Floctafenine

Chemical Name 2-[ [8-(trifluoromethvl)-4-quinolinvl] amino] benzoic acid 2,3-dihvdroxv-propyl ester 

2-Dimethyl-4-hydroxymethyl-1.3-dioxolane Sodium hydride Hydrogen chloride 

Step A Ortho-Trif/uoromethy/anilinomethy/ene Ethyl Malonate - A mixture of 54.8 grams of ortho-trifluoromethylaniline and 73.5 grams of ethoxymethylene ethyl malonate was heated to 120°C under an inert atmosphere and maintained for 1 hour at this temperature while distilling off the ethanol formed. The mixture was cooled and the elimination of ethanol was completed by distillation under reduced pressure. The mixture was cooled to obtain 115 grams of ortho-trifluoromethylanilinomethylene ethyl malonate which was used as is for the following stage. A sample of the product was crystallized from petroleum ether (8P = 65° to 75°C) to obtain a melting point of 94°C. 

Step B 3-Carbethoxy-4-Hydroxy-8-Trifluoromethylquinoline - A mixture of 113 grams of crude ortho-trifluoromethylanilinomethylene ethyl malonate from Step A, and 115 cc of phenyl oxide was heated rapidly under an inert atmosphere. At about 195°C, the ethanol formed began to distill off. At the end of about 30 minutes, the interior temperature reached 250°C and the reaction mixture was heated to reflux. Reflux was maintained for 1 hour and the mixture was then cooled, 25 cc of acetone were added and the mixture was allowed to crystallize. The mixture was filtered and the crystals thus formed were washed and dried to obtain 71.5 grams of 3-carbethoxy-4-hydroxy-8-trifluoromethylquino-line with a melting point of 210° to 214°C, which was used as is for the following stage. 

A sample of this product was crystallized from ethanol to show a melting point of 216°C. 

Step C 3-Carboxy-4-Hydroxy-8-Trifluoromethylquinoline — 70 grams of crude 3-car-bethoxy-4-hydroxy-8-trifluoromethylquinoline, obtained in Step B, were introduced under an inert atmosphere into a mixture of 300 cc of water and 100 cc of aqueous ION solution of sodium hydroxide. The reaction mixture was heated to reflux and maintained there for 2 hours and forty-five minutes. The solution obtained was poured over a mixture of water, ice and 100 cc of aqueous 11.8N solution of hydrochloric acid. The precipitate thus formed was isolated by filtration, washed with water and introduced into a solution of 20 grams of sodium bicarbonate in 2 liters of water. 

Chemical Abstracts Registry No. 23779-99-9 Trade Name Manufacturer 

Roussel Maestretti Albert Roussel Yurtoglu Roussel 

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Commercial trifluoromethylquiaoline-based products are mefloquiae [53230-10-7], an antimalarial, and floctafenine [23779-99-9], an analgesic. The cycli2ation step to constmct the 2,8-bis(trifluoromethyl)quiaoiine nucleus ia mefloquiae employs 2-amiaobea2otrifluoride [88-17-5] and ethyl 4,4,4-trifluoroacetoacetate [372-31-6] (448). 

Ethoxymethyleneethyl malonate Floctafenine Nalidixic acid Pipemidic acid Piromidic acid Rosoxacin... 

C21H22F3N3OS 807-57-8) see Fluphenazine Y-[4-(trifluoromethyl)phenoxyJbenzenepropanamine -(Ci HiftFjNO 83891-03-6) see Fluoxetine (3-trifluoromethylphenyl)acetone (CioHgFjO 21906-39-8) see Fenfluramine (3-trifluoromethylphenyl)acetone oxime (CiijHkjFjNO, 834-19-5) see Fenfluramine [[[2-(trifiuoromethyl)phenyl]amino]methylene]propane-dioic acid diethyl ester (C 3Hi(,F3N04 23779-94-4) see Floctafenine... 

Floctafenine and glifanine are also anthranilic acid derivatives. However, while they are analgesics, they are not NSAIDs. 

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