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With hydrogenchloride; n-butyllithium; dicyclohexyl-carbodiimide;
Example 2 Preparation of 9-(4-bromobutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide Tetrahydrofuran (2400 ml) was added to 9H-fluorene-9-carboxylic acid (100 gm) under stirring. The solution was cooled to 0 to -5 C. and a solution of n-butyllithium (60.9 gm) in n-hexane (340 ml) was then added slowly. The reaction mass was maintained for 1 hour at 0 to -5 C. and 1,4-dibromo butane (133.5 gm) was added to the reaction mass slowly. The reaction mass was maintained for 40 minutes at 0 to -5 C. and temperature of the reaction mass was raised to room temperature. The reaction mass was maintained for 15 hours at room temperature and then cooled to 0 to 5 C. To the reaction mass was added hydrochloric acid solution (1N, 1000 ml) at 0 to -5 C. slowly and temperature of the reaction mass was raised to room temperature. The layers were separated and the aqueous layer was extracted with ethyl acetate. Combined organic layers were dried with sodium sulfate and the solvent was distilled off under vacuum to obtain a residual solid. The residual solid obtained was dissolved in n-hexane (1000 ml) and stirred for 2 hours. The separated solid was filtered and then dried to obtain 98.6 gm of 9-(4-bromobutyl)-9H-fluorene-9-carboxylic acid. 2,2,2-Trifluoroethyl amine (3.1 gm) was dissolved in water (20 ml) and pH was adjusted to 10.5 to 11.0 with sodium hydroxide solution (10%). The solution was extracted three times with methylene chloride. Combined organic layers were dried with sodium sulfate and 9-(4-bromobutyl)-9H-fluorene-9-carboxylic acid was added to the organic layer. The reaction mass was cooled to 0 to 5 C. and a solution of N,N'-dicyclohexylcarbodiimide (11.3 gm) in methylene chloride (60 ml) was then added. The reaction mass was maintained for 2 hours at 0 to 5 C. and the temperature of the reaction mass was raised to room temperature for 30 minutes. The reaction mass was cooled to -5 C., maintained for 30 minutes and filtered to obtain a wet solid. The wet solid was dissolved in n-hexane (30 ml) and cooled to 0 to 5 C. The contents were stirred for 2 hours and filtered. The solid obtained was dried to obtain 8 gm of 9-(4-bromobutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide. Yield: 64.8% Chromatographic purity (by HPLC): 90.25%
A mixture of 9H-fluorene-9-carboxylic acid compound of formula-2a (100 gm), 1,4-dibromobutane (308 gm) and toluene (1000 ml) was stirred for 15 mm at 25-30C undernitrogen atmosphere. Cooled the reaction mixture to 5-10C, sodium tert.butoxide (100.5 gm) was slowly added to it and stirred the reaction mixture for 3 hrs at the same temperature. Water was added to the reaction mixture at 25-30C and stirred for 15 mm at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with water. Both the organic and aqueous layers were separated and washed the aqueouslayer with toluene. Acidified the aqueous layer using aqueous hydrochloric acid solution at25-30C aiid stirred the reaction mixture for 20 mm at the same temperature. Dichioromethane was added to the reaction mixture at 25-30C and stirred for 15 mm at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with aqueous citric acid solution. Distilled off the solvent completely from theorganic layer. Dichioromethane (500 ml) was added to the reaction mixture at 25-30C and stirred for 15 mm at the same temperature. N,N-dimethylformamide (6.9 gm) followed by oxalyl chloride (66.4 gm) were slowly added to the reaction mixture at 25-30C and stirred for 2 hrs at the same temperature. Distilled off the solvent completely from the reaction mixture under nitrogen atmosphere and co-distilled with dichloromethane under reducedpressure. Dichloromethane (500 ml) was added to the obtained compound at 25-30C and stirred for .15 mm at the same temperature. The obtained compound was slowly added to a pre-cooled mixture of water (500 ml), 2,2,2-trifluoroethylamine hydrochloride (64.4 gm) and sodium carbonate (75.6 gm) at 5-10C and stirred the reaction mixture for 45 mm at the same temperature. Both the organic and aqueous layers were separated and washed the organiclayer with aqueous hydrochloric acid solution followed by with aqueous sodium bicarbonate solution and then finally washed with water. Distilled off the solvent completely from the organic layer and then co-distilled with n-heptane under reduced pressure. n-Heptane (100 ml) and isopropanol (5 ml) were added to the reaction mixture at 25-30C. Heated the reaction mixture to 55-60C and stirred for 1 hr at the same temperature. Cooled the reaction ttiture to 25-30C and stirred for 1 hr at the same temperature. Filtered the precipitatedsolid, washed with n-hept?ne and then dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown in figure-5.Yield: 155.0 gm; M.R: 95-102C.
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