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Description  |
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TECHNICAL FIELD
This invention relates to substituted di-t-butylphenols which are
anti-allergic agents. Pharmaceutical compositions containing such
compounds, pharmacological methods for using such compounds and synthetic
intermediates for preparing such compounds are also disclosed.
BACKGROUND OF THE INVENTION
The leukotrienes are a group of biologically active mediators derived from
arachidonic acid through the action of lipoxygenase enzyme systems. There
are two groups of leukotrienes derived from the common unstable precursor
Leukotriene A.sub.4. The first of these are the peptido-lipid
leukotrienes, the most important being Leukotrienes C.sub.4 and D.sub.4.
These compounds collectively account for the biologically active material
known as the slow reacting substance of anaphylaxis.
The leukotrienes are potent smooth muscle contracting agents, particularly
on respiratory smooth muscle, but also on other tissues as well. In
addition, they promote mucous production, modulate vascular permeability
changes and are potent inflammatory mediators in human skin. The most
important compound in the second group of leukotrienes, namely dihydroxy
fatty acids, is Leukotriene B.sub.4. This compound is a potent chemotactic
agent for neutrophils and eosinophils and, in addition, may modulate a
number of other functions of these cells. It also affects other cell types
such as lymphocytes and, for example, may modulate the action of
suppressor cells and natural killer cells. When injected in vivo, in
addition to promoting the accumulation of leukocytes, Leukotriene B.sub.4
is also a potent hyperalgesic agent and can modulate vascular permeability
changes through a neutrophil dependent mechanism. Both groups of
leukotrienes are formed following oxygenation of arachidonic acid through
the action of a lipoxygenase enzyme. See, for example, D. M. Bailey et
al., Ann. Rpts. Med. Chem., 17, 203 (1982).
RESPIRATORY CONDITIONS
Asthma. The leukotrienes are potent spasmogens of human trachea, bronchus,
and lung parenchyma, and when administered to normal volunteers as
aerosols are 3,800 times more potent than histamine at inducing a 50%
decrease in air flow at 30% of vital capacity. They mediate increases in
vascular permeability in animals and promote mucous production in human
bronchial explants. In addition, Leukotriene B.sub.4 may also mediate
mucous production and could be an important mediator of neutrophil and
eosinophil accumulation in asthmatic lungs. Lipoxygenase products are also
thought to be regulators of mast cell degranulation, and recent studies
with human lung mast cells have suggested that lipoxygenase inhibitors
(but not corticosteroids), may suppress antigen-induced mast cell
degranulation. In vitro studies have shown that antigen challenge of human
lung results in the release of leukotrienes and that, in addition,
purified human mast cells can produce substantial amounts of leukotrienes.
There is, therefore good evidence that the leukotrienes are important
mediators of human asthma. Lipoxygenase inhibitors would, therefore be a
new class of drugs for the treatment of asthma. See, for example, B.
Samuelsson, Science, 220, 568-575 (1983).
SKIN DISEASES
Psoriasis. Psoriasis is a human skin disease which affects between two and
six percent of the population. There is no adequate therapy for psoriasis
and related skin conditions. The evidence for leukotriene involvement in
these diseases is as follows. One of the earliest events in the
development of prepapillary lesions is the recruitment of leukocytes to
the skin site. Injection of Leukotriene B.sub.4 into human skin results in
a pronounced neutrophil accumulation. There are gross abnormalities in
arachidonic acid metabolism in human psoriatic skin. In particular, highly
elevated levels of free arachidonic acid can be measured as well as large
amounts of lipoxygenase products. Leukotriene B.sub.4 has been detected in
psoriatic lesions, but not in non-involved skin, in biologically
significant amounts.
ALLERGIC CONDITIONS
Leukotrienes can be measured in nasal washings from patients with allergic
rhinitis and are greatly elevated following antigen challenge.
Leukotrienes may mediate this disease through their ability to regulate
mast cell degranulation, to modulate mucous production and mucocillary
clearance, and to mediate the accumulation of inflammatory leukocytes.
Leukotrienes may also mediate other diseases. These include atopic
dermatitis, gouty arthritis, gall bladder spasms and ulcerative colitis.
In addition, they may have a role in cardiovascular disease because
Leukotrienes C.sub.4 and D.sub.4 act as coronary and cerebral arterial
vasoconstrictors and these compounds may also have negative inotropic
effects on the myocardium. In addition, the leukotrienes are important
mediators of inflammatory disease through their ability to modulate
leukocyte and lymphocyte function.
Many substituted di-t-butylphenols are known. Generally these compounds may
be useful as antioxidants. Some of these compounds are also known to be
active antiinflammatory agents.
Compounds wherein 2,6-di-t-butylphenol is substituted in the 4 position by
an unsubstituted phenyl or certain simply-substituted phenyls are known
antiinflammatory agents. See, for example, U.S. Pat. No. 4,172,151 and
references cited therein. The compound
2,6-di(tertiary-butyl)-4-(4'-carboxyphenylimino)-2,5-cyclohexandiene-1-one
is disclosed in Chemical Abstracts 67:81701n.
No compounds wherein a 2,6-di-t-butylphenol is substituted in the 4
position by an anilino group wherein such anilino group is substituted by
a moiety including carboxy, tetrazolyl, N-methyl-tetrazolyl, or
N-trifluoromethylsulfonyl are known.
SUMMARY OF THE INVENTION
This invention relates to certain di-t-butylphenols containing an anilino
group which contain carboxy, tetrazolyl, N-methyltetrazolyl, or
N-trifluoromethylsulfonyl. These compounds are useful as inhibitors of
mammalian leukotriene biosynthesis. As such, these compounds are useful
therapeutic agents for treating allergic conditions, particularly asthma.
Pharmaceutical compositions comprising such compounds, pharmacological
methods of using such compounds, and synthetic intermediates for preparing
such compounds are also described. Certain of the synthetic intermediates
also exhibit useful pharmacological activity as antiallergic agents.
Certain compounds of the invention are also useful as synthetic
intermediates for preparing certain of the antiallergic compounds which
are disclosed and claimed in U.S. Ser. No. 06/879,472 (Attorney's Docket
Number FN 40825USA4C), filed of even date and commonly assigned,
incorporated herein by reference. Moreover, it is believed that certain of
the antiallergic compounds disclosed in said copending application are
prodrugs of certain antiallergic compounds disclosed herein. For example,
N-(3-carboxyphenyl)-N-(3,5-di-t-butyl-4-hydroxyphenyl)succinamic acid
disclosed in said copending application is believed to possibly be a
prodrug of 3-(3,5-di-t-butyl-4-hydroxyanilino)benzoic acid which is
disclosed herein.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compounds of Formula I:
##STR1##
wherein R is hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen
(preferably chloro or fluoro), amino, lower alkylamino,
di(lower)alkylamino, lower acylamido or hydroxy, and n is 0, 1 or 2 with
the proviso that if n is 2, then all R substituents combined contain no
more than 6 carbon atoms; R' is hydrogen, lower alkyl, acetyl or
trifluoroacetyl; A is carboxyl, tetrazolyl, N-methyltetrazolyl or
##STR2##
and when A is carboxyl, B is a carbon-carbon bond, lower alkylene, lower
alkenylene, lower alkylene containing one ether or thioether link in the
alkylene chain, or
##STR3##
when A is tetrazolyl or N-methyltetrazolyl, B is a carbon-carbon bond,
--CH.sub.2 -- or
##STR4##
and when A is
##STR5##
B is a carbon-carbon bond; and derivatives of compounds wherein A is
carboxyl selected from the group consisting of the lower alkyl esters,
(lower)alkylamino(lower)alkyl esters, pharmaceutically acceptable
(lower)alkylamino(lower)alkyl ester acid-addition salts and
pharmaceutically acceptable carboxylate salts, and derivatives of
compounds wherein B is tetrazolyl selected from pharmaceutically
acceptable alkali metal and alkaline earth salts of the tetrazolyl moiety.
Presently preferred are compounds wherein the group --B--COOH,
--B-tetrazolyl or --B-N-methyltetrazolyl is oriented para or meta to the
##STR6##
linking group.
Presently preferred compounds are those wherein A is carboxyl.
Presently preferred as B is a carbon-carbon bond. When B is alkylene it is
preferably methylene. When B is alkenylene it is preferably ethenylene.
When R is lower alkyl, lower alkoxy or lower alkylthio, it is presently
preferred to be methyl, methoxy, or methylthio respectively. The presently
preferred R group is hydrogen.
By "lower" as used in connection with "alkyl" and "alkylene" is meant that
such groups contain one to about four carbon atoms. Most preferred alkyl
groups contain one or two carbon atoms. By "lower" as used in connection
with "alkenylene" is meant that such groups contain two to about four
carbon atoms.
In the compounds of Formula I wherein A is tetrazolyl, two tautomeric forms
of tetrazolyl exist as is known to those skilled in the art. Tautomerism
does not exist in tetrazolyl moieties where the tetrazolyl ring is
substituted on a nitrogen atom by methyl. Instead, two N-methyl isomers
are obtained, one in which the methyl group is in the 1-position, the
other in which it is in the 2-position. All such tautomers and isomers are
within the scope of this invention.
It is well known to the art that pharmaceutically acceptable salts such as
alkali metal, alkaline earth, aluminum and other metal and amine salts of
pharmaceutically active acids are the equivalents of the acids in terms of
activity, and in some cases may even offer advantages in absorption,
formulation and the like. pharmaceutically-acceptable carboxylate salts of
the compounds of the invention which contain carboxyl as A are prepared in
an inert atmosphere by reaction of the acid with a base and subsequent
evaporation to dryness, preferably under mild conditions. The base may be
organic, e.g., sodium methoxide or an amine, or inorganic, e.g., sodium
hydroxide. Alternatively, the cation of a carboxylate salt, e.g., sodium,
may be displaced by a second cation such as calcium or magnesium when the
salt of the second cation is more insoluble in a selected solvent.
Other useful derivatives of the compounds of the invention which contain
carboxyl as A include alkyl esters, alkylaminoalkyl esters, and salts of
the latter. In the ester derivatives, the hydrogen portion of the
carboxylic acid group is replaced with an alkyl or substituted alkyl,
preferably an alkylaminoalkyl group.
Esters of the compounds of the invention may be obtained as intermediates
during the preparation of the acidic compound. In some cases, the esters
may be prepared directly using standard synthetic methods. These esters
may exhibit antiallergic activity, but they are primarily of interest as
synthetic intermediates, although in some instances hydrolyzable or
salt-forming esters may be of interest as therapeutic agents. Preferred
esters are alkyl esters and alkylaminoalkyl esters having one to four
carbon atoms in the alkyl group. Especially preferred are alkylaminoalkyl
esters such as the dimethylaminoethyl esters which will form salts, e.g.,
hydrochlorides.
Ester derivatives may be obtained by alkylation of an alkali metal salt of
the compound in dimethylformamide with an alkyl iodide or
dialkylaminoalkylchloride, or by starting with esters instead of acids in
Scheme I, Step (1) below.
Pharmaceutically acceptable alkali metal and alkaline earth salts may also
be prepared of compounds of Formula I wherein A is tetrazolyl by methods
known to those skilled in the art.
The preferred compounds of Formula I are
4-(3,5-di-tertiary-butyl-4-hydroxyanilino)benzoic acid,
3-(3,5-di-tertiary-butyl-4-hydroxyanilino)benzoic acid,
5-[3-(3,5-di-tertiary-butyl-4-hydroxyanilino)phenyl]tetrazole, and
5-[4-(3,5-di-tertiary-butyl-4-hydroxyanilino)phenyl]tetrazole.
Compounds of the invention may be prepared by the method of Scheme I,
wherein A, R, and B are as defined above, and R' is hydrogen.
##STR7##
The reaction of step (1) is a Lewis acid catalyzed condensation of the
known compound 2,6-di(tertiary-butyl)-p-benzoquinone (II) and a
substituted aromatic amine (III). Suitable substituted aromatic amines for
preparing compounds of Formula I wherein A is carboxyl are known compounds
such as the aminobenzoic acids, for example, 3- and 4-aminobenzoic acid,
the aminophenylacetic acids, aminophenylbutyric acids,
aminophenylthioacetic acids, aminophenyloxyacetic acids, alkyl
aminophenylacetates, aminophenylcinnamic acids, and the like. Similarly,
suitable tetrazolyl-substituted aromatic amines for providing compounds of
Formula I wherein A is tetrazolyl are known such as 5-(3- or
4-aminophenyl)tetrazoles.
Suitable Lewis acid catalysts include boron trifluoride, tin tetrachloride,
titanium tetrachloride and the like.
The reaction of step (1) is carried out by combining the reactants in an
inert solvent such as an ether, for example, tetrahydrofuran, and heating
gently, if necessary. The products of Formula IV are novel solids which
are readily isolated and may be recrystallized from polar solvents.
The reaction of step (2) is a reduction of the imino quinone system of the
intermediate of Formula IV to an amino phenol. It is readily accomplished
using catalytic reduction with hydrogen gas in an inert solvent when A is
carboxyl. It may be carried out under neutral conditions or in the
presence of base, for example, an equimolar amount of base. Suitable
catalysts include platinum or palladium on charcoal. Chemical reduction
can also be carried out, for example, with sodium thiosulfite, or zinc and
acetic acid to provide compounds wherein A is carboxyl or tetrazolyl.
Chemical reduction is preferred when B contains a double bond.
Compounds of the invention wherein R' is alkyl and A is carboxy are
prepared from a compound of Formula V (obtained above) by reacting the
compound with an alkyl halide, particularly an alkyl bromide or an alkyl
iodide. This reaction may be carried out in a solvent such as
N,N-dimethylformamide, optionally in the presence of base. When base is
present, the carboxyl will generally become esterified, and therefore
subsequent hydrolysis by conventional methods may be desired.
Compounds of the invention wherein R' is acetyl or trifluoroacetyl and A is
carboxy are prepared from a compound of Formula V by reacting the compound
with the appropriate anhydride.
Compounds of Formula I wherein A is N-methyltetrazolyl are preferably
prepared by alkylating an alkali metal salt of the corresponding compound
of Formula I wherein A is tetrazolyl with methyl iodide.
Compounds of Formula IV wherein A is
##STR8##
may be prepared from the corresponding compound of Formula IV wherein A is
carboxy via reaction of that compound with thionyl chloride and subsequent
reaction of the resulting acid chloride with sodium
trifluoromethanesulfonamide. Catalytic reduction provides compounds of
Formula I wherein A is
##STR9##
Compounds of Formula I wherein A is tetrazolyl may also be prepared by the
method of Scheme II wherein R, n and B are as defined above and R' is
hydrogen.
##STR10##
The reaction of step (1) of Scheme II is a Lewis acid catalyzed
condensation similar to step (1) of Scheme I except that here an
aminonitrile of Formula VI is used in place of the substituted aromatic
amine used in step (1) of Scheme I. Compounds of Formula VI are known or
may be prepared by conventional methods. The reaction is conducted as
described in connection with step (1) of Scheme I. The product of step (1)
of Scheme II is a novel intermediate of Formula VII.
The reaction of step (2) of Scheme II is a reduction of the type (and
performed using the method of) step (2) of Scheme I to provide a novel
intermediate of Formula VIII.
In step (3), the intermediate of Formula VIII is reacted with sodium azide
in the presence of ammonium chloride and lithium chloride. The reaction is
preferably conducted in N,N-dimethylformamide and is conducted under a
nitrogen atmosphere and accompanied by heating.
In step (4), the intermediate of formula VIII is hydrolyzed, in an inert
atmosphere, by known means such as with sodium hydroxide in aqueous
ethanol, to provide compounds of Formula X.
Compounds of the invention wherein R' is alkyl and A is carboxy, tetrazolyl
or N-methyltetrazolyl may be prepared by alkylating the intermediate of
Formula VIII by conventional methods prior to conducting step (3) or (4).
Again, as in Scheme 1, compounds of the invention wherein R' is acetyl or
trifluoroacetyl may be prepared from the compounds of Formula IX and X by
reacting the compound with an appropriate anhydride as discussed
previously.
Similarly, N-methyltetrazolyl derivatives may be prepared as described in
connection with Scheme I above.
The anti-allergic activity of the compounds of Formula I may be
demonstrated via a variety of biological assays including in vitro assays
for measuring inhibition of lipoxygenase activity and leukotriene
synthesis, and in vivo assays for inhibiting bronchoconstriction.
More specifically, a suitable assay for demonstrating inhibition of
lipoxygenase activity by the compounds of Formula I utilizes lipoxygenase
isolated from mammalian lung tissue, for example, the lung tissue of
guinea pigs. An example of such an assay is that described by Ben Aziz et
al., Anal. Biochem. 34, 88 (1970), incorporated herein by reference. The
inhibition of lipoxygenase activity is measured by a rapid and sensitive
spectrophotometric technique. The compounds of Formula I of the invention
exhibit an IC.sub.50 (the concentration at which 50% of the enzymatic
activity is inhibited) of less than about 100 micromoles per liter.
Preferred compounds exhibit an IC.sub.50 of less than about 50 micromoles
per liter. Most preferred compounds exhibit an IC.sub.50 of less than
about 10 micromoles per liter.
The activity of the compounds of Formula I may also be demonstrated in a
more specific test for leukotriene biosynthesis inhibition. This test
utilizes the cell free leukotriene biosynthesis system of M. Steinhoff et
al., Biochim. Biophys. Acta. 68, 28 (1980), incorporated herein by
reference, which consists of homogenized rat basophil leukemia cells.
Leukotriene synthesis is initiated by the addition of arachidonate.
Solutions are centrifuged and supernatants assayed using a
radioimmunoassay developed as described by Aeringhaus et al., FEBS Letter
146, 111-114, incorporated herein by reference. Drugs are dissolved in
ethanol or dimethyl sulfoxide and preincubated for five minutes. Phenidone
is used as a positive control. The compounds of Formula I exhibit an
IC.sub.50 of 100 micromoles per liter or less. Preferred compounds exhibit
an IC.sub.50 less than 25 micromoles per liter, and most preferred
compounds exhibit an IC.sub.50 of less than 10 micromoles per liter.
The compounds of Formula I are relatively inactive as inhibitors of
cyclooxygenase. This is important in order for there to be good in vivo
antiallergic activity. A convenient in vitro method for measuring
cyclooxygenase activity is an assay wherein the amount of thromboxane
B.sub.2 production is measured in a whole blood clotting assay. The
thromboxane B.sub.2 production is measured by a radioimmunoassay as
described by Patrono, et al, Thromb. Res. 17, 317 (1980), incorporated
herein by reference. The compounds of Formula I do not show appreciable
activity at concentrations of 100 micromoles per liter.
The in vivo test used to demonstrate anti-allergic activity may be any of
those known to those skilled in the art. Preferably, bronchoconstriction
in sensitized guinea pigs is measured upon antigen challenge. This test is
described in broad terms by Piechuta, et al., Immunology, 38, 385 (1979),
incorporated herein by reference, and more specifically by Hammerbeck and
Swingle, Int. Archs. Allergy Appl. Immun. 74, 84-90 (1984), incorporated
herein by reference. It is used in a modified form as follows: Male
Hartley guinea pigs (250-600 g) are dosed with a compound of Formula I in
an amount generally about 1 to 40 mg/kg. Fifteen minutes later the animals
are aerosol challenged with either water or ovalbumin at a concentration
of 10 mg per ml. The animals are then placed under an inverted dessicator
jar (18.times.14 cm) with a constant flow of air coming into the chamber
from a compressed-air source to prevent hypoxia. Air flow leaving the
chamber and fluctuations due to respiration are monitored through a
separate outlet with a Fleisch No. 0000 pneumotachograph (available from
Beckman Instruments, Inc., Schiller Park, Ill.) coupled to a Beckman Type
R dynograph (available from Beckman Instruments). Aerosolization through a
third outlet is made via a No. 40 DeVilbiss nebulizer (available from The
DeVilbiss Company, Somerset, Pa.) for 90 seconds at 150 mm Hg. The
characteristic respiratory patterns observed are summations of two air
exchange processes occurring simultaneously in the chamber. One exchange
process is due to inspiration and expiration of air into and out of the
animal, while the other exchange process is due to the air flow into and
out of the chamber due to respiratory movements. The tracing obtained is
the mechanical representation of the summation of those flows.
Superimposed on the tracings was a characteristic spiking (`notching`),
which appears to be due to an exaggerated expiratory movement, the
frequency of which correlates with the severity of the bronchoconstrictive
reaction. The frequency of notching for 15 minute periods beginning 4
minutes after the beginning of the aerosol challenge is used for comparing
various treatments. Effects are considered significant if the t value
achieves p<0.05. Compounds of Formula I exhibit an intraperitoneal
ED.sub.40 of 100 mg per kg or less when tested in the above model.
Preferred compounds exhibit an ED.sub.40 of 20 mg per kg or less. Most
preferred compounds of the invention exhibit an ED.sub.40 of 10 mg per kg
or less and are effective orally.
The imine intermediates of Formula IV are also active as an antiallergic
agent and are believed to be reduce in Vivo to the corresponding compounds
of Formula I. Specifically,
4-amino-3-(2,6-di-t-butycyclohexadienon-4-ylideneamino)benzoic acid,
4-(2,6-ditertiary-butylcyclohexadienon-4-ylideneamino)benzoic acid,
4-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)hippuric acid,
4-(2,6-ditertiary-butylcyclohexadienon-4-ylideneamino) cinnamic acid,
4-acetamido-3-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)benzoic
acid, and 3-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino) benzoic
acid have been found to exhibit useful activity in the above described in
vivo assay involving bronchoconstriction. The last compound mentioned
above, when administered in vivo to a dog, has been found to be converted
to the compound 3-(3,5-di-tertiary-butyl-4-hydroxyanilino)benzoic acid.
One of the preferred compounds of Formula I of the invention, namely
3-(3,5-di-tertiary-butyl-4-hydroxyanilino)benzoic acid has been found to
be active as a bronchodilator in the small airways of the guinea pig as
determined using the method described in L. Diamond et al., J. Appl.
Physiol.: Respirat. Environ. Exercise Physiol., 43 (6), 942-948 (1977).
Thus, compounds of Formula I are antiallergic agents exhibiting in vivo
activity in mammals. The pharmaceutical compositions of the present
invention will contain sufficient compound of Formula I in a dosage form
suitable for inhibiting the mammalian biosynthesis of leukotrienes, or for
the treatment desired. The effective concentration of the Formula I
compound in the composition will vary as required by the mode of
administration, dosage form, and pharmacological effect and level desired.
For treating pulmonary conditions such as asthma, the mode of
administration may be oral, parenteral, by inhalation, by suppository and
the like. Suitable oral dosage forms are tablets, elixirs, emulsions,
solutions, capsules, including delayed or sustained release dosage forms.
Dosage forms for administration by inhalation include aerosols and sprays
which may be administered in metered doses if desired.
For treating other allergies or allergic reactions, the compound of Formula
I may be administered by any conventional mode, for example, orally,
parenterally, topically, subcutaneously, by inhalation and the like. The
oral and parenteral dosage forms are as described for pulmonary treatment.
The topical application dosage forms include ointments, sprays, controlled
release patches, powders, solutions and the like.
For treating inflammation, the mode of administration may be oral,
parenteral, by suppository and the like. The various dosage forms are as
described above.
For treating skin diseases such as psoriasis, atopic dermatitis and the
like, oral, topical or parenteral administration is useful. For topical
application to the diseased area, salves, patches, controlled release
patches, emulsions, etc. are convenient dosage forms.
For treating cardiovascular conditions any suitable mode of administration
may be used.
In addition to the common dosage forms listed above, the compounds of
Formula I may also be administered for various utilities and indications
or for inhibiting leukotriene synthesis by conventional controlled release
means and/or delivery devices.
In preparing suitable dosage forms, conventional compounding procedures and
ingredients, for example, diluents, carriers, etc. may be used. Examples
of suitable solid carriers are lactose, terra alba, sucrose, talc,
gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the
like. Examples of suitable liquid carriers are syrup, peanut oil, olive
oil, water, and the like. Similarly, the carrier or diluent can include
any time delay material well known to the art, such as glyceryl
monostearate or glyceryl distearate, these being useful alone or, for
example, in combination with wax.
The following Examples are provided to illustrate the invention, but are
not intended to limit the invention.
EXAMPLE 1
Preparation of 4-(3,5-Di-tertiary-butyl-4-hydroxyanilino)benzoic Acid
Step A
A mixture of 22 g (0.10 mole) of 2,6-di(tertiary-butyl)-p-benzoquinone,
13.7 g (0.10 mole) of 4-aminobenzoic acid, 175 ml of tetrahydrofuran and 1
ml of boron trifluoride: diethyl ether complex was heated on a steam bath
for 1.25 hours. The mixture was allowed to cool to about 20.degree. C over
16 hours under a nitrogen atmosphere. Evaporation provided a solid which
was washed with hexane and recrystallized from ethanol to provide orange
solid
2,6-di(tertiary-butyl)-4-(4'-carboxyphenylimino)-2,5-cyclohexadien-1-one,
m.p. 305.degree.-309.degree. C. Analysis: Calculated for C.sub.21 H.sub.25
NO.sub.3 : % C, 74.3; % H, 7.4; % N, 4.1; Found: % C, 74.2; % H, 7.4; % N,
4.1.
Step B
To a solution of 5.0 g (0.0147 mole) of
2,6-di(tertiary-butyl)-4-(4'-carboxyphenylimino)-2,5-cyclohexadien-1-one
in 300 ml of ethanol was added 0.25 g of 5 percent palladium on charcoal.
It was subjected to hydrogenation in a Paar apparatus and filtered. This
solvent was removed by evaporation under vacuum and the residue was
recrystallized from a 5:2 (v/v) ethanol-water mixture to provide
light-orange crystals of 4-(3,5-di-tertiary-butyl-4-hydroxyanilino)benzoic
acid, m.p. 241.degree.-243.degree. C. Analysis: Calculated for C.sub.21
H.sub.27 NO.sub.3 : % C, 73.9; % H, 8.0; % N, 4.1; Found: % C, 73.9; % H,
7.9; % N, 3.8.
EXAMPLE 2
Using the method of Example 1, 2,6-di(tertiary-butyl)-p-benzoquinone was
reacted with 3-aminobenzoic acid to provide red-orange crystals of
2,6-di(tertiary-butyl)-4-(3'-carboxyphenylimino)-2,5-cyclohexadien-1-one,
m.p. 230.degree.-231.degree. C. Analysis: Calculated for C.sub.21 H.sub.25
NO.sub.3 : % C, 74.3; % H, 7.4; % N, 4.1; Found: % C, 74.1; % H, 7.6; % N,
3.7.
EXAMPLES 3-6
Using the general method of Example 1, the aminobenzene starting materials
of Formula III, shown in Table I below were reacted with
2,6-di(tertiary-butyl)-p-benzoquinone to provide the imine products
indicated in Table I.
TABLE I
__________________________________________________________________________
Example
Starting Material Product of Formula IV
No. of Formula III (m.p. in .degree.C.)
__________________________________________________________________________
3 4-aminophenylacetic acid
##STR11##
##STR12##
##STR13##
5
##STR14##
##STR15##
6
##STR16##
##STR17##
__________________________________________________________________________
EXAMPLE 7
To a mixture of 200 ml of ethanol and 23.8 g (0.0701 mole) of
2,6-di(tertiary-butyl)-4-(4'-carboxylphenylimino)-2,5-cyclohexadien-1-one
was added 2.9 g (0.072 mole) of sodium hydroxide in 20 ml of water. To
this mixture was added 1.0 g of 10% palladium on charcoal, followed by the
addition of 50 ml of water. The mixture was reduced by agitating on a Paar
apparatus for about 16 hours. Celite was added to the mixture, and the
mixture was filtered through a bed of celite. The mixture was acidified
with 6N hydrochloric acid, and the resulting yellow solid precipitate was
collected by filtration to provide
4-[3,5-di(tertiary-butyl)-4-hydroxyanilino]benzoic acid, m.p.
241.degree.-242.degree. C.
EXAMPLE 8
To a mixture of 200 ml of ethanol and 25.0 g (0.0736 mole) of
2,6-di(tertiary-butyl)-4-(4'-carboxyphenylimino)-2,5-cyclohexadien-1-one
and 12 g (0.087 mole) of potassium carbonate warmed on a steam bath was
added 1.0 g of palladium on charcoal. The mixture was reduced using a Paar
apparatus for 2 hours. The mixture was diluted with 300 ml of water,
filtered through celite, and the filtrate acidified with 6N hydrochloric
acid. The yellow solid precipitate was collected by filtration to provide
4-[3,5-di(tertiary-butyl)-4-hydroxyanilino]benzoic acid, m.p.
241.degree.-242.degree. C.
EXAMPLES 9-13
Using the general method of Example 7 or 8 the imine intermediates obtained
in Example 2-6 were reduced to provide compounds of F | | |
