2,2-dimethylpiperazine

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:

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An N-methyl-2-pyrrolidone suspension (5.0 ml) of 5-[8-chloro-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (492.8 mg, 1.19 mmol) and 2,2-dimethylpiperazine (JMC, 1995, Vol. 38, No. 22, 4389) (571.3 mg, 4.75 mmol) was heated at 120° C. to dissolve and the resulting mixture was stirred at 100° C. for 12 hours. The resulting mixture was left standing to cool, poured into methylene chloride-methanol (10:1), and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by medium pressure silica gel column chromatography (methylene chloride:methanol=49:1 to 13:1) to give the title compound (554.4 mg, 95%) as a pale yellow solid. to dissolve The resulting mixture was left to cool washed with saturated aqueous sodium hydrogen carbonate solution The organic layer was dried over anhydrous sodium sulfate the mixture was filtrated the filtrate was concentrated under reduced pressure the resulting residue was purified by medium pressure silica gel column chromatography (methylene chloride:methanol=49:1 to 13:1)

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

Procedure: Following a procedure similar to that described in Preparation 38, but using 0.35 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 0.15 g of N,N'-carbonyldiimidazole and 0.13 g of 2,2-dimethylpiperazine, 250 mg of the title compound were obtained as an amorphous solid. that described in Preparation 38

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

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Palladium(II) acetate (0.112 g, 0.50 mmol) was added to ethyl 5-bromothiophene-2-carboxylate (1.175 g, 5 mmol), 2,2-dimethyl-piperazine (0.571 g, 5.00 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.311 g, 0.50 mmol) and cesium carbonate (2.281 g, 7.00 mmol) in toluene (50.0 ml) at 20° C. under nitrogen. The resulting suspension was stirred at 110° C. for 23 h. The crude product was purified by ion exchange chromatography, using a SCX2 column. The crude material was dissolved in methanol and then applied to the column. The desired product was eluted from the column using 2M NH3 in methanol and pure fractions were evaporated to dryness to afford the crude product as a brown solid. This material was further purified by silica column chromatography, eluting with a gradient of 0 to 4% MeOH in DCM. Pure fractions were evaporated to dryness to afford ethyl 5-(3,3-dimethylpiperazin-1-yl)thiophene-2-carboxylate (0.484 g, 36.1%) as a brown gum. The crude product was purified by ion exchange chromatography The crude material was dissolved in methanol The desired product was eluted from the column were evaporated to dryness to afford the crude product as a brown solid This material was further purified by silica column chromatography eluting with a gradient of 0 to 4% MeOH in DCM Pure fractions were evaporated to dryness

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Palladium(II) acetate (0.112 g, 0.50 mmol) was added to ethyl 5-bromothiophene-2-carboxylate (1.175 g, 5 mmol), 2,2-dimethyl-piperazine (0.571 g, 5.00 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.311 g, 0.50 mmol) and cesium carbonate (2.281 g, 7.00 mmol) in toluene (50.0 ml) at 20° C. under nitrogen. The resulting suspension was stirred at 110° C. for 23 h. The crude product was purified by ion exchange chromatography, using a SCX2 column. The crude material was dissolved in methanol and then applied to the column. The desired product was eluted from the column using 2M NH3 in methanol and pure fractions were evaporated to dryness to afford the crude product as a brown solid. This material was further purified by silica column chromatography, eluting with a gradient of 0 to 4% MeOH in DCM. Pure fractions were evaporated to dryness to afford ethyl 5-(3,3-dimethylpiperazin-1-yl)thiophene-2-carboxylate (0.484 g, 36.1%) as a brown gum. The crude product was purified by ion exchange chromatography The crude material was dissolved in methanol The desired product was eluted from the column were evaporated to dryness to afford the crude product as a brown solid This material was further purified by silica column chromatography eluting with a gradient of 0 to 4% MeOH in DCM Pure fractions were evaporated to dryness

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-fluorobenzamide (0.1 g, 0.27 mmol) and 2,2-dimethylpiperazine (0.124 g, 1.04 mmol) were stirred at 60° C. for 20 mins. Potassium carbonate (0.033 ml, 0.54 mmol) and DMSO (1 ml) were added and the reaction stirred at 120° C. in a sealed tube for 16 days. The reaction mixture was cooled and evaporated. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (6.00 mg, 2.000%) as a colourless gum. The reaction mixture was cooled evaporated The crude product was purified by preparative HPLC Fractions containing the desired compound were evaporated to dryness

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 4-fluorobenzoate (0.151 mL, 1 mmol), 2,2-dimethylpiperazine (0.137 g, 1.20 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (0.349 mL, 2.00 mmol) were dissolved in DMA (2 mL) and sealed into a microwave tube. The reaction was heated to 200° C. for 4 h in the microwave reactor and cooled to room temperature. The crude mixture was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5M ammonia in methanol, fractions were evaporated to dryness to afford an oil. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 10% 2M ammonia/MeOH in DCM. Pure fractions were evaporated to dryness to afford ethyl 4-(3,3-dimethylpiperazin-1-yl)benzoate (0.145 g, 55.3%) as a white solid. 1H NMR (399.9 MHz, CDCl3) δ 1.15 (6H, d), 1.37 (3H, t), 2.38 (1H, d), 2.41 (1H, d), 2.96-3.04 (2H, m), 3.65-3.69 (2H, m), 4.33 (2H, q), 6.84-6.87 (2H, m), 7.89-7.93 (2H, m). MS: m/z 266 (MH+). sealed into a microwave tube cooled to room temperature The crude mixture was purified by ion exchange chromatography The desired product was eluted from the column were evaporated to dryness to afford an oil The crude product was purified by silica column chromatography eluting with a gradient of 0 to 10% 2M ammonia/MeOH in DCM Pure fractions were evaporated to dryness

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,2-Dimethylpiperazine (343 mg, 3.00 mmol) was added in one portion to 5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (388 mg, 1 mmol) in anhydrous dimethylsulfoxide (1.00 ml) at 25° C. The resulting solution was stirred at 100° C. for 18 h. The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH to afford impure material. The concentrated eluent was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (217 mg, 47%) as a yellow solid. The crude product was purified by ion exchange chromatography The desired product was eluted from the column to afford impure material The concentrated eluent was purified by preparative HPLC Fractions containing the desired compound were evaporated to dryness