* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Example 5 Preparation of <strong>[1339928-25-4]N-hydroxy-2-(((2-(6-methoxypyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxamide</strong> choline salt (Compound 5) To a solution of Compound 1 (200 mg, 0.39 mmol) in DCM/MeOH (60 mL/12 mL) was added choline hydroxide (106 mg, 0.39 mmol, 45% in MeOH). The mixture was stirred at room temperature for 2 h and was then concentrated to remove ?30 mL of the solvent. Ethyl acetate (60 mL) was added and the mixture was stirred at room temperature for 2 h. After a small amount of precipitation occurred, the mixture was concentrated to remove ?40 mL of the solvent and additional ethyl acetate (60 mL) was added. The mixture was stirred at room temperature for 2 h and filtered to afford Compound 5 as a white solid (180 mg, 76%). m.p.: 181-185 C. LCMS: 509.3[M+1]+. 1H NMR (400 MHz, DMSO-d6): delta 3.11 (s, 9H), 3.17 (s, 3H), 3.40 (t, J=4.8 Hz, 2H), 3.75 (t, J=4.8 Hz, 4H), 3.84 (br, 2H), 3.90-3.93 (m, 7H), 5.15 (s, 2H), 6.89 (d, J=8.8 Hz, 1H), 7.41 (s, 1H), 8.57 (dd, J=8.8 Hz, 2.4 Hz, 1H), 8.64 (s, 2H), 9.14 (d, J=2.0 Hz, 1H).
76%
In methanol; dichloromethane; ethyl acetate; at 20℃; for 4.0h;
To a solution of Compound 1(200 mg, 0.39 mmol) in DCM/MeOH (60 mL/12 mL) was added choline hydroxide (106 mg, 0.39 mmol, 45% in MeOH). The mixture was stirred at room temperature for 2 h and was then concentrated to remove 30 mL of the solvent. Ethyl acetate (60 mL) was added and the mixture was stirred at room temperaturefor 2 h. After a small amount of precipitation occurred, the mixture was concentrated to remove 40 ml. of the solvent and additional ethyl acetate (60 mL) was added. The mixture was stirred at room temperature for 2 h and filtered to afford Compound 5 as a white solid (180 mg, 76%). m.p.: 181-185C. LCMS: 509.3[M+ljt ?H NMR (400MHz, DMSO-d6): oe 3.11 (s, 9H), 3.17 (s, 3H), 3.40 (t, J= 4.8Hz, 2H), 3.75 (t, J 4.8Hz, 4H),3.84 (br, 2H), 3.90-3.93 (m, 7H), 5.15 (s, 2H), 6.89 (d, J= 8.8Hz, 1H), 7.41 (s, 1H), 8.57 (dd,J= 8.8Hz, 2.4Hz, 1H), 8.64(s, 2H), 9.14 (d,J2.OHz, 1H).
76%
In methanol; dichloromethane; at 20℃; for 2.0h;
To a solution of Compound 1 (200 mg, 0.39 mmol) in DCM/MeOH (60 mL/12 mL) was added choline hydroxide (106 mg, 0.39 mmol, 45% in MeOH). The mixture was stirred at room temperature for 2 h and was then concentrated to remove ?30 mL of the solvent. Ethyl acetate (60 mL) was added and the mixture was stirred at room temperature for 2 h. After a small amount of precipitation occurred, the mixture was concentrated to remove ?40 mL of the solvent and additional ethyl acetate (60 mL) was added. The mixture was stirred at room temperature for 2 h and filtered to afford Compound 5 as a white solid (180 mg, 76%). m.p.: 181-185 C. LCMS: 509.3[M+1]+. 1H NMR (400 MHz, DMSO-d6): delta 3.11 (s, 9H), 3.17 (s, 3H), 3.40 (t, J=4.8 Hz, 2H), 3.75 (t, J=4.8 Hz, 4H), 3.84 (br, 2H), 3.90-3.93 (m, 7H), 5.15 (s, 2H), 6.89 (d, J=8.8 Hz, 1H), 7.41 (s, 1H), 8.57 (dd, J=8.8 Hz, 2.4 Hz, 1H), 8.64 (s, 2H), 9.14 (d, J=2.0 Hz, 1H).
With sodium t-butanolate; In methanol; at 0 - 20℃; for 2.0h;
Example 3 Preparation of <strong>[1339928-25-4]N-hydroxy-2-(((2-(6-methoxypyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxamide</strong> sodium salt (Compound 3) To a suspension of Compound 1 (300 mg, 0.59 mmol) in methanol (30 mL) at 0 C. was added slowly t-BuONa (85 mg, 0.88 mmol). The resulting mixture was warmed to room temperature and continued to stir for 2 h. The reaction was concentrated and the residue was triturated and washed with ethanol followed by filtration to afford Compound 3 as a white solid (230 mg, 73%). m.p.: 178-183 C. LCMS: 509.3 [M+1]+. 1H NMR (400 MHz, DMSO-d6): delta 3.17 (s, 3H), 3.75 (s, 4H), 3.92 (s, 7H), 5.16 (s, 2H), 6.90 (d, J=8.4 Hz, 1H), 7.42 (s, 1H), 8.57 (d, J=8.0 Hz, 1H), 8.65 (s, 2H), 9.14 (s, 1H).
73%
With sodium t-butanolate; In methanol; at 0 - 20℃; for 2.0h;
To a suspension of Compound 1(300 mg, 0.59 mmol) in methanol (30 mL) at 0C was added slowly t-BuONa (85 mg, 0.88 mmol). The resulting mixture was warmed to room temperature and continued to stir for 2 h. The reaction was concentrated and the residue was triturated and washed with ethanol followed by filtration to afford Compound 3 as a white solid (230 mg, 73%). m.p.: 178-183 C. LCMS: 509.3 [M+lj . ?H NMR (400MHz, DMSO-d6): oe 3.17 (s, 3H), 3.75 (s, 4H), 3.92 (s, 7H), 5.16 (s, 2H), 6.90 (d,J= 8.4 Hz, 1H), 7.42 (s, 1H), 8.57 (d, J= 8.0 Hz, 1H), 8.65 (s, 2H), 9.14 (s, 1H).
73%
With sodium t-butanolate; In methanol; at 0 - 20℃; for 2.0h;
To a suspension of Compound 1 (300 mg, 0.59 mmol) in methanol (30 mL) at 0 C. was added slowly t-BuONa (85 mg, 0.88 mmol). The resulting mixture was warmed to room temperature and continued to stir for 2 h. The reaction was concentrated and the residue was triturated and washed with ethanol followed by filtration to afford Compound 3 as a white solid (230 mg, 73%). m.p.: 178-183 C. LCMS: 509.3 [M+1]+. 1H NMR (400 MHz, DMSO-d6): delta 3.17 (s, 3H), 3.75 (s, 4H), 3.92 (s, 7H), 5.16 (s, 2H), 6.90 (d, J=8.4 Hz, 1H), 7.42 (s, 1H), 8.57 (d, J=8.0 Hz, 1H), 8.65 (s, 2H), 9.14 (s, 1H).
With potassium tert-butylate; In methanol; at 0 - 20℃; for 2.5h;Inert atmosphere;
Example 4 Preparation of <strong>[1339928-25-4]N-hydroxy-2-(((2-(6-methoxypyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxamide</strong> potassium salt (Compound 4) To a mixture of Compound 1 (400 mg, 0.78 mmol) in methanol (50 mL) was added t-BuOK (132 mg, 1.17 mmol) at 0 C. under N2. The mixture was stirred at 0 C. for 1 h and continued to stir at room temperature for 1.5 h. The insoluble solid was removed by filtration and the filtrate was cooled to -20 C. Et2O (100 mL) was added to the filtrate. The resulting mixture was stirred at -20 C. for 1 h. Hexanes (70 mL) was added and the mixture was continued to stir at -20 C. for 2 h. The solid was collected by filtration and dried in vacuo to afford Compound 4 as a white solid (150 mg, 35%). m.p.: 174-179 C. LCMS: 509.3[M+1]+. 1H NMR (400 MHz, DMSO-d6): delta 3.16 (s, 3H), 3.74-3.76 (m, 4H), 3.90-3.93 (m, 7H), 5.15 (s, 2H), 6.90 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 8.39 (br, 1H), 8.58 (d, J=8.8 Hz, 1H), 8.62 (s, 2H), 9.15 (s, 1H).
35%
With potassium tert-butylate; In methanol; at 0 - 20℃; for 2.5h;Inert atmosphere;
To a mixture of Compound 1 (400 mg, 0.78 mmol) in methanol (50 mL) was added t-BuOK (132 mg, 1.17 mmol) at 0C underN2. The mixture was stirred at 0C for lh and continued to stir at room temperature for 1 .5h. The insoluble solid was removed byfiltration and the filtrate was cooled to -20C. Et20 (100 mL) was added to the filtrate. The resulting mixture was stirred at -20C for lh. Hexanes (70 mL) was added and the mixture was continued to stir at -20C for 2h. The solid was collected by filtration and dried in vacuo to afford Compound 4 as a white solid (150 mg, 35%). m.p.: 174-179C. LCMS: 509.3[M+1f. ?H NMR (400 MHz, DMSO-d6): oe 3.16 (s, 3H), 3.74-3.76 (m, 4H),3.90-3.93 (m, 7H), 5.15 (s, 2H), 6.90 (d, J= 8.4Hz, 1H), 7.43 (s, 1H), 8.39 (br, 1H), 8.58 (d, J 8.8Hz, 1H), 8.62 (s, 2H), 9.15 (s, 1H).
35%
With potassium tert-butylate; In methanol; at 0 - 20℃; for 2.5h;Inert atmosphere;
To a mixture of Compound 1 (400 mg, 0.78 mmol) in methanol (50 mL) was added t-BuOK (132 mg, 1.17 mmol) at 0 C. under N2. The mixture was stirred at 0 C. for 1 h and continued to stir at room temperature for 1.5 h. The insoluble solid was removed by filtration and the filtrate was cooled to -20 C. Et2O (100 mL) was added to the filtrate. The resulting mixture was stirred at -20 C. for 1 h. Hexanes (70 mL) was added and the mixture was continued to stir at -20 C. for 2 h. The solid was collected by filtration and dried in vacuo to afford Compound 4 as a white solid (150 mg, 35%). m.p.: 174-179 C. LCMS: 509.3[M+1]+. 1H NMR (400 MHz, DMSO-d6): delta 3.16 (s, 3H), 3.74-3.76 (m, 4H), 3.90-3.93 (m, 7H), 5.15 (s, 2H), 6.90 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 8.39 (br, 1H), 8.58 (d, J=8.8 Hz, 1H), 8.62 (s, 2H), 9.15 (s, 1H).
With sulfuric acid; In methanol; dichloromethane; at 20℃;
Example 6 Preparation of <strong>[1339928-25-4]N-hydroxy-2-(((2-(6-methoxypyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxamide</strong> sulfate (Compound 6) To a suspension of Compound 1 (200 mg, 0.39 mmol) in DCM/MeOH (30 mL/7.5 mL) was added sulfuric acid (77 mg, 0.79 mmol, in 1 mL MeOH) to form a clear solution. The reaction mixture was stirred at room temperature overnight. The precipitation occurred and tert-butyl methyl ether (60 mL) was then added. The resulting mixture was continued to stir for 1 h at room temperature. The solid was collected by filtration to afford Compound 6 as a white solid (180 mg, 76%). M.p.: 243-246 C. LCMS: 509.3 [M+1]+. 1H NMR (400 MHz, DMSO-d6): delta 3.26 (s, 3H), 3.78 (t, J=4.8 Hz, 4H), 3.96 (s, 3H), 4.03 (t, J=4.4 Hz, 4H), 5.24 (s, 3H), 6.98 (d, J=8.4 Hz, 1H), 7.50 (s, 1H), 8.54 (dd, J=8.8 Hz, 2.4 Hz, 1H), 8.76 (s, 2H), 9.12 (d, J=2.0 Hz, 1H), 11.06 (br, 1H).
76%
With sulfuric acid; In methanol; dichloromethane; at 20℃;
To a suspension of Compound 1(200 mg, 0.39 mmol) in DCMIMeOH (30 mL/7.5mL) was added sulfuric acid (77 mg, 0.79 mmol, in 1 mL MeOH) to form a clear solution.The reaction mixture was stirred at room temperature overnight. The precipitation occurred and tert-butyl methyl ether (60 mL) was then added. The resulting mixture was continued to stir for 1 h at room temperature. The solid was collected by filtration to afford Compound 6 as a white solid (180 mg, 76%). m.p.: 243-246C. LCMS: 509.3 [M+ljt ?HNMR (400 MI-Tz, DMSO-d6): oe 3.26 (s, 3H), 3.78 (t, J = 4.8 Hz, 4H), 3.96 (s, 3H), 4.03 (t, J = 4.4 Hz, 4H), 5.24 (s, 3H), 6.98 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 8.54 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 8.76 (s, 2H), 9.12 (d, J = 2.0 Hz, 1H), 11.06 (br, 1H).
76%
With sulfuric acid; In methanol; dichloromethane; at 20℃;
To a suspension of Compound 1 (200 mg, 0.39 mmol) in DCM/MeOH (30 mL/7.5 mL) was added sulfuric acid (77 mg, 0.79 mmol, in 1 mL MeOH) to form a clear solution. The reaction mixture was stirred at room temperature overnight. The precipitation occurred and tert-butyl methyl ether (60 mL) was then added. The resulting mixture was continued to stir for 1 h at room temperature. The solid was collected by filtration to afford Compound 6 as a white solid (180 mg, 76%). m.p.: 243-246 C. LCMS: 509.3 [M+1]+. 1H NMR (400 MHz, DMSO-d6): delta 3.26 (s, 3H), 3.78 (t, J=4.8 Hz, 4H), 3.96 (s, 3H), 4.03 (t, J=4.4 Hz, 4H), 5.24 (s, 3H), 6.98 (d, J=8.4 Hz, 1H), 7.50 (s, 1H), 8.54 (dd, J=8.8 Hz, 2.4 Hz, 1H), 8.76 (s, 2H), 9.12 (d, J=2.0 Hz, 1H), 11.06 (br, 1H).
methyl 2-(N-((2-(6-methoxypyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-methylamino)pyrimidine-5-carboxylate[ No CAS ]
[ 1339928-25-4 ]
Yield
Reaction Conditions
Operation in experiment
76%
With hydroxylamine; In methanol; dichloromethane; at 20℃; for 5.0h;Sealed tube;
Preparation of Compound 1 from Compound 108-2 To a suspension of compound 108-2 (31 g, 61.1 mmol) in dichloromethane (310 mL) at room temperature was added above freshly prepared hydroxylamine methanol solution (1.79M, 744 ml). The reaction flask was sealed and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture turned into a clear solution. The reaction solution was filtered to remove any insoluble solid. To the filtrate was then added water (310 mL) and there was no solid formed during the addition. Acetic acid (18.5 mL) was added to adjust pH to 10.20 (continuously monitored by pH meter) while stirring. There was no internal temperature change during acetic acid addition. The resulting reaction mixture was continued to stir for another 4 h. White solid gradually formed. The suspension was filtered and washed with minimum amount of methanol (100 mL*3). The collected white solid was re-suspended in methanol (620 mL) and water (124 mL) to form a suspension. To the above suspension was added additional acetic acid (11 g) to adjust the pH to 5-6. The change of the solid form was observed. The suspension was continued to stir for another 2 h and filtered through filter paper and washed with minimum amount of methanol (100 mL*3). The collected white solid was dried in oven (50 C.) for 12 h to afford the title Compound 1 as a white solid (23.6 g, 76.0%).
76%
With hydroxylamine; In methanol; dichloromethane; at 20℃; for 5.0h;Sealed tube;
To a suspension of compound 108-2 (31 g, 61.1 mmol)in dichloromethane (310 mL) at room temperature was added above freshly prepared hydroxylamine methanol solution (1 .79M, 744 ml). The reaction flask was sealed and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture turned into a clear solution. The reaction solution was filtered to remove any insoluble solid. To the filtrate was then addedwater (310 mL) and there was no solid formed during the addition. Acetic acid (18.5 mL) was added to adjust pH to 10.20 (continuously monitored by pH meter) while stirring. There was no internal temperature change during acetic acid addition. The resulting reaction mixture was continued to stir for another 4 h. White solid gradually formed. The suspension was filtered and washed with minimum amount of methanol (lOOmL x 3). Thecollected white solid was re-suspended in methanol (620mL) and water (124mL) to form a suspension. To the above suspension was added additional acetic acid (1 ig) to adjust the pH to 5-6. The change of the solid form was observed. The suspension was continued to stir for another 2 h and filtered through filter paper and washed with minimum amount of methanol (100 mL x 3). The collected white solid was dried in oven (50C) for 12 h to afford the title Compound 1 as a white solid (23.6g, 76.0%). m. p.: 25 5-259C. LCMS (m/z): 509.3 [M+1f ?H NMR (400 MHz, DMSO-d6): oe 3.24 (s, 3H), 3.76 (t, J 5.2 Hz, 4H), 3.92 (t, J= 5.2Hz, 4H), 3.92 (s, 3H), 5.20 (s, 2H), 6.91 (d, J= 8.4Hz, 1H), 7.45 (s, 1H), 8.57 (dd, J= 8.4Hz, 2.4Hz, 1H), 8.75 (s, 2H), 9.07 (s, 1H), 9.14 (d, J= 2.4Hz, 1H),11.14 (s,1H).
76%
With hydroxylamine hydrochloride; potassium hydroxide; In methanol; dichloromethane; at 20℃; for 5.0h;Sealed tube;
To a suspension of compound 108-2 (31 g, 61.1 mmol) in dichloromethane (310 mL) at room temperature was added above freshly prepared hydroxylamine methanol solution (1.79M, 744 ml). The reaction flask was sealed and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture turned into a clear solution. The reaction solution was filtered to remove any insoluble solid. To the filtrate was then added water (310 mL) and there was no solid formed during the addition. Acetic acid (18.5 mL) was added to adjust pH to 10.20 (continuously monitored by pH meter) while stirring. There was no internal temperature change during acetic acid addition. The resulting reaction mixture was continued to stir for another 4 h. White solid gradually formed. The suspension was filtered and washed with minimum amount of methanol (100 mL*3). The collected white solid was re-suspended in methanol (620 mL) and water (124 mL) to form a suspension. To the above suspension was added additional acetic acid (11 g) to adjust the pH to 5-6. The change of the solid form was observed. The suspension was continued to stir for another 2 h and filtered through filter paper and washed with minimum amount of methanol (100 mL*3). The collected white solid was dried in oven (50 C.) for 12 h to afford the title Compound 1 as a white solid (23.6 g, 76.0%).
Method B: To a suspension of Compound 1 (1.5 g, 2.95 mmol) in dichloromethane/MeOH (40 mL/10 mL) was added methanesulfonic acid (341 mg, 3.55 mmol) in 2 mL MeOH at room temperature (15 C.) to form a clear solution. The reaction mixture was stirred at room temperature overnight. The reaction mixture was still clear. Ethyl acetate (40 mL) was added to the mixture and continued to stir for 3 h at room temperature. The resulting precipitate was collected by filtration to afford Compound 2 as a white solid (1.45 g, 83%). (0175) m.p.: 179-185 C. LCMS: 509.3 [M+1]+. 1H NMR (400 MHz, DMSO-d6): delta 2.35 (s, 3H), 3.26 (s, 3H), 3.78 (t, J=9.6 Hz, 4H), 3.95 (s, 3H), 4.03 (t, J=9.2 Hz, 4H), 5.24 (s, 2H), 6.99 (d, J=8.8 Hz, 1H), 7.50 (s, 1H), 8.54 (dd, J=8.8 Hz, 2.4 Hz, 1H), 8.76 (s, 2H), 9.12 (d, J=2.4 Hz, 1H), 11.11 (br, 1H).
83%
In methanol; dichloromethane; at 15℃;
To a suspension of Compound 1(1.5 g, 2.95 mmol) in dichloromethane/ MeOH (40 mL / 10 mL) was added methanesulfonic acid (341 mg, 3.55 mmol) in 2 mL MeOH at room temperature (15C) to form a clear solution. The reaction mixture was stirred at room temperature overnight. The reaction mixture was still clear. Ethyl acetate (4OmL) was added to the mixture and continued to stir for 3 h at roomtemperature. The resulting precipitate was collected by filtration to afford Compound 2 as a white solid (1.45g, 83%).m.p.: 179-185 C. LCMS: 509.3 [M+lj . ?H NMR (400 MHz, DMSO-d6): oe 2.35 (s, 3H), 3.26 (s, 3H), 3.78 (t, J= 9.6 Hz, 4H), 3.95 (s, 3H), 4.03 (t, J 9.2 Hz, 4H), 5.24 (s, 2H), 6.99 (d, J= 8.8 Hz, 1H), 7.50 (s, 1H), 8.54 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 8.76 (s,2H), 9.12 (d,J=2.4Hz, 1H), 11.11 (br, 1H).
83%
In methanol; dichloromethane; at 20℃;
To a suspension of Compound 1 (1.5 g, 2.95 mmol) in dichloromethane/MeOH (40 mL/10 mL) was added methanesulfonic acid (341 mg, 3.55 mmol) in 2 mL MeOH at room temperature (15 C.) to form a clear solution. The reaction mixture was stirred at room temperature overnight. The reaction mixture was still clear. Ethyl acetate (40 mL) was added to the mixture and continued to stir for 3 h at room temperature. The resulting precipitate was collected by filtration to afford Compound 2 as a white solid (1.45 g, 83%). m.p.: 179-185 C. LCMS: 509.3 [M+1]+. 1H NMR (400 MHz, DMSO-d6): delta 2.35 (s, 3H), 3.26 (s, 3H), 3.78 (t, J=9.6 Hz, 4H), 3.95 (s, 3H), 4.03 (t, J=9.2 Hz, 4H), 5.24 (s, 2H), 6.99 (d, J=8.8 Hz, 1H), 7.50 (s, 1H), 8.54 (dd, J=8.8 Hz, 2.4 Hz, 1H), 8.76 (s, 2H), 9.12 (d, J=2.4 Hz, 1H), 11.11 (br, 1H).
ethyl-2-(((2-(6-methoxypyridin-3-yl)-4-morpholinothieno [3,2-d]pyrimidin-6-yl) methyl) (methyl)amino)pyrimidine-5-carboxylate[ No CAS ]
[ 1339928-25-4 ]
Yield
Reaction Conditions
Operation in experiment
96%
With hydroxylamine; In methanol; dichloromethane; at 20℃; for 14.0h;Sealed tube;
Preparation of Compound 1 from Compound 108-1 Compound 108-1 (10 g, 19 mmol) was suspended in the above freshly prepared hydroxylamine methanol solution (1.79M, 350 ml). To this mixture was added dichloromethane (100 mL). The reaction flask was sealed and the mixture was stirred at room temperature for 5 h before it turned into clear solution. Reaction was stirred for additional 9 h. and was filtered to remove any insoluble solid. The filtrate was adjusted to pH 6-7 with the addition of acetic acid to form solid precipitate. The solid was collected by filtration and washed with water and minimum amount of methanol, dried in vacuo at 60 C. for 5 h to afford compound 1 as a white solid (9.2 g, 96%). m.p. 177-180 C. LCMS: 509.3 [M+1]+. 1H NMR (400 MHz, DMSO-d6): delta 3.24 (s, 3H), 3.76 (t, J=5 Hz, 4H), 3.92 (t, J=5 Hz, 4H), 3.92 (s, 3H), 5.20 (s, 2H), 6.90 (d, J=8.8 Hz, 1H), 7.44 (s, 1H), 8.57 (dd, J=8.8 Hz, 2.4 Hz, 1H), 8.75 (s, 2H), 9.01 (s, 1H), 9.14 (d, J=2.0 Hz, 1H), 11.08 (s, 1H).
96%
With hydroxylamine hydrochloride; In methanol; dichloromethane; at 20℃; for 14.0h;Sealed tube;
Compound 108-1 (10 g, 19 mmol) was suspended in the above freshly prepared hydroxylamine methanol solution (1.79M, 350 ml). To this mixture was added dichloromethane (100 mL). The reaction flask was sealed and the mixture was stirred at room temperature for 5 h before it turned into clear solution. Reaction was stirred foradditional 9 h. and was filtered to remove any insoluble solid. The filtrate was adjusted topH 6-7 with the addition of acetic acid to form solid precipitate. The solid was collectedby filtration and washed with water and minimum amount of methanol, dried in vacuo at60C for 5h to afford compound 1 as a white solid (9.2g, 96%). m.p. 177-180C. LCMS:509.3 [M+1f. ?H NMR (400 MHz, DMSO-d6): oe 3.24 (s, 3H), 3.76 (t, J 5 Hz, 4H),3.92 (t, J 5 Hz, 4H), 3.92 (s, 3H), 5.20 (s, 2H), 6.90 (d, J= 8.8 Hz, 1H), 7.44 (s, 1H),8.57 (dd, J= 8.8 Hz, 2.4Hz, 1H), 8.75 (s, 2H), 9.01 (s, 1H), 9.14 (d, J= 2.0 Hz, 1H), 11.08 (s,1H).
96%
With hydroxylamine hydrochloride; potassium hydroxide; In methanol; dichloromethane; at 20℃; for 14.0h;Sealed tube;
A mixture of NH2OH.HCl (80 g, 1.12 mol) in MeOH (400 mL) was heated at 60-65 C. for 1 h to form a clear solution. It was then cooled in an ice-water bath. To the cold mixture was added a solution of KOH (96 g, 1.68 mol) in MeOH (240 mL) dropwise while maintaining the reaction temperature at 0-10 C. The resulting mixture was stirred at 0 C. for 30 minutes and then filtered through a constant pressure funnel filled with anhydrous Na2SO4 (700 g). The filtrate was collected under an ice-bath and stored in refrigerator for future use. Compound 108-1 (10 g, 19 mmol) was suspended in the above freshly prepared hydroxylamine methanol solution (1.79M, 350 ml). To this mixture was added dichloromethane (100 mL). The reaction flask was sealed and the mixture was stirred at room temperature for 5 h before it turned into clear solution. Reaction was stirred for additional 9 h. and was filtered to remove any insoluble solid. The filtrate was adjusted to pH 6-7 with the addition of acetic acid to form solid precipitate. The solid was collected by filtration and washed with water and minimum amount of methanol, dried in vacuo at 60 C. for 5 h to afford compound 1 as a white solid (9.2 g, 96%). m.p. 177-180 C. LCMS: 509.3 [M+1]+. 1H NMR (400 MHz, DMSO-d6): delta 3.24 (s, 3H), 3.76 (t, J=5 Hz, 4H), 3.92 (t, J=5 Hz, 4H), 3.92 (s, 3H), 5.20 (s, 2H), 6.90 (d, J=8.8 Hz, 1H), 7.44 (s, 1H), 8.57 (dd, J=8.8 Hz, 2.4 Hz, 1H), 8.75 (s, 2H), 9.01 (s, 1H), 9.14 (d, J=2.0 Hz, 1H), 11.08 (s, 1H).