CA2022100A1 - Process for the preparation of carboxylic acids and esters - Google Patents

Abstract

PROCESS FOR THE PREPARATION OF CARBOXYLIC ACIDS AND ESTERS
Abstract The invention relates to the preparation of carboxylic acids and alkyl esters of the general Formula I

(I) (wherein R1 and R2 are identical and stand for lower alkyl;
R3 and R4 are identical and stand for hydrogen or lower alkyl and R5 represents hydrogen or lower alkyl) by subjecting a compound of the general Formula II
(II) to ammonolysis with aqueous ammonium hydroxide in the presence of a strong inorganic base and a cupric(II)compound and, if desired, N-dialkylating the 4-amino-compound of the general Formula III
(III) thus obtained.
The advantage of the process resides in the fact that inexpensive, readily available starting materials can be used and the process can be performed economically on industrial scale too.
The compounds of the general Formula I are known pharmaceutical intermediates.

Description

2 ~ 2 2 ~ ~ v PROCESS FOR THE PREPARhTION OF CARBOXYLIC ACIDS AND ESTERS

This invention relates to a new and improved process ;;~
for the preparation of known carboxylic acids and alkyl esters.
More particularly,the invention is concerned with a process for the preparation of carboxylic acids and alkyl esters of the general Formula I ~:.

R O
R3R4N ~ CoOR5 (I) R20 ,.' .';, , ~"'` '..
(wherein Rl and R2 are identical and stand for lower alkyl; .
R3 and R4 are identical and stand for hydrogen or lower .
alkyl and R5 represents hydrogen or lower alkyl).
The 4-amino-3,5-dialkoxy and 4-(N,N-dialkylamino)-3,5--dialkoxy-benzoic acids and alkyl esters of the general Formula I are useful pharmaceutical intermediates which can ~ :
be used e.g. in the preparation of Aditoprim, a known anti- ~:
bacterial and sulfonamidepotentiating agent / the chemical Formula of Aditoprim is 2,4-diamino-5-(3,5-dimethoxy-4- :
-dimethylaminobenzyl)-pyrimidine7. The specific intermediate of the general Formula I useful in the synthesis of Aditoprim A4665-62 PT/Gi ~ -.,.. ,.,, ,, , .,, , .. ,, . . . ~ -- 2 - 2~2~Q~ ~

is the 4-dimethylamino-3,5-dimethoxy-benzoic acid and the methyl ester thereof. According to prior art the latter compound can be prepared by N-alkylating the 4-a~ino-3,5--dimethoxy-benzoic acid or the methyl ester thereof. Thus, ; ;
the 4-amino-3,5-dimethoxy-benzoic acid can be regarded as a key intermediate.
In the prior art sever~ methods are disclosed for the - preparation of 4-amino-3,5-dimethoxy-benzoic acid and the methyl ester thereof. According to the method of I. Kompis -and A. Wick / Helv. Chim. Acta 60 /8/, 3205-34 (1977)7 di- ' methyl-2,5-dimethoxy-terephthalate is subjected to a regio-. : :~ .:
selective Lossen-decomposition. The reaction is accomplished in polyphosphoric acid as medium with the aid of hydroxil ;~
amine. The starting material used is, however, very expensive and difficultly available; for this reason the process can be realized only in laboratory while it is un-suitable for industrial scale production.
According to German Patent specification No. 2,443,682 4-acetamido-3,5-dimethoxy-toluene is oxidized with potassium permanganate in a mixture of pyridine and water to the corresponding benzoic acid derivative, whereupon the acid thus obtained is esterified and the acetamido group is converted into an amino group. The drawback of this process resides in the fact that because of the oxidation reaction carried out with potassium permanganate it can not be accomplished economically on industrial scale. No yields are disclosed in the patent specification.
In U.S. patent No. 4,515,948 a very complicated six-step - 3 _ 2 0 2 2 ~

synthesis is disclosed for the preparation of methyl-4--dimethylamino-3,5-dimethoxybenzoate. As starting material 3-hydroxy-5-keto-3-cyclohexane carboxylic acid is used :~
~, .. .,: . i, .
which is first subjected to azo-coupling, whereupon the 4-phenylazo-3-hydroxy-5-keto-3-cyclohexene-carboxylic acid thus obtained is esterified with methanol, the methyl ester formed is aromatized by means of treatment with acetamide ~ -and bromine, the methyl-4-phenylazo-3,5-dihydroxybenzoate ~-is methylated, the methyl-4-phenylazo-3,5-dimethoxy-benzoate ~
10 formed is reduced to methyl-4-amino-3,5-dimethoxy-benzoate ~ -and in the last step the amino group is alkylated. This process is accompanied by a number of disadvantages. On the one hand,it is a complicated multistep process while,on the other,the starting material is expensive and difficultly avaiIable. This process is unsuitabIe for industrial-scale manufacture.
It is the object of the present invention to elaborate ~`
a process suitable for the economical industrial-scale production of the valuable intermediates of the general 20 Formula I by using inexpensive and readily available -~
starting materials. ;~
According to the present invention the compounds of the general Formula I are prepared by reacting a compound of the general Formula II
R10 ~;

~ Br 4/ \~ CoOR5 ;~

:; R2 ,', ~` ~; '':
~-,'~''' ::
.

^- 2 ~ ~. 2 ~

(wherein Rl, R2 and R5 are as stated above) in the presence of 3 strong inorganic base and a cupric(II)compound with aqueous ammonia, if desired, setting free the carboxylic acid of the general Formula III
--RlO
H2N ~ CoOR5 (III) R 0 -~

(wherein R5 stands for hydrogen and Rl and R2 are as statPd above) from the salt thereof and, if desired, purifying or esterifying the said carboxylic acid, if desired, alkylating a compound of the general Formula III thus obtained (wherein ~ - -15 Rl, R2 and R5 are as stated above) in a known manner and, ~;
if desired, converting an ester of the general Formula I ~
thus obtained (wherein R5 stands for lower alkyl and Rl, R2, ;`
R3 and R4 are as stated above) into the corresponding carboxylic acid of the general Formula I (wherein R stands 20 for hydrogen and Rl, R2, R3 and R4 are as stated above). ~ ~-The present invention is based on the recognition that 4-bromo-3,5-dialkoxy-benzoic acids and alkyl esters of the ~-general Formula IIcan be converted into 4-amino-3,5-dialkoxy--benzoic acids or alkyl esters of the general Formula III ~ ;~
of satisfactory quality with excellent yields by treatment with aqueous ammonium hydroxide. This recognition is surpris-ing and unexptected. It is namely known that the compounds ;
of the general Formula II can not be converted into the ~-, . :~

~5 - 2 ~
. .:
corresponding 4-dialkylamino-derivatives by treat~ent with dialkyl amines. On reacting a compound of the general `
Formula II with aqueous dimethyl amine,the bromine in posi~
tion 4 is though split off with a yield of 75-100 %, but `

5 several side reactions take place, numerous side products - --are formed and for this reason the desired 4-dimethylamino~
-derivative is not formed at all or is obtained only in traces. Thus,it could not be aforeseen that the treatment of a compound of the general Formula II with aqueous ammonium ;~
hydroxide would yield the corresponding 4-amino-3,5-dialkoxy--benzoic acid of the general Formula III in a purity suitable - - ;
for pharmaceutical purposes. `~
Ammonolysis of the starting materials of the general ., :
Formula II can be carried out at a temperature between 110 C

and 140 C, preferably at 118-128 C. The reaction is ,: . .
accomplished in the presence of a strong inorganic base. ~
- ,.:
Preferably an alkali hydroxide (e.g. sodium or potassium `
hydroxide), alkali carbonate (e.g. sodium or potassium carbonate) or alkali bicarbonate (e.g. sodium or potassium bicarbonate) can be used. Sodium or potassium hydroxide proved to be particularly suitable for this purpose. The ---strong inorganic base is used preferably in a stoichiometrical amount, related to the starting material of the general Formula II, or with a deviation in the range of +10%. ~ `;
The reaction is carried out in the presence of a cupric-(II)compound as catalyst. Inorganic or organic cupric(II)-compounds can be used as catalyst. According to a preferable embodiment of the invention cupric(II)sulfate or cupric(II)- -oxide may be used. It is particularly preferred to use as : .
cupric(II)compound a cupric(II)-bromo-dialkoxy-benzoate contain~
ing an alkoxy group which corresponds to the alkoxy group being present in the ~ ~
starting material of the general Formula II. Thus in case of the ~ -preparation of 4-amino-3,5-dimethoxy-benzoic acid or 4-amino-3,5-di-n-propoxy-benzoic acid one may preferably use as catalyst cupric(II)-4-bromo-3,5- ;~--dimethoxy-benzoate and cupric(II)-4-bromo-3,5-di-n-propoxy- ~
~. --benzoate, respectively. The cupric(II)compound may be added in an amount of 5-20 molar%, preferably 8-12 molar %.
The concentration of the aqueous ammonium hydroxide is advantageously at least 20% by weight and particularly preferably it exceeds 30% by weight. One may work particular~
ly advantageously by u~ing a 35% by weight aqueous ammonium ~;
hydroxide solution.
According to a form of realization of the process of the present invention anhydrous 4-bromo-3,5-dialkoxy-benzoic acid or its alky] ester of the general Formula II is used. In this case the concentration of the aqueous ammonium hydroxide solution is at least 20% by weight and preferably it is higher ~ ~ -than 30% by weight. According to another form of realization of the process of the present invention a moist compound of the general Formula II is used; this starting material is dissolved in water and gaseous ammonia is introduced into the aqueous solution.
The reaction time amounts preferably to 7-15 hours and ;
the reaction takes place preferably within 8-11 hours.
From a reaotion mixture comprising a salt of an acid of the general Formula III, wherein R5 stands for hydrogen, - 7 ~ 2 ~ 2 2 ~

the cupric salt is removed, the filtrate is diluted and the;
carboxylic acid is set free from the salt thereof by acidifica- -`
tion. A mineral acid may be used in the acidification reaction.
The carboxylic acid of the general Formula III (wherein R5 stands for hydrogen) is isolated and washed. The product thus obtained is of satisfactory purity and can be directly used in the alkylation step without purification.
The carboxylic acid of the general Formula III (wherein ~ ~ -R5 stands for hydrogen) may be esterifie~ if desired,to the corresponding alkyl ester by methods known per se.
The carboxylic acid or alkyl ester of the general ~ ~ ~i Formula III thus obtained (wherein R5 stands for hydrogen ;~
. . ~
or lower alkyl) may be converted, if desired, into the corresponding compound of the general Formula I, in which ~ ;
R3 and R4 are lower alkyl. The said alkylation reaction can ;
be accomplished by methods known per se. The compounds of the general Formula III fall under the scope of the general ~
Formula I and represent a sub-group thereof wherein R and : ~ `
R4 stand for hydrogen. As alkylating agent the corresponding ;~
dialkyl sulfate or alkyl halide may be used. One may proceed preferably by reacting a 4-amino-derivative of the general -Formula III with a dialkyl sulfate in an organic solvent ~ ;
(e.g. a lower alkanol, preferably methanol or ethanol) in the presence of an alkali hydroxide, alkali carbonate or ~ -alkali bicarbonate.
One may also proceed by alkylating a 4-amino-compound ``-... .
; of the general Formula III with a lower alkanol in the presence ---of an anhydrous mineral acid (e.g. hydrogen chloride). The .. ..

., ~, 2 ~ 2 2 ~

reaction may be carried out under heating in a closed vessel.
The reaction may be accomplished at a temperature of 120--180 C, preferably at 130-150 C. The reaction takes ~ ~
place within a few hours, the average reaction time is about ~;
7-17 hours, advantageously about 8-9 hours.
The 4-bromo-3,5-dialkoxy-benzoic acids and esters of the general Formula II used as starting material can be prepared from 3,5-dihydroxy-benzoic acid or esters thereof -~
in a known manner with very high yieldsof about 80-90 %.
The advantage of the process of the present invention is that the intermediates of the general Formula I can be prepared in satisfactory purity by using inexpensive and readily available starting materials, economically on industrial scale too. `~
Further details of the present invention are to be found in the following Examples without limiting the scope of ;~
protection to the said Examples.
Exam~le 1 .
Into a 1 litre stainless tube reactor 25 g of crystalline cupric(-II)sulfate, 275 g of anhydrous methyl-4-bromo-3,5--dimethoxy-benzoate or 261 g-of anhydrous 4-bromo-3,5-di-:- . .: --:
;~ methoxy-benzoic acid and 40 g of sodium hydroxide are weighed -in. The tube rsactor is cooled to a temperature below 0 C
in a salt-ice bath,whereupon 800 g of a 25% or 580 g of a 35~ aqueous ammonium hydroxide solution are added. The tube reactor is sealed and its content is heated in an oil bath ~ ~
to 118-128 C within 45 minutes. The reaction mixture is ;`~-heated at this temperature for 8-11 hours. The a~monolysis ~ _ 9 _ 2 0 2 2 ~

having been completed the ammonia is removed from the tube -reactor, whereupon the pH is adjusted to a value of 7.0+0.5 and the precipitated cupric(II)dimethoxy benzoate is filtered off. About 20% of the product thus formed precipitates in the form of a copper compound. The isolated copper compound is reintroduced into the synthesis and can be used as ~ ~ ~
catalyst in the place of cupric(II)sulfate. - :
The product is diluted with 1500 ml of water and the pH is adjusted to 4-5 by adding diluted hydrochloric acid.
The precipitated crude 4-amino-3,5-dimethoxy-benzoic acid is filtered off and washed. Yield 63-70~. The active ingredient - ;
content of the crude product amounts to 100-110 g. `
The crude 4-amino-3,5-dimethoxy-benzoic acid thus obtain~
ed can be directly used in the methylation reaction. The product may be purified, if desired, by dissolving in crude diluted hydrochloric acid, tre~ting the solution with calite or activated charcoal and adjusting the pH to 4-5. Thus pure `
4-amino-3,5-dimethoxy-benzoic acid is obtained.
Exam~le 2 The crude product comprising 100-110 g of 4-amino-3,5--dimethoxy-benzoic aoid is dissolved in 1100 ml of methanol at room temperature. To the solution at first 230 g of sodium ~-hydrogen carbonate are added at 40 C whereupon 210 g of di- ~-methyl sulfate are introducedat 40-45 C within 30-40 minutes. "--25 After the evolution of gas has stopped the reaction mixture J'. `""".
- is refluxed for half an hour, whereupon it is clarified with --calite or activated charcoal and filtered. Thus 90-105 g of methyl-4-(N,N-dimethylamino)-3,5-dimethoxy-benzoate are obtained. The overall yield of the two reaction steps amounts -'' '`' '';
.' ` ~.

- lo - 2~2~ 3 to 17-55% ~ ;
In course of the isolation the methyl-3,4,5-trimethoxy- -~
. . :
-benzoate may be recovered by known methods, if desired, -~
~ .
and can be converted into 3,4,5-trimethoxy-benzoic acid ~ ;
by saponification.
ExamPle 3 One proceeds in an analogous manner to Examples 1 and `~
2 except that 320 g of anhydrous ethyl-4-bromo-3,5-dimethoxy~
-benzoate or 290 g of anhydrous 4-bromo-3,5-dimethoxy-benzoic ;
10 acid, 55 g of potassium hydroxide and 8 g of cupric(II)- ~ -;
oxide are used as starting material. Thus 115-135 g of ethyl--4-amino-N,N-diethyl-3,5-diethoxy-benzoate are obtained.
Yield 47-55%. ;
ExamPle 4 One proceeds in an analogous manner to Examples 1 and ~;
2 except that 360 g of anhydrous propyl-4-bromo-3,5-di-n--propoxy-benzoate or 330 g of anhydrous 4-bromo-3,5-di-n--propoxy-benzoic acid, 40 g of sodium hydroxide and 70 g ~ ~
of cupric(II)-4-bromo-3,5-di-n-propoxy-benzoate are used ~`
as starting material. Thus 180-210 g of propyl-4-(N,N-di-propyl-amino)-3,5-di-n-propoxy-benzoate are obtained. Yield 47-55%.
"
Exam~le 5 One proceeds in an analogous manner to Example 1 except that 460 g of methyl-4-bromo-3,5-dimethoxy-benzoate (moisture ;~
content 40%) or 435 g of 4-bromo-3,5-dimethoxy-benzoio acid -(moisture content 40%), 40 g of sodium hydroxide and 25 g of crystalline cupric(II)sulfate are used as starting ''',...
: ~:

~`!, `, ., ,, ''..." ., 2 0 2 2 ~

material. In place of aqueous ammonium hydroxide 230 g of water are added and 225 g of gaseous ammonia are introduced. Thus 90-105 g of methyl-4-(N,N-dimethylamino)--3,5-dimethoxy-benzoate are added. Yield 57-66%.
ExamPle 6 420 g of crude 4-amino-3,5-di-n-propoxy-benzoic acid are dissolved in 420 g of tri-isopropanolamine; the latter ~-acts both as solvent and acid-binding agent. 190 g of 1- - ~
-bromo-propane are added, whereupon the reaction mixture ~`
is refluxed for 4 hours and the product is isolated as described in Example 1. Thus 180-210 g of propyl-4-(N,N- --dipropylamino)-3,5-di-n-propoxy-benzoate are obtained. -~
Yield 47-55%.
ExamPle 7 :
Into a reactor verified for a pressure of 50 bar 105 g of 4-amino-3,5-dimethoxy-benzoic acid prepared according ` ;
to Example 1 are wèighed in whereupon 800 g of alcohol -comprising 3.3 moles of hydrogen chloride/litre are added.
The reaction mixture is heated at 130 C for 8-9 hours, whereupon the methyl chloride formed is removed in vacuo.
The solution is admixed with 2.2 1 of water having a temperature of 0-5 C and washed with 130-150 ml of toluene. -The pH of the aqueous solution is adjusted to 7 with -ammonia, the precipitated product is filtered, washed and ~;
dried in vacuo. Thus 96-110 g of methyl-4-(N,N-dimethyl-amino)-3,5-dimethoxy-benzoate are obtained. The overall yield of the two reaction steps amounts to 49-57%.

.;~ ~

Claims (11)

1. A process for the preparation of carboxylic acids and alkyl esters of the general Formula I
(I) (wherein R1 and R2 are identical and stand for lower alkyl;
R3 and R4 are identical and stand for hydrogen or lower alkyl and R5 represents hydrogen or lower alkyl), which c o m p r i s e s reacting a compound of the general Formula II
(II) (wherein R1, R2 and R5 are as stated above) in the presence of a strong inorganic base and a cupric(II)compound with aqueous ammonia, if desired, setting free the carboxylic acid of the general Formula III

(III) (wherein R5 stands for hydrogen and R1 and R2 are as stated above) from the salt thereof and, if desired, purifying or esterifying the said carboxylic acid; if desired, alkylat-ing a compound of the general Formula III thus obtained (wherein R1, R2 and R5 are as stated above) in a known manner and, if desired, converting an ester of the general Formula I thus obtained (wherein R5 stands for lower alkyl and R1, R2, R3 and R4 are as stated above) into the correspond-ing carboxylic acid of the general Formula I (wherein R5 stands for hydrogen and R1, R2, R3 and R4 are as stated above).

2. A process according to Claim 1, which c o m p r i s e s using the cupric(II)compound in an amount of 5-20 molar %, preferably 8-12 molar %.

3. A process according to Claim 1 or 2, which c o m p r i s e s using as cupric(II)compound cupric(II)sulfate, cupric(II)oxide or a cupric(II)-4-bromo-3,5-dialkoxy-benzoate which corresponds to the alkoxy groups being present in the starting material of the general Formula II.

4. A process according to any of Claims 1-3, which c o m p r i s e s using an alkali hydroxide, preferably sodium or potassium hydroxide, as strong inorganic base.

5. A process according to Claim 4, which c o m p r i s e s using the strong inorganic base in an approximately equi-molar amount, preferably ?10% of the equimolar amount, related to the starting material of the general Formula II.

6. A process according to any of Claims 1-5, which c o m p r i s e s carrying using an aqueous ammonium hydroxide solution having a concentration of at least 20% by weight, preferably at least 30% by weight.

7. A process according to Claim 6, which c o m p r i s e s using a 35% aqueous ammonium hydroxide solution.

8. A process according to any of Claims 1-7, which c o m p r i s e s carrying out the reaction at a temperature between 110 °C and 140 °C, preferably at 118-128 °C.

9. A process according to any of Claims 1-8, which c o m p r i s e s carrying out the reaction within a period of 7-15 hours.

10. A process according to Claim 1, which c o m p r i s e s alkylating a carboxylic acid or alkyl ester of the general Formula III with a dialkyl sulfate or alkyl halide.

11. A process according to Claim 1, which c o m p r i s e s alkylating a carboxylic acid or alkyl ester of the general Formula III by heating with a lower alcohol in the presence of an anhydrous mineral acid.