfoxide followed by the
dropwise addition of a solution of 8.2 ml. (0.072
mole) of dimethyl malonate in 10 ml. of dimethyl
sulfoxide, with stirring. After completion of the
addition, stirring was continued for 1 hour, and then
a solution of 10 g. (0.036 mole) of 4-bromo-3-nitro-
diphenyl in 50 ml. of dimethyl sulfoxide was added.
The reaction mixture was heated to 100C. for 1 hour,
cooled, and poured onto a mixture of ice-water
containing 5 g. of ammonium chloride. The mixture
thus obtained was extracted with ethyl acetate, and
the extracts were washed with sodium chloride solution
and dried using magnesium sulfate. Evaporation in
vacuo to give an oil, which was chromatographed using
~ilica gel and then recrystallized from methanol to
afford 6 g. of dimethyl 2-(3-nitro-4-diphenylyl)-
malonate, m.p. 82-83C.
A portion (5 g.) of the above nitro compound was
- reduced with hydrogen over a platinum catalyst, in a
mixture of 50 ml. of tetrahydrofuran and 10 ml. of
methanol, at a pressure of ca 5 kg/cm2, to give the
corresponding amine. The latter compound was refluxed
in ethanol for 16 hours, and then the product was
recovered by solvent evaporation and recrystallized
from methanol to give 1.1 g. of ethyl 6-phenyl-2-
oxindole-l-carboxylate, m.p. 115-117C.
The above ethyl ester (1.0 g.) and 100 ml. of 6N
hydrochloric acid was heated under reflux for 3 hour~
and then allowed to stand at room temperature for 3
S5~i
-47-
PREPARATION 13 (Cont.)
days. The solid was collected by filtration and
dried, to give 700 mg. of 6-phenyl-2-oxindole, m.p.
175-176C.
PREPARA~ION 14
S-Acetvl-2-oxindole
To 95 ml. of carbon disulfide was added 27 g.
~0.202 mole) of aluminum chloride, followed by the
dropwise addition of a solution of 3 ml. (0.042 mole)
of acetyl chloride in 5 ml. of carbon disulfide, with
stirring. Stirring was continued for 5 minutes and
then ~.4 g. (0.03; mole) of 2-oxindole was added. The
resulting mixture was heated under reflux for 4 hours
and cooled. The carbon disulfide was removed by
decantation and the residue was triturated under
water and recovered by filtration. After drying, 3.2
g. of the title compound was obtained, m.p. 225-
227C.
Reaction of 2-oxindole with benzoyl chloride and
with 2-thenoyl chloride in the presence of aluminum
chloride, substantially according to the above
~ procedure, afforded the following compounds:
5-benzoyl-2-oxindole, m.p. 203-205C. (from
CH30H) and
5 (2-thenoyl)-2-oxindole, m.p. 211-213C. ~from
CH3CN).
~ ~8'~55~
-48-
P~EPARATION 15
S-Bromo-2-oxindole, 5-nitro-2-oxindole and 5-
amino-2-oxindole can be prepared as described in
Beckett et al., Tetrahedron, 24, 6093 (1968). 5-
S Amino-2-oxindole can be acylated to give 5-alkanamido-
2-oxindole and 5-benzamido-2-oxindole, using standard
procedures.
5-n-Butyl-2-oxindole can be prepared by reaction
of 5-n-butylisatin with hydrazine hydrate followed by
sodium methoxide in ethanol, according to the procedure
of Preparation 4. 5-n-Butylisatin can be prepared
from 4-n-butylaniline by treatment with chloral
hydrate and hydroxylamine, followed by cyclization
with sulfuric acld, according to the procedure of
Parts A and B of Preparation 6.
5~Ethoxy-2-oxindole can be prepared by conversion
of 3-hydroxy-6-nitro-toluene into 3-ethoxy-6-nitro-
toluene by standard methods (potassium carbonate and
ethyl iodide in acetone), followed by conversion of the
3-ethoxy-6-nitrotoluene into 5-ethoxy-2-oxindole by the
method described by Beckett et al., (Tetrahedron, 24,
6093 [1968]), for the conversion of 3-methoxy-6-nitro-
toluene intG 5-methoxy-2-oxindole. 5-n-Butoxy-2-
oxindole can be prepared in like manner, but substituting
n-butyl iodide for ethyl iodide.
5,6-Dimethoxy-2-oxindole can be prepared by the
method of Walker, Journal of the American Chemical
Soc~etY, 77, 3844 (1955).
7-Chloro-2-oxindole can be prepared by the method
described in United States Patent No. 3,882,236.
4-Thiomethyl-2-oxindole and 6-thiomethyl-2-oxindole
can be prepared by the method described in United
States Patent No. 4,006,161. S-n-Butylthio-2-oxindole
can be prepared in like manner, but substituting 4-
butylthioaniline for the 3-methylthioaniline.
1i~89556
-49-
.
PREPARATION 15 (Cont.)
5,6-Methylenedioxy-2-oxindole can be prepared by
the method of McEvoy et al., Journal of Orqanic
Chemistrv, 38, 3350 (1973). 5,6-Ethylenedioxy-2-
oxindole can be prepared in analogous fashion.
6-Fluoro-2-oxindole can be prepared according to
Protiva et al., Collection of Czechoslovakian Chemical
Communications, _ , 2108 (1979) and United States
Patent No. 4,160,032.
6-~rifluoromethyl-2-oxindole can be prepared
according to Simet, Journal of Orqanic Chemi~trv, 28,
3580 (1963).
6-Methoxy-2-oxindole can be prepared according
to Wieland et al., Chemische Berichte, 96, 253 (1963).
5-Cyclopropyl-2-oxindole and 5-cycloheptyl-2-
oxindole can be prepared by reaction of 5-cyclo-
propylisatin and 5-cycloheptylisatin, respectively,
with hydrazine hydrate followed by sodium methoxide
in ethanol, according to the procedure of Preparation
4. 5-Cyclopropylisatin and 5-cycloheptylisatin can
be prepared from 4-cyclopropylaniline and 4-cyclo-
heptylaniline, respectively, by treatment wlth
- chloral hydrate and hydroxylamine, followed by
cyclization with sulfuric acid, according to Parts A
and B of Preparation 6.
