Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
This invention relates to a process for preparing
"-(lower)alkoxy-6-aminobenzamides which are useful as inter-
mediates for the production of 2'-carbamoyl-3'-(lower)alkoxy
oxanilic acid (lower)alkyl esters having anti-allergic activity.
The invention sought to be patented comprises a
method for preparing a 2-(lower)alkoxy-6-aminobenzamide which
comprises:
(a) displacing a halogen atom from a 2,6-dinitro-
benzoyl halide by the amino group to afford 2,6-dinitrobenzamide;
(b) displacing one nitro group from 2,6-dinitro-
2~ benzamide by a (lower)alkoxy group to afford a 2-(lower)alkoxy-
6-nitrobenzamide; and
(c) reducing the nitro group of a 2-(lower)alkoxy-
6-nitrobenzamide.
As used herein and in the claims, the term "halide"
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. ~' ' ' "-,' .' '' . ', '"' ' ~., . . ,.' ' ' ~ '' '
: . - ' ' , ' . , . ` ~ ' - ; , . ,. .',
means a chlorine, bromine, or iodine atom. The term "(lower)-
alkoxy" means a methoxyl or an ethoxyl group. The term
"(lower)alkyl" means a straight chain or branched alkyl group
of from 1 to 6 carbon atoms.
The 2-(lower)alkoxy-6-aminobenzamides produced by
the process of the invention can be converted to 2'-carbamoyl-
3'-(lower)alkoxy oxanilic acid (lower)alkyl esters by conden-
sation with an appropriate (lower)alkyl oxalyl chloride in
dichloromethane in the presence of pyridine. For example,
2-methoxy-6-aminobenzamide (0.053 mole) is reacted with ethyl
oxalyl chloride (0.055 mole) in dichloromethane (100 ml.) in
the presence of pyridine (0.06 mole) at lO~C. with stirring
to give 2'-carbamoyl-3'-methoxy-oxanilic acid ethyl ester.
The 2'-carbamoyl-3'-(lower)alkoxy oxanilic acid
(lower3alkyl esters possess anti-allergic activity as demon-
strated in a standard biological test procedure. The pro-
cedure used to establish the anti-allergic activity of said
compounds is reported in Immunology, Vol. 16, pp. 749-760
(1969). In this test, anti-allergic activity is assessed
by administering the test compound to a sensitized rat
(inoculated with sera from rats immunized with egg albumin
and pertussis vaccine) and measuring the size of the bleb
which appears on the back of the rat after an injection with
Evans blue dye and egg albumins. The anti-allergic results
are expressed as the per-cent inhibition of bleb size as
compared to control animals that do not receive the test
compound.
When tested as described above, 2'-carbamoyl-3'-
methoxy-oxanilic acid methyl ester, at a dose of 20~ mg. per
AHP-6216 f
kg. of host body weight, gave 10~/o inhibition of mean bleb size
by I. P. administration and 94% by PØ administration. The
mechanism of anti-allergic action of the final products is
believed to be similar to that of INTAL~ (disodium cromoglycate)
and is thought to involve the blocking of reactions in the
mast cells leading to the production and release of mediators.
In carrying out the process of the invention, in
step (a) as hereinabove-described, the displacement of a halo-
gen atom by the amino group is carried out by dissolving the
2,6-dinitrobenzoyl halide in a reaction-inert organiG solvent
and then bubbling ammonia through the solution until precipi-
tation of the amide is complete. Preferred solvents are
benzene, toluene, 1,2-dichloroethane, carbon tetrachloride,
or dioxane. The reaction will readily take place at room
temperature but higher temperatures may be employed, if desired.
The product is isolated by conventional purification procedures
such as crystallization from an appropriate solvent. It wi~l
be appreciated that the ammonia reagent can be generated in
s u from an ammonia precursor for example, ammonium carbonate.
In step (b), the displacement of a nitro group by a
(lower)alkoxy group is carried out by treating a solution of
2,6-dinitrobenzamide in anhydrous methanol or ethanol with an
appropriate alkali metal (lower)alkoxide, i. e. sodium, potas-
sium, or lithium methoxide or sodium, potassium or lithium
ethoxide. The particular solvent employed will depend upon
the alkoxide used. The reaction is conveniently carried out
at reflux temperature and the reaction time is from 1 to 24
hours. The product is isolated by conventional purification
procedures, such as by crystallization from an appropriate
solvent.
: , . . .
-- 3 --
AHP-6216 f
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~3~
In step (c), the reduction of the nitro group is
carried out using a reducing agent capable of reducing a
nitro group without reducing the amide carbonyl. Suitable
reducing agents will be apparent to those skilled in the art.
Preferred reducing agents are hydrazine in the presence of
Raney nickel catalyst [See Balcomb et al., J. Am. Chem. Soc.,
75, 4334 (1953) and Butler et al., J. Chem. Soc.; 1959, 2396]
and hydrogen in the presence of a noble or a base metal cata-
lyst, such as platinum, palladium, rhodium, ruthenium, nickel,
cobalt, and the like. Other suitable reducing agents are iron-
hydrochloric acid, iron-acetic acid, and ferrous sulfate-ammo-
nium hydroxide. The reduction reactions are carried out in a
reac$ion-inert organic solvent. For the hydrazine-Raney nickel
method, a lower alkanol, such as methanol, ethanol, isopropanol,
or propanol, is preferred. The product is isolated by con-
ventional purification procedures, such as by crystallization.
The 2,6-dinitrobenzoyl halides employed as starting
materials for the process of the invention are prepared from
2,6-dinitrobenzoic acid by methods which are conventional for
preparing acid halides. For example, 2,6-dinitrobenzoyl chloride
is prepared by the reaction of the acid, with thionyl chloride,
phosphorous oxychloride, or phosporous pentachloride. The
chlorination can be accomplished without a solvent or in sol-
vents such as benzene, toluene, 1,2-dichloroethane, carbon
tetrachloride, or dioxane. Treatment of the resultant acid
halide in any of the above-mentioned solvents with ammonia
as in step (a) affords 2,6-dinitrobenzamide.
The process of the invention is particularly suited
to large-scale production since high temperatures are avoided.
The process of the invention is illustrated and
demonstrated in the following examples:
AHP-6216 f
7~
Example 1
To a reaction flask charge 106 g. (0.5 mole) 2,6-
dinitrobenzoic acid and 50 ml. toluene. Add a solution of
75 g. (0.63 mole) thionyl chloride in 50 ml. toluene to the
slurry which has been heated to 65-105~C. Adjust the tempera-
ture to 105 ~ 2C. and stir at this temperature for 1 hour to
obtain complete solution. The resultant toluene solution,
upon concentration to dryness in vacuo, affords 110.9 g. of
, .
crude 2,6-dinitrobenzoyl chloride as a light tan solid melting
at 87-90C. Purified 2,6-dinitrobenzoyl chloride is obtained
,~ .... - ... .
by crystallization from benzene, the melting point being
raised to 94-97C.
Example 2
Suspend 10.6 g. 2,6-dinitrobenzoic acid in 50 ml.
1,2-dichloroethane. Add 7.5 ml. SOC12 and heat the mixture
at reflux until a complete solution is obtained. Concentra-
tion of the resultant solution to dryness affords 11.6 g.
of crude 2,6-dinitrobenzoyl chloride which melts at 85-89C. -
"
Example 3
:,- .
Suspend 10.6 g. 2,6-dinitrobenzoic acid in
~ ., .
50 ml. dioxane and add a solution of 7.5 ml. SOC12 in
5 ml. dioxane. Heat to reflux for several hours to obtain ~ ~
a complete solution. Evaporate the solvent in vacuo ~ ~ -
and stir the residue with warm toluene. Filter off the
toluene insolubles (2.0 g.) which is unreacted
:
- 5 -
A~IP~6216 f
9 l3~
2,6-dinitrobenzoic acid (M.P. 200-203C). Concentration of the
toluene filtrate affords 8.7g. of crude 2,6-dinitrobenzoyl
chloride which melts at 85C.
Example 4
Mix 21.2 g. 2,6-dinitrobenzoic acid and 22.9 g.
PCl5 in a suitable vessel and warm the mixture of solids by
immersing in a warm water bath. A liquid melt forms at 40-50C.
which is further heated to about 60C. for l/2 hour. Con-
centrate in vacuo to remove POCl3 which forms. Add several
portions of toluene and again concentrate to insure removal of
POCl3. Finally, take up the residue in 25 ml. toluene. After
cooling, 7 g. of pure 2,6-dinitrobenzoyl chloride is isolated
which melts at 93-96C. Concentration of the toluene filtrate
affords a second crop of 15.8 g. having a melting range of
87-90C.
'. ~ ~'' '
Example 5
Suspend 10.6 g. 2,6-dinitrobenzoic acid and 11.5 g.
PCl5 in lOO ml. CCl4. Heat the mixture to reflux for several
hours. Upon cooling 2,6-dinitrobenzoyl chloride c~ystallizes
as fine needles, which when isolated and dried weigh 9.9 g.
(86.1%) and melts at 90-93C.
,
~1P-6216
7 ~ ~
. .
Example 6
Reflux a suspension of 10.6 g. 2,6-dinitrobenzoic
acid and 20 ml. POC13 for two hours. Concentrate the clear
amber solution in vacuo to remove excess POC13, then chase
... .... .
residual POC13 with several portions of toluene. Finally,
dissolve the concentrate in 50 ml. toluene. Filter off the
insolubles (unreacted acid). Concentration of the toluene
filtrate affords a 76.5% yield of 2,6-dinitrobenzoyl chloride.
Example 7
Dissolve 1 g. of 2,6-dinitrobenzoyl chloride (as
obtained in Example 2) in 10 ml. 1,2-dichloroethane. Bubble
ammonia into the solution until no more solids precipitate.
After isolation, washing and drying, 0.9 g. crude 2,6-dinitro-
benzamide (98%) is obtained which melts at 248-253C.
''' ' '` ' ''
.
Example 8
,, .
Dissolve 1 g. of 2,6-dinitrobenzoyl chloride (as ~
obtained in Example 5) in 10 ml. CC14 and bubble NH3 through ~ -
the solution until no more solids precipitate. After isolation ~ -
and drying, 0.7 g. 2,6-dinitrobenzamide is obtained which
exhibits the typical IR spectrum and which melts at 255-257C.
" ~'
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,
.. . . . . . . .
AHP-6216 f
Example 9
Dissolve 1 g. of the 2,6-dinitrobenzoyl chloride (as
obtained in Example 3) in dioxane and bubble ammonia through
the solution. Remove the bulk of the solvent by concentration
_n vacuo and replace with water. Isolation of the solids which
form affords 0.5 g. of 2,6-dinitrobenzamide.
Example 10
A solution of 10 g. 2,6-dinitrobenzoyl chloride (as
obtained in Example 1) in five volumes of toluene is treated
with excess ammonia to yield 8.4 g. (91.6% of theory) of 2,6-
dinitrobenzamide; M.P. 254-257C. ~ -
Example 11
To a reaction flask equipped with stirrer, thermo-
meter, condenser and dropping funnel charge 106 g. (0.5 mole)
2,6-dinitrobenzoic acid and 500 ml. toluene. Add a solution
of 75 g. (0.63 mole) thionyl chloride in 50 ml. toluene to
the slurry which has been heated to 65-10~C. Adjust the
temperature to 105 ' 2C. and stir at this temperature for 1
hour to obtain complete solution. Distill 150 ml. of solvent
at atmospheric pressure (to remove excess SOC12). With
vigorous agitation bubble an excess of anhydrous ammonia
into the reaction solution at temperatures from 25-85C.
Crystals of 2,6-dini$robenzamide begin to form immediately
AHP-6216 f
upon introduction of NH3. Cool the resultant slurry to 25C.,
isolate by filtration and wash with toluene followed by
methanol. Slurry the methanol damp cake in 350 ml. water,
filter and dry the product to constant weight; yield, 9g.3 g.
(94.1% of theory); M.P. 250-253C.
Example 12
Repeat as in Example 11, except benzene is used
rather than toluene. Thionyl chloride is added to the
benzene suspension of 2,6-dinitrobenzoic acid at 70C., then
the temperature is raised to reflux and maintained at this
temperature for 12-20 hours. The reaction solution is treated
with excess ammonia and the product isolated, washed, and dried,
as described in Example 11; to yield 104.5 g. 2,6-dinitro-
benzamide (98.~/o of theory) which melts at 250-253C.
Example 13
Repeat as in Example 11, except that the toluene
reaction solution is stirred for 3 hours at 60C. in the
presence of 100 g. ammonium carbonate. The solids which form -
are isolated, slurried in water to remove excess (NH4)2C03,
then dried to provide 64 g. of 2,6-dinitrobenzamide.
Example 14
To a reaction flask equipped for reflux, charge
52.8 g. (0.25 mole) 2,6-dinitrobenzamide and 500 ml. methanol.
7~h
Heat the suspension to 55C., then with stirring slowly add
a solution of 13.8 g. (0.255 mole) sodium methoxide in 200 ml.
anhydrous methanol. Raise the temperature to reflux and main-
tain at reflux for 3 hours. Cool the solution obtained to
60C. and stir with 2.5 g. activated carbon (supplied under
the trademark Darco G60) for 15 minutes at 60-65C. Filter
the hot mixture through a filter aid (supplied under the
trademark Celite). Cool the filtrate to room temperature with
stirring, then chill to 0-5C. and stir for several hours.
Filter off the crystals and wash with cold methanol. Upon
drying to constant weight at 50C., 28 g. of 2-methoxy-6-nitro-
benzamide is obtained as cream-colored crystals which melt
at 194-195C.
Example 15
Add 8.1 g. (0.15 mole) sodium methoxide with stirring
to 150 ml. anhydrous methanol. The temperature rises to 40C.
Then add 15.8 g. (0.075 mole) 2,6-dinitrokenzamide with
stirring and wash in with 50 ml. methanol. Heat the slurry
to reflux (66-68C.) and maintain at reflux for 13 hours.
Filter the hot solution, then cool with stirring to crystallize.
A total of 11.1 g. (75.~/o of theory) of 2-methoxy-6-nitro-
benzamide is obtained which melts at 197-199C. and shows -
only one spot by TLC.
Example 16
Stir 15.8 g. 2,6-dinitrobenzamide (0.075 mole~ into
150 ml. anhydrous methanol and heat to 60C. Add a solution
-- 10 --
A~IP-6216 f
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of 8.1 g. (0.15 mole) NaOCH3 in 60 ml. methanol over 12 minutes
at 60C. Heat the mixture to reflux (66C) and maintain at
reflux 17 hours. Distill 105 ml. methanol at atmospheric
pressure, then cool the concentrate to 25C. Add 105 ml. water
slowly with stirring, then cool the slurry to 0-5C. and stir
for 2-1/4 hours. Isolate by filtration, wash with cold
methanol, then dry to constant weight at 50C. 12.9 g. (87.8% -
yield) 2-methoxy-6-nitrobenzamide is obtained which melts at
194-197C., contains only one component as determined by TLC
and assays 99.9% pure by GLC. ~ -
.
Example 17
-~' "' '.
Dissolve 0.5 g. sodium wire in 30 ml. anhydrous
ethanol. Add 2.1 g. 2,6-dinitrobenzamide and heat the mix- ~
ture at reflux for 12-16 hours~ Concentrate the dark solu- -
tion to about 1/2 volume, then cool to room temperature and -~
slowly add 15 ml. H20. Chill in an ice-bath, then filter and
wash the product with cold ethanol. The dried 2-ethoxy-6-
nitrobenzamide (0.75 g.) melts at 197-200C. and exhibits
typical IR absorption.
Z0 Example 18
Charge a 300 ml. reactor with 9.8 g. (0.05 mole)
2-methoxy-6-nitrobenzamide and 100 ml. ethanol. Add a small
spoon spatula portion of active Raney nickel catalyst (Grace
No. 28) which has previously been washed with water and then
with ethanol and warm the mixture to 45C. under nitrogen.
Add a solution of 7.5 ml. (0.1275 mole) 85% hydrazine
hydrate in 20 ml. ethanol with stirring over 10 minutes at
-- 1 1 --
AHP-6216 f
7~
45-48C. Add small portions of Raney nickel catalyst. Each
addition of Raney nickel causes a vigorous evolution of gas
and the temperature rises to 70-72C. Continue the addition
of Raney nickel catalyst until the evolution of gas begins
to diminish and the temperature no longer increases. Heat
the mixture to reflux for 20 minutes, then cool to just below
the boiling point. Carefully filter the hot suspension through
ma~k)
Celiter(catalyst is pyrophoric).
Concentrate the pale green filtrate to dryness in
vacuo to obtain 8.0 g. of green crystals which melt at 134-
139C. Solubilize the crude product in 130 ml. boiling water,
filter while hot, then cool the filtrate with stirring. After
isolation and drying, 6.3 g. of recrystallized 2-methoxy-6-
aminobenzamide is obtained which melts at 142-144C. -
Example 19
'
Stir 5 g. water-wet active Raney nickel catalyst
in 10 ml. water, filter and wash on the filter with fresh
water. Transfer the water-wet catalyst to a 300 ml. re-
actor under a nitrogen purge. Add 10 ml. ethanol, stir20 briefly, then remove the ethanol with a filter stick.
Repeat the ethanol washing several times. After the last
ethanol wash add 50 ml. fresh ethanol and warm the suspen-
sion to 45C. under nitrogen.
In a separate flask charge 9.8 g. (0.05 mole) 2-
methoxy-6-nitrobenzamide, 7.5 ml. 85% hydrazine hydrate and ~ -
50 ml. ethanol. Add this stirred supension portionwise to
the suspension of catalyst over a period of 15 minutes,
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.. . . . . : . ,, ~ . - .:.
AHP-6216 f
1'7~
allowing the temperature to rise to 60-65C., and then main-
tain this reaction temperature by the rate of addition. Stir
at 60-65C. for an additional 5 minutes after addition is
complete, then heat to reflux (77C) and maintain at reflux
for 10 minutes.
Cool the reaction mixture to 75C. and filter through
a bed of Celite rinsing the flask and filter with ethanol
(caution: pyrophoric; immerse filtered catalyst and filter aid
in water). Concentrate the colorless filtrate to dryness in
vacuo to obtain 8.6 g. of 2-methoxy-6-aminobenzamide; M.P. 137-
142C.; assay by non-aqueous titration, 97.6%; TLC, one major
component, two faint impurity spots.
Example 20
2-Methoxy-6-nitrobenzamide (49 g.; 0.25 mole) is
reacted as described in Example 19. Concentrate the reaction
filtrate to approximately one-fifth its original volume, then
stir the concentrate at 0-5C. Collect the resultant white
crystals by filtration, wash with cold ethanol and dry; 28.5 g.
2-methoxy-6-aminobenzamide is obtained which is 99.5% pure
by non-aqueous titration; M.P. 147.5-150C.
Example 21 -
A rapidly stirred solution of 0.05 mole 2-methoxy-6-
nitrobenzamide in acetic acid and ethanol (2:1) is hydrogenated
in the presence of platinum black at 35-45C. and essentially
atmospheric pressure. After the uptake of hydrogen ceases,
filter off the catalyst and concentrate the filtrate to remove
':
_ 13 --
AHP-6216 f
the bulk of the acetic acid. Di~solve the concentrate in
water and adjust to pH 6-8 with dilute sodium hydroxide.
Cool and isolate the 2-methoxy-6-aminobenzamide which pre-
cipitates on neutralization. After drying, 1.4 g. of 2-
methoxy-6-aminobenzamide is obtained which melts at 144-147C.
and which shows the typical IR spectrum.
Example 22
Suspend 5 g. 2-methoxy-6-nitrobenzamide and 3.5 g.
iron filings in 50 ml. water. Add 1 ml. concentrated hydro-
chloric acid and heat at steam-bath temperature for several
hours. Filter the hot mixture. Upon cooling, brown crystals
form in the filtrate. These solids, 2.1 g. after drying, are
shown by TLC to be a mixture of 2-methoxy-5-aminobenzamide
and 2-methoxy-6-nitrobenzamide.
Example 23
Repeat as in Example 22, but using 10-15% aqueous
acetic acid rather than the dilute HCl. From the cooled
filtrate 3.1 g. of light tan solids are obtained which melt
at 118-130C. and are shown by TLC to consist of a mixture
of 6-amino- and fi-nitro-2-methoxybenzamide.
:'~
Example 24
Dissolve 140 g. FeS04 in 240 ml. water and heat to
90C. Add 10.2 g. 2-methoxy-6-nitrobenzamide and 3 ml. 0.2 N
- 14 -
- ~ . , , . ,, ,.. ,, , . . , . .. ., . , , , .. . .. ~
AHP-6216 f
hydrochloric acid. Add 60 ml. concentrated ammonium hydroxide
to the hot mixture in increments over a period of about 40
minutes.
Filter the hot mixture. Isolate and dry the crystals
which form in the cooled filtrate. 2.3 g. of 2-methoxy-6-
aminobenzamide is obtained which melts at 141-143C. and which
exhibits the typical IR spectrum.
Extraction of the filter cake with hot ethanol
affords an additional 2.5 g. of product.
:'
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