SU786888A3 - Method of preparing polysubstituted 4-alkylaminobenzoic acid esters - Google Patents

Description

(54) METHOD FOR OBTAINING POLESIDE DISPENSERS OF 4-ALKYL-AMINOBENZOIC ACID

one

This invention relates to a process for the preparation of new substituted 4-alkipaminobenzoic acid esters of the general formula

O x y

II I I

CO — CH — C — CH — RJ, (11 unbranched or at the beginning , and X and Y come together to denote a carbon-carbon bond or a ring in a cyclic, ether (-0-) ring, where the alkylaminobenzoyl-oxyl group and X can be substituted e. Compounds of formula 1 possess hypolypemic activity and the ability to lower serum lipid concentrations in the body, in connection with MS5GUT be useful for the treatment of atherosclerosis.

The literature describes 4- (monoalkylamino) benzoic acids and its derivatives with the general formula

where RQ is lower alkoxyethyl, 1-methyl-4-piperidyl, 2-pyridylmethyl, 4-pyridylmethyl, possessing hypolipemic activity, which can be obtained by reacting lower alkyl 4- (monoalkylamino) benzoates with a suitable alkylating agent 1, Other substances with hypolipemic activity are known, such as cetamiphen, lineetol and clofibrate 2. However, there is no information in the literature about the .4-alkylaminobenzoic acid esters of the above structure. In accordance with the invention, a process for the preparation of compounds of the formula 1, which consists of. that 4-alkylaminobenzoic acid or its salt is reacted with an appropriate MHO-substituted alkylating agent, namely halides, sulfonates, or epoxides in aqueous or anhydrous solvents. The process is carried out at a temperature of 20-1 ° C. Hexamethylphosphamide, dimethylformamide, acetonitrile, etc. can be used as solvents. Example. 2,3-dioxypropyl-4, - (n-hexadecylamino) benzoate. The solution, cocTOHiwn from 7.34 g of 4- (n-hexadecylamino) benzoic acid, 4.80 g of 25% aqueous sodium hydroxide and 12.6 g of 3-iodo-1,2-propanediol in 50 ml of hexamethylphosphoramide The mixture is stirred for 24 hours at ambient temperature, diluted with 10 ml of ether and stirred for 5 days at ambient temperature. This mixture is treated with water and extracted with ether. The dried extracts were evaporated to give 2, 3-dioxypropyl-4- (n-hexadecylamino) benzoate, m.p. 112 s. PRI mme R 2. 2,3-Dioxypropyl-4- (n-hexadecylamino) benzoate. A solution of 7.20 g of 4- (n-hexadecyls of but) -benzoic acid in 25 ml of hexamethylphosphoramide is added to a stirred mixture of 0.8 g of sodium hydride (57% in mineral oil) and 25 g of hexamethylphosphoramide. The solution, which is formed after 1 hour, is treated with 11.0 g of 1-HLOR-2,3-propane diol, and then stirred for 18 hours. Dilution with water followed by filtration gives a more solid substance, which crystallizes from ethanol, giving 2,3-dioxypropyl, 4- (n-hexadecylamino) benzoate, m.p. 112-113s. Froze 2,3, -Dioxypropyl-4- (n-hexadecylamino) benzoate. A solution of 7.35 g of 4- (n-hexadecylamino) benzoic acid in 50 MP of hexamethylphosphoramide is treated; 4.80 g of 25% aqueous sodium hydroxide, and then 11.0 g of 3-chloro-1,2-propanediol, then heated at 6 h. The mixture is diluted with water and ether and filtered to give a white solid. A cross istilization with acetonitrile, and then, from carbon tetrachloride, an analytically pure 2,3, -dioxypropyl-4- ( n-hexadecylamino) benzoate, t, pl. 112-113 ° C. PRI me R 4. Hydrochloride 4- (n-hexadecylamino) -benzoic acid. A solution of 2.0 g of 4- (n-hexadecylamino) -benzoic acid in methylene chloride is stirred at and treated with anhydrous hydrogen chloride. The mixture obtained is cooled and filtered, whereby 4- (n-hexadecylamino) -benzoic acid hydrochloride is obtained in the form of a white solid. Example 5. 4-n-Hexadecylamino) -benzoyl chloride hydrochloride. A mixture consisting of 1.0 g of 4- (n-hexadecylamino) benzoic acid hydrochloride and 5.00 ml of thionylchloro. the mixture is allowed to stand at ambient temperature for 20 hours and then concentrated in vacuo to give 4- (n-hexadecylamino) benzoyl chloride hydrochloride as an orange solid. EXAMPLE 5: 2,3, -Epoxypropyl-4- (n-hexadecylamino) benzoate. A mixture consisting of 89.0 g of epichloro hydrin, 92.0 g of 4- (n-tensadecylamino) -benzoate of sodium and 350 ml of hexamethylphosphoramide, stirred at 105 ° C for 5 hours, cooled and poured into 1.0 l of water. The white solid is filtered, recrystallized from acetonitrile, and then from hexamethylene chloride, and 2,3-epoxypropyl-4- (n-hexadecylamino) benzoate is obtained, m.p. 86-b9c. PRI me R 6. 4-Oxybutyl-4- (n-hexadecylamino) benzoate. A mixture consisting of 7.66 g of 4- (n-hexadecylamino) sodium benzoate, 7.55 g of 4-chloro-1-butane and 20 ml of hexamethylphosphoramide is stirred at 2 hours, cooled and then poured into water . The solid is filtered off and then dissolved in methylene chloride. The solution is washed with water, dried and evaporated. The remaining solid is crystallized from hexane and get 4-hydroxybutyl-4- (hexadecylamino) -benzoate in the form of a white solid, so pl. 61-bZ C. Example 7. 3-hydroxypropyl-4- (n-hexadecylamino) benzoate. According to the method of example 6 is treated with 3-bromopropanol 4- (n-hexadecylamino) benzoate, which gives 3-hydroxypropyl-4- (n-hexschycylamino) benzoate, so pl. 67-b9c. Example 8. 1,3-dioxypropyl-4- (n-hexadecylamino) benzoate. A solution consisting of 3.8 g of 4- (n-hexadecylate sodium) -benzoate, 3.7 g of epichlorohydrin and 0.7 ml of water in hexamethylphosphoramide is heated to within 5 hours. Then add 0.7 ml water and then 1 ml of 1N. sulfuric acid. The reaction mixture is cooled. After adding dimethoxyethane and benzene, the organic layer is separated and washed with water. The solvent was removed in vacuo to give a white solid, which was recovered from 15 ml of acetonitrile to give 2, 3-dioxypropyl-4- (n-hexadecylamino) benzoate. Example 9: 2,3-Dioxypropyl-4- (n-hexadecylamino) benzoate. 1 Solution consisting of 4- (n-hexacylamino) benzoic acid and

1.0 p of 2,3-epoxypropan-1-ol in 100 ml of hexamethylphosphoramide is heated at 8 hours. After adding ether and water, the ether layer is separated and extracted several times with ether. After evaporation of the extracts, the mixture is separated by chromatography on silica gel and recrystallized from acetonitrile.

I'll try it on. 2, 3, -dioxypropyl-4- (n-non-1-decylamino) benzoate.

A solution of 8.05 g of 4- (n-nonadecylamino) benzoic acid in 25 ml of methylphosphoramide hexa is treated with sodium hydride and then 1-chloro-2,3-pr.opanediol and the expected product is obtained in the form of a white solid

Example 11. 2,3-Dioxypropyl-4- (n-octylamino) benzoate.

A solution of 4.97 g of 4- (n-octylamino) -benzoic acid in 25 ml of hexamethylphosphoramide is treated with sodium hydride and -1-chloro-2,3, -propanediol to obtain white crystals.

Example 12. 2,3, -Dioxypropyl -4- (n-tridecylamino) benzoate.

A solution of 6.36 g of 4- (n-tridecylamine 6), benzoic acid in 25 ml of hexamethylphosphoramide is treated with sodium hydride and 1-HLOR-2,3-propanediol to obtain the desired product as a white solid.

Claims (2)

1. US patent number 3868416, cl. 260-518, pub. 1975. 2. Mashkovsky M. D. Medicinal products; 14.05.72. v.2, p. 139142.