4,4,4-trifluorobutan-1-amine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was synthesized in two steps. The first as described for Intermediate example I-97, starting from 5-(methoxycarbonyl)pyridine-2-carboxylic acid and 4,4,4-trifluorobutan-1-amine, and the second as described for Intermediate example I-98 at 55° C., starting from the product received in the first step which was first purified by column chromatography using a gradient of ethyl acetate in heptane. Total yield (two steps) 34%; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.16 (t, 1 H), 9.09 (dd, 1 H), 8.44 (dd, 1 H), 8.14 (dd, 1 H), 3.38 (q, 2 H), 2.20-2.36 (m, 2 H), 1.71-1.81 (m, 2 H); MS (ESI) m/z 277[M+H+], m/z 275[M−H+]; at 55° C. was first purified by column chromatography Total yield (two steps) 34%

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with 4,4,4-trifluoro-butylamine following general procedure B to afford 8-methoxy-4-(4,4,4-trifluoro-butylamino)-quinoline-3-carboxylic acid ethyl ester (210 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (170 mg) following general procedure E. The above ethylamide (0.48 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 3-ethyl-7-methoxy-1-(4,4,4-trifluoro-butyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (70 mg). LCMS: m/z 382 [M+1]+.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with 4,4,4-trifluoro-butylamine following general procedure B to afford 8-methoxy-4-(4,4,4-trifluoro-butylamino)-quinoline-3-carboxylic acid ethyl ester (210 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (170 mg) following general procedure E. The above ethylamide (0.48 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 3-ethyl-7-methoxy-1-(4,4,4-trifluoro-butyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (70 mg). LCMS: m/z 382 [M+1]+.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1 mmol from theophylline-7-acetic acid (238 mg) and 4,4,4-trifluorobutan-1-amine (127 mg) was dissolved in 3 ml of DMSO. An equimolar amount of N,N′-dicyclohexylcarbodiimide (206 mg) was added and the solution was stirred for 48 h at ambient temperature. The solvent was filtered and concentrated under high vacuum. The oily residue, dissolved in minimal amount of ethyl acetate was subjected to flash chromatography. The following eluents were used: ethyl acetate:petroleum ether (2:1), ethyl acetate and ethyl acetate:methanol (9:1). The fractions containing the new spot (Rf=0.07, TLC, ethyl acetate) were collected and evaporated. The white powder was recrystallized from ethyl acetate/petroleum ether. The solvent was filtered concentrated under high vacuum The oily residue, dissolved in minimal amount of ethyl acetate The fractions containing the new spot (Rf=0.07, TLC, ethyl acetate) were collected evaporated The white powder was recrystallized from ethyl acetate/petroleum ether

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 0.35 g (2.75 mmol) of 4,4,4-trifluoro-butylamine (CAS 819-46-5) in 20 ml of dichloromethane, cooled to −15° C., is added dropwise 1.00 g (4.96 mmol) of 4-nitrophenyl chloroformate (CAS 7693-46-1) dissolved in 15 ml of dichloromethane, while maintaining the temperature at −15° C. 0.48 ml (2.75 mmol) of diisopropylethylamine in 10 ml of dichloromethane still at −15° C. is then added. Stirring is continued at −15° C. for 45 minutes, and the temperature of the mixture is then allowed to return to 0° C. over 30 minutes. 20 ml of saturated aqueous sodium hydrogen carbonate solution are then added. The organic phase is separated out by settling and dried over sodium sulfate, and the solvent is partially evaporated off under reduced pressure to a volume of about 8 ml. This solution is chromatographed on a column of 40 g of silica gel, eluting with a mixture of 20% cyclohexane in dichloromethane, to give 0.76 g of 4-nitrophenyl 4,4,4-trifluorobutylcarbamate in the form of a white solid. to return to 0° C. over 30 minutes The organic phase is separated out dried over sodium sulfate the solvent is partially evaporated off under reduced pressure to a volume of about 8 ml This solution is chromatographed on a column of 40 g of silica gel eluting with a mixture of 20% cyclohexane in dichloromethane

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 150 mg (0.186 mmol, approx. 66% purity) of the compound obtained in example 16A was dissolved in 1-methyl-2-pyrrolidone (3 ml) in a reaction vessel suitable for a microwave and 0.4 ml of 4,4,4-trifluorobutylamine was added. Then it was sealed with a corresponding septum and it was heated in the microwave at 150° C. for 3 h. After cooling, the reaction mixture was purified by preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 47 mg of the title compound was obtained (48% of theor.). was added Then it was sealed with a corresponding septum and it After cooling the reaction mixture was purified by preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with 4,4,4-trifluoro-butylamine following general procedure B to afford 8-methoxy-4-(4,4,4-trifluoro-butylamino)-quinoline-3-carboxylic acid ethyl ester (210 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (170 mg) following general procedure E. The above ethylamide (0.48 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 3-ethyl-7-methoxy-1-(4,4,4-trifluoro-butyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (70 mg). LCMS: m/z 382 [M+1]+.

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir: