N,N-di(propan-2-yl)formamide

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: A solution of oxalyl chloride (Aldrich) (1.97 g, 15.2 mmoles) in dichloromethane (6 mL) was added in several portions to a stirred, ice-bath cooled solution of diisopropylformamide (Aldrich) (2.00 g, 15.17 mmoles) in dichloromethane (25 mL). The ice-bath was removed, and the solution was stirred at ambient temperature for 10 minutes. Solid 5-(4-ethylphenoxy)pyrimidin-4(3H)-one (1.00 g, 4.62 mmoles) was added, and the mixture was refluxed with stirring for 45 minutes. The solution was cooled and poured into a cold solution of vigorously stirred, saturated aqueous sodium bicarbonate (80 mL). The organic layer was washed with cold saturated aqueous sodium bicarbonate (80 mL), with cold water (80 mL) and then dried over sodium sulfate. The dry solution was spin evaporated in vacuo to give the intermediate 4-chloro-5-(4-ethylphenoxy)pyrimidine as an orange liquid. The liquid was dissolved in ethanol (50 mL) and trans-4-hydroxycyclohexylamine hydrochloride (Aldrich) (1.79 g, 11.45 mmoles) was added. A solution of sodium ethoxide, which had been prepared from sodium hydride (60% in mineral oil) (Aldrich) (0.41 g, 10.25 mmoles) and ethanol (15 mL) was added. The flask was rinsed with ethanol (10 mL), and the reaction was refluxed with stirring for 65 hours. The volatiles were removed by spin evaporate in vacuo to a small volume, and the residue was triturated with water (100 mL). The gummy residue was extracted with dichloromethane (150 mL). The solution was washed with water (80 mL), dried over sodium sulfate and spin evaporated in vacuo. This material was dissolved in ethyl acetate-hexanes and chromatographed on Silica Gel 60 (E. M. Science, 230-440 mesh) (13×4 cm column bed) using ethyl acetate as the eluent for the first 1.2 L and then with 5% ethanol in ethyl acetate. The fractions that contained homogeneous product were spin evaporated in vacuo to give a syrup. The pure 5-(4-ethylphenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine was converted to the hydrochloride by the same procedure described in Example 4. The residue was triturated under ethyl acetate to give a white solid which was collected, washed with ethyl acetate and dried in vacuo to give 1.25 g (77% yield) of 5-(4-ethylphenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine hydrochloride as a white solid, mp 245-243° C. The ice-bath was removed the mixture was refluxed with stirring for 45 minutes The solution was cooled poured into a cold solution of vigorously stirred The organic layer was washed with cold saturated aqueous sodium bicarbonate (80 mL), with cold water (80 mL) dried over sodium sulfate evaporated in vacuo

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

Procedure: A solution of oxalyl chloride (Aldrich) (1.97 g, 15.2 mmoles) in dichloromethane (6 mL) was added in several portions to a stirred, ice-bath cooled solution of diisopropylformamide (Aldrich) (2.00 g, 15.17 mmoles) in dichloromethane (25 mL). The ice-bath was removed, and the solution was stirred at ambient temperature for 10 minutes. Solid 5-(4-ethylphenoxy)pyrimidin-4(3H)-one (1.00 g, 4.62 mmoles) was added, and the mixture was refluxed with stirring for 45 minutes. The solution was cooled and poured into a cold solution of vigorously stirred, saturated aqueous sodium bicarbonate (80 mL). The organic layer was washed with cold saturated aqueous sodium bicarbonate (80 mL), with cold water (80 mL) and then dried over sodium sulfate. The dry solution was spin evaporated in vacuo to give the intermediate 4-chloro-5-(4-ethylphenoxy)pyrimidine as an orange liquid. The liquid was dissolved in ethanol (50 mL) and trans-4-hydroxycyclohexylamine hydrochloride (Aldrich) (1.79 g, 11.45 mmoles) was added. A solution of sodium ethoxide, which had been prepared from sodium hydride (60% in mineral oil) (Aldrich) (0.41 g, 10.25 mmoles) and ethanol (15 mL) was added. The flask was rinsed with ethanol (10 mL), and the reaction was refluxed with stirring for 65 hours. The volatiles were removed by spin evaporate in vacuo to a small volume, and the residue was triturated with water (100 mL). The gummy residue was extracted with dichloromethane (150 mL). The solution was washed with water (80 mL), dried over sodium sulfate and spin evaporated in vacuo. This material was dissolved in ethyl acetate-hexanes and chromatographed on Silica Gel 60 (E. M. Science, 230-440 mesh) (13×4 cm column bed) using ethyl acetate as the eluent for the first 1.2 L and then with 5% ethanol in ethyl acetate. The fractions that contained homogeneous product were spin evaporated in vacuo to give a syrup. The pure 5-(4-ethylphenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine was converted to the hydrochloride by the same procedure described in Example 4. The residue was triturated under ethyl acetate to give a white solid which was collected, washed with ethyl acetate and dried in vacuo to give 1.25 g (77% yield) of 5-(4-ethylphenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine hydrochloride as a white solid, mp 245-243° C. The ice-bath was removed the mixture was refluxed with stirring for 45 minutes The solution was cooled poured into a cold solution of vigorously stirred The organic layer was washed with cold saturated aqueous sodium bicarbonate (80 mL), with cold water (80 mL) dried over sodium sulfate evaporated in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of phosphorus oxychloride (10.58 g) and diethyl ether (50 ml) is stirred at 0° C. for 10 min. Diisopropylformamide (8.91 g) in diethyl ether (20 ml) is then added drop-wise over a period of 10 min. The resulting mixture is then stirred at room temperature for 30 min. The formed precipitate is allowed to settle and the supernatant removed. Dichloromethane (60 mL) is then added to the mixture. Diisopropylamine (6.98 g) in dichloromethane (20 ml) is then added drop-wise at 0° C. over 10 min. The mixture is then warmed at room temperature and stirred for a further 1.5 h. Diethyl ether (30 ml) is added and the resulting precipitate is removed by filtration. The mother liquor is concentrated in vacuo. Acetone (30 ml) is added and the mixture filtered. The mother liquor is then concentrated in vacuo and subsequently is crystallised with diethyl ether (30 ml) to give N,N,N′,N′-tetraisopropylformamidinium chloride (18, R6=iPr, R7=iPr). 1H NMR (DMSO-d6), 7.49 (1H), 4.15-3.95 (4H), 1.33 (12H), 1.31 (12H). The resulting mixture is then stirred at room temperature for 30 min The mixture is then warmed at room temperature stirred for a further 1.5 h the resulting precipitate is removed by filtration The mother liquor is concentrated in vacuo Acetone (30 ml) is added the mixture filtered The mother liquor is then concentrated in vacuo subsequently is crystallised with diethyl ether (30 ml)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of phosphorus oxychloride (10.58 g) and diethyl ether (50 ml) is stirred at 0° C. for 10 min. Diisopropylformamide (8.91 g) in diethyl ether (20 ml) is then added drop-wise over a period of 10 min. The resulting mixture is then stirred at room temperature for 30 min. The formed precipitate is allowed to settle and the supernatant removed. Dichloromethane (60 mL) is then added to the mixture. Diisopropylamine (6.98 g) in dichloromethane (20 ml) is then added drop-wise at 0° C. over 10 min. The mixture is then warmed at room temperature and stirred for a further 1.5 h. Diethyl ether (30 ml) is added and the resulting precipitate is removed by filtration. The mother liquor is concentrated in vacuo. Acetone (30 ml) is added and the mixture filtered. The mother liquor is then concentrated in vacuo and subsequently is crystallised with diethyl ether (30 ml) to give N,N,N′,N′-tetraisopropylformamidinium chloride (18, R6=iPr, R7=iPr). 1H NMR (DMSO-d6), 7.49 (1H), 4.15-3.95 (4H), 1.33 (12H), 1.31 (12H). The resulting mixture is then stirred at room temperature for 30 min The mixture is then warmed at room temperature stirred for a further 1.5 h the resulting precipitate is removed by filtration The mother liquor is concentrated in vacuo Acetone (30 ml) is added the mixture filtered The mother liquor is then concentrated in vacuo subsequently is crystallised with diethyl ether (30 ml)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of phosphorus oxychloride (10.58 g) and diethyl ether (50 ml) is stirred at 0° C. for 10 min. Diisopropylformamide (8.91 g) in diethyl ether (20 ml) is then added drop-wise over a period of 10 min. The resulting mixture is then stirred at room temperature for 30 min. The formed precipitate is allowed to settle and the supernatant removed. Dichloromethane (60 mL) is then added to the mixture. Diisopropylamine (6.98 g) in dichloromethane (20 ml) is then added drop-wise at 0° C. over 10 min. The mixture is then warmed at room temperature and stirred for a further 1.5 h. Diethyl ether (30 ml) is added and the resulting precipitate is removed by filtration. The mother liquor is concentrated in vacuo. Acetone (30 ml) is added and the mixture filtered. The mother liquor is then concentrated in vacuo and subsequently is crystallised with diethyl ether (30 ml) to give N,N,N′,N′-tetraisopropylformamidinium chloride (18, R6=iPr, R7=iPr). 1H NMR (DMSO-d6), 7.49 (1H), 4.15-3.95 (4H), 1.33 (12H), 1.31 (12H). The resulting mixture is then stirred at room temperature for 30 min The mixture is then warmed at room temperature stirred for a further 1.5 h the resulting precipitate is removed by filtration The mother liquor is concentrated in vacuo Acetone (30 ml) is added the mixture filtered The mother liquor is then concentrated in vacuo subsequently is crystallised with diethyl ether (30 ml)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of phosphorus oxychloride (10.58 g) and diethyl ether (50 ml) is stirred at 0° C. for 10 min. Diisopropylformamide (8.91 g) in diethyl ether (20 ml) is then added drop-wise over a period of 10 min. The resulting mixture is then stirred at room temperature for 30 min. The formed precipitate is allowed to settle and the supernatant removed. Dichloromethane (60 mL) is then added to the mixture. Diisopropylamine (6.98 g) in dichloromethane (20 ml) is then added drop-wise at 0° C. over 10 min. The mixture is then warmed at room temperature and stirred for a further 1.5 h. Diethyl ether (30 ml) is added and the resulting precipitate is removed by filtration. The mother liquor is concentrated in vacuo. Acetone (30 ml) is added and the mixture filtered. The mother liquor is then concentrated in vacuo and subsequently is crystallised with diethyl ether (30 ml) to give N,N,N′,N′-tetraisopropylformamidinium chloride (18, R6=iPr, R7=iPr). 1H NMR (DMSO-d6), 7.49 (1H), 4.15-3.95 (4H), 1.33 (12H), 1.31 (12H). The resulting mixture is then stirred at room temperature for 30 min The mixture is then warmed at room temperature stirred for a further 1.5 h the resulting precipitate is removed by filtration The mother liquor is concentrated in vacuo Acetone (30 ml) is added the mixture filtered The mother liquor is then concentrated in vacuo subsequently is crystallised with diethyl ether (30 ml)

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

Procedure: A solution of oxalyl chloride (Aldrich) (1.97 g, 15.2 mmoles) in dichloromethane (6 mL) was added in several portions to a stirred, ice-bath cooled solution of diisopropylformamide (Aldrich) (2.00 g, 15.17 mmoles) in dichloromethane (25 mL). The ice-bath was removed, and the solution was stirred at ambient temperature for 10 minutes. Solid 5-(4-ethylphenoxy)pyrimidin-4(3H)-one (1.00 g, 4.62 mmoles) was added, and the mixture was refluxed with stirring for 45 minutes. The solution was cooled and poured into a cold solution of vigorously stirred, saturated aqueous sodium bicarbonate (80 mL). The organic layer was washed with cold saturated aqueous sodium bicarbonate (80 mL), with cold water (80 mL) and then dried over sodium sulfate. The dry solution was spin evaporated in vacuo to give the intermediate 4-chloro-5-(4-ethylphenoxy)pyrimidine as an orange liquid. The liquid was dissolved in ethanol (50 mL) and trans-4-hydroxycyclohexylamine hydrochloride (Aldrich) (1.79 g, 11.45 mmoles) was added. A solution of sodium ethoxide, which had been prepared from sodium hydride (60% in mineral oil) (Aldrich ) (0.41 g, 10.25 mmoles) and ethanol (15 mL) was added. The flask was rinsed with ethanol (10 mL), and the reaction was refluxed with stirring for 65 hours. The volatiles were removed by spin evaporate in vacuo to a small volume, and the residue was triturated with water (100 mL). The gummy residue was extracted with dichloromethane (150 mL). The solution was washed with water (80 mL), dried over sodium sulfate and spin evaporated in vacuo. This material was dissolved in ethyl acetate-hexanes and chromatographed on Silica Gel 60 (E.M. The ice-bath was removed the mixture was refluxed with stirring for 45 minutes The solution was cooled poured into a cold solution of vigorously stirred The organic layer was washed with cold saturated aqueous sodium bicarbonate (80 mL), with cold water (80 mL) dried over sodium sulfate evaporated in vacuo

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

Procedure: A solution of 4.5 mL of oxalyl chloride in 35 mL of dichloromethane was added dropwise over 25 minutes to an ice water bath-cooled solution of 7.0 mL of N,N-diisopropylformamide in 65 mL of dichloromethane with magnetic stirring. After a few minutes, 4.74 g of 2-amino-4-hydroxy-5-iodopyrimidine was added in one portion. The bath was removed and the solution was stirred at room temperature for 30 minutes, then refluxed for one and one half hours. The solution was cooled and poured into an equal amount of ice-cold saturated aqueous sodium bicarbonate with stirring. The two phases were partitioned and the organic layer washed with additional bicarbonate(2×), water(1×) and finally saturated aqueous brine. After drying over sodium sulfate and filtration, the solution was evaporated in vacuo to yield 10.13 g of a reddish oil. The oil was purified by column chromatography on silica gel, eluting with dichloromethane. Like fractions were pooled, evaporated and triturated with hexanes to give white free flowing crystals, 5.94 g, m.p. 97–100° C. After a few minutes The bath was removed refluxed for one and one half hours The solution was cooled poured into an equal amount of ice-cold saturated aqueous sodium bicarbonate with stirring The two phases were partitioned the organic layer washed with additional bicarbonate(2×), water(1×) and finally saturated aqueous brine After drying over sodium sulfate and filtration the solution was evaporated in vacuo

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

Procedure: To 250 mg (1.21 mmol) of 6-nitroquinazoline-2,4(1H,3H)-dione were added 5.00 ml (53.64 mmol) of phosphorus oxychloride and 0.18 ml (1.21 mmol) of diisopropylformamide, and the resulting mixture was subjected to heating under reflux for 24 hours. After phosphorus oxychloride was removed in vacuo, the mixture was dissolved in 5 ml of acetonitrile, followed by addition of 328 mg (2.42 mmol) of 2,2,2-trifluoroethylamine hydrochloride and 1.69 ml (12.10 mmol) of triethylamine under ice cooling and stirring under ice cooling for 30 minutes. To the reaction solution was added water, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, 1.50 ml (20.00 mmol) of allylamine was added thereto, followed by stirring overnight, adding water to the reaction solution, extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 50 mg (12.6%) of the title compound. to heating under reflux for 24 hours After phosphorus oxychloride was removed in vacuo the mixture was dissolved in 5 ml of acetonitrile followed by extraction with ethyl acetate washing with brine drying over anhydrous sodium sulfate After the solvent was distilled off by stirring overnight to the reaction solution, extraction with ethyl acetate washing with brine drying over anhydrous sodium sulfate After the solvent was distilled off the residue was purified by a silica gel column

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

Procedure: To 250 mg (1.21 mmol) of 6-nitroquinazoline-2,4(1H,3H)-dione were added 5.00 ml (53.64 mmol) of phosphorus oxychloride and 0.18 ml (1.21 mmol) of diisopropylformamide, and the resulting mixture was subjected to heating under reflux for 24 hours. After phosphorus oxychloride was removed in vacuo, the mixture was dissolved in 5 ml of acetonitrile, followed by addition of 183 mg (1.21 mmol) of 1-adamantylamine and 0.84 ml (6.05 mmol) of triethylamine under ice cooling and stirring under ice cooling for 30 minutes. To the reaction solution was added water, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 90 mg (20.7%) of the title compound. to heating under reflux for 24 hours After phosphorus oxychloride was removed in vacuo the mixture was dissolved in 5 ml of acetonitrile followed by extraction with ethyl acetate washing with brine drying over anhydrous sodium sulfate After the solvent was distilled off the residue was purified by a silica gel column