CS199675B2 - Method of preparing p-acetamidophenyl-diethyl-aminoacetate - Google Patents

Description

The invention relates to a process for the preparation of p-acetamidophenyl diethylaminoacetate of the formula I

p-Acetamidophenol is commonly used in medicine because of its analgesic effect; a disadvantage of this compound is that it is practically insoluble in water.

It is therefore an object of the present invention to provide a process for the preparation of a p-acetamidophenol derivative that is very soluble in water and which provides aqueous solutions that are stable over time. The active p-acetamidophenol is rapidly released from this derivative in the body. Said derivative is p-acetamidophenyl diethylaminoacetate corresponding to the following formula I

199875 which is used in particular in the form of its acid addition salts, in particular in the form of its chlorohydrate.

The process according to the invention consists in reacting p-acetamidophenyl haloacetate, in particular p-acetamidophenyl chloroacetate, with an equivalent of diethylamine in the presence of a hydrohalic acid acceptor formed during said reaction, whereupon isolate the formed p-acetamidophenyl diethylaminoacetate.

The hydrohalic acid acceptor may preferably be an excess of diethylamine or triethylamine.

Although the above reaction may be conducted at conventional reaction temperatures of the physical properties of the starting materials and final products, it is preferred to operate at a maximum of 50 ° C, particularly preferably at between 40 and 50 ° C ^P

It is, of course, possible to operate at a temperature of more than 50 ° C, but it consumes more energy without increasing the yield. Conversely, at a reaction temperature above 50 ° C, the yield of the desired product decreases quite rapidly,

The conversion of p-acetamidophenyl diethylaminoacetate into its non-toxic pharmaceutically acceptable acid addition salt is carried out in a manner known per se, i.e. by treatment with the corresponding acid.

In the following, the process according to the invention will be explained in more detail in two examples, which are not intended to limit the scope of the invention in any way.

Example 1

22.8 g of p-acetamidophenyl chloroacetate are added in small portions with stirring to 40 cm ^{3 of} diethylamine; if necessary, maintain the temperature of the reaction mixture at a temperature range of 40 to 50 ° C using a cold water cooling bath. After the heat ceases in the reaction mixture, the reaction mixture is allowed to warm to 45 ° C for two hours with stirring, then cooled, diluted with 250 cm ^{3 of} ice water and extracted with ether. It is then dried over magnesium sulphate and the ether is evaporated in vacuo to give p-acetamidophenyldiethylaminoacetate as a thick oil.

The base thus obtained is used in the crude state to prepare an acid addition salt.

To prepare the corresponding chlorohydrate, dissolve the above residue in acetone (150 cm ³ ), acidify the solution with ethereal hydrochloric acid to pH 11, then allow the reaction mixture to stand for one hour and then filter, wash with acetone, dry and recover 13.2 g of p-acetamidophenyl diethylaminoacetate chlorohydrate crystals.

Melting point 228 ° C.

Example 2

To a solution of 7.5 g of diethylamine in 30 cm @ ^{3 of} triethylamine, 22.8 g of p-acetamidophenyl chloroacetate is added in small portions with stirring, optionally maintaining the reaction mixture at 40 to 50 ° C using a cold water cooling bath. Thereafter, the same procedure as in the preceding Example 1 was followed to obtain 12 grams of p-acetamidophenyl diethylaminoacetate chlorohydrate.

Melting point 228 ° C.

The pharmacological properties of the p-acetamidophenol derivative according to the invention will be illustrated in the following.

The analgesic activity of the product was determined by the following method:

groups of six male mice (SPF, OFI species) weighing 19-20 g were administered the intravenously tested product. At the same time, 0.3 cm ³ / mouse of a 0.02% phenylbenzoquinone solution was injected intraperitoneally. At 5 and 10 minutes after the latter injection, the number of pain reactions (abdominal torsea) was calculated.

The inhibition of the indicated reactions in percent is evaluated in Table I below.

Table I mg / kg I.V. Inhibition (%)

26

41

68

94

The antipyretic effect of the product according to the invention was determined by the following method:

groups of five rabbit males (Fauve de Bourgogne) weighing 2 to 3 kilograms were administered intravenously with 1 cm ³ / kg salmonella abortus equi endotoxin solution in both physiological saline at a concentration of phi / kg.

Two and a half hours thereafter, the test animals were administered intravenously the product of the invention in saline.

The rectal temperature was then recorded at regular intervals using an Ellab thermocouple. The probe was inserted into the rectum to a depth of 80 mm.

In Table II, temperatures are given in degrees Celsius.

mg / lkg l.V. T — 2 h 30 min

(B)

Table II

T — 0 T + 1h T + 1h T + 1h T + 2h min 30 min

128

38.8 + 0.10 °

38.8 + 0.06 °

38.8 + 0.12 °

38.8 + 0.21 °

40.9 + 0.15 °

41.1 + 0.19 °

41.2 + 0.24 °

41.3 + 0.34 °

41.3 ° ± 0.08 °

41.2 ° ± 0.16 °

40.8 ° ± 0.24 °

41.2 ° + 0.07 °

41.4 ° ± 0.06 °

41.0 ° + 0.22 °

40.6 ° + 0.19 °

40.3 ° + 0.22 °

41.2 ° ± 0.1 °

40.9 ° ± 0.21 °

40.4 ^p + 0.22 °

40.1 ° ± 0.26 °

40.8 ° ± 0.13 °

40.7 ° ± 0.50 °

40, T ° ± 0.28 °

39.6 ° + 0.22 °

In conclusion, the product of the invention has pharmacological properties comparable to the pharmacological properties of paracetamol. It can be administered in jellies or tablets containing 200 mg of active ingredient, and in ampoules containing 100 mg of active ingredient. Orally administered 3 to 6 times daily; the daily dose for intravenous administration is 100 to 300 mg.

Claims (4)

OBJECT OF THE INVENTION A process for the preparation of p-acetamidophenyl diethylaminoacetate of formula (I) or a non-toxic pharmaceutically acceptable acid addition salt of said compound, comprising reacting p-acetamidophenyl haloacetate with diethylamine equivalent in the presence of a hydrohalic acid acceptor formed during the reaction; The formed p-acetamidophenyl diethylaminoacetate is isolated and optionally converted to the non-toxic acid addition salt by treatment with the corresponding acid. 2. The process according to claim 1, wherein an excess of diethylamine is used as the hydrohalic acid acceptor. 3. The process of claim 1 wherein the hydrohalic acid acceptor is triethylamine. 4. Process according to claim 1, characterized in that the reaction is carried out at a temperature of at most 50 ° C, preferably at a temperature of 40 to 50 ° C.