2,2-diethoxy-N,N-dimethylethanamine

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 1.1 g., (0.005 mole) of 2-(3-aminophenyl)oxazolo[4,5-b]pyridine and 50 ml. of ethanol is reacted with dimethylaminoacetaldehyde [from 0.96 g. (0.006 mole) dimethylaminoacetaldehyde diethylacetal]by gentle heating to complete the intermediate Schiff base formation. The mixture is then cooled and 60 mg., (0.0015 mole) of sodium borohydride is added, and the mixture allowed to stir overnight at room temperature. Water is added, the solvents are removed in vacuo, and the residue is distributed between water and methylene chloride. The organic layer is dried and concentrated in vacuo to give crude 2-[3-(2-dimethylaminoethyl)aminophenyl]oxazolo[4,5-b]pyridine, purified via column chromatography using an alumina column with an ethylacetate-ether mixture (v/v 0-60% ethylacetate) as eluant. A mixture of 1.1 g by gentle heating The mixture is then cooled the solvents are removed in vacuo The organic layer is dried concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 1.1 g., (0.005 mole) of 2-(3-aminophenyl)oxazolo[4,5-b]pyridine and 50 ml. of ethanol is reacted with dimethylaminoacetaldehyde [from 0.96 g. (0.006 mole) dimethylaminoacetaldehyde diethylacetal]by gentle heating to complete the intermediate Schiff base formation. The mixture is then cooled and 60 mg., (0.0015 mole) of sodium borohydride is added, and the mixture allowed to stir overnight at room temperature. Water is added, the solvents are removed in vacuo, and the residue is distributed between water and methylene chloride. The organic layer is dried and concentrated in vacuo to give crude 2-[3-(2-dimethylaminoethyl)aminophenyl]oxazolo[4,5-b]pyridine, purified via column chromatography using an alumina column with an ethylacetate-ether mixture (v/v 0-60% ethylacetate) as eluant. A mixture of 1.1 g by gentle heating The mixture is then cooled the solvents are removed in vacuo The organic layer is dried concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Water (1 mL) and concentrated hydrochloric acid (2.4 mL) were added to dimethylaminoacetaldehyde diethyl acetal (2.00 g) and heating was carried out for 3 hours at 40° C. Sodium disulfite (3.0 M aqueous solution, 3.6 mL) and ethanol (10 mL) were added on an ice bath and stirring was performed for 1 hour and 30 minutes at room temperature. Filtration was carried out followed by concentration. The resulting residue was evaporated to dryness under reduced pressure at 60° C. to obtain the title compound (1.29 g). heating was performed for 1 hour and 30 minutes at room temperature Filtration was carried out followed by concentration The resulting residue was evaporated to dryness under reduced pressure at 60° C.

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirring solution of 2-chloro-5-[5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenylamine (0.121 g, 0.386 mmol), (dimethylamino)acetaldehyde diethyl acetal (0.720 mL, 3.94 mmol), glacial acetic acid (24.0 mL) and water (0.100 mL, 5.55 mmol) was added sodium cyanoborohydride (0.140 g, 2.22 mmol). The solution was heated at 60° C. for 5 days and then the solution was stirred at room temperature until a precipitate formed. The suspension was filtered, the filter cake was washed with EtOAc (10 mL) and then the filtrate was concentrated by rotary evaporation. The residue was purified by flash column chromatography (silica gel, elution with EtOAc:hexanes, 1:3.5), gave 0.027 g (20%) of the title compound as a white solid. 1H NMR (CDCl3): 7.60 (d, 1H, J=5.2 Hz), 7.44–7.35 (m, 3H), 7.13 (d, 1H, J=5.2 Hz), 4.33 (br s, 1H), 3.37–3.28 (m, 2H), 1.36 (t, 3H, J=7.1 Hz). formed The suspension was filtered the filter cake was washed with EtOAc (10 mL) the filtrate was concentrated by rotary evaporation The residue was purified by flash column chromatography (silica gel, elution with EtOAc:hexanes, 1:3.5)

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirring solution of 2-chloro-5-[5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenylamine (0.121 g, 0.386 mmol), (dimethylamino)acetaldehyde diethyl acetal (0.720 mL, 3.94 mmol), glacial acetic acid (24.0 mL) and water (0.100 mL, 5.55 mmol) was added sodium cyanoborohydride (0.140 g, 2.22 mmol). The solution was heated at 60° C. for 5 days and then the solution was stirred at room temperature until a precipitate formed. The suspension was filtered, the filter cake was washed with EtOAc (10 mL) and then the filtrate was concentrated by rotary evaporation. The residue was purified by flash column chromatography (silica gel, elution with EtOAc:hexanes, 1:3.5), gave 0.027 g (20%) of the title compound as a white solid. 1H NMR (CDCl3): 7.60 (d, 1H, J=5.2 Hz), 7.44–7.35 (m, 3H), 7.13 (d, 1H, J=5.2 Hz), 4.33 (br s, 1H), 3.37–3.28 (m, 2H), 1.36 (t, 3H, J=7.1 Hz). formed The suspension was filtered the filter cake was washed with EtOAc (10 mL) the filtrate was concentrated by rotary evaporation The residue was purified by flash column chromatography (silica gel, elution with EtOAc:hexanes, 1:3.5)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 40 g of dimethylaminoacetaldehyde diethylacetal are heated to 40° C. in a mixture of 48 g conc. hydrochloric acid and 20 ml of water for 3 h. Then a solution of 42.4 g sodium pyrosulphite in 72 ml of water (sodium hydrogen sulphite solution) is added dropwise and the mixture is stirred for 1 h. 200 ml of ethanol are added and then the mixture is stirred for 2 h at 0° C. The suspension is suction filtered, washed with 160 ml of ethanol and dried at 45° C. in vacuo. the mixture is stirred for 2 h at 0° C suction filtered washed with 160 ml of ethanol dried at 45° C. in vacuo

反応条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred mixture of 2,2-diethoxy-N,N-dimethylethanamine (1.67 g, 10.4 mmol) and water (1.8 mL) at room temperature and under a nitrogen atmosphere was added an aq. 37% HCl (1.75 mL, 20.8 mmol). After addition the mixture was stirred at 45° C. (bath) for 27 h. It was cooled to 0° C. (bath). This is called solution A. KOH (2.98 g, 53.2 mmol) was dissolved in water (9 mL) at room temperature under a nitrogen atmosphere. It was cooled to 0° C. (bath). This is called solution B. To a stirred heterogeneous mixture of compound 236 (1.97 g, 4.16 mmol) and THF (9 mL) at room temperature and under a nitrogen atmosphere was added minimum amount of DMA (4.5 mL) to give a homogeneous solution. LiCl (176 mg, 4.16 mmol) was added and stirred at 0° C. (bath) for 15 min. The cold solution B was added and stirred at 0° C. for 2 min. Then the cold solution A was added and the final reaction mixture was continued to stir at 0° C. under a nitrogen atmosphere. The reaction was monitored by TLC (DCM-MeOH=10:1). After stirred for 35 min. it was poured into water (300 mL). Petroleum ether (300 mL) was added and stirred at room temperature for 15 min. Petroleum ether layer was decanted. More petroleum ether (300 mL) was added and stirred for 10 min. The solid was collected by suction filtration; washed with water (5×20 mL); petroleum ether/ethyl acetate=10:1×30 mL); dried under reduced pressure over silica gel/KOH to give compound 9 (1.61 g, 95%) which was found only 85.2% pure by HPLC. Thus, the sample was purified by a silica column (ethyl acetate/MeOH=10:1). The fractions containing the required product were combined and evaporated to give a yellow/orange solid. The solid was dissolved in warm ethyl acetate (30 mL) and precipitated with petroleum ether (90 mL). Solid was collected; washed with petroleum ether/ethyl acetate=3:1 (3×20 mL) and dried to give (2E)-N-[4-(4-chloro-3-ethynylanilino)pyrido[3,4-d]pyrimidin-6-yl]-4-(dimethylamino)-2-butenamide (9) (1.1 g, 65%) as a yellow/orange solid, mp 173-176° C.; 1H NMR δ [(CD3)2SO] 10.92 (s, 1H), 10.31 (s, 1H), 9.03 (s, 1H), 9.00 (s, 1H), 8.66 (s, 1H), 8.18 (d, J=2.2 Hz, 1H), 7.96 (dd, J=8.9, 2.2 Hz, 1H), 7.57 (d, J=8.9 Hz, 1H), 6.88 (dt, J=15.4, 6.0 Hz, 1H), 6.52 (br d, J=15.4 Hz, 1H), 4.58 (s, 1 H), 3.09 (br d, J=5.8 Hz, 2H), 2.19 (s, 6H). Anal. Calcd for C21H19ClN6O.0.8MeOH.0.1-ethyl acetate: C, 60.42; H, 5.25; N, 19.04%. Found C, 60.15; H, 4.90; N, 18.76%. After addition the mixture It was cooled to 0° C. (bath) It was cooled to 0° C. (bath) to give a homogeneous solution stirred at 0° C. (bath) for 15 min stirred at 0° C. for 2 min the final reaction mixture to stir at 0° C. under a nitrogen atmosphere After stirred for 35 min. it stirred at room temperature for 15 min Petroleum ether layer was decanted More petroleum ether (300 mL) was added stirred for 10 min The solid was collected by suction filtration washed with water (5×20 mL) dried under reduced pressure over silica gel/KOH

反応条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred mixture of 2,2-diethoxy-N,N-dimethylethanamine (1.56 g, 9.70 mmol) and water (1.6 mL) at room temperature and under a nitrogen atmosphere was added an aq. 37% HCl (1.62 mL, 19.3 mmol). After addition the mixture was stirred at 45° C. (bath) for 25 h. It was cooled to 0° C. (bath). This is called solution A. KOH (2.76 g, 49.3 mmol) was dissolved in water (8 mL) at room temperature under a nitrogen atmosphere. It was cooled to 0° C. (bath). This is called solution B. To a stirred heterogeneous mixture of compound 235 (1.76 g, 3.85 mmol) and THF (8 mL) at room temperature and under a nitrogen atmosphere was added minimum amount of DMA (4 mL) to give a homogeneous solution. LiCl (163 mg, 3.85 mmol) was added and stirred at 0° C. (bath) for 15 min. The cold solution B was added and stirred at 0° C. for 2 min. Then the cold solution A was added and the final reaction mixture was continued to stir at 0° C. under a nitrogen atmosphere. The reaction was monitored by TLC (DCM-MeOH=10:1). After stirred for 30 min. it was poured into water (300 mL). Petroleum ether (300 mL) was added and stirred at room temperature for 10 min. Petroleum ether layer was decanted. More petroleum ether (300 mL) was added and stirred for 10 min. The solid was collected by suction filtration; washed with water (4×20 mL); dried under reduced pressure over silica gel/KOH to give compound 8 (1.38 g, 92%) which was found only 89.7% pure by HPLC. Thus, the sample was stirred with MeOH (ca. 40 mL) for 30 min. The insoluble material was filtered off and to the filtrates was added one volume of water to precipitate out the required product. The solid was collected, washed with water/MeOH=3:1 (3×15 mL) and dried to give (2E)-4-(dimethylamino)-N-[4-(3-ethynyl-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]-2-butenamide (8) (1.28 g, 85%) as a yellow/brown solid, mp 152-155° C.; 1H NMR δ [(CD3)2SO] 10.93 (s, 1H), 10.29 (s, 1H), 9.02 (s, 1H), 8.99 (s, 1H), 8.61 (s, 1H), 8.04 (dd, J=6.4, 2.7 Hz, 1H), 7.94-7.85 (m, 1H), 7.35 (t, J=9.1 Hz, 1H), 6.87 (dt, J=15.4, 6.0 Hz, 1H), 6.52 (br d, J=15.4 Hz, 1H), 4.53 (s, 1H), 3.09 (br d, J=6.0 Hz, 2H), 2.19 (s, 6H). Anal. Calcd for C21H19FN6O.0.8H2O.0.7MeOH: C, 61.00; H, 5.52; N, 19.67%. Found C, 61.26; H, 5.25; N, 19.47%. After addition the mixture It was cooled to 0° C. (bath) It was cooled to 0° C. (bath) to give a homogeneous solution stirred at 0° C. (bath) for 15 min stirred at 0° C. for 2 min the final reaction mixture to stir at 0° C. under a nitrogen atmosphere After stirred for 30 min. it stirred at room temperature for 10 min Petroleum ether layer was decanted More petroleum ether (300 mL) was added stirred for 10 min The solid was collected by suction filtration washed with water (4×20 mL) dried under reduced pressure over silica gel/KOH

反応条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred mixture of 2,2-diethoxy-N,N-dimethylethanamine (2.25 g, 14.0 mmol) and water (2.4 mL) at room temperature and under a nitrogen atmosphere was added an aq. 37% HCl (2.35 mL, 28.0 mmol). After addition the mixture was stirred at 45° C. (bath) for 23 h. It was cooled to 0° C. (bath). This is called solution A. KOH (4.02 g, 71.7 mmol) was dissolved in water (12 mL) at room temperature under a nitrogen atmosphere. It was cooled to 0° C. (bath). This is called solution B. To a stirred heterogeneous mixture of compound 234 (3.21 g, 5.60 mmol) and THF (12 mL) at room temperature and under a nitrogen atmosphere was added minimum amount of DMA (6 mL) to give a homogeneous solution. LiCl (237 mg, 5.60 mmol) was added and stirred at 0° C. (bath) for 15 min. The cold solution B was added and stirred at 0° C. for 2 min. Then the cold solution A was added and the final reaction mixture was continued to stir at 0° C. under a nitrogen atmosphere. The reaction was monitored by TLC(DCM-MeOH=25:1). After 1 h it was poured into water (200 mL). Petroleum ether (200 mL) was added and stirred at room temperature for 30 min. Petroleum ether layer was decanted. More petroleum ether (200 mL) was added and stirred for 15 min. The solid was collected by suction filtration; washed with water (5×20 mL); dried under reduced pressure over silica gel/KOH to give (2E)-N-[4-(3,4-dibromoanilino)pyrido[3,4-d]pyrimidin-6-yl]-4-(dimethylamino)-2-butenamide (7) (2.76 g, 98%) as a beige solid, mp 176-179° C.; HPLC: 97.2% pure; 1H NMR δ [(CD3)2SO] 10.95 (s, 1H), 10.35 (s, 1H), 9.03 (s, 1H), 9.00 (s, 1H), 8.67 (br s, 1 H), 8.37 (br s, 1 H), 7.89 (br d, J=7.8 Hz, 1H), 7.77 (d, J=8.8, 1H), 6.87 (dt, J=15.4, 6.0 Hz, 1H), 6.52 (br d, J=15.4 Hz, 1H), 3.08 (br d, J=5.3 Hz, 2H), 2.19 (s, 6H). Anal. Calcd for C19H8Br2N6O.0.5H2O: C, 44.30; H, 3.72; N, 16.31. Found C, 44.24; H, 3.81; N, 15.98. After addition the mixture It was cooled to 0° C. (bath) It was cooled to 0° C. (bath) to give a homogeneous solution stirred at 0° C. (bath) for 15 min stirred at 0° C. for 2 min the final reaction mixture to stir at 0° C. under a nitrogen atmosphere stirred at room temperature for 30 min Petroleum ether layer was decanted More petroleum ether (200 mL) was added stirred for 15 min The solid was collected by suction filtration washed with water (5×20 mL) dried under reduced pressure over silica gel/KOH

反応条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred mixture of 2,2-diethoxy-N,N-dimethylethanamine (2.25 g, 14.0 mmol) and water (2.4 mL) at room temperature and under a nitrogen atmosphere was added an aq. 37% HCl (2.35 mL, 28.0 mmol). After addition the mixture was stirred at 45° C. (bath) for 23 h. It was cooled to 0° C. (bath). This is called solution A. KOH (4.02 g, 71.7 mmol) was dissolved in water (12 mL) at room temperature under a nitrogen atmosphere. It was cooled to 0° C. (bath). This is called solution B. To a stirred heterogeneous mixture of compound 234 (3.21 g, 5.60 mmol) and THF (12 mL) at room temperature and under a nitrogen atmosphere was added minimum amount of DMA (6 mL) to give a homogeneous solution. LiCl (237 mg, 5.60 mmol) was added and stirred at 0° C. (bath) for 15 min. The cold solution B was added and stirred at 0° C. for 2 min. Then the cold solution A was added and the final reaction mixture was continued to stir at 0° C. under a nitrogen atmosphere. The reaction was monitored by TLC(DCM-MeOH=25:1). After 1 h it was poured into water (200 mL). Petroleum ether (200 mL) was added and stirred at room temperature for 30 min. Petroleum ether layer was decanted. More petroleum ether (200 mL) was added and stirred for 15 min. The solid was collected by suction filtration; washed with water (5×20 mL); dried under reduced pressure over silica gel/KOH to give (2E)-N-[4-(3,4-dibromoanilino)pyrido[3,4-d]pyrimidin-6-yl]-4-(dimethylamino)-2-butenamide (7) (2.76 g, 98%) as a beige solid, mp 176-179° C.; HPLC: 97.2% pure; 1H NMR δ [(CD3)2SO] 10.95 (s, 1H), 10.35 (s, 1H), 9.03 (s, 1H), 9.00 (s, 1H), 8.67 (br s, 1 H), 8.37 (br s, 1 H), 7.89 (br d, J=7.8 Hz, 1H), 7.77 (d, J=8.8, 1H), 6.87 (dt, J=15.4, 6.0 Hz, 1H), 6.52 (br d, J=15.4 Hz, 1H), 3.08 (br d, J=5.3 Hz, 2H), 2.19 (s, 6H). Anal. Calcd for C19H8Br2N6O.0.5H2O: C, 44.30; H, 3.72; N, 16.31. Found C, 44.24; H, 3.81; N, 15.98. After addition the mixture It was cooled to 0° C. (bath) It was cooled to 0° C. (bath) to give a homogeneous solution stirred at 0° C. (bath) for 15 min stirred at 0° C. for 2 min the final reaction mixture to stir at 0° C. under a nitrogen atmosphere stirred at room temperature for 30 min Petroleum ether layer was decanted More petroleum ether (200 mL) was added stirred for 15 min The solid was collected by suction filtration washed with water (5×20 mL) dried under reduced pressure over silica gel/KOH

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred mixture of 2,2-diethoxy-N,N-dimethylethanamine (2.11 g, 13.1 mmol) and water (2.2 mL) at room temperature and under a nitrogen atmosphere was added an aq. 37% HCl (2.19 mL, 26.1 mmol). After addition the mixture was stirred at 40° C. (bath) for 21 h. It was cooled to 0° C. (bath). This is called solution A. KOH (1.87 g, 33.4 mmol) was dissolved in water (10 mL) at room temperature under a nitrogen atmosphere. It was cooled to 0° C. (bath). This is called solution B. To a stirred heterogeneous mixture of compound 232 (2.76 g, 5.22 mmol) and THF (10 mL) at room temperature and under a nitrogen atmosphere was added minimum amount of DMA (5.5 mL) to give a homogeneous solution. LiCl (221 mg, 5.22 mmol) was added and stirred at 0° C. (bath) for 15 min, The cold solution B was added and stirred at 0° C. for 2 min. Then the cold solution A was added and the final reaction mixture was continued to stir at 0° C. under a nitrogen atmosphere. The reaction was monitored by TLC (DCM-MeOH=10:1). After 35 min, it was poured into water (300 mL). Petroleum ether (300 mL) was added and stirred at room temperature for 15 min. Petroleum ether layer was decanted. More petroleum ether (300 mL) was added and stirred for 15 min. The solid was collected by suction filtration; washed with water (4×30 mL); dried under reduced pressure over silica gel/KOH to give (2E)-N-[4-(3-bromo-4-chloroanilino)pyrido[3,4-d]pyrimidin-6-yl]-4-(dimethylamino)-2-butenamide (5) (2.37 g, 98%) as a pale yellow solid, mp 168-171; HPLC: 96.8% pure; 1H NMR δ [(CD3)2SO] 10.92 (s, 1H), 10.34 (s, 1H), 9.10-8.95 (m, 2H), 8.67 (br s, 1 H), 8.38 (br s, 1 H), 7.97 (br d, J=8.3 Hz, 1H), 7.65 (d, J=8.8, 1H), 6.88 (dt, J=15.4, 6.0 Hz, 1H), 6.52 (br d, J=15.4 Hz, 1H), 3.09 (dd, J=6.0, 1.1 Hz, 2H), 2.19 (s, 6H). Anal. Calcd for C19H18BrClN6O.H2O: C, 47.57; H, 4.20; N, 17.52. Found C, 47.80; H, 4.25; N, 17.51. After addition the mixture It was cooled to 0° C. (bath) It was cooled to 0° C. (bath) to give a homogeneous solution stirred at 0° C. (bath) for 15 min stirred at 0° C. for 2 min the final reaction mixture to stir at 0° C. under a nitrogen atmosphere After 35 min stirred at room temperature for 15 min Petroleum ether layer was decanted More petroleum ether (300 mL) was added stirred for 15 min The solid was collected by suction filtration washed with water (4×30 mL) dried under reduced pressure over silica gel/KOH