ethyl 3-ethoxy-3-iminopropanoate;hydrochloride

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

実験手順: A mixture comprising N-(3,4-diaminophenyl)guanidine hydrochloride (9.9 g, 49 mmol), ethoxycarbonimidoylacetic acid ethyl ester hydrochloride (12.4 g, 59 mmol) and acetic acid (20 mL) was heated in an oil bath at 110° C. and stirred for 1.5 hours, cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethanol (15 mL) and then ethyl acetate (10 mL) was added to the solution to give a precipitate in suspension. The suspension was filtered and an excess of ethyl ether was added to the filtrate to give a second precipitate. The precipitate was collected by filtration, washed with additional ethyl ether and dried in vacuo to provide ethyl 5-guanidino-1H-benzoimidazol-2-ylacetate hydrochloride (14.1 g, 94% yield) as an off white solid; 1H-NMR (300 MHz, DMSO-d6): 10.2 (s), 7.8 (d), 7.7 (m), 7.3 (d), 4.5 (s), 4.2 (q), 1.2 (t). concentrated in vacuo The residue was dissolved in ethanol (15 mL) ethyl acetate (10 mL) was added to the solution to give a precipitate in suspension The suspension was filtered an excess of ethyl ether was added to the filtrate to give a second precipitate The precipitate was collected by filtration washed with additional ethyl ether dried in vacuo

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

実験手順: 2-Nitro-4-(2-thienyl)phenylamine (1.0 eq) and 10% Pd/C (0.1 eq) were suspended in anhydrous EtOH at room temperature. The reaction flask was evacuated and subsequently filled with H2. The resulting mixture was allowed to stir under a hydrogen atmosphere for 3 hours. Ethyl 3-ethoxy-3-iminopropanoate hydrochloride (2.0 eq) was then added and the resulting mixture was heated at reflux for 12 hours. After this time, the solution was filtered through a plug of Celite, concentrated, dissolved in 50 ml of 2N HCl and washed with CH2Cl2. The aqueous layer was brought to pH 12 with concentrated NH4OH(aq) and extracted with CH2Cl2. The combined organic layers were dried with MgSO4 and concentrated to yield a brown oil which was purified by silica gel chromatography (5:95 MeOH:CH2Cl2) to provide a yellow solid. LC/MS m/z 287.1 (MH+), Rf 1.98 minutes. The reaction flask was evacuated subsequently filled with H2 the resulting mixture was heated at reflux for 12 hours After this time, the solution was filtered through a plug of Celite concentrated dissolved in 50 ml of 2N HCl washed with CH2Cl2 extracted with CH2Cl2 The combined organic layers were dried with MgSO4 concentrated to yield a brown oil which was purified by silica gel chromatography (5:95 MeOH:CH2Cl2) to provide a yellow solid

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

実験手順: A solution of 1,2-phenylenediamine (1.0 eq) and ethyl 3-ethoxy-3-iminopropanoate hydrochloride (1.3 eq) in ethanol was stirred at 90° C. overnight. The reaction was cooled to room temperature and the solvent was removed in vacuo. Water and CH2Cl2 were added to the residue. The organic layer was separated, dried over Na2SO4 and the solvent removed. The solid recovered was used without purification. LC/MS m/z 205.2 (MH+), Rf 1.44 minutes. the solvent was removed in vacuo Water and CH2Cl2 were added to the residue The organic layer was separated dried over Na2SO4 the solvent removed The solid recovered was used without purification

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

実験手順: 2-Nitro-4-(2-thienyl)phenylamine (1.0 eq) and 10% Pd/C (0.1 eq) were suspended in anhydrous EtOH at room temperature. The reaction flask was evacuated and subsequently filled with H2. The resulting mixture was allowed to stir under a hydrogen atmosphere for 3 hours. Ethyl 3-ethoxy-3-iminopropanoate hydrochloride (2.0 eq) was then added and the resulting mixture was heated at reflux for 12 hours. After this time, the solution was filtered through a plug of Celite, concentrated, dissolved in 50 ml of 2NHCl and washed with CH2Cl2. The aqueous layer was brought to pH 12 with concentrated NH4OH(aq) and extracted with CH2Cl2. The combined organic layers were dried with MgSO4 and concentrated to yield a brown oil which was purified by silica gel chromatography (5:95 MeOH:CH2Cl2) to provide a yellow solid. LC/MS m/z 287.1 (MH+), Rf 1.98 minutes. The reaction flask was evacuated subsequently filled with H2 the resulting mixture was heated at reflux for 12 hours After this time, the solution was filtered through a plug of Celite concentrated dissolved in 50 ml of 2NHCl and washed with CH2Cl2 extracted with CH2Cl2 The combined organic layers were dried with MgSO4 concentrated to yield a brown oil which was purified by silica gel chromatography (5:95 MeOH:CH2Cl2) to provide a yellow solid

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

実験手順: A solution of 1,2-phenylenediamine (1.0 eq) and ethyl 3-ethoxy-3-iminopropanoate hydrochloride (1.3 eq) in ethanol was stirred at 90° C. overnight. The reaction was cooled to room temperature and the solvent was removed in vacuo. Water and CH2Cl2 were added to the residue. The organic layer was separated, dried over Na2SO4 and the solvent removed. The solid recovered was used without purification. LC/MS m/z 205.2 (MH+), Rf 1.44 minutes. the solvent was removed in vacuo Water and CH2Cl2 were added to the residue The organic layer was separated dried over Na2SO4 the solvent removed The solid recovered was used without purification

反応条件: temp:22.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of the product of Step 1 (54.2 g, 277 mmol) and 4-bromo-3-methoxyaniline (56.0 g, 277 mmol) in EtOH (500 mL) was stirred under nitrogen, at 22° C., for 20 hours. The mixture was filtered and concentrated, then stirred in ether (100 mL), filtered and concentrated. The residue was chromatographed on silica gel 60 (gradient elution, 0-50% EtOAc in hexane) to give the title product. 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=8.4 Hz, 1H); 6.43 (d, J=2.0 Hz, 1H); 6.30 (dd, J=8.4 & 2.4 Hz, 1H); 4.28 (q, J=7.1 Hz, 2H); 4.15 (q, J=7.1 Hz, 2H); 3.85 (s, 2H); 3.21 (s, 2H); 1.34 (t, J=7.2 Hz, 3H); 1.26 (t, J=7.0 Hz, 3H) ppm. LRMS (ESI) m/z 344.0 [(M+H)+; calcd for C14H19BrNO4: 344.0]. The mixture was filtered concentrated stirred in ether (100 mL) filtered concentrated The residue was chromatographed on silica gel 60 (gradient elution, 0-50% EtOAc in hexane)

反応条件: temp:22.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A stirred solution of ethyl cyanoacetate (30 mL, 281 mmol) and EtOH (18.1 mL, 278 mmol) in anhydrous Et2O (28.1 mL), at 0° C., was bubbled with HCl gas until saturated. The reaction was stirred at 22° C. for 20 hours and then concentrated to give the title product. 1H NMR (400 MHz, CDCl3) δ 4.73 (q, J=7.1 Hz, 2H); 4.24 (q, J=7.2 Hz, 2H); 3.89 (s, 2H); 1.51 (t, J=7.0 Hz, 3H); 1.30 (t, J=7.2 Hz, 3H) ppm. concentrated

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

実験手順: A solution of 1,2-phenylenediamine (1.0 eq) and ethyl 3-ethoxy-3-iminopropanoate hydrochloride (1.3 eq) in EtOH was stirred at 90° C. overnight. The reaction was cooled to room temperature and the solvent removed in vacuo. Water and CH2Cl2 were added to the residue. The organic layer was separated, dried over Na2SO4 and the solvent removed. The solid recovered was used without purification. LC/MS m/z 205.2 (MH+), Rt 1.44 minutes. the solvent removed in vacuo Water and CH2Cl2 were added to the residue The organic layer was separated dried over Na2SO4 the solvent removed The solid recovered was used without purification

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2,3,4-Trifluoroaniline (58.8 g) is added in a single portion with stirring to a solution of 2-ethoxycarbonyl-1-ethoxyethylideneamine hydrochloride (90 g) in ethanol (820 cc). After 48 hours' stirring at a temperature in the region of 20° C., the suspension obtained is filtered; the filtrate is concentrated under reduced pressure (20 kPa) at a temperature in the region of 50° C. The oily residue is taken up with water (250 cc). The mixture obtained is extracted with ethyl ether (3×200 cc). The combined organic extracts are washed with water (4×150 cc), dried over magnesium sulphate and concentrated under reduced pressure (20 kPa) at approximately 30° C. 2,3,4-Trifluoro-N-[1-ethoxy-2-(ethoxycarbonyl)ethylidene]aniline (122 g) is obtained in the form of a yellow oil, which is used without further purification for the subsequent steps. the suspension obtained is filtered the filtrate is concentrated under reduced pressure (20 kPa) at a temperature in the region of 50° C The mixture obtained is extracted with ethyl ether (3×200 cc) The combined organic extracts are washed with water (4×150 cc) dried over magnesium sulphate concentrated under reduced pressure (20 kPa) at approximately 30° C

反応条件: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: After all the 5-(4-methyl-piperazin-1-yl)-2-nitroaniline had disappeared from the reaction, the solution was purged with N2 for 15 minutes. The diamine intermediate is air sensitive so care was taken to avoid exposure to air. 500 g (2.56 mol) of ethyl 3-ethoxy-3-iminopropanoate hydrochloride was added to the reaction mixture over a period of about 30 minutes. The reaction was stirred at 45-55° C. (internal temperature) under N2 until the diamine was completely consumed as determined by HPLC. The typical reaction time was about 2 hours. After the reaction was complete, the reaction was filtered while warm through a pad of Celite. The reaction flask and Celite were then washed with 200 proof EtOH (3×285 mL). The filtrates were combined in a 5000 mL flask, and about 3300 mL of ethanol was removed under vacuum producing an orange oil. Water (530 mL) and then 1M HCL (350 mL) were added to the resulting oil, and the resulting mixture was stirred. The resulting solution was vigorously stirred while 30% NaOH (200 mL) was added over a period of about 20 minutes maintaining the internal temperature at about 25-30° C. while the pH was brought to between 9 and 10. The resulting suspension was stirred for about 4 hours while maintaining the internal temperature at about 20-25° C. The resulting mixture was filtered, and the filter cake was washed with H2O (3×300 mL). The collected solid was dried to a constant weight at 50° C. under vacuum in a vacuum oven providing 345.9 g (90.1%) of [6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-acetic acid ethyl ester as a pale yellow powder. In an alternative work up procedure, the filtrates were combined and the ethanol was removed under vacuum until at least about 90% had been removed. Water at a neutral pH was then added to the resulting oil, and the solution was cooled to about 0° C. An aqueous 20% NaOH solution was then added slowly with rapid stirring to bring the pH up to 9.2 (read with pH meter). The resulting mixture was then filtered and dried as described above. The alternative work up procedure provided the light tan to light yellow product in yields as high as 97%. the solution was purged with N2 for 15 minutes was completely consumed the reaction was filtered while warm through a pad of Celite The reaction flask and Celite were then washed with 200 proof EtOH (3×285 mL) The filtrates were combined in a 5000 mL flask about 3300 mL of ethanol was removed under vacuum producing an orange oil was added over a period of about 20 minutes The resulting suspension was stirred for about 4 hours while maintaining the internal temperature at about 20-25° C The resulting mixture was filtered the filter cake was washed with H2O (3×300 mL) The collected solid was dried to a constant weight at 50° C. under vacuum in a vacuum oven

反応条件: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: After all the 5-(4-methyl-piperazin-1-yl)-2-nitroaniline had disappeared from the reaction, the solution was purged with N2 for 15 minutes. The diamine intermediate is air sensitive so care was taken to avoid exposure to air. 500 g (2.56 mol) of ethyl 3-ethoxy-3-iminopropanoate hydrochloride was added to the reaction mixture over a period of about 30 minutes. The reaction was stirred at 45-55° C. (internal temperature) under N2 until the diamine was completely consumed as determined by HPLC. The typical reaction time was about 2 hours. After the reaction was complete, the reaction was filtered while warm through a pad of Celite. The reaction flask and Celite were then washed with 200 proof EtOH (3×285 mL). The filtrates were combined in a 5000 mL flask, and about 3300 mL of ethanol was removed under vacuum producing an orange oil. Water (530 mL) and then 1M HCL (350 mL) were added to the resulting oil, and the resulting mixture was stirred. The resulting solution was vigorously stirred while 30% NaOH (200 mL) was added over a period of about 20 minutes maintaining the internal temperature at about 25-30° C. while the pH was brought to between 9 and 10. The resulting suspension was stirred for about 4 hours while maintaining the internal temperature at about 20-25° C. The resulting mixture was filtered, and the filter cake was washed with H2O (3×300 mL). The collected solid was dried to a constant weight at 50° C. under vacuum in a vacuum oven providing 345.9 g (90.1%) of [6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-acetic acid ethyl ester as a pale yellow powder. In an alternative work up procedure, the filtrates were combined and the ethanol was removed under vacuum until at least about 90% had been removed. Water at a neutral pH was then added to the resulting oil, and the solution was cooled to about 0° C. An aqueous 20% NaOH solution was then added slowly with rapid stirring to bring the pH up to 9.2 (read with pH meter). The resulting mixture was then filtered and dried as described above. The alternative work up procedure provided the light tan to light yellow product in yields as high as 97%. the solution was purged with N2 for 15 minutes was completely consumed the reaction was filtered while warm through a pad of Celite The reaction flask and Celite were then washed with 200 proof EtOH (3×285 mL) The filtrates were combined in a 5000 mL flask about 3300 mL of ethanol was removed under vacuum producing an orange oil was added over a period of about 20 minutes The resulting suspension was stirred for about 4 hours while maintaining the internal temperature at about 20-25° C The resulting mixture was filtered the filter cake was washed with H2O (3×300 mL) The collected solid was dried to a constant weight at 50° C. under vacuum in a vacuum oven

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

実験手順: After all the 5-(4-methyl-piperazin-1-yl)-2-nitroaniline had disappeared from the reaction, the solution was purged with N2 for 15 minutes. Next, 440.0 g (2.25 mol) of ethyl 3-ethoxy-3-iminopropanoate hydrochloride was added as a solid. The reaction was stirred at 40-50° C. (internal temperature) until the reaction was complete. The reaction was monitored by following the disappearance of the diamino compound by HPLC. The typical reaction time was 1-2 hours. After the reaction was complete, it was cooled to room temperature and filtered through a pad of Celite filtering material. The Celite filtering material was washed with absolute EtOH (2×250 mL), and the filtrate was concentrated under reduced pressure providing a thick brown/orange oil. The resulting oil was taken up in 850 mL of a 0.37% HCl solution. Solid NaOH (25 g) was then added in one portion, and a precipitate formed. The resulting mixture was stirred for 1 hour and then filtered. The solid was washed with H2O (2×400 mL) and dried at 50° C. in a vacuum oven providing 251.7 g (74.1%) of [6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-acetic acid ethyl ester as a pale yellow powder. the solution was purged with N2 for 15 minutes it was cooled to room temperature filtered through a pad of Celite filtering material The Celite filtering material was washed with absolute EtOH (2×250 mL) the filtrate was concentrated under reduced pressure providing a thick brown/orange oil a precipitate formed The resulting mixture was stirred for 1 hour filtered The solid was washed with H2O (2×400 mL) dried at 50° C. in a vacuum oven