3.4.5- Trimethoxybenzoyl chloride

Further substitution of benzoic acid leads to a drug with antiemetic activity. Alkylation of the sodium salt of p-hydroxy-benzaldehyde (8) with 2-dimethylaminoethyl chloride affords the so-called basic ether (9). Reductive amination of the aldehyde in the presence of ammonia gives diamine, 10. Acylation of that product with 3,4,5-trimethoxybenzoyl chloride affords trimetho-benzamide (11). ... 

To a solution of 13 parts of compound A and 12 parts by volume of absolute pyridine in 80 parts by volume of absolute dioxane there are added dropwise and under constant stirring 35 parts of 3,4.5-trimethoxybenzoyl chloride dissolved in 70 parts by volume of absolute dioxane in the course of 30 minutes. The mixture is stirred for a further 3 hours at a temperature of 100°C and the excess solvent is then evaporated in vacuo. The residue of the evaporation is treated with ethyl acetate and saturated sodium carbonate solution, whereafter the organic phase is separated, treated with water, dried with sodium sulfate and the solvent is removed in vacuo. The residue thus obtained is taken up In ether and separated from 4 parts of insoluble trimethoxybenzoic acid anhydride by filtration. After evaporation of the ether there are obtained 32.5 parts of N,N -dimethyl-N,N -bis-[3-(3,4,5-trlmethoxybenzoxy)-propyl] -athylene diamine, corresponding to a yield of 86% of the theoretical. MP 75°C to 77°C. 

To 9.7 grams (0.05 mol) of 4-(2-dimethylaminoethoxy)benzylamine, dissolved in 100 ml of acetonitrile, was added all at once 12 grams (0.051 mol) of 3,4,5-trimethoxybenzoyl chloride, dissolved in 75 ml of acetonitrile. The mixture was stirred and refluxed for 8 hours, and then cooled. The crystalline solid, which had formed, was filtered off, washed with acetonitriie and recrystallized from acetonitriie, to give 4-(2-dimethylaminoethoxy)-N-(3,4,5-trimethoxybenzoyl)benzyiamine hydrochloride, MP 1B5°to 1B6°C. 

Problem 21.11 i Write the mechanism of the reaction just shown between 3,4,5-trimethoxybenzoyl chloride and morpholine to form trimetozine. Use curved arrows to show the electron flow in each step. 

Trimethoxybenzoyl chloride, reduction to 3,4,5-tri-methoxy benazaldehyde, 51, 8 TRIMETHYL-p-BENZOQUINONE, 52,... 

In many reactions the simple saturated nitrogen heterocycles—piperidine, pyrrolidine, piperazine, and morpholine—behave simply as secondary amines that happen to be cyclic. They do the sorts of things that other amines do, acting as nucleophiles in addition and substitution reactions. Morpholine, for example, is acylated by 3,4,5-trimethoxybenzoyl chloride to form the tranquillizer and muscle relaxant trimetozine, and N-methyl piperazine can be alkylated in an S l reaction with diphenylmethyl chloride to give the travel-sickness drug cyclizine. 

Since HCl is formed during the reaction, 2 equivalents of the amine must be used. One equivalent reacts with the acid chloride, and 1 equivalent reacts with the HC] by-product to form an aniinonium chloride salt. If however, the amine component is valuable, amide synthesis is often carried out using 1 equivalent of the amine plus 1 equivalent of an inexpensiv base such as NaOH. For example, the sedative trimetozine is prepa industrially by reaction of 3,4,5-trimethoxybenzoyl chloride with the aniij morpholine in the presence of 1 equivalent of NaOH. 

Trimethoxybenzoyl chloride was reduced to 3,4,5,-trimethoxybenzaldehyde by the complex hydride more conveniently than by Rosenmund reduction (74%). °... 

It is prepared by the interaction of 3,4,5-trimethoxybenzoyl chloride with 3-diethylaminopropyl alcohol with the elimination of hydrochloric acid. 

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