DE2060329C3 - Process for the preparation of substituted benzamides - Google Patents

Description

R-O

C-NH ₂

(D

O-CH3

wherein R is a saturated or unsaturated straight-chain or branched alkyl radical with 6 to 18 carbon atoms, characterized in that an acid of the general formula

R-O

OH

(H)

O-CH ₃

wherein R has the meaning given above, reacts with urea or thiourea in the absence of solvents at a temperature of 160 to 240 ^{0 C.} J5

It is known that the benzamides of the general formula

R-O

NH ₂

(D

O-CH ₃

wherein R is an alkyl radical having 6 to 18 carbon atoms stands, a strong anti-epilepsy and anti-spasmodic effect (antiepileptic-anticonvulsant Effect), but have no drowsy or hypnotic effect, what from the point of view the therapeutic effect is very favorable (HU-PS 1 53 246).

According to the method known from literature (HU-PS 1 53 246), the benzamides are the

R - O - - C - OH
O-CH ₃

in which R has the meaning given above, with thionyl chloride into the corresponding acid chlorides transferred and then the acid chlorides thus obtained are reacted with ammonia. This The process can be carried out with good yields, but has the following Disadvantages on:

a) The desired product is obtained in two stages

b) The acid chloride formed as an intermediate product is decomposed and conditioned by the moisture the use of thionyl chloride. But it is well known that with thionyl chloride in anhydrous Medium must be worked and the hydrogen chloride formed and the formed Sulfur dioxide has a corrosive effect if the reaction is not carried out in a glass vessel

30 turns.

Because of these disadvantages, the known process is complicated and complicated when producing larger quantities requires a lot of work.

The invention is based on the object, in addition to eliminating the disadvantages of the known process, of providing such a process which enables the benzamides of the general formula I to be prepared in a simple manner and in good yield.
The invention is based on the discovery that the benzamides of the general formula 1 are obtained in a single stage and in higher yields than before and with excellent quality when the acids of the general formula II are reacted with urea or thiourea.

This finding is surprising for several reasons. In literature (Rec. Trav. Chim. 75, 164 [1956]) the production of acid amides by reacting acids with urea was only possible in the case of some aliphatic alicyclic and arylaliphatic acids

5i) described; aromatic and heterocyclic acids have not been synthesized in this way and thiourea has not heretofore been used for this purpose. It is found in the literature mentioned that the yield is reduced considerably (even up to 10 to 18%) when the number of substituents is increased. It is also known that aromatic carboxylic acids can be decarboxylated by heating in alkaline media (J. Chem. Soc. 1945, 311). Experiments by the applicant have shown that when 4-hydroxy-3,5-dimethoxybenzoic acid, which is structurally closest to 3,4,5-trimethoxybenzoic acid, is heated with urea to a temperature of 200 ^° C., no 4-hydroxy 3,5-dimethoxybenzamide obtained, but by decarboxylation

M pyrogallol-1,3-dimethyl ether is formed.

The above finding is also surprising because it is known that methoxy-substituted Benzoic acids in alkaline solution to methyl

are capable of secession; for example, protocatechuic acid can be obtained from vanillic acid (Org. Synth, Col VoL IIL 745 [1967]).

So it is surprising and unexpected that when carrying out this reaction with benzoic acids general formula II the acid amides of general formula I with a good quality and in high quality Yields can be obtained.

The invention therefore relates to a process for the preparation of substituted benzamides of the general formula

R-O

-NH,

O-CH ₃

R-O

C-OH

O -CH.,

example 1

Preparation of 4-n-decyloxy-3,5-dimethoxybenzamide Embodiment A

It was a mixture of 57 g (0.17 mol) of 4-n-decyloxy-3 _r 5-dimethoxybenzoic acid and 113 g (0.187 mol) of urea was heated for 2 hours at 190 to 220 ⁰ C. After cooling, the reaction product was dissolved in 300 cm ^{3 of} dichloroethane dissolved. The organic layer was extracted first with 2 × 100 cm ^{3 of} 4% sodium hydroxide solution and then with 100 cm ^{3 of} water and dried over magnesium sulfate. After the solvent had been distilled off, 51.5 g of crude product (91.1% of theory) were obtained. These were recrystallized from 52 cm ^{3 of} methanol. 47.0 g (83% of theory) of pure product with a melting point of 119 to 121 ^° C. were thus obtained.

wherein R is a saturated or unsaturated straight-chain or branched alkyl radical having 6 to 18 Carbon atoms, which is characterized in that an acid of the general formula

Embodiment B

57 g (0.17 mol) of 4-n-decyloxy-3,5-dimethoxybenzoic acid and 12.8 g (0.17 mol) of thiourea were reacted for 2 hours at 200 to 235 ° C. After cooling, the reaction product was converted into 300 cm ^{3 of} dichloroethane dissolved and then worked up in the manner described above under embodiment A. After the solvent had been distilled off, 50.6 g (89.7% of theory) of crude product remained, which were recrystallized ^{from 51 cm 3 of methanol.} Yield: 45.8 g (81% of theory); Melting point: 119 to 121 ⁰ C.

wherein R has the meaning given above, is reacted with urea or thiourea in the absence of solvents at a temperature of 160 to 240 ^{0 C.}

The acid of the general formula II is heated to a ^{temperature of 160 to 240 ° C. with urea or thiourea for a few hours.} After the reaction mixture has been worked up, the compounds of the general formula I are obtained.

The main advantages of the method according to the invention are as follows:

a) The synthesis gives the desired end product in a single step

b) The compounds containing a shorter alkyl chain or a hydroxyl group in the reaction occurring decarboxylation does not take place, but the desired product is formed in high yield (crude yield: 90 to 95% of theory; yield of pure product: 75 to 85% of theory) and with good quality.

c) The implementation of the implementation is very simple, does not require any particular apparatus and the Increasing the scale does not cause the yield and quality to deteriorate.

The method according to the invention is explained in more detail with reference to the following example.

Example 2
Preparation of 4-n-hexyloxy-3,5-dimethoxybenzamide

28.1 g (0.1 mol) of 4-n-hexyloxy-3,5-dimethoxybenzoic acid and 6.6 g (0.11 mol) of urea were reacted for ^{2 hours at 190 to 220 ° C.} Dissolved reaction product in 150 cm ^{3 of} dichloroethane and then worked up in the manner described in Example 1, embodiment A. After the solvent had been distilled off, 24.6 g (88.0% of theory) of crude product remained, which ^{were recrystallized from 25 cm 3 of} 80% methanol. Yield: 21.7 g (77.5% of theory); Melting point: 156 to 158 ° C.

Example 3

Production of
4-n-octadecyloxy-3,5-dimethoxybenzamide

A mixture of 10.5 g (0.03 mol) of 4-n-octadecyloxy-3,5-dimethoxybenzoic acid and 2.74 g (0.036 mol) of thiourea was heated to 200-235 ° C. for 2 hours. After cooling, the reaction product was dissolved in 100 cm ^{3 of} chloroform. The solution obtained was extracted twice with 50 cm ^{3 of} 4% strength sodium hydroxide solution and then with 50 cm ^{3 of} water and dried over magnesium sulfate. After the solvent had been distilled off, 9.2 g (87.5% of theory) of crude product were obtained. These were recrystallized from 15 cm ^{3 of} 80% strength methanol. Yield: 8.55 g (81.2% of theory); Melting point: 115 to

Claims (1)

Claim: Process for the preparation of substituted benzamides of the general formula general formula I prepared in such a way that the Acids of the general formula P-CH ₃
O