MEBEVERINE

Originator

Duspatalin,Duphar,France,1965

Uses

Relaxant (smooth muscle).

Definition

ChEBI: 3,4-dimethoxybenzoic acid 4-[ethyl-[1-(4-methoxyphenyl)propan-2-yl]amino]butyl ester is a methoxybenzoic acid.

Manufacturing Process

(A) Sodium-3,4-Dimethoxybenzoate: A solution of 91 g of 3,4- dimethoxybenzoic acid in 500 ml of boiling, absolute alcohol was added quickly to a solution of 11.5 g of sodium in 300 ml of absolute alcohol; after cooling to room temperature the resulting precipitate was filtered off and washed with 2 x 50 ml of absolute alcohol and 4 x 200 ml of ether and dried in air to constant weight; yield 92.5 g, MP about 265°C. The filtrate was bulked with the alcohol and ether washings, left to stand overnight, and a further precipitate then filtered off, washed with 3 x 100 ml of ether, and dried in air to constant weight. Yield 22.5 g, MP about 265°C. Total yield therefore 115 g (=113%).
(B) 4'-Chlorobutyl-3,4-Dimethoxybenzoate: 92 g of the sodium salt described under (A) (it contains at the most 81.5 g of sodium 3,4-dimethoxybenzoate) was boiled in 900 ml of tetramethylene dichloride for 90 hours; after cooling the mixture was filtered and the residue washed with 3 x 50 ml of ether. The filtrate was evaporated to dryness in vacuo and the residue (102 g) was distilled in vacuo. Fraction 1: 50° to 55°C/0.5 mm; 19 g (probably tetramethylene dichloride). Fraction 2: 175° to 184°C/0.5 mm; 77.5 g (=71%); Cl= 12.6% (calculated 13.0%). Remark: The second fraction partially solidified or became more viscous on standing, and even during the distillation.
(C) 4'-Iodobutyl-3,4-Dimethoxybenzoate: 32.5 g of 4'-chlorobutyl-3,4- dimethoxybenzoate and 19.5 g of sodium iodide (10% excess) were boiled in 150 ml of methyl ethyl ketone for 2.5 hours; after cooling and filtering off the sodium chloride produced, the reaction was found not to be entirely completed; boiling was then continued for another two hours; the reaction mixture was cooled, and the solid filtered off and washed with 2 x 100 ml of ether.
The filtrate was evaporated to dryness in vacuo and the residue was dissolved in 300 ml of ether and 100 ml of water; the layers were separated and the water layer was once again extracted with 100 ml of ether; then the ether layers were boiled and washed again with a solution of 3.5 g of sodium thiosulfate in 100 ml of water. The ether layer was dried over sodium sulfate. Finally the solution was filtered and the ether was evaporated; the residue was an almost colorless oil, which partially solidified or became more viscous after being left to stand for some time. Yield: 40 g (=92%), I=34.2% (calculated 34.9%).
(D) 4'-[N-Ethyl-1''-Methyl-2''-(4'''-Methoxyphenyl)Ethylamino]Butyl-3,4- Dimethoxybenzoate Hydrochloride: 10.3 g of 4'-iodobutyl-3,4- dimethoxybenzoate and 11.0 g of N-ethyl-p-methoxyphenylisopropylamine (obtained by catalytic reduction of an alcoholic solution of an excess quantity (60%) of p-methoxy-phenyl-acetone, to which was added a 33% (weight-for-weight) aqueous solution of ethylamine, with Pt as a catalyst), were boiled in 200 ml of methyl ethyl ketone for 20 hours, cooled and the iodine ion was determined; the reaction was found to be complete. Then the methyl ethyl ketone was evaporated in vacuo and the residue was dissolved in 300 ml of water and 30 ml of ether; the layers were separated and the water layer was extracted twice more with 20 ml portions of ether.

Therapeutic Function

Spasmolytic