Originator
Flogar, A.B.C. , Italy ,1976
Manufacturing Process
1 g of 1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indoleacetic acid [J. Am. Chem. Soc. 85, 488-489 (1963)] is treated in a nitrogen stream with 10 ml thionyl chloride in which it promptly dissolves. The solution is quickly evaporated in vacuum and the residue (which typically is of a deep browngreen color) is distempered, twice or three times, with a few ml anhydrous benzene which is removed in vacuum each time. The resulting residue is thoroughly distempered with 5 ml anhydrous ether which dissolves most of the color impurities, and separated by filtering, purified by crystallizing from plenty of anhydrous ether, yielding a crystalline mass of needles of strawyellow color, melting point 124°C to 127°C. Yield: 0.700 g. Found: Cl % 18.62 (calculated 18.84).
The product is relatively stable towards water and aqueous alkalies in which it proves to be insoluble even after dwelling therein several hours at room temperature. It reacts, better if at elevated temperature, with lower alcohols with which it forms the corresponding esters, and with ammonia under suitable conditions for forming the amide (melting point 219°C to 221°C).
A solution of 1.330 g sodium hydroxide in 20 ml water is slowly admixed with 2.330 g hydroxylamine hydrochloride while cooling, whereupon 1 g chloride of 1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indoleacetic acid is distempered in this neutral or slightly alkaline solution by vigorously stirring during a few minutes.
The acid chloride reacts with the free hydroxylamine with considerable rapidity apparently without dissolving. The reaction is completed when a sample of the suspension shows to become clear on adding aqueous alkali. The crystalline pale-yellow mass of product is separated by filtering, lavishly washed with water and dried in vacuum. The crude product yield is actually quantitative. The product is purified with excellent yields by repeatedly crystallizing from hot dioxane and washing with ether: melting point 181°C to 182°C (dec.).
