Quinoline, 4-hydroxy-2-trifluoromethyl

Fluorination. Direct fluorination of quinoline was accompanied by extensive fragmentation of the heteroring, but trifluoromethyl hypofluorite in trichlorofluoromethane at -70°C converted 5-fluoro-8-hydroxyquino-line into the 5,7-difluoro-8-hydroxy product (72JMC987). Quinoline, itself, was perfluorinated by fluorine and cobalt(III) fluoride (56JCS783), whereas cesium tetrafluorocobaltate at around 350°C converted it into a mixture of saturated polyfluoro compounds (82JFC413). It is much more satisfactory to introduce fluorine by nucleophilic methods. 

There have been some further examples of the use of the Conrad-Limpach reaction on substituted 5-aminoquinolines for the synthesis of 4-hydroxy-1,7-phenanthrolines, although the products (see Section IV,F,1) should properly be designated as phenanthrolinones.169 Hot diphenyl ether is often employed as the medium for ring closure.170 Ethyl trifluoro-acetoacetate has been used successfully in place of ethyl aceto-acetate, and this variation has allowed entry to 2-trifluoromethyl-substituted 1,7-phenanthrolines.96 Extensions of the Conrad-Limpach type of synthesis starting with m-phenylenediamine (20) and utilizing diethyl ethoxymethylene malonate or ethyl ethoxalylacetate, reagents frequently used in quinoline syntheses, have afforded, after hydrolysis,... 

Hydroxy-2-(trifluoromethyl)pyridine derivatives 80 (Scheme 31) were linked [53] to the acetamide moiety in the usual way. Pyridyloxy-acetamides 81 smoothly rearranged into the respective 4-aminopyridines 82 when heated with potassium carbonate in DMF at 150 °C. Acid hydrolysis provided amines 83. In a similar way, hydroxy-quinolines and hydroxy-acridines were transformed into the respective amines [50,54]. 

Step G 4-[Ortho-(2, 3 -Dihydroxypropyloxycarbonyl)-Phenyl]-Amino-S-Trifluoromethyl-quinoline Acetonide - 100 cc of toluene were added to 80 cc of 2,2-dimethyl-4-hydroxy-methyl-1,3-dioxolane and the toluene was distilled off under reduced pressure to eliminate the water present. To the anhydrous 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane thus obtained, 0.25 gram of an oily 50% suspension of sodium hydride and then 21.3 grams of 4-... 

The importance of the carboxylic acid moiety for activity is clearly illustrated by the next group of compounds. Removal of the carbethoxy substituent provided 7,8-dimethoxypyrimido[4,5-b]quinolin-4(3H)-one (LIN) which is inactive at 3 mg/kg i.v. in the PCA procedure. Interestingly, the 2-methyl analog (LIV) exhibits excellent oral activity while displaying only weak intravenous activity. This may be rationalized on the basis of metabolic oxidation of this compound to the carboxylic acid (LX, Figure 10). The fact that the 2-ethyl (LV), 2-trifluoromethyl (LVI), and 2-acetyI (LVIl) analogs are considerably less active, and the 2-phenyl (LVI II) and 2-hydroxy (LIX) analogs are inactive, supports this explanation. 

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