CA1061798A - Process for the preparation of 2-alkoxy-6-aminobenzamides - Google Patents

Abstract

PROCESS FOR THE PREPARATION OF

Abstract of the Disclosure 2-Alkoxy-6-aminobenzamides are prepared in three steps from 2,6-dinitro-benzoyl halides. The products are useful as intermediates for preparing 2'-carbamoyl-3'-(lower)alkoxy oxanilic acid (lower)alkyl esters having anti-allergic activity.

Description

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"

;;

.. ." . . ,... .... :
. : ' ' . ~' ' ' "-,' .' '' . ', '"' ' ~., . . ,.' ' ' ~ '' ' : . - ' ' , ' . , . ` ~ ' - ; , . ,. .', 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.
: , . . .

AHP-6216 f .

~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 :

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.

" ~' '" ~ -'' .
. ~ ..

_ 7 -:

, .. . . . . . . .

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 A~IP-6216 f 7~

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 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, .. . . . . : . ,, ~ . - .:.

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

- ~ . , , . ,, ,.. ,, , . . , . .. ., . , , , .. . .. ~

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.

:'

Claims (4)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A method for preparing a 2-(lower)alkoxy-6-amino-benzamide which comprises: displacing a halogen atom from a 2,6-dinitrobenzoyl halide by the amino group by reaction of said halide in an inert organic solvent with ammonia in order to produce a 2,6-dinitrobenzamide; displacing one nitro group from 2,6-dinitrobenzamide by a (lower)alkoxy group by reaction with an alkali metal lower alkoxide in methanol or ethanol to produce a 2-(lower)alkoxy-6-nitrobenzamide; and reducing the nitro group of a 2-(lower)alkoxy-6-nitrobenzamide.

2. A process as defined in claim 1 wherein the (lower)alkoxy group is methoxy.

3. A process as defined in claim 1 wherein the (lower)alkoxy group is ethoxy.

4, A process as claimed in claim 1, 2, or 3 in which the inert organic solvent is selected from benzene, toluene, 1,2-dichloroethane; carbon tetrachloride and dioxane.