N,N-dimethylpropanamide

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:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 12 g of 1-(2,2-difluoro-1,3-benzodioxol-4-yl)propanone are prepared by condensation of N,N-dimethylpropionamide with the lithiated anion of 2,2-difluoro-1,3-benzodioxole obtained according to the procedure described in patent EP 333658, are then dissolved in 14.6 ml (0.11 mol) of N,N-dimethylformamide dimethyl acetal and heated at 70° C. according to the procedure described in Example No. 1. 25 g (0.05 mol) of enaminone thus obtained are dissolved in 130 ml of acetic acid and then 3.3 ml (0.069 mol) of hydrazine hydrate are added. The crude product obtained is purified by trituration in pentane. obtained

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 12 g of 1-(2,2-difluoro-1,3-benzodioxol-4-yl)propanone are prepared by condensation of N,N-dimethylpropionamide with the lithiated anion of 2,2-difluoro-1,3-benzodioxole obtained according to the procedure described in patent EP 333658, are then dissolved in 14.6 ml (0.11 mol) of N,N-dimethylformamide dimethyl acetal and heated at 70° C. according to the procedure described in Example No. 1. 25 g (0.05 mol) of enaminone thus obtained are dissolved in 130 ml of acetic acid and then 3.3 ml (0.069 mol) of hydrazine hydrate are added. The crude product obtained is purified by trituration in pentane. obtained

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Phosphorus oxychloride (0.47 g, 0.28 ml, 3.00 mmol) was added dropwise to previously cooled (0 to 5° C.) N,N-dimethyl propionamide (0.30 g, 0.27 ml, 3.00 mmol) maintaining the temperature between about 0° C. to about 5° C. The resulting reaction mixture was then allowed to warm to room temperature (about 25° C.), which was then stirred at room temperature (about 25° C.) for 20 minutes. The reaction mixture was then diluted with 1,2-dichloroethane (15 ml), the resulting mixture was cooled to 0° C., to it was then added 2-(4-chlorophenyl)-1-ethyl-3-methyl-1H-pyrrole (compound 51a, 0.6 g, 2.73 mmol) in 1,2-dichloroethane (15 ml) dropwise. The reaction mixture so formed was heated to reflux for 30 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was then allowed to cool to room temperature, and to it was then added a solution of sodium acetate trihydrate (1.23 g, 15.0 mmol) in 14 ml water. The reaction mixture so obtained was heated to reflux for 30 minutes. Two phases formed in the reaction mixture were then separated. The aqueous layer was extracted with dichloromethane (3×30 ml). The combined organic layer was washed with water (1×30 ml) and dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 10% ethyl acetate in hexanes as an eluent to obtain the title compound (0.5 g, 66.4%). maintaining the temperature between about 0° C. to about 5° C The resulting reaction mixture the resulting mixture was cooled to 0° C., to it The reaction mixture so formed was heated to reflux for 30 minutes to cool to room temperature The reaction mixture so obtained was heated to reflux for 30 minutes Two phases formed in the reaction mixture were then separated The aqueous layer was extracted with dichloromethane (3×30 ml) The combined organic layer was washed with water (1×30 ml) dried over anhydrous Na2SO4 The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by flash column chromatography

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Phosphorus oxychloride (1.496 g, 0.896 ml, 9.76 mmol) was added dropwise to previously cooled (0 to 5° C.) N,N-dimethyl propionamide (0.987 g, 1.073 ml, 9.76 mmol) maintaining the temperature between about 0° C. to about 5° C. The resulting reaction mixture was then allowed to warm to room temperature (about 25° C.), which was then stirred at room temperature (about 25° C.) for 15 minutes. The reaction mixture was then diluted with 1,2-dichloroethane (17 ml), the resulting mixture was cooled to 0° C., to it was then added 2-(4-chlorophenyl)-3-methyl-1H-pyrrole (prepared according to the procedure given in Tetrahedron Letters 46 (2005) 4539-4542, 1.7 g, 8.87 mmol) in 1,2-dichloroethane (17 ml) dropwise. The reaction mixture so formed was heated to reflux for 30 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was then allowed to cool to room temperature, and to it was then added a solution of sodium acetate trihydrate (6.64 g, 48.8 mmol) in 14 ml water. The reaction mixture so obtained was heated to reflux for 30 minutes. Two phases formed in the reaction mixture were then separated. The aqueous layer was extracted with dichloromethane (3×50 ml). The combined organic layer was washed with saturated sodium bicarbonate solution (1×50 ml) followed by washing with water (1×50 ml), and then the organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product. The crude product was then purified by flash column chromatography using 10% ethyl acetate in hexanes as an eluent to obtain the title compound (1.82 g, 83%) maintaining the temperature between about 0° C. to about 5° C The resulting reaction mixture the resulting mixture was cooled to 0° C., to it The reaction mixture so formed was heated to reflux for 30 minutes to cool to room temperature The reaction mixture so obtained was heated to reflux for 30 minutes Two phases formed in the reaction mixture were then separated The aqueous layer was extracted with dichloromethane (3×50 ml) The combined organic layer was washed with saturated sodium bicarbonate solution (1×50 ml) by washing with water (1×50 ml) the organic layer was dried over anhydrous Na2SO4 The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product The crude product was then purified by flash column chromatography

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N,N-dimethyl propionamide (3.24 g, 3.52 ml, 32.08 mmol) was cooled at 0-5° C. and to this was added POCl3 (4.9 g, 2.9 ml, 32.08 mmol) slowly in a dropwise manner. The resulting mixture was then stirred at room temperature (about 25° C.) for 20 minutes. The reaction mixture was then diluted with 1,2-dichloroethane (60 ml) and cooled to 0° C. To the cooled reaction mixture was then added a solution of 2-(4-chlorophenyl)-1,3-dimethyl-1H-pyrrole (prepared according to the procedure given in Tetrahedron Letters 46 (2005) 4539-4542, 6.0 g, 29.17 mmol) in 1,2-dichloroethane (60 ml) dropwise. The reaction mixture was then heated to reflux for 30 minutes. The progress of the reaction was monitored by TLC. The mixture so obtained was allowed to cool to room temperature and was diluted with aqueous solution of sodium acetate trihydrate (21.8 g, 160.4 mmol in 45 ml water). The mixture so obtained was further heated to reflux for 30 minutes, two layers were separated. The aqueous layer was extracted with dichloromethane (3×100 ml). The combined organic layer was washed with water (1×100 ml) and dried over anhydrous Na2SO4. The solvent from the reaction mixture was evaporated under reduced pressure to obtain a crude product. This crude product was purified by column chromatography over silica gel (100-200 mesh) using 4-6% ethyl acetate in hexanes as an eluent to obtain the title compound (6.55 g, 85.8%) cooled to 0° C To the cooled reaction mixture prepared The reaction mixture was then heated to reflux for 30 minutes The mixture so obtained to cool to room temperature The mixture so obtained was further heated to reflux for 30 minutes two layers were separated The aqueous layer was extracted with dichloromethane (3×100 ml) The combined organic layer was washed with water (1×100 ml) dried over anhydrous Na2SO4 The solvent from the reaction mixture was evaporated under reduced pressure to obtain a crude product This crude product was purified by column chromatography over silica gel (100-200 mesh)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N,N-dimethyl propionamide (3.24 g, 3.52 ml, 32.08 mmol) was cooled at 0-5° C. and to this was added POCl3 (4.9 g, 2.9 ml, 32.08 mmol) slowly in a dropwise manner. The resulting mixture was then stirred at room temperature (about 25° C.) for 20 minutes. The reaction mixture was then diluted with 1,2-dichloroethane (60 ml) and cooled to 0° C. To the cooled reaction mixture was then added a solution of 2-(4-chlorophenyl)-1,3-dimethyl-1H-pyrrole (prepared according to the procedure given in Tetrahedron Letters 46 (2005) 4539-4542, 6.0 g, 29.17 mmol) in 1,2-dichloroethane (60 ml) dropwise. The reaction mixture was then heated to reflux for 30 minutes. The progress of the reaction was monitored by TLC. The mixture so obtained was allowed to cool to room temperature and was diluted with aqueous solution of sodium acetate trihydrate (21.8 g, 160.4 mmol in 45 ml water). The mixture so obtained was further heated to reflux for 30 minutes, two layers were separated. The aqueous layer was extracted with dichloromethane (3×100 ml). The combined organic layer was washed with water (1×100 ml) and dried over anhydrous Na2SO4. The solvent from the reaction mixture was evaporated under reduced pressure to obtain a crude product. This crude product was purified by column chromatography over silica gel (100-200 mesh) using 4-6% ethyl acetate in hexanes as an eluent to obtain the title compound (6.55 g, 85.8%) cooled to 0° C To the cooled reaction mixture prepared The reaction mixture was then heated to reflux for 30 minutes The mixture so obtained to cool to room temperature The mixture so obtained was further heated to reflux for 30 minutes two layers were separated The aqueous layer was extracted with dichloromethane (3×100 ml) The combined organic layer was washed with water (1×100 ml) dried over anhydrous Na2SO4 The solvent from the reaction mixture was evaporated under reduced pressure to obtain a crude product This crude product was purified by column chromatography over silica gel (100-200 mesh)

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

Procedure: To a solution of N,N-Dimethylpropionamide (0.202 g, 2.0 mmol) in CHCl3 (2 mL) was added phosphorous oxychloride (POCl3, 0.066 g, 0.43 mmol) and the mixture was agitated on an orbital shaker at room temperature for 1 h. Triethylamine (0.22 g, 2.2 mmol) and 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.10 g, 0.40 mmol) were added, and the mixture was agitated at 50° C. for 3 h, cooled to room temperature, partitioned between chloroform and water, the phases separated, and the organics evaporated under reduced pressure. Purification by reverse phase chromatography afforded the title compound (0.042 g, 31% yield) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 8.87 (s, 1H), 8.04 (d, J=2.5 Hz, 1H), 7.46-7.40 (m, 2H), 7.07-6.99 (m, 2H), 5.30 (s, 2H), 3.13 (s, 6H), 2.55 (q, J=7.7 Hz, 2H), 1.15 (t, J=7.7 Hz, 3H); HPLC-MS (ESI) m/z 321 (M+H)+. the mixture was agitated at 50° C. for 3 h cooled to room temperature partitioned between chloroform and water the phases separated the organics evaporated under reduced pressure Purification by reverse phase chromatography

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

Procedure: To a solution of N,N-Dimethylpropionamide (0.202 g, 2.0 mmol) in CHCl3 (2 mL) was added phosphorous oxychloride (POCl3, 0.066 g, 0.43 mmol) and the mixture was agitated on an orbital shaker at room temperature for 1 h. Triethylamine (0.22 g, 2.2 mmol) and 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.10 g, 0.40 mmol) were added, and the mixture was agitated at 50° C. for 3 h, cooled to room temperature, partitioned between chloroform and water, the phases separated, and the organics evaporated under reduced pressure. Purification by reverse phase chromatography afforded the title compound (0.042 g, 31% yield) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 8.87 (s, 1H), 8.04 (d, J=2.5 Hz, 1H), 7.46-7.40 (m, 2H), 7.07-6.99 (m, 2H), 5.30 (s, 2H), 3.13 (s, 6H), 2.55 (q, J=7.7 Hz, 2H), 1.15 (t, J=7.7 Hz, 3H); HPLC-MS (ESI) m/z 321 (M+H)+. the mixture was agitated at 50° C. for 3 h cooled to room temperature partitioned between chloroform and water the phases separated the organics evaporated under reduced pressure Purification by reverse phase chromatography

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

Procedure: To a solution of 11.33 g. (0.112 mole) of N,N-dimethylpropionamide in 110 ml. of acetonitrile (dried over molecular sieves) is added 8.3 ml. of phosphorous oxychloride at 5°-10° C. The mixture is stirred at room temperature for 90 minutes. To the resulting yellow solution is added 13.7 g. (0.040 mole) of 6-amino-2,3-bis(4-methyl-1-piperazinyl)quinoxaline (prepared as in Example 1) in several portions with stirring. The mixture is placed in an oil bath at 65° C. and stirred for 16 hours. The reaction mixture is cooled and is poured into 400 ml. of ice plus water, stirred for 10 minutes and filtered. The filtrate is made alkaline to a pH greater than 13 with 5 N sodium hydroxide and extracted with five 100 ml. portions of chloroform. The combined extract is washed with two 100 ml. portions of water, dried over anhydrous potassium carbonate and anhydrous calcium sulfate and stripped of solvent by water pump evacuation to yield a residual oil which is crystallized on standing. The residue formed is recrystallized from 350 ml. of acetonitrile and is filtered and the solid collected is dried in vacuo at 78° C. over phosphorous pentoxide. The yellow solid obtained is dissolved in 160 ml. of hot acetonitrile, treated with activated charcoal, recrystallized by cooling at -10° C. and is filtered and dried as above to give 4.0 g. of yellow solid, m.p. 173°-175° C. at 5°-10° C To the resulting yellow solution is added 13.7 g The mixture is placed in an oil bath at 65° C. stirred for 16 hours The reaction mixture is cooled is poured into 400 ml filtered extracted with five 100 ml The combined extract is washed with two 100 ml portions of water, dried over anhydrous potassium carbonate and anhydrous calcium sulfate to yield a residual oil which is crystallized The residue formed is recrystallized from 350 ml of acetonitrile and is filtered the solid collected is dried in vacuo at 78° C. over phosphorous pentoxide The yellow solid obtained is dissolved in 160 ml recrystallized by cooling at -10° C. is filtered dried as above to give 4.0 g