IE44420B1 - Process for the preparation of (2,carbamoylphenyl)2-acetoxxybenzoate - Google Patents

Description

This invention relates to a process for the preparation of (2-carbamoylphenyl) 2-acetoxybenzoate, which has utility in pharmaceutical compositions having analgesic, antipyretic and anti-inflammatory activity in mammals, including man.

Acetyl salicylic acid (aspirin) is a widely used analgesic, antipyretic and anti-inflammatory drug, but it causes bleeding in the upper gastro-intestinal tract •X following oral administration. In most cases such bleeding is so slight as to be harmless, but it can be a major problem in some patients especially those who - regularly take high doses, for example those who suffer from rheumatoid disease.

O-hydroxybenzamide (salicylamide) is also a known , 15 analgesic, antipyretic and anti-inflammatory drug.

Salicylamide does not appear to cause gastro-intestinal bleeding, but unfortunately suffers from other disadvantages, the most significant being extensive inactivation by various metabolic processes in the gastro-intestinal mucosol cells and liver. It appears that inactivation is due to conjugation of the phenolic hydroxyl group with sulphate and glucoronic acid. In man, approximately 1.5 gms of salicylamide must be consumed before the enzymes responsible for this conjugation are saturated and significant quantities of unmetabolised salicyamide pass into the bloodstream to exert pharmacological action.

Despite these drawbacks, aspirin and salicylamide are widely used, both singly and in purely physical mixtures.

The salicylamide ester of aspirin was prepared by two routes by Anschutz and Reipenkroger (Ann. (1924) 439, 1, pp. 5-7) but these authors were concerned only with the chemistry of the substances and its preparation.

Certainly the publication contains no hint of the possible pharmacological properties of the ester.

We have prepared the salicylamide ester of aspirin and we find that it is stable for long periods in acid at the pH encountered in the stomach, yet is rapidly enzymatically hydrolysed in blood. Although it appears to have little or no analgesic, antipyretic or antiinflammatory activity in its own right, it is absorbed from the gastro-intestinal tract into the blood, where it is hydrolysed to the active species. The gastrointestinal bleeding problems associated with aspirin and the extensive inactivation problems of salicyamide are not encountered with the condensation product. The known synergy between aspirin and salicyamide can be more readily exploited with the condensation product than with simple mixtures, since it is not necessary to give the high doses of salicyamide which would otherwise be required to overcome its metabolic inactivation.

In Patent Specification No. 347/77 there is claimed a pharmaceutical composition adapted for oral administration to human beings comprising (2-carbamoylphenyl) 2-acetoxybenzoate formula (I) CH. c=p il C-0 (I) and one or more pharmaceutically acceptable oral carriers. This invention provides a process for the preparation of (2-carbamoylphenyl) 2-acetoxybenzoate of formula (I) above, which process comprises reacting a salt of salicylamide with an acetyl salicylic acid halide, particularly the.acid chloride, in an inert organic liquid medium, which is preferably anhydrous. Suitable media include anhydrous toluene, benzene and chloroform.

The salt of salicyamide may be one which is insoluble in the reaction medium, and In such cases, a solution of the acetyl salicylic acid halide would be added to a suspension of the salicyamide salt. Examples of salts of salicyamide include the alkali metal salts, especially the sodium salt.

On occasions it may be possible to prepare jthe acid chloride in situ, as the reaction takes place. Since mild alkaline hydrolysis of (2-carbamoylphenyl) 2-acetoxybenzoate causes rearrangement to disalicylamide, the reaction conditions should be chosen to avoid this rearrangement product. Similarly, heating of the compound in boiling water produces 2-(2'-hydroxyphenyl)4H-1,3-benzoxazin-4-one and consequently the reaction conditions should be chosen to avoid this rearrangement product.

The following Example, in which the temperatures are in degrees Centigrade, illustrates the preparation - 5 14420 of (2-carbamoylphenyl) 2-acetoxybenzoate:Example Stage 1 - Preparation of acetyl salicyloyl chloride The acid chloride is prepared by reacting aspirin with an excess of thionyl chloride using urea to catalyse the reaction.

In a 2-litre, 3-neck flask equipped with a water bath, stirrer and thermometer is placed 200 ml of thionyl chloride (2.75 mols). To this is added about half the 360 g (2 mols) of aspirin. The fairly mobile suspension is stirred and warmed to 30° and 4 g of urea then added. Initiation of the reaction appears to be enhanced by minimal agitation. Evolution of HCl gas, and a fairly rapid fall in temperature indicate that the reaction has started, and a slow to medium stirring rate is then maintained. The temperature of the mixture is held at 25°C. As mobility increases the remaining aspirin is fed in via a powder funnel in the third neck of the flask, fitted with a Y piece, one arm leading to a gas outlet connected to a scrubber for absorbing HCl and SO^. It is important to avoid the ingress of air containing moisture during this stage of the reaction. The completion of the reaction is indicated by the appearance of the reaction mixture which becomes a clear pale yellow fluid. At this stage a further 30 mins stirring at 25-30° is given. This is followed by the addition of approximately 500 ml of 60-80° petroleum ether at ca 30° with vigorous stirring. On cooling the acid chloride is thrown out of solution as a heavy crystalline off-white solid. It is filtered off, washed with petroleum ether and dried quickly in a forced draught oven at 35-40°.

Exposure to air should be kept to a minimum.

The compound has a melting point of 47-50°. The method can give a weight yield of about 90% of material, ca 93% pure (indicated by halogen estimation).

· Stage 2 - Preparation of (2-Carbamoylphenyl) 2-acetoxybenzoate gm of spray-dried sodium salicylamide was slurried with 100 ml of toluene,' and stirred in an ice bath. To this was slowly added a solution of 20 gm of acetyl salicyloyl chloride dissolved in 75 ml of toluene. After approx, % hour the white precipitate is completely formed. This is filtered off and dried at 35-40°. The reaction yields approx. 30 gm of product. The dried compound is slurried with 250 ml of a saturated sodium bicarbonate15 solution which removes sodium chloride and excess ; salicylate. The solid is then filtered off and dried again at 35-40° followed by recrystallisation from an ethanol/methanol mixture. This yields white crystals which melt anywhere between 152-17O°C. depending on the method of assessment. The compound was soluble in water at room temperature to about 50 mg/100 ml. Thin layer chromatography arid a negative ferric chloride test for phenol hydroxyl group showed that the product did not contain significant amounts of starting material. Infra red, ultra violet, nuclear magnetic resonance and mass spectra were consistent with the formula given earlier in this Specification.

Claims (3)

1. CLAIMS:1. A process for the preparation of (2-carbamoylphenyl) 2-aeetoxybenzoate of formula (1):- 5 which process comprises reacting a salt of salicylamide with an acetyl salicylic acid halide in an inert organic liquid medium.

2. A process as claimed in claim 1, wherein the acetyl salicylic acid halide is the chloride. 10

3. A process as claimed in Claim 1, substantially as hereinbefore described in the example.