Originator
Glifanan,Roussel,France,1965
Definition
ChEBI: A carboxylic ester that is 2,3-dihydroxypropyl anthranilate in which the amino group is substituted by a 7-chloroquinolin-4-yl group. A non-steroidal anti-inflammatory drug, glafenine and its hydrochloride salt were used for the relief of all types of pain
but high incidence of anaphylactic reactions resulted in their withdrawal from the market.
Manufacturing Process
Step A: Preparation of (2,3-isopropylidenedioxy)-propyl o-nitrobenzoate - 59.6
g of 2,2-dimethyl-4hydroxymethyl-1,3-dioxolane were dissolved under
agitation in 60 cc of anhydrous pyridine. The solution was cooled to +5°c and
86.5 g of o-nitrobenzoyl chloride (prepared by Leckermann et al., Ber. vol.80,
p.488, 1947) were slowly introduced into it. The reaction mixture was agitated
for a period of two hours at room temperature and then was poured into 500
cc of ether. The mixture was filtered and the filtrate was washed successively
with 0.5 N sulfuric acid solution, with aqueous sodium bicarbonate solution
and finally with water until the wash waters were neutral. The washed solution
was dried over sodium sulfate and filtered again. The filtrate was distilled to
dryness under vacuum to obtain 116.5 g (being a yield of 92%) of (2,3-
isopropylidenedioxy)-propyl o-nitrobenzoate in the form of a yellow oil which
distilled at 178°C to 180°C at a pressure of 1 mm.
Step B: Preparation of (2,3-isopropylidenedioxy)-propyl anthranilate - 80 g of
(2,3-isopropyl-idenedioxy)propyl o-nitrobenzoate, obtained as described in
Step A, were subjected to hydrogenation for a period of one hour in 800 cc of
absolute alcohol in the presence of 2 g of palladized carbon black as catalyst.
The reaction mixture was filtered and the filtrate was evaporated under
vacuum to obtain 70.5 g (being a yield of 98.5%) of (2,3-
isopropylidenedioxy)-propyl anthranilate in the form of a yellow oil which
distilled at 159°C to 160°C under 0.5 mm of pressure.
Step C: Preparation of the (α-monoglyceride of 4-(2'-carboxyphenylamino)-7-
chloro-quinoline - A mixture of 48 g of (2,3-isopropylidenedioxy)-propyl
anthranilate, 36 g of 4.7-dichloro-quinoline, 36 cc of concentrated hydrochloric
acid and 300 cc of water was agitated while heating to reflux for a period of
two hours. The reaction mixture was filtered and the filtrate was allowed to
stand at a temperature of 0°C for a period of three hours. The hydrochloride
salt was then vacuum filtered and the salt was taken up in 600 cc 50%
methanol at reflux. The solution was made alkaline by the addition of 120 cc
of ammonia solution and iced for a period of one hour. The crystalline
precipitate obtained was vacuum filtered, washed with water and dried to
obtain 38.5 g (being a yield of 56%) of the α-monoglyceride of 4-(2'-
carboxyphenylamino-7-chloro-quinoline having a melting point of 165°C.
The product occurred in the form of pale yellow prisms and was insoluble in
water, ether, benzene, diluted alcohols, olive oil and chloroform, slightly
soluble in absolute alcohol, dioxane, tetrahydrofuran and acetone, and soluble
in dilute aqueous acids and alkalis.
World Health Organization (WHO)
Glafenine, a quinolylanthranilate derivative, was introduced in
1965 for use as an analgesic. By the late 1970s its use had been associated with
severe allergic responses, including anaphylactoid reactions, which led to its
withdrawal in one country whereas in others a warning to this effect is required in
the product information. In 1992, on the advice of the Committee for Proprietary
Medicinal Products of the European Communities, glafenine was eventually
withdrawn worldwide by the major manufacturer.
![1-GLYCERYL N-[7-CHLORO-4-QUINOLYL]ANTHRANILATE HYDROCHLORIDE Structure](https://www.chemicalbook.com/CAS/GIF/3820-67-5.gif)
