Note: Descriptions are shown in the official language in which they were submitted.
~2~3~90
64680-316D
This divisional application is divided out of parent
application Serial No. 476,599 filed on March 15, 1985.
The parent application relates to novel intermediates of
formula II and a process for preparing them. The present division-
al application relates to a process for preparing compounds of
formula III starting from compounds of formula II. Compounds of
formulae II and III, and the relevant processes, are hereinafter
defined.
The process for making 2-oxindole-1-carboxamides com-
prises reacting a 2-oxindole with chlorosulfonyl isocyanate to
produce a novel N-chlorosulfonyl-2-oxindole-1-carboxamide which
is then hydrolyzed to a 2 oxindole-l-carboxamide. Said 2-oxindole-
l-carboxamides are useful as interm~diates for analgesic and anti-
inflammatory agents.
The reactions of chlorosulfonyl isocyanate with various
nucleophiles, including amines to produce N-chlorosulfonylamido
(ClSO2NHCO) derivatives thereof, and subsequent hydrolysis of said
derivatives to afford amides is described by Graf., An~ew. Chem.
Internat Edit, 7, 175 (1968); Rasmussen et al., Chem. Rev. 389-
390 (1976); and Szabo, Aldrichimica Acta 10, 23 (1977).
The preparation of 2-oxindole-1-carboxamides by cycliza-
tion of the appropriate (2 ureidophenyl)acetic acid by means of,
for example, trifluoroacetic anhydride/trifluoroacetic acetic acid
is described in Canadian application Serial No. 476,605 of Saul B.
Kadin, entitled 3-Substituted 2-Oxindole-l-Carboxamides as
Analgesic and Anti-inflammatory Agents which was flled on March 15,
1985.
~3~
64680-316D
The process represents an improved process for making 2-
oxindole-l-carboxamides of formula III in good yield and purity
from starting materials which are readily available.
There is provided a convenient process for making 2-
oxindole-l-carboxamides by reaction of a 2-oxindole with chloro-
sulfonyl isocyanate to produce a novel intermediate N-chlorosul-
fonyl-2-oxindole-1-carboxamide which is then hydrolyzed to a 2-
oxindole-l-carboxamide. The process, the intermediate and the
final products are presented below:
lo Y ~ I ClSO~NCO ~ ~ ~
C=O
H NH
II S2Cl
hydrolysis
Cl=O
NH
III 2
wherein R is hydrogen or -CO-Rl, wherein Rl i~s as de~ined below,
and
X is 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 hav-
ing 1 to 4 carbons, trifluoromethyl, alkylsulfinyl having 1 to 4
carbons, alkylsulfonyl having 1 to 4 carbons, nitro, phenyl, alkan-
oyl having 2 to 4 carbons, benzoyl, thenoyl, alkanamido
i;3490
- 3
having 2 to 4 carbons, benzamido and N,N-dialkylsulfamoyl
having 1 to 3 carbons in each of said al~yls; and Y is
selected from the group consisting of hydrogen, fluoro,
chloro, bromo, alkyl having 1 to 4 carbons, cycloalXyl
having 3 to 7 carbons, alkoxy having 1 to 4 carbons,
alkylthio having l to 4 carbons and trifluorome~hyl;
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 ~aken together and when attached
to adjacent carbon atoms, form a divalent radical Z,
wherein Z is selected from the group consisting of
/~ ~ '~
zl z2 ~3
~_ /W_
and
z4 z5
wherein W is oxygen or sulfur.
Compounds of formula III wherein R is hydrogen
are valuable intermediates for preparation of analgesic
and antiinflammatory compounds of formula IV:
j~C-R1 IV
O=C-NH2
wherein X and Y are a~ defined above; and
~3490
--4--
~ 1 is selected from the group con3isting of
alkyl having 1 to 6 carbons, cycloalkyl having 3 to 7
carbons, cycloalkenyl having 4 to 7 carbons, phenyl,
substituted phenyl, phenylalkyl having 1 to 3 carbons
in said alXyl, Isubstituted phenyl) alkyl havin~ 1 to
3 carbons in said alkyl, phenoxyal~yl having 1 to 3
carbons in said alkyl, (substituted phenoxy)alkyl
~ having 1 to 3 carbons in said alkyl, (thiophenoxy)-
1 0 alkyl having- 1 to 3 carbons in said alkyl, naphthyl,
bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]hept-5-en-2-
yl and l CF12 ) n~Q~R
wherein the substituent on said substituted
phenyl, said ~ubstituted phenyl)alkyl and sa~d
(substituted phenoxy~alkyl is selected from the group
consisting of fluoro, chloro, bromo, alkyl having 1
to 4 carbons, alkoxy having 1 to 4 carbons and
trifluoromethyl; n is zero, 1 or 2; Q is a divalent
radical derived from a compound selected from the
group consisting of furan, thiophene, pyrrole,
pyrazole, imidazole, thiazole, isothiazole, oxazole,
i oxazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole,
1,2,5-thiadiazole, tetrahydrofuran, tetrahydrothiophene,
tetrahydropyran, tetrahydrothiopyran, pyridine,
pyrimidine, pyrazine, benzo[b]furan and benzotb]-
thiophene; and R is hydro~en or al~yl havin~ 1 to 3
carbons.
Favored compounds of formula IV are those wherein:
(i) one of X and Y i5 hydrogen and ~he other is 5 or
~- chloro, fluoro or trifluoromethyl; or (li) X is 5-
chloro or 5-fluoro and Y is 6-chloro or 6-fluoro.
Said compounds exhibit a higher level of analgesic
and antiinflammatory activity than do other of said
formula IV compounds.
.
~3~90
- 5 - 6480-316D
Thus, the process is useful for preparing analgesic and
antiinflammatory compounds of the formula IV, wherein X, Y and
are as defined previously. These compounds are derivatives of
2-oxindole, the bicyclic amide of the formula
X 4
y 7 H O
More particularly, these analgesic and antiinflammatory agents
have a carboxamido substituent, -C(=O)-NH2, 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 substituted by X and Y groups.
X and Y can be certain monovalent substituents as defined pre-
viously, or X and Y when on adjacent carbon atoms on the benzo
ring can represent a methylenedioxy group, -OCH2O-, or an ethylene-
dioxy 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
carbocyclic or heterocyclic ring. Certain divalent ~roups for 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,
~2.~3~0
--6--
it is to be under~tood that when Z i~ 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 z5, the formula IV emhraces both of the
following formulae:
o
~;~C--Rl .
O=C-NH
and
0
O-C-NH2
The compounds of formula III are prepared from
the appropriate 2-oxindoles of fonmula I by the two-
step sequence shown above. The required 2-oxindoles
(R=H) are prepared by methods known to those skilled
- in the art. The following references describe
preparation of various 2-oxindoles: ~The Chemistry
of Heterocyclic Compounds~, Indoles, Part Two, Edited
by ~oulihan, Wiley-Interscience, N.Y., pp. 142-143,
(1973); ~Rodd's Chemistry of Carbon Compounds~,
Second Edition, Edited by S. Coffey; Vol. IV-A,
Elsevier Scientific Publishing Company, pp. 448-450,
3~9(~ _
--7-- .
(1973); Walker, J. Am. Chem. Soc., 77, 3844-3850
(1955); Wright et al., J. Am. Chem. Soc., 78, 221-224
(1956); McEvoy et al., J. Org. Ch~m. 38, 3350 (1973);
Gassman et al., J. Org. Ch~m., 42, 1340 (1977);
S Beckett et al., Tetrahedron 24, 6093 (1968); Protiva
et al., Coll. Czech. Chem. Comm. 44, 2108 (19791; and
~.S. Patents Nos. 3,882,236; 4,~06,161 and 4,160,032.
Add~tionally, preparations of representative sub-
stituted 2-oxindoles are presented herein.
The gtarting materials of formula I wherein R is
_co-~l wherein ~1 is as defined above are prepared by
acylating the appropriate compound of formula I
wherein R is hydrogen by methods known to those
~killed in the art. For example, the acyl ~oiety
-CO-R1 i~ attached by reacting a compound of the
formula I with an activated derivative of the ap-
propriate 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), accordin~ to standard procedures.
Typical derivatives of the acid of the formula
Rl-C(=O)OH which can be used include acid chlorides,
acid anhydrides of the formula Rl-Ct=O)-O-C(=O)-Rl,
Rl-C(-o)-o-C(=o)-R3 and ~l-c(-o)-o-c(=o)-oR4~ and
simple alkyl esters of the formula Rl-C(2o)-oR4~
wherein R3 is a bulky low molecular weight al~yl
group such as t-butyl and R4 is a low molecular
weight alkyl group. ~sually, a small excess of the
derivative of the acid of formula Rl-C(=O)-O~ is
used, and the alkoxide salt is usually present in an
æmount from one to two molar equivalents, based on
said derivative of the acid of formula Rl-C(=O)OR.
The reaction between the derivative of the acid of
the formula ~l-C(=O)OR and the compound of formula I,
~3
-8-
wherein R is hydrogen, 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. ~nder 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 i8 then cooled, diluted with an excess of
water, and acidified. The product of formula I,
wherein R is _Co-~l can then ~e reco~red by fil-
tration or by the standard procedure of solvent
extraction.
The first step of the process of thi invention,
reaction of the appropriate 2-oxindole with chloro-
sulfonyl isocyanate, is conducted in a reaction-inert
solvent medium; i.e., a solvent which does not react
with the chlorosulfonyl isocyanate or the 2-oxindole-
l-chlorosulfonylamide product of for~ula II. Said
solvent need not bring about complete solution of the
reactants. Representative solvent~ are dialkyl ethers
such as diethyl ether; diisopropyl ether; aromatic
hydrocarbons such as benzene, xylene and toluene;
chlorinated hydrocarbons such as methylene chloride
and chloroform; and acetonitrile.
The reaction is generally c~nducted at temperatures
ranging from -20C. to the reflux temperature of the
solvent used. In general, temperatures of from 25C.
to 110C. are favored. Temperatures down to -70~.,
can be used if desired. ~owe~er, temperatures below
0C. are generally a~oided for practical reasons.
The 2-oxindole and chlorosulfonyl isocyanate are
generally reacted in molar proportions ranging from
equimolar to 30% excess of chlorosulfonyl isocyanate,
~53~30
i.e., l:l to 1:1.3. Larger exces~es of chlorosulfonyl
i~ocyanate appear to afford no advantages and are not
used for reasons of economy.
The thus-psoduced chlorosulfonamide derivatives
of formula II can be isolated, if desired, or can be
converted directly in the same reaction vessel without
igolation to formula III compounds. Isolation of the
intermediate chlorosulfonamido compounds of formula II
is achieved by procedures known to those s~illed in
the art; e.g. by filtration, evaporation of solvent or
extraction.
The second step of the process, hydrolysis of the
chlorosulfonamido derivatives (formula II) is carried
out by treating the fo~mula II compounds, with or
without isolation thereof, with water, aqueous acid or
aqueous base. Water alone is generally favored as ~he
hydrolyzing agent even in instances wherein ~he
hydrolysis step involves a two phase system. The rate
of hydrolysis is sufficiently rapi~ as to overcome any
solubility problems of reactants. ~dditionally, from
the standpoint of large scale reactions, the use ~f
water alone is more economical than are the other
hydrolysis methods.
The use of an aqueous inorganic or organic acid
a~ hydrolyzing agent sometimes overcomes the develop-
ment of two phase reaction systemsO This is often the
case when aqueous acetic acid is used. The amount of
acid is not critical to the hydrolysis step~ It can
ranye from less than equimolar quantities to greater
than equimolar quantities. Also not critical is the
concentration of the acid used. In general, when
aqueous acid is used for the hydrolysis step, from
~3~3Q
--10--
about 0.1 mole of acid per mole of formula II compound
to up to 3 moles of acid per mole of formula II
compound is used. Acid concentrations of from about 1
molar to 6 molar are generally used for ease of handling.
The use of aqueous acid is often resorted to when the
formula II intermediate is isolated and a single phase
hydrolysis mixture is desired. Representative acids
are hydrochloric, sulfuric, phosphoric, acetic, formic,
citric and benzoic acids.
The compounds of formula IV are prepared from the
appropriate 2-oxindole-1-carboxamide compound of the
formula III, wherein R is hydrogen, and X and Y are as
previously defined. This is accomplished by attaching
the substituent -C(=O)-Rl to the 3-position of the
2-oxindole nucleus. The -C(=O)-Rl substituent is
attached by reacting said compound of the formula III
with an activated derivative of a carboxylic acid of
the formula Rl-C(=O)OH. The reaction is carried out
by treating said compound of formula III in an inert
solvent with one molar equivalent, or a slight excess,
of an activated derivative of a compound of formula
Rl-C(=O~OH, in the presence of from one to four
e~uivalents 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-dimethyl-
acetamide, N-methylpyrrolidone or dimethyl sulfoxide,
is commonly used. Conventional methods for activating
the acid of formula Rl-C(=O)OH are used. For example,
acid halides, e.g., acid chlorides, symmetrical acid
anhydrides, Rl-C(=O)-O-C(=O)-Rl, mixed acid anhydrides
with a hindered low-molecular weight carboxylic acid,
3~30
Rl-C(=o)-o-C(=o)-R3, where R3 i5 a bulky lower-al~yl
group such a~ t-butyl, and mixed carboxylic-carbonic
anhydrides, Rl ~(-O)-0-C(=O)-OR~, wherein R4 is a
low-molecular weight alkyl group, can all be u-~ed.
In addition, N-hydroxyimide esters (such as N-hydroxy-
succinimide and N-hydroxyphthalimide esters), 4-
nitrophenyl esters, thiol esters (such as thiol
phenyl esters) and 2,4,5-trichlorophenyl esters, and
the like, can be used. Moreover, in those cases in
which Rl is a heteroaryl group ~e.g., furyl), simple
alkyl esters of the formula R1-C(=o)-o~R4, where R4
is a low-molecular weight al~yl group (e.g., ethyl),
can sometimes be used as the activated derivative of
the acid of formula Rl-C(=O)-O~ when attaching the
-C(=O)-Rl substituent to the 3-position of the 2~
oxindole compound of formula III, wherein R is hydrogen.
A wide variety of basic agents can be used in
the reaction between a compound of formula III,
wherein R is hydrogen and the activated derivative of
the acid of the formula Rl-C(-O)O~. ~owever, preferred
basic agents are tertiary amines, such as trimethylamine,
triethylamine, tributylamine, N-methylmorpholin~, N-
methylpiperidine and 4-(N,N-dimethylamino)pyridine.
The reaction between a compound of the formula
III, wherein R is hydrogen, and the activated derivative
of the acid of formula Rl-C(=O)-OR is usually carried
out in the temperature range from -10 to 25 C.
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
recrystallization.
~2 ~3 ~9
-12-
The analgesic activity of Gompounds of formula IVhas been demons~rated in mice by showing blocXade of
the abdominal ~tretching 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 ~womey, A~ents and
Actions, 10: 31-37, 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 administration and testing.
The compounds of formula IV wexe 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/kg). The
route of administration was oral, with concentrations
varied to allow a constant injection volume of 10
ml/kg of mouse. The aforesaid method of Milne and
~womey was used to determine efficacy and potency.
Mice were treated with compounds orally, and one hour
later received PBQ, 2 mg~g intraperitoneally.
Individual mice were then immediately placed in a
warmed lucite chamber, and, starting five minutes
after PB~ 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 (~ > 5~ provided dose-response
~ 3~90
-13-
data for generation of an MP~50, the best estimate of
the dose that reduces abdominal constriction of 50% of
control levels.
I The antiinflammatory activity of ~ompounds of
1 5 formula IV has been demonstrated in rats by a method
based on the standard carraqeenin-induced rat-foot
edema test. (Winter et al , Proc. Soc. Exp. Biol.
Med., 111: 544, 1963)~
~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 a glass cylinder, connected
to a Statham Pressure Transducer. The output from the
1s transducer was fed through a control unit to a micro-
voltameter. The vol~me 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 injec'ion
of carrageenin constitutes the individual response.
The analgesic activity of compounds of formula IV
makes them useful for acute administration to mammals,
including humans, for the control of pain, e.g., post-
operative pain and the pain of trauma. The anti-
inflammatory activity of said compounds makes them
useful for chronic administration to mammals, including
humans, for the control of inflammatory diseases, such
as the arthritides, especially rheumatoid arthritis.
~3~90
--1 4--
When a compound of formula IV ~ 9 to be used for
either of said purposes, it can he administered to a
mammalian subject alone, or, preferably, in combination
with pharmaceutically-acceptable carriers or diluents
in a pharmaceutical composition, according to standard
pharmaceutical practice via the oral or parenteral
(includes intravenous, intramuscular, intraperitoneal,
subcutaneous and topical3 routeO
In a pharmaceuti~al composition comprising a
compound of formula I~, 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. ~owever, in
any given ca~e, the ratio chosen will depend on such
factors as the solubility of the active component, the
dosage contemplated and the precise route of adminis-
tration.
For oral use, said formula IV compound, can ~e
administered in the form of tablets or capsules, or as
an aqueous solution or suspen~ion. Commonly used
carriers for tablets include lactose and corn starch.
Lubricating agents, such as magnesium stearate, are
commonly added. ~seful diluents for capsule dosage
forms are lactose and dried corn starch. When aqueous
suspensions are required for oral use, the active
ingredient is combined with emulsifiying and ~uspending
agents. If desired, certain sweetening and~or flavoring
agents can be added. For intramuscular, intraperi-
toneal, su~cutaneous and intravenous use, sterile
solutions of the active ingredient are usually prepared,
and the pH of said solutions suitably adjusted and
buffered. For intravenous use, the total concentration
of solutes should be controlled to render the preparation
isotonic.
o
64680-316D
When a compound of formula IV is used in a human subject,
the daily dosage, normally determined by the prescribing physician,
will vary according to the age, weight and response of the
individual patient, as well as the severity of the patient's
symptoms. However, for acute administration to relieve pain, an
effective dose in most instances will be 0.1 to 1.0 g as needed
(e.g., every four to six hours). For chronic administration as
an anti-inflammatory agent, in most instances an effective dose
will be from 0.5 to 3.0 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 provided
soley for the purpose of illustration. No attempt was made to
optimize the yield of said examples and preparations.
- 15 -
3~90
-16-
EXAMPLE 1
2-Oxindole-l-Carboxamide
Chlorosulfonyl isocyanate ~1.20 g, 8.~ mmoles)
was added to a mixture of 2-oxindole (0.94 g, 7.1
mmole~ in ether (30 ml) and the reaction stirred at
room temperature for 20 hours. The ether was removed
under vacuum and the residue treated with water ~10
ml) and lN HCl ( 10 ml). ~thyl acetate (125 ml) was
added and the mixture ~tirred for one hour. The ethyl
acetate phase was separated, washed with lN ~C1
(1 x 50 ml), brine (2 ~ 100 ml) and dried (MgSO4).
Concentration afforded 0.97 g ~77%) of crude product.
Recrystallization from ethanol gave 0.18 g; m.p. 178-
180C.
3 ~0
-17-
EXAMPLE 2
2 Oxindole-l-Carboxamide
A mixture of 2-oxindole (5.86 g, 44.0 mmoles) in
toluene (160 ml) was azeotroped for one hour to dry
the toluene. Then, chlorosulfonyl isocyanate ~7.47 g,
52.8 mmole) was added. Hydrogen chloride was ~mmediately
evolved. The mixture was stirred and refluxed for lS
minutes and then c~oled to room temperature. Water
(50 ml) was added to the cooled mixture ~some HCl was
initially e~olved) and the mixture stirred for 1.5
hours. The solid which formed was collscted by
filtration and dried (4.10 g). ~he filtrate was
extracted with ethyl acetate (100 ml), the resulting
extract washed with brine (2 x lOQ ml) and dried
(MgS04). Evaporation of the extract under reduced
pressure gave 4.16 g of solid. The combined solids
were recrystallized by dissolution in acetonitrile
(200 ml) followed by concentration of the solution
under reduced pressure to about 75 ml. The small
amount of amorphous material which separated was
filtered off, the filtrate decolorized and concentrated
under reduced pressure to about 50 ml volume, then
~eeded. The dark red crystals which separated were
filtered and dried (3.0 g; 38~). It was identical to
the product of Example 1.
~ 3~9(:1
18-
E~AMP~E_3
2-Oxindole-l-Carboxamide
To a slurry of 2-oxindole (13.3 g, 0.10 mole) in
toluene (150 ml) was added chlorosulfonyl isocyanate
!'' ' 5 ~5.6 g, 0.11 mole) and the reaction ~ixture heated on
a steam bath for ten minutes (a clear 801ution formed
v within about three minutes followed almost immediately
by formation of a precipitate). It was then cooled in
in ice bath for 30 minutes, the solid fil~ered off and
~! 1 0 air dried.
The thus obtained chlorosulfonamido intermediate
was added to a 2:1 mixture of acetic acid/water (240
ml) and the resul~ing ~lurry heated on a steam bath
; for ten minutes. It was ~ooled in an ice ~ath and the
off white solid which formed filtered off and a~r
dried, Concentration of the mother liguor to a slush
~ and filtration thereof gave 1.2 g of product. The
!~` combined solids was recrystallized from about 250 ml
of ethanol; yield = 11.48 g (65%). It was identical
to the Ex le I product,
.'
~ 53
_ ~;L9--
EXAMPLE 4
6-Fluoro-S-Me~yl-2 Oxindole-l-Carboxamide
Following the procedure of Example 2, the title
~ompound was prepared from 6-fluoro-5-methyl-2-oxindole
(1.0 g, 6.0 mmole~, chlorosulfonyl isocyanate (1.03 g,
7.3 mmole), toluene (30 ml). Water (5 ml) was used
for the hydrolysis step. Yield = 0.58 g, 46~. M.P.
200-203~C.
Analysls Calcd. for Clo~gN2O2F:
C, 57.69; ~t 4.36; N, 13.46.
Found: C, 57.02; ~, 4.41; N, 12.85.
~ sample of the chlorosulfonamide intermediate
was removed prior to hydrolysis and subjected to mass
spectrum analysis for exact mass determination:
Clo~gN2o4scl 307.9848.
~3 ~9 O
--20-
EXAMPLES 5-13
- Substituted-2-Oxindole-l-Carboxamides
The following compounds are prepared according to
the procedure of Example 3 from appropriately
sub~tituted-2-oxindoles.
3~
_ _ ,. ~ ~ ~ ~ ~o
Z
,
_ ~ o o~
~ _
~ O ~ O ~ N
0 _ _~_ ~ 0
u~
0 ~: C~
~: .
,,
;~ ~: U~
c~ ~ ~ ~ .o ~ ~ a~
. ~ ~ ~ ~ ~ ~ U~
_ _
I ~ U~
C~ ~ ~_
_~ o ~ ~ ~ I I U I U .D U
~ f", ~ _ ~ O ~
Il~ f _ f~ f~ r~ N
O ~ ~ 0 F~
C _ ~ ~ O~O CC~ ~ C~
~ e ~ ~
o~ o ~ 0
D ~4 ~ ~ ~o cc o ` ~ O ~
' ,,~ _ r~,~ ~ ~ ~ ~ c~ -;r ~
~ o o
_ ~ O ~ ~ U'~ ;~, O o
o e ¢ 5:~ o O ~ O ~ O O _
= :~: c~
G) _ O
~O
F _
o
~o ~ o f
. , ~
~ .
_ ,~ ~ oo ~ o fJ~ O ~ n
o E u~ o cs~ o a~ o ~ -3 ~
. . . -
rl ~ ~ a~ ~
c~ tlO ~ o ~ o _~ ~
_ , ~ ~ u
. ~ ~ o ~ o ~ ~ . 3 ~ ~
. ~ --Cl~ f~ ~ ~J U
~e ~ 3~ e O e
Ox ~ ~ ~
3 ~ ~ ~ ~ U N
X C ~ O ~ 2
~ (11 ~
. ~ r f~ n
_ . ~I 'J
~ f,~ 0 ~ O ~
~C f~ ~ ~ U
_,~J _
-22
EXAMPI.E 14
_
5!6~Methylenedioxy-2-oxiA~ole~ rb~x~m~d~
5 r 6-Methylenedioxy-2-oxindole l-carboxamide was
prepared by reaction of 5,6 methylenedioxy-2-oxindole
~ with chloro~ulfonyl lsocyanalte, followed by hydrolysis,
using the procedure of E~ample 3~ The product melted
at 237-238C. ~dec,3 after recrystallization from
acetic acid.
--23--
EXAMPLE 1 5
By reaction of the appropri~te 2 ~ oxindole with
chlorosulfonyl isocyanate, followed by hydrolysis,
using the procedure of Example 3, the followinq
5 tricycl ~ c compounds can be p:repared:
7~ C~
O=C-N~2
X and Y*
4-cR2-c~2-c~2-5
5 CE~2~C~2 -C~32- 5
6- C~2-c~2-c~2-c~2 7
5-CR=C~-C~=C~
2 C~2 6
S--C~2 -CEl --O--6
~12 C~2 6
5-O-CH=C~I-6
5-S-C~=CH--6
5--C~l=C~--S--6
*In this colllmn, the numeral to the left O~ he
formula indicates the point attachment of that end of
20 the formula to the 2-oxindole nucleus and the numeral
to the right indicates the point of attachment of
that end of the formula to the 2-oxindole nucleu~.
5~3~9
2~--
EXAMPLE 16
6-Methyl hio~2~0xindole-l~Carboxamide
.. . ..
Chlorosulfonyl i~ocyanate ~5~66 g, 0.04 mole) was
added to a slurry of 6-methylthio-2-oxindole ( 6 . O ~,
0.033 mole) in acetonitrile (60 ml) at 5 to 10C.
The reaction mlxture was ~tirred for one hour. Water
(lOQ ml~ was then added to ~aid mixture w~th good
stirring for ten ~inutesr The aqueous solution was
extracted with ethyl acetate (600 ml), washed suc-
cessiv~ly with water and brine, dried (MgS04) andevaporated under reduced pressure to give a gray solid
which was recrystallized from acetonitrile. Yield =
3.0 g. An additional O.71 g of product was obtained
from the mother liquor. Total yield = 3.71 q (50.6%~;
m.p. 176~179C.
O
--2S--
5 ~ 6 Dimethoxy-2-OxiLndole-l-Carboxan ~ de
. .
Following the procedure of Example 16 the title
compound was prepared from 5,~-dimethoxy-2-oxindole
5 (8.0, 0.042 mole), ehloro~ulfonyl i-~ocyanate (7.08 g,
0.05 mole~ and acetonitrile (75 ml). The crude
product obtained upon evaporation of the ethyl acetate
extract was recryxtallized from acetonitrile~acetic
acid ~ Yield = 6.02 9 (60%); m.p. 206.5-209DC.
Similarly, 5,6~methylenedioxy-2-oxindole-1~
carboxamide is prepared from 5,6-methylenedioxy-2-
oxindole.
~3~30
-26-
~XAMP:LE 18
6-Trifluorometh~1-2-Ox~ndole~ arboxamide
To a slurry of 6-trifluoromethyl-2-oxindole (8.0
g, 0.04 mole) in acetonitrile ~80 ml3 was added chloro~
sulfonyl isocyanate (6.65 g, 0.047 mole) and the
mixture stirred for 4~ mintues~ Water (100 ml~ was
then added and ~he aqueous mixture stirred for one
hour. The precipitate which formed was filtered off
and recrystallized from acetonitrile to give 0.92 g of
title product~ Extraction of the filtration from the
aqueou~ reaction mixture with ethyl acetate (300 ml)
followed by dryiny the extract over MgSO4 and then
evaporating it un~er redu~ed pressure gave additional
product. Recrystallization from acetonitrile gave
additional (2.2 g) prodllct.
Additional product l1.85 g) was recovered by
combining the mother liquors from the acetonitrile
recrystallizations and concentratiny same under
reduced pressure. Total yield = 4.97 g (51%) m.p.
2~ 207.5~210~.
~27--
EXAMPLES 19-24
~ epetition of the procedure of Example 18 but
u~ing ~he appropriate substituted 2-oxindole afforded
the following compounds.
X,~
Y~ 11 1
~~~0
CONH2
o
--~8-
,~ ~ ~ lo~
I D~ _ I ~ ~ ~ O ~ ,~
o~ a
g X ~ _ ~ _l o ~ ~ o o
~ 5~ ~D ~ ~U~ ~ O `O
~ 1,._ ~o ,~ C~ ~ ~
O ¢ 3~~ O u^~ O ~ O Irl ~a U! -
-- r ~t ~ O O
O
~ , _ - ~ ~ 'O
~o ~ S~ o U~ ~ ~ ~ C
. ~o ~r~ ~ o ~
C~ CO ~ O ~ 1~ ~
. .. ___ , O ~::
U~ o C J il 1
1~ -__, ~ , O E~
X ~ ~ ~ ~ ~ C
. . __ _ ~ ~ ~ 3 00 ~
~ G~ O ~
æ ~ v~
~3~
-29-
EXAMPLE 25
3-(2-Furoyl)-6-Fluoro-2~0xindole-1-Carboxamide
Following substantially the procedure of Example
18, the title was prepared in 17~ yield from: 3-(2-
furoyl)-6-fluoro-2-oxindole (0.30 g, 1.2 mmole),
chlorosulfonyl isocyanate (0.20 g, 1.4 mmole), aceto-
nitrile (15 ml), and water (10 ml), Yield = 0,060 g;
m.p. = 231-235C.
30- -
EXAMPLE 26
Substituted 2-Oxindolle-l-Ch~ wlf~ide~
The procedure of ~xamplle 16 was followed, using
the appropriate substituted 2-oxindole as reactant~
Prior to the hydrolysl~ ~tep, the intermediate chloro-
sulfonyl derivative was recovered by filtration, if a
solid was present; or by evaporation from a ~mall
volume of the reaction mixture if no precipit~te
formed. A sample of the thu5 obtained intermediate
was then ~ubjected to exact m~ss determination.
Y~
O-C-NH-S02Cl
2-Oxindole CSI ml _Intermediate
Y g. q. Solvent Formula Exact Ma~s
. _ _
6--F H l.S 1.70 lS C9E~6N204FSC1 291.9721
6-CF3 E~ 0.5 0.35 10 CloH6N2O4F35~1 341-3693
5-F 6-C1 1.59 1.4255a C9El6N 2O4FSC12 3~6.g340
S-NO2 H 1.75 0.35 SS C9H6~36~C1 318.9675
6-Br ~ 0.40 0.31 5a C9R6N2O4sBrcl 351.8863
5~OC~3 6-OCEI3 1 . O O . 8 5 12 Cl 1 Hl lN 2O6 SCl 3 4 4 . 0 0 34
6-SC~3 H 0.20 0.18 3a CloH9N2O4S2Cl 319.g636
4-SCH3 ~ 0.20 0.18 3a CloElgN2O4S2C1 319.9696
6 F 5-CE{3 0.16 0.14 10 CloEi8N204FClS 307.9848
a = toluene used as solvent
A
--31--
~XAMPLE 27-
.
6-Phenyl-2-oxindole-1-carboxamide-
. . . _
To ~.5 g. (21.5 mmole) of 6-phenyl-2oxindole in
a mixture of 100 ml. of toluene and 25 ml. of tetra~
hydrofuran was added, with stirrin~, at 5C., 2.2 ml.
(25.8 m~ole) of chloros~lfonyl isocyanate. Stirring
was continued for 1 hour at 0-5C. and then 100 ml. of
water W25 added. The 601id was reco~ered by fil-
tration and added to a mixture of 40 ml. of glacial
acetic acid and 80 ml. of water. The resulting
mixture was hea~ed at 100C. for 1 hour, cooled and
filteredO The residue was dried to give 3.1 g. of the
title compound, mp. lB8-189r.
EXAMPLE 2B_
5-Benzo 1-2-oxindole-1-carboxamide
Y ~
A mixture of 10.1 g. (42 mmole) of 5-benzoyl-2-
oxindole, 4~4 ml. (51 mmole~ of chlorosulfonyl iso-
cyanate and 300 ml. of tetrahydrofuxan was stirred at
room temperature for 6 hours, and then the solvent was
removed by evaporation in vacuo. The residue was
ad~ed to 150 ml. of glacial acetic acid and 300 ml. of
water and the resulting mixture was heated under
reflux for 2 hours. The reaction mixture was cooled
and the supernatant liquid was removed by decantation.
The remaininy gummy re~idue was triturated under
acetonitrile to give a solid which was recoYered by
filtration and then recrystalli2ed from a 1~1 mixture
of n-propanol and acetonitrile. This gave 4.1 g. of
the title compound as a solid, m~. 210-211C.
~;3~
-32-
EXAMPLE 29
Reaction of 5-acetyl-2-oxindole and 5-(2-thenoyl)-
2-oxindole with chlorosulfonyl isocyanate, followed by
hydrolysis with aqueous acetic acid, substantially
according to the procedure of Example 28, afforded the
following compounds:
5-acetyl-2-oxindole-1-car~oxamide, 34% yield, mp
225C. (dec~) ~from CH3CN) and
5-~2-thenoyl)-2-oxindole-1-carboxamide, 51~ yield, mp
200C. (dec.) (from C~30~/CH3CN),
respectively.
~v~
-33-
~XAMPLE 30
2-oxir.dole-1-c~rboxamide
To a ~tlrred slurry of 1,5 9~ (~.4 mmole) of 3
~2-thenoyl)-5-chloro-2-oxindole in.l5 ml. of dry
acetonltrile wa~ added 0.52 ml. ~5O9 mmole) of chloro-
~u~fonyl ~80Cy~nate~ and the r~action mixture wa~
fitirred at room temperature for 2 hours. A ~mall
~ample was removed, f~ltered and evaporated in vacuo
to give a small gample of N-chlorosulfonyl-3-(2
~henoyl)-5-chloro-2-oxindole-1-carboxamide, mp 166-
169Co To the remainder of the react~on mixture, 30
~1. of water wa~ added 810wly With ~tirr~n~ and
stirring wa~ continued for 1 hour. The reaction
mixture ~as then poured into 50 ml. of lN hydrochloric
acid containing ice chip~, and the resulting mixture
was stirred ~or 20 minutes. The yellow ~olid was
recovered by filtratlon, washed with wa~er and
diisopropyl ether and recrystallized from glacial
aceti~ acid t~ gi~e 200 mg. of a f~rst crop of the
title compound, mp 213-215C. The mother liquors
from whi~h the fir~t crop had been recovered depos~ted
a further yellow solid. The latter solid wa~ recovered
by filtration to give ~70 mg. of a second crop of the
title compound. The second cr~p was recrystallized
from glacial acetic acid and combined with the f~st
. crop and recry~tallized from glacial acetic acid.
. Th~s gave 280 mg. of the title compound, mp 232-.
234C~
.
i3~
-14-
PREP~AT~ON 1
5-Chloro-2-oxindole
To a stirred slurry of 100 g (0.55 mol) of 5-
chloroi~a~in in 930 ml of ethanol wa added 40 ml
~0 826 mol~ of hydrazi~e hydrate, re~ulting in a red
solution The qolution was heated under reflux for ~05
hours, during which time a precipitate appeared. The
reaction mixture was stirred overnight, and then the
precipita e was recovered by filtration to give 5-
chloro-3-hydrazono-2-oxindole as a yellow olld, which
was dried in a va~uum oven. The dried solid weighed
105.4 g. ~
The dried ~olid was then added pcxtionwise,
during 10 minutes, to a solution of 125.1 g of sodium
ethoxide in 900 ml of ab~olute ethanol. The resultant
solution was heated under reflux for 10 minute~ 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 de~olorized with
activated carbon and then poured into a mixture of 1
liter of water and 180 ml of ~oncentrated hydrochloric
acid containing ice chip~. A tan ~olid precipitated
and it was collected by filtration and washed thoroughly
with water. The solid was dried and then it was
washed with die~hyl ether~ Finally it was recrystal-
lized ~rom ethanol to give 4~.9 g of the title ~ompound,
Tllp 193-lg5C. (dec).
In an analogous fashion, 5-methyl~satin was
conver~ed ~nto 5-methyl-2-oxindole by ~reatment with
30 hydrazine hydrate followed sodium ethoxide in ethanol.
The product melted at 173-174C.
33~
-35-
P~EPARATION 2
4,5-Dimethyl-2-oxindole and
5,6-dimethyl-2~oxindole
:
3,4-Dimethylaniline was converted into 3,4-di-
methyl isonitro~oace~anil ide by reaction with chloralhydrate and hydroxylamine, using the method de~cri~ed
in ~Organic Synthese~,~ Collective Volume I, page 327.
The 3,4-dimethyl-i~onitro~oacetanilide was cyclized
with sulfuric acid, according to the method of Ba~er
et al~, ournal of ~ ChemistrY, 17, 149 (1952),
to give 4,5-dimethylisatin (m.p. 225-226 C.) and
5,6--dimethylisatin (m.p. 217--218 C. ) .
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, 3ubstantially according to the procedure of
Preparation 1.
In like manner, 5,6-dimethylisatin was converted
into 5,6~dimethyl-2-oxindole, m.p. 196.5-198 C., by
treatment with ~ydrazine hydrate, followed by sodium
ethoxide in eth nol, substantially according to the
procedure of Preparation 1.
36-
REPARATION 3
4-Ch oro-2-oxindole and 6 chloro-2-oxindole
A ~onitro~o-3-chloroacetanil ide
. To a ~tirred solution of 113.23 g ~0.686 mol) of
chloxal hydra~e in 2 li~ers of water wa~ added 419 g
(2 95 mol) of sodium xulfate, followed by a ~olution
prepared from 89.25 g l~ 70 mol) of 3-chloroaniline, 62
ml of concentrated hydrochloric acid and 500 ~1 of
water. A thick precipitate formed -~o the rea~tion
mixture was then added, with stirring, a solution of
155 g (2.23 mol) of hydroxytamine in 500 ml of water.
- Stirring was ~ontinued and the reaction mixture wa~
warmed slowly and i~ wa~ maintained between 60 and
75C. for approximately 6 hours, during which time an
additional 1 liter of water had ~een added to facili-
tate stirring. The reaction mixture was ~hen cooled
and ~he precipitate was recove.red by filtration. The
wet solid was dried ~o give 136.1 g of iRonitroso-3-
chloroacetanilide.
B. 4-Chloroisatin and 6-chloroi~atin
To 775 ml of concentrated su~furic acid, prehea~ed
~ to 70C , was added, with stirring, 136 g of isonitroso-
- 3-chloroacetanilide at s~ch a rate as to maintain the
reaction medium a~ a temperature between 7S and 85C
Whe~ all the solid had been added, the reaction mixture
wa-~ heated at 90C for an additional 3~ minute~. The
reaction ~ixture was then ~ooled, and poured 510wly
onto ca 2 liters of ice, with ~irring. Additional ice
was added a~ necessary to ~a$ntain the ~emperature
below room temperature. A ~ed-orange precipitate
formed whi~h was recovered by filtration, washed with
water and dried The res~l~ant solid was ~lurried in
~3,~!0
-37-
PREPAR~TI~ ~
2 liter~ of water, and then lt was brought into
solution by the addition of oa 700 ml of 3N sodium
hydroxide. The solution was f~ltered, and then p~ was
adjus~ed to 8 with concentrilted hydro~hloric acid. At
thi~ point, 120 ml of a mixt:ure of 80 parts water and
20 parts concentrated hydrochloric acid wa.~ added.
The solid which precipitated was recovered by fil-
tration, washed with water and dried to give S0 g of
crude 4-chloroisatin. mhe filtrate from which the 4-
chloroisatin had been reco~ered was further acidified
to p~ 0 using concentrated hydrochloric acid, where-
upon a further precipitate for~ed. ~t 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-
259C.
The crude 6-chloroisatin was recrystallized from
acetic acid to give 36.2 g of material ~elting at 261-
262C~
C. 4-Chloro-2-oxindole
To a stirred clurry of 43.3 g of 4-chloroisatin
~ in 350 ml of ethanol was added 17.3 ml of hydrazine
hydrate, and then th~ reaction ~ixture was heated
under reflux for 2 hours. The reac~ion mixture was
cooled, and the precipitate was rec~vered by fil-
tration to give 43~5 g of 4-chloro-3-hydrazono-2-
oxindole, mp 235-236C_
To a stirred solution of 22 q o~ sodium in 450 ml
o anhydrouc ethanol was added, portionwise, 43.5 g of
4 chloro-3-hydrazono-2-oxindole, and the re~ulting
solution was heated unaer reflux for 30 minute~
-38-
PR~PARATION 3 ~Cont.?
The cooled solution was then concentrated to a gum,
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, dxied and recrystal-
lized from ethanol, giving 22~4 9 of 4-chloro-2-
oxindole, mp 216-218C (dec).
10 D. 6--Chloro--2-oxindole
Reaction of 36.2 g of 6-chloroisatin wi~h hydrazine
hydrate followed by sodium ethoxide in ethanol, sub-
stantially accordlng to C above, afforded 14.2 g of fi-
chloro-2-oxindole, mp 196-198C.
PREPARATION 4
5,6-Difluoro-2-oxindole
Reaction of 3,4-difluoroaniline with chloral
hydrate and hydroxylamlne followed cyclization with
sulfuric acid, in a manner analogous ~o Parts ~ and B
of Preparation 3, gave 5,6-difluoroisatin, which was
reacted with hydrazine hydrate followed by sodium
methoxide in ethanol, in a manner analogous to
Preparation 1, to give the title compound, m.p. 187-
l9CC.
o
-
-39
PREPMA'rION 5
- ~ 2-oxindole
~ o a st~rred solution of 11.1 g (0 1 mol) of 4-
fluoroaniline in 200 ml of dichloromethane, at -60 to
-65C, was added, dropwise, a qolution of lO.B ~ ~0.1
mol3 of t-butyl hypochlorite in 25 ml of dichlor~-
~ethane~ Stirring was continued for 10 minutes at -60
to -65C, and then wa-~ added, dropwise, a solution of
13 . 4 g r O .1 mol ) of ethyl 2--(methyl thio ) acetate in 25
ml of dichloromethane. Stirring wa~ continued at
-60~C. for 1 hour and then was added, dropwise, at -60
to -65C, a 301utiQn of 11.1 g (0.11 mol) of tri-
ethylamine in 25 ml of dichloromethane The cooling
bath was remo~ed, and when the reaction mixture had
warmed to room tempera~ure, 100 ml of water was
added. The phases were separated, and the organic
phase was washed with saturated ~odium chloride
solution, dried (~a2So4) and evaporated in vacuo. The
residue was dissolved in 350 ml of diethyl ether, to
which was added 40 ml of 2N hydrochloric acid T~i~
mixture was stirred at room temperature overnight.
The pha es were separated and the ether phase was
washed with water, followed by ~aturated ~odium
chloride. The dried (Na2So4) ether phase was evapo-
sated in vacuo to give 17 g of an orange-brown solid
which was triturated under isopropyl ether. The solid
was then recrystallized form ethanol, to give 5.58 g
of 5-fluoro-3-methylthio-2-oxindole, mp 151.5-152.5C.
AnalYsis: Calcd for C9~8ONFS: C, 54.80; ~, 4.09; N,
7.10%. Found: C, 54~74; R, 4.11; N, 7~11%.
A ~ample of the above 5-fluoro-3-~ethylthio-2-
oxindole (986 mg, 5.0 ~moll was added to 2 teaspoonsful
of Raney nickel under 50 ml of absolute e~hanol, and
then the reaction mixture was heated under reflux for
-40-
PREPARATION 5 (Cont.)
2 hours. The cataly3t was removed by decanta~ion and
was washed with absolu~e ethanol. The combined
ethanol solutions were evaporated in vacuo ~nd the
S re~idue was dis-~olved ln dichlorome~hane. The di-
chloromethane solution ~ax dried (Na2SO43 and evaporated
~n acuo to give 4~5 mg of 5-fluoro-2-oxindole, mp
121-134~.
In analogous fa~hion, 4-trifluoromethylaniline
was re Icted wi~ch t-butyl hypochlorite, ethyl 2-(methyl--
~hio)acetate and triethylamine followed by reduction
o~ the 3-thiomethyl 5-trifluoromethyl-2-oxindole thu~
obtained with Raney nickel, to give S-trifluoromethyl-
2-oxindole, mp 189.5-190 5C.
~41-
~REPARATION 6
6-Fluoro-S~meth 1-2~oxindole
An intimate mixture of l:L,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. ~fter 4 hours, th~ reaction mixture was
oooled and then added to 100 ml of lM hydrochloric
acid and S0 ml of ice. A tan solid formed, which was
collected by filtration and recrystallized from
10 aqueous eth2nol. Three cropF: were obtained, weighing
4.49 g, 2.28 g and 1.0 g, respectively. The first two
crop~ comprised a mixture of isomers (4-fluoro-5-
methyl and 6-fluoro-s-methyl-2-oxindoles~. The crop
weighing 1.0 g was further recrystalli~ed from water
~o give 280 mg of the title compound, mp 168.S-171C.
-42-
PREPAR~TION 7
~ ox~ndole
To 3.46 g. 10~072 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 ~n l0 ml. of dimethyl
sulfoxide, with stirring. After completion of the
addition, stirrinq was continued for 1 hour, and then
a solution of l0 g~ (0.036 mole) of 4-bromo-3~nitro-
diphenyl in 50 ml. of dimethyl sul foxide wa~ added .
The reac~ion mixture was heated to 100C. for l hsur,
cooled, and poured onto a mixture of i~e-water
containing 5 g. of ammonium chloride. The mixture
- thus obtained was extra~ted 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
silioa gel and then recrystallized from methanol to
afford 6 g. of dimethyl 2-(3-nitro-4-diphenylyl3-
malonate, m.p. 82-83C.
A portion (5 g.) of the above nitro compound ~as
reduced with hydrogen over a platinum catalyst, in a
mixture of 50 ml. of tetrahydrofuran and l0 ml. of
methanol, at a pressure of ca 5 kg/cm2, to give the
corresponding amine. The latter compound was refluxed
in ethanol for l6 hours, and then the product was
recovered by solvent evaporation and recrystallized
from methanol to give l.l g. of ethyl 6-phenyl-2-
oxindole-l-carboxylate, m.p. llS-ll7C.
The above ethyl ester (l.0 g.) and l00 ml. of 6N
hydrochloric acid was heated under reflux for 3 hours
and then allowed to stand at room temperature for 3
3 ~
-43-
P~EPAP~TION ? (Cont.)
days. The ~olid was collected by filtration and
dried, to give 700 mg. of 6-phenyl-2 oxindole, m.p.
175-176~.
5 . PREPARATION 8
5-Acetyl-2-ox~ndole
To 95 ml. of carbon disulfide was added 27 g.
(0.202 mole) of aluminum chloride, followed by the
dropwise addition of a ~olution of 3 ml. ~0.042 mole1
of acetyl chloride in 5 ml. of carbon disulfide, with
~tirring. Stirring was continued for 5 mlnutes and
then 4.4 g. (0.033 mole) of 2-oxindole wa~ 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-
2~7C
Reaction of 2-oxindole with ben20yl chloride and
with 2-thenoyl chloride ln the presence of aluminum
chloridç~, substantial ly according to the above
procedure, afforded the following compounds:
5-benzoyl-2-oxindole, m.p. 203-205C. (from
CH3O~) and
5-(2-thenoyl)-2-oxindole, m.p. 211-213C. (from
C~3CN) .
.
53 ~90
--44~
PREPARATION 9
-
5-Bromo-2-oxindole can be prep~red by bromination
of 2-oxindole; see fur~her Beckett et al., Tetrahedron,
24, 6093 (1968~ and Sumpter e~t alO, Journ 1 of the
American Chemical Society, 67, 1656 (1945).
5-n-Butyl-2-oxinaole can be prepared by reaction
of 5-n butylisatin wi~h hydr~zine hydrate followed by
sodium methoxide in ethanol, a~cording to the procedure
of Preparation 1. S-n-~utylisatin ~an be prepared from
lo 4-n-butylaniline by *reatment with chloral hydrate and
hydroxylamine, followed by cyclization with sulfuric
acid, a~cording to the procedure of Parts A and B of
Preparation 3.
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-e~hoxy-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-ni~ro-
toluene into 5-methoxy-2 oxindole. 5-n-Butoxy-2-
oxindole can be prepared in like manner, but ~ubstitutins
n-butyl iodide for ethyl iodide.
5,6-Dimethoxy-2-oxindole can be prepared by the
method of Walker, Journal of the ~merican Chemi~al
Society, 77, 3844 (1955).
7-Chloro-2-oxindole can be prepared by the method
described ln ~nited States Patent NoO 3,882,236.
4-Thiomethyl-2-oxindole and 6-thiomethyl-2-oxindole
can be prepared by the method described in ~nited
States Patent No. 4,006,16}. 5-n-Butylthio-2-oxindole
can be prepared in like manner, but s~kstitu*ing
4-butylthioaniline for the 3-methylthioaniline.
- -45--
PP~PARATION 9 ~Contd)
5,S-Methylenedioxy-2~oxindole can be prepared by
the me~hod of McEvoy et al., Journal of Orqanic
Chemistry~ 38, 3350 (1973). 5,6-Ethylenedioxy-2-oxindole
can be prepared in analogous fashion.
- 6-Fluoro2-oxindole can be prepared according to
Proti~a et al., Collection of Czechoslovakian Chemical
~ _ . .
Communications, 44, 2108 (1979~ and ~nited States
Patent ~o. 4~160,032.
6-Trifluoromethyl-2-oxindole can be prepared
according to Simet, Journal of Organic ~ y, 28,
35B0 (1963).
6 Methoxy-2-oxindole can be prepared according to
Wieland et al. r Chemische Berichte, 96, 2S3 (1963).
S-Nitro-2-oxindole can be prepared hy the method
of. Sumpter et al., Journal of the American Ch~mical
Society, 67, 499 ~1945).
S-Cyclopropyl-2-oxindole and 5-cycloheptyl-2-
oxindole can be prepared by reaction of S-cyclopropyl-
lsatin and 5-cycloheptyli~atln, respectively, with
hydrazine hydra~e followed by sodium methoxide in
ethanol, according to the procedure of Preparation 1.
5-~yclopropylisatin and 5-cycloheptylisatin can be
prepared from 4-cyclopropylaniline and 4-cycloheptyl-
aniline, respectively, by treatment with chloralhydrate and hydroxylamine, foll~wed by cyclization
with sulfuric acld, according to Parts A and B of
Preparation 3.
,
3 ~
--46-
PREPA~ATIION 1 û
__
5-Amino-2-oxindole-1-carboxamide
-
To a solution of 5.0 g. of $-nitro-2-oxindole-1-
carboxamide in 110 ml. of N,N-dimethylformamide was
added 0.5 g. of 10% palladium-on-carbon, and the
resulting mixture was ~haken under an atmosphere of
hydrogen at an initial pressuxe of 5 kg/cm2 until
hydrogen uptake ceased. The catalyst was removed by
filtration, and the filtrate was diluted with brine
10 and extracted with ethyl acetate. Th~ ex~racts were
dried (MgSO4) and evaporated in vacuo to ~ive a darX-
colored oil which solidified after trituration under
water. Thi~ afforded 3.0 g. of the title compound as
a yellow solid, mp 189-191C.
o
-47-
PREPARATION 11
~ 3 ~2-FuroylL~2-oxindole
To a ~tirred solution of 5.5 g (0024 mole) of
sodium in 150 ml of ethanol was added 13.3 g (0.10
mole~ of 2-oxindole at room temperature. The re-
sulting slurry was cooled ~o ise-bath temperature, and
then 15.7 g (0.12 mole) of 2-furoyl chloride wa~
added, dropwise, during 10-15 minu es. The ice-ba~h
was removed~ and an additional 100 ml of e~hanol was
added and then the reaction mixture wa~ heated under
reflux for 7 hours. The reaction mixture was allowed
to ~tand overnight and then-the ~olid was filtered
off. The ~olid 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 solid was collected ~y filtration. The solid
residue was recrystallized from 150 ml of a~etic acid,
affording 8.3 g of yellow crystals, mp 209-210
(dec).
2a AnalYsis: Calcd. for C13~903N: C, 68.72; ~i 3~99; ~-
6.17%. Found: C, 68.25; R, 4.05; N, 6.20%.
Reaction of 2-oxindole with the appropriate acid
chloride using the above me~hod,~gave the following
additional products:
3-(2-thenoyl1-2-oxindole, mp 189-190C, 1~%
yield;
3-~2-C2-thienyl]acetyl)-2-oxindole, mp 191-
192.5C, 38% yield; and
3-~2-phenoxyacetyl) 2~oxindole, mp 135-136C, 42%
yield.
3,.~
-48-
PP P~RATION 12
~ 2-oxindole
To a ~tirred 801ution ol. 2.8 g ~0.12 mole) of
sodium in 200 ml of ethanol was ad~ed 13.3 g (0.10
mole~ of 2-oxindole, followect by 16~8 g of ethyl 3-
furoate. The mixture was heated under reflux for 47
hours, cooled and then the ~olvent was removed by
evaporation ~n vacuo. The residue wa~ triturated
under 200 ml of ether, and the solid was collected by
filtration and discarded. The filtra~e was e~aporated
in vacuo, and the re~idue triturated under isopropyl
alcohol and recovered by filtration. The solid wa~
su~pended in 250 ml of water, which was then acidified
with concentra~ed hydrochloric acid. This mixture was
lS stirred to give a solid, which was recovered by fil-
tration. Thi~ latter solid was recrystallized from
- acetic acid followed by acetonitrile to give 705 mg of
the title compound, mp 185-186C.
AnalYsis: Calcd. for C13~9O3N: C, 68.72; ~, 3099; N,
6.17%. Found: r, 68.72; ~, 4.14; N, 6.14%.
~3~
-49-
P~EPARATION 13
A stlrred slurry of 21.1 g (0.1 mole~ of 5-chloro-
2-oxindole-1-carboxamlde and 26.9 g (0.22 mole) of
4~N,N-dimethylamino)pyridine in 200 ml of N,N-dimethyl-
formamide was cooled to ice-~ath temperature, and then
a ~olut~on of 16.1 g (0.11 mole) of 2~thenoyl chloride
in 50 ml of N,N-dimethylformamide was added dropwi~e.
Stirring was continued for ca. 30 minutes, and then
the react:ion mixture was poured lnto a mixture of
1 liter of water and 75 ml of 3N hydrochloric acid.
The result~ng mixture was cooled in an ice-bath, and
then the solid was collected by filtration. The solid
was recrytallized from 1800 ml of acetic acid to give
26 7 6 g of the title compound as fluffy, yellow cry~tal~
m~pO 230 C. (dec.).
A sample of the title compound from a ~imilar
- experiment gave the following results on elemental
analy~
Analy~is: Calcd. for C14~9ClN203S:
C~ 52.42; ~, 2.83; N, 8.74%.
Found: C, 52.22; ~, 2.81; N, 8.53%.
~ 3~
--50--
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-52-
P~EPARATION 15
5-Chloro-3-acet~1-2-oxindole-1-carboxam~de
A stirred slurry of 842 mg (4~0 mmole~ of
5-chloro-2-oxindole-1-carboxæmide and 1.08 9 t8.8 mmole)
of 4-(N,N-dimethylamino)pyricline in 15 ml of
N,N-dlmethylformamide was cooled ~o ice-bath temperature,
and then a solution of 449 mg (4.4 mmole) of acetic
anhydride in 5 ml of N,N-dimethylformamide wa~ added
dropwise. Stirring was continued fsr ca~ 30 ~inutes,
and then the reaction mixture was poured into a mixture
of 75 ml of water and 3 ml of 3N hydrochloric acla.
The re~ulting mixture was cooled in a~ ice-bath and
~he solid was recovered by filtrati~n. The solid wa~
recrystallized from acetic acid to g~ve 600 mg of fluffy,
pale pink crystal~, m.p. 237.5 C. (dec.).
AnalYsis: Calcd. for CllHgClN203:
C, 52.29t ~, 3.59; N, 11.09%.
Found: C, 52.08; H, 3.63; N, 11~04%.
