* 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.
Reference：
[1] Journal of Materials Chemistry, 2000, vol. 10, # 4, p. 867 - 871
2
[ 67-56-1 ]
[ 108-77-0 ]
[ 3140-73-6 ]
Yield
Reaction Conditions
Operation in experiment
89.5%
With sodium hydrogencarbonate In water at 100℃; for 36 h; Large scale
CDMT was synthesized using the general procedure described above (Example 7) : in a reactor as described previously, there were introduced by means of an auger dispenser and/or a dispenser for liquids, 36 kg of NaHCC>3, 9.0 L of methanol, and 7.5 L of water. Then, there were introduced under stirring by means of an auger dispenser 10 kg of cyanuric chloride in approx. 2-3 h and then the mixture was heated at 100°C for 36 h. At the end of the reaction, the work-up was carried out by adding 1-5 volumes of water (9-45 L) with subsequent stirring for 480 min. The suspension was filtered, and the product collected and dried in a vacuum. An amount of 8.5 kg (48.3 mol) was recovered with a yield of 89.5percent and a purity of 96.7percent (3.3percent of water) . This method was used up to 150 kg of CDMT. For larger production volumes, it is recommended to arrange a number of reactors side by side in parallel. XH NMR (CDC13, 300 MHz, ppm) δΗ: 4.07; 13C NMR (75 MHz, CDCI3, ppm) 5C: 172.72, 172.54, 56.04. FT-IR: 1540, 928, 806 cm-1
69.6%
With sodium hydrogencarbonate In water at 10 - 35℃; for 12 h;
The methanol 72.9g, distilled water 8.96g and sodium bicarbonate 46.6g (0.56mol) formed in the solution is placed in a ice-water cooling to 10 °C left and right, by adding trichloro prepares 34.1g (0.18mol), then 35 °C stirring reaction in water bath 12h. The reaction liquid under mechanical stirring into 480 ml distilled water, stirring 30 min. Filtering, washing 3 times, drying the white solid obtained 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) 22.5g, yield 69.6percent, melting point 73-76°C. (Melting point of fire 72-74.6 °C)N-methyl morpholine to 13.2 ml (0.119mol) of added under stirring vigorously CDMT20.6g (0.12mol) dissolved in THF (300 ml) in solution, stirring the mixture at room temperature for reaction 30 min. Filtering, washing THF 5 times, drying to obtain the white solid 4 - (4,6-dimethoxy-triazine) - 4-methyl-morpholine hydrochloride (DMT-MM)32.1g, yield 97.5percent.
235 kg
for 6 h; Reflux; Large scale
The reaction mixture was heated slowly to methanol reflux in stages, and then the reaction was carried out for 6 hours. The reaction was carried out in a nitrogen atmosphere.The distillation was carried out in a reaction kettle, and the distillation and condensation were carried out by water-cooling and freeze-thawing. The distillation was carried out in a reaction kettle.3) dilution crystallization: distillation residue 545 kg input analysis the cauldron added water to dilute in water crystallization 1150 kg;4) filtering / washing, drying: adding the crystalline solid is washed with water, filtered, dried to obtain the crude product 275 kg;The solid phase was dried to obtain the final product of 2-chloro-4,6-dimethoxy-propan-1-one, which was purified by distillation. 1, 3, 5 - triazine 235 kg.
Reference：
[1] Molecules, 2016, vol. 21, # 6,
[2] Patent: WO2016/103185, 2016, A2, . Location in patent: Page/Page column 34
[3] Journal of Materials Chemistry C, 2018, vol. 6, # 13, p. 3288 - 3297
[4] Patent: CN103497211, 2016, B, . Location in patent: Paragraph 0113
[5] Synthetic Communications, 1996, vol. 26, # 18, p. 3491 - 3494
[6] Organic and Biomolecular Chemistry, 2010, vol. 8, # 22, p. 5126 - 5132
[7] Chemische Berichte, 1903, vol. 36, p. 3195
[8] Journal of the American Chemical Society, 1951, vol. 73, p. 2986,2989
[9] Journal of the American Chemical Society, 1995, vol. 117, # 20, p. 5484 - 5491
[10] Acta Poloniae Pharmaceutica - Drug Research, 2010, vol. 67, # 6, p. 725 - 728
[11] Asian Journal of Chemistry, 2015, vol. 27, # 11, p. 4130 - 4134
[12] Journal of Molecular Structure, 2016, vol. 1125, p. 121 - 135
[13] Patent: CN106146421, 2016, A, . Location in patent: Paragraph 0036; 0037; 0038; 0039; 0040; 0041; 0042
[14] Journal of Chemistry, 2016, vol. 2016,
3
[ 108-77-0 ]
[ 3140-73-6 ]
Yield
Reaction Conditions
Operation in experiment
89.2%
With sodium hydrogencarbonate In methanol; water
Example 1 In a 500-ml four-necked flask equipped with a stirrer and a thermometer, 44.1 g (0.525 mol) of sodium hydrogencarbonate and 160.2 g (water content: 650 ppm, 5.0 mol) of methanol were placed. With stirring at a temperature of not higher than 10° C., 46.1 g (0.25 mol) of cyanuric chloride was added, followed by stirring at 20° C. for 1 hour. Then, the reaction was conducted at 60° C. for 3.5 hours. The weight of the reaction solution from which a salt formed had been removed was 192 g, and the water content was 49,500 ppm. After cooling, methanol was distilled off. To the residue, 200 ml of water was added, and the objective product was extracted with 250 ml of ethyl acetate. The organic layer was washed with 100 ml of water and then vacuum concentrated to obtain 39.2 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine as a white solid. The yield was 89.2percent. From the gas chromatography analysis, the purity proved to be 96.3percent (percent by area).
88.3%
With potassium hydrogencarbonate In methanol; water
Example 2 In a 500-ml four-necked flask equipped with a stirrer and a thermometer, 52.6 g (0.525 mol) of potassium hydrogencarbonate and 160.2 g (water content: 340 ppm, 5.0 mol) of methanol were placed. With stirring at a temperature of not higher than 10° C., 46.1 g (0.25 mol) of cyanuric chloride was added, followed by stirring at 20° C. for 1 hour. Then, the reaction was conducted at 50° C. for 2.5 hours. The weight of the reaction solution from which a salt formed had been removed was 193 g, and the water content was 49,600 ppm. After cooling, methanol was distilled off. To the residue, 200 ml of water was added, and the objective product was extracted with 250 ml of ethyl acetate. The organic layer was washed with 100 ml of water and then vacuum concentrated to obtain 38.8 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine as a white solid. The yield was 88.3percent. From the gas chromatography analysis, the purity proved to be 96.0percent (percent by area).
87.5%
With potassium hydrogencarbonate In methanol; water; ethyl acetate
Example 6 In a 1-liter (1000-ml) four-necked flask equipped with a stirrer and a thermometer, 52.6 g (0.525 mol) of potassium hydrogencarbonate, 80.1 g (5.0 mol, water content: 530 ppm) of methanol and 100 ml of ethyl acetate were placed. With stirring at a temperature of not higher than 10° C., 46.1 g (0.25 mol) of cyanuric chloride was added, followed by stirring at 20° C. for 1 hour. Then, the reaction solution was refluxed at 62° C. for 6 hours. The weight of the reaction solution from which a salt formed had been removed was 202 g, and the water content was 46,300 ppm. Then, 150 ml of ethyl acetate and 200 ml of water were added, followed by liquid separation. The organic layer was washed with 200 ml of water and then vacuum concentrated to obtain 38.4 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine as a white solid. The yield was 87.5percent. From the gas chromatography analysis, the purity proved to be 93.8percent (percent by area).
84.3%
With sodium hydrogencarbonate In methanol; water; ethyl acetate
Example 5 In a 1-liter (1000-ml) four-necked flask equipped with a stirrer and a thermometer, 44.1 g (0.525 mol) of sodium hydrogencarbonate, 80.1 g (2.5 mol, water content: 560 ppm) of methanol and 100 ml of ethyl acetate were placed. With stirring at a temperature of not higher than 10° C., 46.1 g (0.25 mol) of cyanuric chloride was added, followed by stirring at 20° C. for 1 hour. Then, the reaction solution was refluxed at 62° C. for 10 hours. The weight of the reaction solution from which a salt formed had been removed was 205 g, and the water content was 46,000 ppm. Then, 150 ml of ethyl acetate and 200 ml of water were added, followed by liquid separation. The organic layer was washed with 200 ml of water and then vacuum concentrated to obtain 37.0 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine as a white solid. The yield was 84.3percent. From the gas chromatography analysis, the purity proved to be 96.1percent (percent by area).
84.8%
With sodium hydrogencarbonate In methanol; water
Example 3 In a 1-liter (1000-ml) four-necked flask equipped with a stirrer and a thermometer, 88.2 g (1.05 mol) of sodium hydrogencarbonate and 160.2 g (water content: 460 ppm, 5.0 mol) of methanol were placed. With stirring at a temperature of not higher than 10° C., 92.2 g (0.5 mol) of cyanuric chloride was added, followed by stirring at 20° C. for 1 hour. Then, the reaction was conducted at 60° C. for 3.5 hours. The weight of the reaction solution from which a salt formed had been removed was 233 g, and the water content was 80,300 ppm. After cooling, methanol was distilled off. To the residue, 400 ml of water was added, and the objective product was extracted with 500 ml of ethyl acetate. The organic layer was washed with 400 ml of water and then vacuum concentrated to obtain 74.4 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine as a white solid. The yield was 84.8percent. From the gas chromatography analysis, the purity proved to be 97.4percent (percent by area).
82.8%
With potassium hydrogencarbonate In methanol; water
Example 4 In a 1-liter (1000-ml) four-necked flask equipped with a stirrer and a thermometer, 105.1 g (1.05 mol) of potassium hydrogencarbonate and 160.2 g (5.0 mol, water content: 530 ppm) of methanol were placed. With stirring at a temperature of not higher than 10° C., 92.2 g (0.5 mol) of cyanuric chloride was added, followed by stirring at 20° C. for 1 hour. Then, the reaction was conducted at 50° C. for 4 hours. The weight of the reaction solution from which a salt formed had been removed was 230 g, and the water content was 79,800 ppm. After *cooling, methanol was distilled off. To the residue, 400 ml of water was added, and the objective product was extracted with 500 ml of ethyl acetate. The organic layer was washed with 400 ml of water and then vacuum concentrated to obtain 72.7 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine as a white solid. The yield was 82.8percent. From the gas chromatography analysis, the purity proved to be 94.9percent (percent by area).
67.2%
With sodium hydrogencarbonate In methanol; water
Comparative Example 1 In a 500-ml four-necked flask equipped with a stirrer and a thermometer, 63.0 g (0.75 mol) of sodium hydrogencarbonate, 98.5 g (3.08 mol, water content: 187 ppm) of methanol and 12.1 g (0.675 mol) of water were placed. With stirring at a temperature of not higher than 10° C., 46.1 g (0.25 mol) of cyanuric chloride was added, followed by stirring for 30 minutes. Then, the reaction was conducted at 35° C. for 15 hours. The weight of the reaction solution from which a salt formed had been removed was 158 g, and the water content was 143,000 ppm. After cooling, methanol was distilled off. To the residue, 400 ml of water was added, and the objective product was extracted with 300 ml of ethyl acetate. The organic layer was washed with 100 ml of water and then vacuum concentrated to obtain 29.5 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine. The yield was 67.2percent. From the gas chromatography analysis, the purity proved to be 94.0percent (percent by area).
Stage #1: With sodium hydride In tetrahydrofuran at 0 - 50℃; for 0.75 h; Stage #2: at 0℃; for 2 h;
Acetamide (27 mg, 0.46 mmol) in THF (600 μL) was added to a suspension of sodium hydride (20 mg, 0.51 mmol) in THF (300 μL) at 0 °C. After stirring for 45 min at 50 °C, the reaction mixture was cooled to 0 °C. A THF (200 μL) solution of 2,4-dichloro-6-methoxy-1,3,5-triazine (6, 100 mg, 0.56 mmol) was added dropwise to the resulting suspension, and the mixture was stirred for 2 h at 0 °C. To the mixture was added CH2Cl2 and 1 M KHSO4at 0 °C. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane/EtOAc 9:1 to 1:1) to afford I (4 mg, 4percent), 2-acetamido-4,6-dichloro-1,3,5-triazine (7a) (27 mg, 28percent), CDMT (25 mg, 31percent), and 6 (18 mg, 18percent recovery).
Reference：
[1] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 1897 - 1903
General procedure: To a stirred solution of CDMT (1.5 mmol) in dry CH2Cl2(15 mL), N-methylmorpholine (NMM) (6.0 mmol) was added dropwise and allowed to stir for 10 min. To the white suspension containing DMTMM salt, the Schiff base (1.0mmol) and the carboxylic acid (1.5 mmol) were added and the mixture was stirred overnight. The mixture was washed successively with saturated NaHCO3 (15 mL) and brine (15mL), dried with Na2SO4 and concentrated in vacuo. 2-azetidinones 3a-k, 3n-o were purified by crystallizationfrom EtOAc and 2-azetidinones 3l-m by short column chromatographyon silica gel
97.5%
at 20℃; for 0.5 h;
The methanol 72.9g, distilled water 8.96g and sodium bicarbonate 46.6g (0.56mol) formed in the solution is placed in a ice-water cooling to 10 °C left and right, by adding trichloro prepares 34.1g (0.18mol), then 35 °C stirring reaction in water bath 12h. The reaction liquid under mechanical stirring into 480 ml distilled water, stirring 30 min. Filtering, washing 3 times, drying the white solid obtained 2-chloro -4,6-dimethoxy -1, 3, 5-triazole (CDMT) 22.5g, yield 69.6percent, melting point 73-76°C. (Melting point of fire 72-74.6 °C)N-methyl morpholine to 13.2 ml (0.119mol) of added under stirring vigorously CDMT20.6g (0.12mol) dissolved in THF (300 ml) in solution, stirring the mixture at room temperature for reaction 30 min. Filtering, washing THF 5 times, drying to obtain the white solid 4 - (4,6-dimethoxy-triazine) - 4-methyl-morpholine hydrochloride (DMT-MM)32.1g, yield 97.5percent.
Reference：
[1] Tetrahedron Letters, 1999, vol. 40, # 29, p. 5327 - 5330
[2] Tetrahedron, 1999, vol. 55, # 46, p. 13159 - 13170
[3] Tetrahedron Letters, 2010, vol. 51, # 1, p. 20 - 22
[4] Letters in Organic Chemistry, 2015, vol. 12, # 1, p. 44 - 49
[5] Tetrahedron Letters, 2002, vol. 43, # 18, p. 3323 - 3326
[6] Chemistry - A European Journal, 2008, vol. 14, # 3, p. 909 - 918
[7] Patent: CN103497211, 2016, B, . Location in patent: Paragraph 0112; 0114
[8] Patent: EP1178043, 2002, A1, . Location in patent: Page 19
[9] Patent: EP1178043, 2002, A1, . Location in patent: Page 18-19
[10] Journal of Organic Chemistry, 1998, vol. 63, # 13, p. 4248 - 4255
[11] Journal of Organic Chemistry, 1999, vol. 64, # 24, p. 8962 - 8964
[12] Synlett, 2000, # 2, p. 275 - 277
[13] Journal of the American Chemical Society, 2005, vol. 127, # 48, p. 16912 - 16920
[14] Journal of Organic Chemistry, 2007, vol. 72, # 22, p. 8584 - 8587
[15] Patent: WO2004/52850, 2004, A2, . Location in patent: Page 73
[16] Polish Journal of Chemistry, 2008, vol. 82, # 7, p. 1413 - 1423
[17] Tetrahedron Letters, 2009, vol. 50, # 8, p. 946 - 948
[18] European Journal of Organic Chemistry, 2009, # 17, p. 2748 - 2764
[19] Patent: WO2009/80366, 2009, A1, . Location in patent: Page/Page column 8-9
[20] Angewandte Chemie, International Edition, 2009, vol. 48, # 15, p. 2755 - 2758
[21] Bulletin of the Korean Chemical Society, 2010, vol. 31, # 7, p. 2061 - 2064
[22] Acta Poloniae Pharmaceutica - Drug Research, 2010, vol. 67, # 6, p. 725 - 728
[23] Macromolecules, 2010, vol. 43, # 22, p. 9534 - 9540
[24] Dyes and Pigments, 2011, vol. 90, # 2, p. 129 - 138
[25] Bioconjugate Chemistry, 2013, vol. 24, # 4, p. 724 - 733
[26] Polyhedron, 2014, vol. 85, p. 627 - 634
[27] Polyhedron, 2015, vol. 85, p. 627 - 634
12
[ 3140-73-6 ]
[ 3945-69-5 ]
Yield
Reaction Conditions
Operation in experiment
97.4%
With 4-methyl-morpholine In tetrahydrofuran; methanol
Example 107 Into a 500-ml four neck distillation flask were added 17.56 g (0.1 mol) of a 2-chloro-4,6-dimethoxy-1,3,5-triazine, 200 ml of a tetrahydrofuran and 9.6 g (0.3 mols) of methanol, which were, then, stirred at 5 to 10° C. for 10 minutes. Then, 10.6 g (0.105 mols) of a 4-methylmorpholine was added thereto to effect the reaction at 5 to 10° C. for 4 hours. The precipitated crystals were filtrated by means of suction, washed with 100 ml of a tetrahydrofuran, and were dried at room temperature under a reduced pressure for 3 hours to obtain 27.02 g of a white solid of a 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride represented by the above-mentioned general formula (I) as a quaternary ammonium salt. The white solid contained water in an mount of 0.3percent by weight and its yield was 97.4percent.
96.9%
With 4-methyl-morpholine In tetrahydrofuran; methanol
Example 108 Into a 500-ml four neck distillation flask were added 17.56 g (0.1 mol of a 2-chloro-4,6-dimethoxy-1,3,5-triazine, 200 ml of a tetrahydrofuran and 9.6 g (0.3 mols) of methanol, which were, then, stirred at 5 to 10° C. for 10 minutes. Then, 10.6 g (0.105 mols) of a 4-methylmorpholine was added thereto to effect the reaction at 5 to 10° C. for 3 hours. The precipitated crystals were filtrated by means of suction, washed with 100 ml of a tetrahydrofuran, and were dried at room temperature under a reduced pressure for 3 hours to obtain 26.88 g of a white solid of a 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride represented by the above-mentioned general formula (I) as a quaternary ammonium salt. The white solid contained water in an mount of 0.3percent by weight and its yield was 96.9percent.
94.6%
With 4-methyl-morpholine In ethyl acetate
Comparative Example 1 Into a 2000-ml four neck distillation flask were added 87.8 g (0.5 mols) of a 2-chloro-4,6-dimethoxy-1,3,5-triazine and 1000 ml of an ethyl acetate, which were then stirred at 5 to 10° C. for 10 minutes. Next, 53.1 g (0.525 mols) of a 4-methylmorpholine was added thereto, and the mixture was stirred at 5 to 10° C. for 24 hours. The precipitated crystals were filtrated by means of suction, washed with 400 ml of the ethyl acetate and was dried at room temperature under a reduced pressure for 4 hours to obtain 131.3 g of a white solid of a 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride. The amount of water was 0.3percent by weight and the yield was 94.6percent.
94%
With 4-methyl-morpholine In tetrahydrofuran
Comparative Example 4 Into a 500-ml four neck distillation flask were added 17.56 g (0.1 mol) of a 2-chloro-4,6-dimethoxy-1,3,5-triazine and 200 ml of a tetrahydrofuran, which were, then, stirred at 5 to 10° C. for 10 minutes. Then, 10.6 g (0.105 mols) of a 4-methylmorpholine was added thereto to effect the reaction at 5 to 10° C. for 6 hours. The precipitated crystals were filtrated by means of suction, washed with 100 ml of a tetrahydrofuran, and were dried at room temperature under a reduced pressure for 3 hours to obtain 26.1 g of a white solid of a 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride represented by the above-mentioned general formula (I) as a quaternary ammonium salt. The white solid contained water in an mount of 0.4percent by weight and its yield was 94.0percent.
93.8%
With 4-methyl-morpholine In water; ethyl acetate
Example 1 Into a 2000-ml four neck distillation flask were added 87.8 g (0.5 mols) of a 2-chloro-4,6-dimethoxy-1,3,5-triazine, 1000 ml of an ethyl acetate and 27 g (1.5 mols) of water, which were then stirred at 5 to 10° C. for 10 minutes. Next, 53.1 g (0.525 mols) of a 4-methylmorpholine was added thereto to conduct the reaction at 5 to 10° C. for 6 hours. The conversion of the triazine compound at this moment was nearly 100percent. The precipitated crystals were filtrated by means of suction, washed with 400 ml of the ethyl acetate and was dried at room temperature under a reduced pressure for 4 hours to obtain 141.7 g of a white solid of a 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride. The amount of water was 8.4percent by weight and the yield was 93.8percent. Analysis by using a high-performance liquid chromatography indicated the purity of the product to be 99.5percent in terms of area percent. The product was, then, preserved at 20 to 25° C. for 3 weeks and was measured for its purity to be 98.0percent.
93.8%
With 4-methyl-morpholine In water; ethyl acetate
Example 106 Into a 500-ml four neck distillation flask were added 21.95 g (0.125 mols) of a 2-chloro-4,6-dimethoxy-1,3,5-triazine, 250 ml of an ethyl acetate and 6.75 g (0.375 mols) of water, which were, then, stirred at 5 to 10° C. for 10 minutes. Then, 13.25 g (0.131 mols) of a 4-methylmorpholine was added thereto to effect the reaction at 5 to 10° C. for 6 hours. The precipitated crystals were filtrated by means of suction, washed with 100 ml of the ethyl acetate, and were dried at room temperature under a reduced pressure for 16 hours to obtain 32.62 g of a white solid of a 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride represented by the above-mentioned general formula (I) as a quaternary ammonium salt. The white solid contained water in an mount of 0.6percent by weight and its yield was 93.8percent.
93.2%
With 4-methyl-morpholine In water; ethyl acetate
Example 5 Into a 2000-ml four neck distillation flask were added 87.8 g (0.5 mols) of a 2-chloro-4,6-dimethoxy-1,3,5-triazine, 1000 ml of an ethyl acetate and 27 g (1.5 mols) of water, which were then stirred at 5 to 10° C. for 10 minutes. Next, 53.1 g (0.525 mols) of a 4-methylmorpholine was added thereto, and the mixture was stirred at 5 to 10° C. for 6 hours. Further, water was added thereto in an amount of 27 g (1.5 mols) and the mixture was stirred for 10 minutes. The conversion of the triazine compound at this moment was nearly 100percent. The precipitated crystals were filtrated by means of suction, washed with 400 ml of the ethyl acetate and was dried at room temperature under a reduced pressure for 4 hours to obtain 159.4 g of a white solid of a 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride. The amount of water was 19.1percent by weight and the yield was 93.2percent. Analysis by using a high-performance liquid chromatography indicated the purity of the product to be 99.5percent in terms of area percent. The product was, then, preserved at 20 to 25° C. for 3 weeks and was measured for its purity to be 98.7percent.
91.2%
With 4-methyl-morpholine In water; ethyl acetate
Example 6 Into a 2000-ml four neck distillation flask were added 87.8 g (0.5 mols) of a 2-chloro-4,6-dimethoxy-1,3,5-triazine, 1000 ml of an ethyl acetate and 27 g (1.5 mols) of water, which were then stirred at 5 to 10° C. for 10 minutes. Next, 53.1 g (0.525 mols) of a 4-methylmorpholine was added thereto, and the mixture was stirred at 5 to 10° C. for 6 hours. Further, water was added thereto in an amount of 54 g (3.0 mols) and the mixture was stirred for 10 minutes. The conversion of the triazine compound at this moment was nearly 100percent. The precipitated crystals were filtrated by means of suction, washed with 400 ml of the ethyl acetate and was dried at room temperature under a reduced pressure for 7 hours to obtain 176.7 g of a white solid of a 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride. The amount of water was 28.6percent by weight and the yield was 91.2percent. Analysis by using a high-performance liquid chromatography indicated the purity of the product to be 99.2percent in terms of area percent. The product was, then, preserved at 20 to 25° C. for 3 weeks and was measured for its purity to be 98.5percent.
With sodium hydrogencarbonate at 25 - 50℃; for 4h;
89.5%
With sodium hydrogencarbonate In water at 100℃; for 36h; Large scale;
8 Example 8. Synthesis of 2-chloro-4 , 6-dimethoxy-l , 3 , 5- triazine (CDMT)
CDMT was synthesized using the general procedure described above (Example 7) : in a reactor as described previously, there were introduced by means of an auger dispenser and/or a dispenser for liquids, 36 kg of NaHCC>3, 9.0 L of methanol, and 7.5 L of water. Then, there were introduced under stirring by means of an auger dispenser 10 kg of cyanuric chloride in approx. 2-3 h and then the mixture was heated at 100°C for 36 h. At the end of the reaction, the work-up was carried out by adding 1-5 volumes of water (9-45 L) with subsequent stirring for 480 min. The suspension was filtered, and the product collected and dried in a vacuum. An amount of 8.5 kg (48.3 mol) was recovered with a yield of 89.5% and a purity of 96.7% (3.3% of water) . This method was used up to 150 kg of CDMT. For larger production volumes, it is recommended to arrange a number of reactors side by side in parallel. XH NMR (CDC13, 300 MHz, ppm) δΗ: 4.07; 13C NMR (75 MHz, CDCI3, ppm) 5C: 172.72, 172.54, 56.04. FT-IR: 1540, 928, 806 cm-1
86%
With sodium hydrogencarbonate at 0 - 50℃; for 4h;
80%
With sodium hydrogencarbonate at 0 - 50℃; for 4h;
75%
With sodium hydrogencarbonate In water at 0 - 40℃; for 0.833333h;
69.6%
With sodium hydrogencarbonate In water at 10 - 35℃; for 12h;
3.6
The methanol 72.9g, distilled water 8.96g and sodium bicarbonate 46.6g (0.56mol) formed in the solution is placed in a ice-water cooling to 10 °C left and right, by adding trichloro prepares 34.1g (0.18mol), then 35 °C stirring reaction in water bath 12h. The reaction liquid under mechanical stirring into 480 ml distilled water, stirring 30 min. Filtering, washing 3 times, drying the white solid obtained 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) 22.5g, yield 69.6%, melting point 73-76°C. (Melting point of fire 72-74.6 °C)N-methyl morpholine to 13.2 ml (0.119mol) of added under stirring vigorously CDMT20.6g (0.12mol) dissolved in THF (300 ml) in solution, stirring the mixture at room temperature for reaction 30 min. Filtering, washing THF 5 times, drying to obtain the white solid 4 - (4,6-dimethoxy-triazine) - 4-methyl-morpholine hydrochloride (DMT-MM)32.1g, yield 97.5%.
65%
With sodium hydrogencarbonate In water at 35℃; for 12h;
57%
With sodium hydrogencarbonate at 0 - 55℃;
57%
With sodium hydrogencarbonate at 0 - 55℃; for 4.5h; Large scale;
With water; zinc
With sodium hydrogencarbonate
With sodium hydrogencarbonate for 0.5h; Heating;
With sodium hydrogencarbonate In water for 0.5h; Reflux;
Synthesis of 2-chloro-4,6-dimethoxy-1,3,5-triazine (2)
To 57 mL of methanol and 5 mL of water 16.8 g (0.2 mol) ofsodium bicarbonate and 18.5 g (0.1 mol) of cyanuric chloride (1) were added. The temperature of reaction mixture increased to 35 °C. The reaction mixture was further refluxed for 0.5 h until CO2 was completely removed. Then the contents were poured onto ice cold water and filtered. The white solid product (2) obtained was dried in desiccators (Scheme-I). m.p. 74-76 °C,1H NMR (400 MHz, DSMO-d6) δ ppm: 4.05 (s, 6H).
With sodium hydrogencarbonate at 0 - 60℃; for 5h;
235 kg
With sodium hydrogencarbonate for 6h; Reflux; Large scale;
3 Example 3 A process for preparing 2 - chloro - 4, 6 - dimethoxy - 1, 3, 5 - triazines, comprises the following steps:
The reaction mixture was heated slowly to methanol reflux in stages, and then the reaction was carried out for 6 hours. The reaction was carried out in a nitrogen atmosphere.The distillation was carried out in a reaction kettle, and the distillation and condensation were carried out by water-cooling and freeze-thawing. The distillation was carried out in a reaction kettle.3) dilution crystallization: distillation residue 545 kg input analysis the cauldron added water to dilute in water crystallization 1150 kg;4) filtering / washing, drying: adding the crystalline solid is washed with water, filtered, dried to obtain the crude product 275 kg;The solid phase was dried to obtain the final product of 2-chloro-4,6-dimethoxy-propan-1-one, which was purified by distillation. 1, 3, 5 - triazine 235 kg.
With sodium hydrogencarbonate at 0 - 60℃; for 5h;
With sodium hydrogencarbonate at 0 - 50℃; for 4h; Inert atmosphere;
42 %
With sodium hydrogencarbonate at 50℃; Inert atmosphere;
With 4-methyl-morpholine In toluene at 20℃; for 1h; Inert atmosphere; Sealed tube;
92%
With 4-methyl-morpholine In dichloromethane
2 Example 2: Preparation of compound III-2
In a 250-mL two-necked round-bottom flask, add 1.7 g of 2-chloro-4,6-dimethoxytriazine IV, 1.2 g of benzoic acid and 1.1 g of N-methylmorpholine (NMM). 100 mL of reaction solvent dichloromethane was added. After monitoring the completion of the reaction by TLC, the excess solvent was removed by concentrating under reduced pressure, and the residue was purified by 100-200 mesh silica gel column chromatography to obtain compound III-2. The eluent was petroleum ether at 60-90 degrees Celsius: ethyl acetate, and the volume ratio was 4:1, the product is 2.4 g of white powder, the yield is 92%.
76%
With 4-methyl-morpholine In dichloromethane 1.) 0 to 5 deg C, 5 h 2.) r.t., 10 h;
70%
With 4-methyl-morpholine In dichloromethane at 0 - 5℃; for 12h;
With 4-methyl-morpholine In tetrahydrofuran at 20℃; for 1h;
Stage #1: 2-chloro-4,6-dimethoxy-1 ,3,5-triazine With 4-methyl-morpholine In dichloromethane at 0 - 5℃;
Stage #2: benzoic acid In dichloromethane at 20℃;
With 4-methyl-morpholine In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere;
With 4-methyl-morpholine In 1,4-dioxane at 20℃; for 0.583333h;
With 4-methyl-morpholine In tetrahydrofuran at 25℃; for 1h;
With 4-methyl-morpholine In toluene at 25℃; for 1h;
81 %Chromat.
With 4-methyl-morpholine In 1,4-dioxane at 25℃; for 15h;
With 4-methyl-morpholine In toluene at 20℃; for 1h; Inert atmosphere;
General procedure for the synthesis of diaryl ketones under heterogeneous palladium catalysis
General procedure: A mixture of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (1.0 mmol), aromatic acid (1.0 mmol), and 4-methylmorpholine (NMM) (1.0 mmol) in toluene (5 mL) was stirred at room temperature for 1 h under Ar. After completion of the reaction, the flask was charged with MCM-41-2P-Pd(OAc)2 (2 mol%), K3PO4 (2.0 mmol) and arylboronic acid (1.0 mmol). The reaction mixture was stirred at 110 C for 1 h. After being cooled to room temperature, the reaction mixture was diluted with ethyl acetate (10 mL) and filtered. The palladium catalyst was washed with DMF (2 × 5 mL), distilled water (2 × 5 mL), acetone (2 × 5 mL), and dried at 70 C in vacuo for 1 h and reused in the next run. The filtrate was concentrated under vacuum and the residue was purified by chromatography on silica gel (eluent: light petroleum ether/ethyl acetate) to afford the diaryl ketone product 3.
With potassium hydroxide In tetrahydrofuran at 20℃;
75%
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 3h;
29
EXAMPLE 29 Preparation of 1H-indole-3-carboxylic acid[4-(4,6-dimethoxy-[1,3,5]triazine-2-ylxoxy)-phenyl]-amide 4-nitrophenol (1.0 g, 7.2 mmol) was dissolved in DMF (30 ml), and the solution was stirred with NaH (290 mg, 7.2 mmol) and 2-chloro-4,6-dimethoxytriazine (3.19 g, 20.1 mmol) at room temperature for 3 hours. Subsequently, the product was filtered, washed, and dried under reduced pressures to yield a liquid product (1.54 g, 75%). The liquid product (1.0 g, 3.6 mmol) was added to a mixed solution of THF (20 ml), water (2 ml), and acetic acid (1.7 ml), Fe (1.98 g, 36 mmol) was added to the mixture, and the resulting solution was stirred at 70° C. for 12 hours. And then the product was filtered, washed, and dried to prepare 4-(4,6-dimethoxy-[1,3,5]triazine-2-yloxy)-phenylamine (0.89 g, 91%).
75%
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 3h;
29
4-nitrophenol (1.0 g, 7.2 mmol) was dissolved in DMF (30 m), and the solution was stirred with NaH (290 mg, 7.2 mmol) and 2-chloro-4,6-dimethoxytriazine (3.19 g, 20.1 mmol) at room temperature for 3 hours. Subsequently, the product was filtered, washed, and dried under reduced pressures to yield a liquid product (1.54 g, 75 %).
75%
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 3h;
29
4-nitrophenol (1.0 g, 7.2 mmol) was dissolved in DMF (30 ), and the solution was stirred with NaH (290 , 7.2 mmol) and 2-chloro-4,6-dimethoxytriazine (3.19 g, 20.1 mmol) at room temperature for 3 hours. Subsequently, the product was filtered, washed, and dried under reduced pressures to yield a liquid product (1.54 g, 75 %).
With sodium hydroxide In acetone for 4h; Heating;
With caesium carbonate In N,N-dimethyl-formamide at 20℃;
1 Synthesis of key Intermediate 2,4-dimethoxy-6-(4-nitrophenoxy)-1,3,5-triazine
5g 2-chloro-4,6-dimethoxy-1,3,5-triazine, 4.4g p-nitrophenol, 18.6g Cs2CO3 and 75mL DMF were added to a 100mL eggplant-shaped flask, then stirred at room temperature overnight. The reaction was monitored by thin layer chromatography (TLC). After the reaction was completed, a large amount of water was added to the reaction solution to precipitate a yellow solid, suction filtered to obtain 7 g solid. LRMS (EI) m/z: 279 (M+H)+. (directly used in the next step without purification) _
With sodium azide In water; acetonitrile at 35℃; for 2h;
96%
With sodium azide In water; acetonitrile at 35℃; for 2.5h;
96%
With sodium azide In water; acetonitrile at 35℃; for 2h;
90%
With sodium azide In water; acetonitrile at 35℃; for 2.5h; Inert atmosphere;
87%
With sodium azide In N,N-dimethyl-formamide at 20℃; for 4h;
2-azido-4,6-dimethoxy-1,3,5-triazine
A stock solution of NaN3 (1.3002 g, 30 mmol) in DMF (30 mL) was prepared in a 100 mL round-bottom flask equipped with a magnetic stir bar, was added a solution of 2-chloro-4,6-dimethoxy-1,3,5-triazine (1.7550 g, 15 mmol) in DMF (15 mL) for 4 hours at room temperature. On completion, water (150 mL) was added and the resulting mixture was extracted with EtOAc (3 x 40 mL). The combined organic phases were washed with brine (3 x 90 mL), dried over magnesium sulfate and concentrated to give the title compound as a white powder (2.3862 g, 87%).
With sodium azide In ethanol at 30 - 40℃; Yield given;
General procedure: To a stirred solution of CDMT (1.5 mmol) in dry CH2Cl2(15 mL), N-methylmorpholine (NMM) (6.0 mmol) was added dropwise and allowed to stir for 10 min. To the white suspension containing DMTMM salt, the Schiff base (1.0mmol) and the carboxylic acid (1.5 mmol) were added and the mixture was stirred overnight. The mixture was washed successively with saturated NaHCO3 (15 mL) and brine (15mL), dried with Na2SO4 and concentrated in vacuo. 2-azetidinones 3a-k, 3n-o were purified by crystallizationfrom EtOAc and 2-azetidinones 3l-m by short column chromatographyon silica gel
97.5%
In tetrahydrofuran; at 20℃; for 0.5h;
The methanol 72.9g, distilled water 8.96g and sodium bicarbonate 46.6g (0.56mol) formed in the solution is placed in a ice-water cooling to 10 C left and right, by adding trichloro prepares 34.1g (0.18mol), then 35 C stirring reaction in water bath 12h. The reaction liquid under mechanical stirring into 480 ml distilled water, stirring 30 min. Filtering, washing 3 times, drying the white solid obtained 2-chloro -4,6-dimethoxy -1, 3, 5-triazole (CDMT) 22.5g, yield 69.6%, melting point 73-76C. (Melting point of fire 72-74.6 C)N-methyl morpholine to 13.2 ml (0.119mol) of added under stirring vigorously CDMT20.6g (0.12mol) dissolved in THF (300 ml) in solution, stirring the mixture at room temperature for reaction 30 min. Filtering, washing THF 5 times, drying to obtain the white solid 4 - (4,6-dimethoxy-triazine) - 4-methyl-morpholine hydrochloride (DMT-MM)32.1g, yield 97.5%.
73%
In tetrahydrofuran; at 20℃; for 1h;Inert atmosphere;
4-(4,6-Dimethoxy-1 ,3,5- triazin-2-yl)-4-methyl morpholinium chloride (DMTMM Cl) was freshly prepared according to the literature.23 A/-methyl morpholine (1 .73 g, 17.1 mmol) was added to a solution of 2-chloro- 4,6-dimethoxy-1 ,3,5-triazine (3.00 g, 17.1 mmol) in dry THF (100 ml_). The mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The precipitate was collected by filtration under nitrogen atmosphere. After 2 hours of constant nitrogen flow through the precipitate and 2 hours under high vacuum DMTMM Cl (3.44 g, 73%) was afforded as colorless crystals, which were aliquoted into 2 mL-Eppendorf vials and stored at -20C. 1 H-NMR: (400 MHz, DMSO-cfe): <5 [ppm] = 4.60-4.50 (2H, d,br, -N+CH2-), 4.10-4.00 (8H, m, -OCH3 and CH3N+CH2), 3.65-3.90 (4H, m, -OCH2-), 3.45 (3H, s, -N+CH3).
In ethyl acetate; at 23 - 29℃;
Generation of DMT-MM To a solution OF 2-CI-4, 6-DIMEO-1, 3,5-triazene (CDMT) (6.2 mg, 35 mmol; 1.5 eq. ) in 70 mL of EtOAc kept in a room temperature water bath were added 4 mL (36.38 mmol) of neat N-methylmorpholine (MM). Solid 4- (4, 6-DIMETHOXY-1, 3,5- triazin-2-yl) -4-methylmorpholinium chloride (DMT-MM) started to precipitate out. The suspension containing DMT-MM was stirred for 30 min at room temperature at which time it became a thick paste. The temperature rose from 23 to 28-29C during the reaction. The temperature of the reaction is kept down to minimize competing demethylation to form di-MeO-N morfolino-triazene (DMMT).
In acetonitrile; at 20 - 25℃; for 1.01667h;
Example 13 g of 4-chloro-2,6-dimethoxy-l,3,5- triazine were mixed with 100 ml of acetonitrile at 20-25 0C forming solution.5.2 ml of N-methylmorpholine were added via syringe to the reaction mixturePrecipitation of white solid was observed after 1 minute of stirring. Suspension was stirred at 20-25 0C for Ih.; 6 g of 2-chloro-4,6-dimethoxy- 1 ,3,5-triazine were mixed with 200 ml of acetonitrile at 20-25 C forming slightly opalescent solution. 10.4 ml of N-methylmorpholine were added and solution turned clear. Precipitation of white solid was observed after 1 minute of stirring. Suspension was then stirred at 20-25 C for Ih.
In tetrahydrofuran; for 49h;
1) 23 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) was placed in 300 ml of tetrahydrofuran (THF);2) 13.2 ml of 4-methylmorpholine (NMM) was added to the solution in step 1), vigorously stirred for 1 h; the solid was collected by filtration and washed with THF for 5 times, and dried under vacuum for 48 h to obtain a DMT-MM condensing agent;3) 1g heparin, 0.874g of the DMT-MM
With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); [di(cyclohexyl)phosphino]bis(2-pyrimidyl)amine In 1,4-dioxane at 60℃; for 24h;
100 % Chromat.
With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 15h;
With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); potassium carbonate In water; acetonitrile at 60℃; for 2h; Inert atmosphere; Sealed vessel;
4.6. Typical preparative procedure
Typical preparative procedures were performed on 10.0 mmol scale using a Mettler-Toledo FlexiWeigh 30 automated solid handling unit to pre-weigh the aryl halide (10.0 mmol, 1.0 equiv), aryl boronic acid (12.0 mmol, 1.2 equiv) and Pd-118 (65.2 mg, 0.1 mmol, 1.0 mol %). Acetonitrile (10.0 mL) was added, followed by K2CO3 added as a stock aqueous solution (10.0 mL water containing 2.07 g, 15.0 mmol, 1.5 equiv). NB. No internal standard was added for preparative reactions. Reaction mixtures were sealed under a N2 atmosphere and heated to 60 °C with magnetic stirring. HPLC analysis showed that reactions using aryl bromides were complete within 1 h but that aryl chlorides typically required 24 h.After reaction mixtures had cooled to room temperature, stirring was stopped and the phases were allowed to separate. The lower aqueous phase was removed and discarded (cutting away any interfacial catalyst residues if present) and the acetonitrile phase concentrated to dryness to give typically a light to dark brown solid or dark-coloured gum. Solids were triturated with methanol (20 mL) for 1-2 h, then isolated by filtration, washed once or twice with methanol (4 mL each wash) and dried under vacuum. Oils were purified by flash silica gel chromatography as noted below. All isolated compounds gave 1H NMR data in agreement with published values. Literature data is given for mp values for comparison.
(4,6-dimethoxy-[1,3,5]triazin-2-yl)-ethoxycarbonylmethyl-dimethyl-ammonium; chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In water; at 25℃;pH 8;Aqueous phosphate buffer;
A total volume of 2 mL of 20 mM phosphate buffer solution (pH 8) containing 15 mM of various types of sodium fatty acids described in Table 2 below, 20 mM n-butylamine hydrochloride, 15 mM 2-chloro-4,6-dimethoxy-1,3,5-triazine, and 1.5 mM of tertiary amine described in Table 2 below was stirred at 25 C for an optional time. After the reaction was terminated, the product was determined by gas chromatography in the same manner as in Example 4. The ratio of relative rate in stoichiometric reaction of each product is shown in Table 2.
With O4P(3-)*3K(1+)*5H2O; tris(1-adamantyl)phosphine; C28H26N2O8Pd2S2 In tetrahydrofuran at 20℃; for 5h; Inert atmosphere; Schlenk technique;
93%
With O4P(3-)*3K(1+)*5H2O; tris(1-adamantyl)phosphine; {2-[((acetyl-κO)amino)phenyl-κC](tri-1-adamantylphosphine)palladium}(p-toluenesulfonate) In tetrahydrofuran at 20℃; for 5h;
To a mixture of 2-chloro4,6-dimethoxy-1,3,5-triazine (88 mg, 0.50 mmol, 1 equiv), thiophen-2-ylboronic acid (96 mg, 0.75 mmol, 1.5 equiv), and K3P045H20 (0.45 mg, 1.5 mmol,3 equiv) was added THF (400 j.tL) then a THF stock solution of 3 and PAd3 (100 jiL, 0.25 jimol of Pd/PAd3). The mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with ethyl acetate then extracted with water. The combine organic layers were evaporated and the crude product was purified by flash chromatography. After drying, 104 mg (93%) of 39 was obtained as a white solid. NMR spectroscopic data agreed with literature values.
89%
With potassium carbonate In water; butan-1-ol at 100℃; for 12h;
84%
With potassium phosphate; dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl; 4 A molecular sieve In tert-Amyl alcohol at 100℃; for 6h;
57 S-Ethyl-3-(4-nitrophenyl)-2-[(4,6-dimethoxy-1,3,5-triazin-2-yl)amino]propionate
EXAMPLE 57 S-Ethyl-3-(4-nitrophenyl)-2-[(4,6-dimethoxy-1,3,5-triazin-2-yl)amino]propionate 2-Chloro-4,6-dimethoxy-1,3,5-triazine (8.05 g, 45.8 mmol) was added to a solution of (S)-4-nitrophenylalanine ethyl ester hydrochloride (5.0 g, 38.2 mmol) and DIPEA (13.6 ml, 78.3 mmol) in acetonitrile (80 ml) and the reaction was stirred at room temperature for 16 h, concentrated in vacuo and the residue partitioned between EtOAc (100 ml) and NaHCO3 solution (100 ml). The organic layer was washed with 10% citric acid solution 100 ml), NaHCO3 solution (100 ml) and water (10 ml), dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography (silica; EtOAc/Hexane 1:1) to give the title compound (6.66 g, 97%): δH (CDCl3) 8.10 (2H, d, J 9.0 Hz), 7.30 (2H, d, J 9.0 Hz), 6.10 (1H, m), 5.0 (1H, m), 4.1 (2H, q, J 7.1 Hz), 3.92 (3H, s), 3.90 (3H, s), 3.30 (2H, m), 1.25 (3H, t, J 7.1 Hz); m/z (EI+, 70 V) 378.
97%
With N-ethyl-N,N-diisopropylamine In acetonitrile
57 S-Ethyl-3-(4-nitrophenyl)-2-[(4,6-dimethoxy-1,3,5-triazin-2-yl)amino]propionate
EXAMPLE 57 S-Ethyl-3-(4-nitrophenyl)-2-[(4,6-dimethoxy-1,3,5-triazin-2-yl)amino]propionate 2-Chloro-4,6-dimethoxy-1,3,5-triazine (8.05 g, 45.8 mmol) was added to a solution of (S)-4-nitrophenylalanine ethyl ester hydrochloride (5.0 g, 38.2 mmol) and DIPEA (13.6 ml, 78.3 mmol) in acetonitrile (80 ml) and the reaction was stirred at room temperature for 16 h, concentrated in vacuo and the residue partitioned between EtOAc (100 ml) and NaHCO3 solution (100 ml). The organic layer was washed with 10% citric acid solution (100 ml), NaHCO3 solution (100 ml) and water (100 ml), dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography (silica; EtOAc/Hexane 1:1) to give the title compound (6.66 g, 97%): δH (CDCL3) 8.10 (2H, d, J 9.0 Hz), 7.30 (2H, d, J 9.0 Hz), 6.10 (1H, m), 5.0 (1H, m), 4.1 (2H, q, J 7.1 Hz), 3.92 (3H, s), 3.90 (3H, s), 3.30 (2H, m), 1.25 (3H, t, J 7.1 Hz); m/z (E+, 70V) 378.
97%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 16h;
57 EXAMPLE 57
EXAMPLE 57 S-Ethyl-3-(4-nitrophenyl)-2-[(4,6-dimethoxy-1,3,5-triazin-2-yl)amino]propionate 2-Chloro-4,6-dimethoxy-1,3,5-triazine (8.05 g, 45.8 mmol) was added to a solution of (S)-4-nitrophenylalanine ethyl ester hydrochloride (5.0 g, 38.2 mmol) and DIPEA (13.6 ml, 78.3 mmol) in acetonitrile (80 ml) and the reaction was stirred at room temperature for 16 h, concentrated in vacuo and the residue partitioned between EtOAc (100 ml) and NaHCO3 solution (100 ml).. The organic layer was washed with 10% citric acid solution (100 ml), NaHCO3 solution (100 ml) and water (100 ml), dried (MgSO4) and concentrated in vacuo.. The crude product was purified by chromatography (silica; EtOAc/hexane 1:1) to give the title compound (6.66 g, 97%): δH (CDCl3) 8.10 (2H, d, J 9.0 Hz), 7.30 (2H, d, J 9.0 Hz), 6.10 (1H, m), 5.0 (1H, m), 4.1 (2H, q, J 7.1 Hz), 3.92 (3H, s), 3.90 (3H, s), 3.30 (2H, m), 1.25 (3H, t, J 7.1 Hz); m/z (EI+, 70V) 378.
With 4-methyl-morpholine In tetrahydrofuran at 0 - 5℃; for 12.5h;
3; 4 3. Example
Solution of 2-CHLOR-4, 6-DIMETHOXY-1, 3,5-triazine (CDMT) (0.175 g, 1 M-MOLE) in 5 ML THF was mixed with N-methylmorpholine (0.11 ml, 1 mmole) for 30 minutes at temperature of 0-5C. Then, easily migrated epimeride 4b, where R3=H, and R4=3, 4-dimethoxyphenyl (0.433 g, 1 MMOL) was added and mixed for 12 hours. N-methylmorpholine chloride was filtered off, and filtrate was evaporated until dry under reduced pressure. It gave respective triazine ester of the formula 6B, where R3=H, R4=3, 4-dimethoxyphenyl, and R=R6=OCH3, with the quantitative yield. TLC: eluent CHCI3, RF=0, 7. 1H-NMR (250 MHz, CDC13) : 5= 3.52 (s, 6H); 3.80 (S, 3H); 3.85 (s, 3H); 5.34 (d, J=, 1H); 6.19 (d, J=, 1H), 6.74 (bs, 1H) ; 7.07 (bs, 1H) ; 7.11 (bs, 1H) ; 7.21 (bs, 1H) ; 7.28-7. 80 (m, 10H) [ppm] IR (CCI4) : 1750 [CM-']4. Example Solution of 2-CHLOR-4, 6-dimethoxy-1,3, 5-triazine (CDMT) (0.175 g, 1 mmole) in 5 ml THF was mixed with N-methylmorpholine (0.11 ml, 1 mmole) for 30 minutes at temperature of 0-5°C. Then, hardly migrating epimeride 4b, where R3=H, and R4=3, 4-dimethoxyphenyl (0.433 g, 1 MMOL) was added and mixed for 12 hours. N-methylmorpholine chloride was filtered off, and filtrate was evaporated until dry under reduced pressure. It gave respective triazine ester of the formula 6b, where R3=H, R4=3, 4-dimethoxyphenyl, and R5=R6=OCH3, with the quantitative yield. TLC: eluent CHCI3, Rf=0. 6 1H-NMR (250 MHz, CDCl3) : ZU 3.56 (S, 6H); 3. 80 (S, 3H); 3.85 (s, 3H); 5.34 (d, J=, 1H); 6.19 (d, J=, 1H), 6.74 (BS, 1H) ; 7.07 (bs, 1H) ; 7.14 (bs, 1H) ; 7.21 (bs, 1H) ; 7.28-7. 80 (m, 10H) [ppm] IR (CCI4) : 1740 [CM~11
100%
Stage #1: 2-chloro-4,6-dimethoxy-1 ,3,5-triazine With N-methylcyclohexylamine In DMF (N,N-dimethyl-formamide) at 0 - 5℃; for 0.5h;
Stage #2: C25H23NO6 In DMF (N,N-dimethyl-formamide) for 12h;
9 9. Example
Solution of 2-CHLOR-4, 6-dimethoxy-1,3, 5-triazine (CDMT) (0.175 g, 1 mmole) in 5 mi DMF was mixed with N-METHYLPIPERIDINE (0.104 ml, 1 mmole) for 30 minutes at temperature of 0-5C. Then, mixture of epimerides of acids 4b, where R3=H, and R4=3,4- dimethoxyphenyl (0.433 g, 1 MMOL) was added, mixed for 12 hours and evaporated until dry under reduced pressure. After washing off, respective triazine ester of the formula 6b, where R3=H, R4=3, 4-dimethoxyphenyl, and R5=R6=OCH3 was obtained with the quantitative yield. The triazine ester, in the presence of magnesium bromide and 4- (N, N- dimethylamin) pyridyne, was coupled with protected Bacctain III of the generalized formula 3, where R2=Si (C2HS) 3. The product was CHROMATOGRAPHICALLY and SPECTRALLY identical to that described in the 2. Example.
With 4-methyl-morpholine; In ethyl acetate; at 23 - 27℃; for 2.33333 - 3.5h;
Separately, 23.5 g of N-Methylmorpholine is added to a mixture of 33.1 g of 4-Amino-chloro-benzoic acid 34.4 g of 2- Chloro-4,6-dimethoxytriazine (DMT-Cl) in 300 ml of ethyl acetate over 20-30 minutes at ambient temperature for 2-3 hours at 23- 27C to obtain the DMT active ester of <strong>[2486-71-7]4-Amino-3-chlorobenzoic acid</strong>. The mixture is cooled to 0 to +5C and 30 0 ml of purified water are added to the solution keeping temperature in the same range. The solution of the deprotected t-leucirae product as the citrate salt is added at 0C to +5C over 30-60 minutes, the reaction mixture is then brought to pH 6.5-7. 5 by adding 30% sodium hydroxide (approx. amount: 71 ml), and stirred 6-7 hrs at 20 to 25C. After completion of the reaction, the phases are separated and the organic layer added to sodium bisulfate solution (15 g of sodium bisulfate in 235 ml of water) and stirred for 3 hrs at 20C to 25C. The phases azre separated and the organic layer is washed four times with water (150 ml each), twice with sodium bicarbonate solution (total: 20 g of sodium bicarbonate in 400 ml of water), and once with 1 50 ml of water. To the solution is added 10 g of activated charcoal and 10 g of Dicalite and filtered and the solids washed with 100 ml of ethyl acetate. The filtrate was distilled under vacuum to a volume of 200 ml at < 40C when the resultant mixture crystallizes. Ethyl acetate (150 ml) was added to a total volume of 350 ml. N- heptane (300 ml) was added over 2 hrs and after stirring the slurry for 3 hrs at 20 to 25, the solid was filtered, washed with ethyl acetate/N-Heptane (100 ml, 1: 1) and dried at 60C under vacuum.
N-(4,6-dimethoxy-2,4,6-triazin-2-yl)-quinuclidinium p-toluenosulphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
In acetonitrile at 0℃; for 2h;
IV
To a mixture of 17.8 g (100 mmol) of lithium p-toluenosulfonate in 30 ml acetonitrile, cooled down to a temperature approximating to 0°C, simultaneously added drop by drop solution of 1.76 g (10 mmol) CDMT in 20 ml of acetonitrile and solution of 1.11 g (10 mmol) of quinuclidine in 5 ml acetonitrile. Then, the stirring of the mixture was continued at a temperature of 0°C for 2 hours, next the precipitate was separated by filtration. The precipitate was washed with 2 portions by 25 ml acetonitrile and the collected filtrates were evaporated to dryness. The residue was washed with ethyl ether and crystallized from acetonitrile. It was obtained 2.95 g of p-toluensulfonate of N-(3,5-dimethoxy-2,4,6-triazinyl-1-)-quinuclidine in the form of thick oily liquid, what equals to 70% yield. The new compound was characterized with the following data: [] Results of elementary analysis of the formula: C19H26N4O5S (422.51) calculated:%C 54.01;%H 6.20;%N 13.26;%S 7.59found:%C 54.04;%H 6.16,%N 13.38,%S 7.22.
With 4-methyl-morpholine; In tetrahydrofuran; methanol;
Example 107 Into a 500-ml four neck distillation flask were added 17.56 g (0.1 mol) of a 2-chloro-4,6-dimethoxy-1,3,5-triazine, 200 ml of a tetrahydrofuran and 9.6 g (0.3 mols) of methanol, which were, then, stirred at 5 to 10 C. for 10 minutes. Then, 10.6 g (0.105 mols) of a 4-methylmorpholine was added thereto to effect the reaction at 5 to 10 C. for 4 hours. The precipitated crystals were filtrated by means of suction, washed with 100 ml of a tetrahydrofuran, and were dried at room temperature under a reduced pressure for 3 hours to obtain 27.02 g of a white solid of a 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride represented by the above-mentioned general formula (I) as a quaternary ammonium salt. The white solid contained water in an mount of 0.3% by weight and its yield was 97.4%.
96.9%
With 4-methyl-morpholine; In tetrahydrofuran; methanol;
Example 108 Into a 500-ml four neck distillation flask were added 17.56 g (0.1 mol of a 2-chloro-4,6-dimethoxy-1,3,5-triazine, 200 ml of a tetrahydrofuran and 9.6 g (0.3 mols) of methanol, which were, then, stirred at 5 to 10 C. for 10 minutes. Then, 10.6 g (0.105 mols) of a 4-methylmorpholine was added thereto to effect the reaction at 5 to 10 C. for 3 hours. The precipitated crystals were filtrated by means of suction, washed with 100 ml of a tetrahydrofuran, and were dried at room temperature under a reduced pressure for 3 hours to obtain 26.88 g of a white solid of a 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride represented by the above-mentioned general formula (I) as a quaternary ammonium salt. The white solid contained water in an mount of 0.3% by weight and its yield was 96.9%.
94.6%
With 4-methyl-morpholine; In ethyl acetate;
Comparative Example 1 Into a 2000-ml four neck distillation flask were added 87.8 g (0.5 mols) of a 2-chloro-4,6-dimethoxy-1,3,5-triazine and 1000 ml of an ethyl acetate, which were then stirred at 5 to 10 C. for 10 minutes. Next, 53.1 g (0.525 mols) of a 4-methylmorpholine was added thereto, and the mixture was stirred at 5 to 10 C. for 24 hours. The precipitated crystals were filtrated by means of suction, washed with 400 ml of the ethyl acetate and was dried at room temperature under a reduced pressure for 4 hours to obtain 131.3 g of a white solid of a 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride. The amount of water was 0.3% by weight and the yield was 94.6%.
94.0%
With 4-methyl-morpholine; In tetrahydrofuran;
Comparative Example 4 Into a 500-ml four neck distillation flask were added 17.56 g (0.1 mol) of a 2-chloro-4,6-dimethoxy-1,3,5-triazine and 200 ml of a tetrahydrofuran, which were, then, stirred at 5 to 10 C. for 10 minutes. Then, 10.6 g (0.105 mols) of a 4-methylmorpholine was added thereto to effect the reaction at 5 to 10 C. for 6 hours. The precipitated crystals were filtrated by means of suction, washed with 100 ml of a tetrahydrofuran, and were dried at room temperature under a reduced pressure for 3 hours to obtain 26.1 g of a white solid of a 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride represented by the above-mentioned general formula (I) as a quaternary ammonium salt. The white solid contained water in an mount of 0.4% by weight and its yield was 94.0%.
93.8%
With 4-methyl-morpholine; In water; ethyl acetate;
Example 1 Into a 2000-ml four neck distillation flask were added 87.8 g (0.5 mols) of a 2-chloro-4,6-dimethoxy-1,3,5-triazine, 1000 ml of an ethyl acetate and 27 g (1.5 mols) of water, which were then stirred at 5 to 10 C. for 10 minutes. Next, 53.1 g (0.525 mols) of a 4-methylmorpholine was added thereto to conduct the reaction at 5 to 10 C. for 6 hours. The conversion of the triazine compound at this moment was nearly 100%. The precipitated crystals were filtrated by means of suction, washed with 400 ml of the ethyl acetate and was dried at room temperature under a reduced pressure for 4 hours to obtain 141.7 g of a white solid of a 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride. The amount of water was 8.4% by weight and the yield was 93.8%. Analysis by using a high-performance liquid chromatography indicated the purity of the product to be 99.5% in terms of area %. The product was, then, preserved at 20 to 25 C. for 3 weeks and was measured for its purity to be 98.0%.
93.8%
With 4-methyl-morpholine; In water; ethyl acetate;
Example 106 Into a 500-ml four neck distillation flask were added 21.95 g (0.125 mols) of a 2-chloro-4,6-dimethoxy-1,3,5-triazine, 250 ml of an ethyl acetate and 6.75 g (0.375 mols) of water, which were, then, stirred at 5 to 10 C. for 10 minutes. Then, 13.25 g (0.131 mols) of a 4-methylmorpholine was added thereto to effect the reaction at 5 to 10 C. for 6 hours. The precipitated crystals were filtrated by means of suction, washed with 100 ml of the ethyl acetate, and were dried at room temperature under a reduced pressure for 16 hours to obtain 32.62 g of a white solid of a 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride represented by the above-mentioned general formula (I) as a quaternary ammonium salt. The white solid contained water in an mount of 0.6% by weight and its yield was 93.8%.
93.2%
With 4-methyl-morpholine; In water; ethyl acetate;
Example 5 Into a 2000-ml four neck distillation flask were added 87.8 g (0.5 mols) of a 2-chloro-4,6-dimethoxy-1,3,5-triazine, 1000 ml of an ethyl acetate and 27 g (1.5 mols) of water, which were then stirred at 5 to 10 C. for 10 minutes. Next, 53.1 g (0.525 mols) of a 4-methylmorpholine was added thereto, and the mixture was stirred at 5 to 10 C. for 6 hours. Further, water was added thereto in an amount of 27 g (1.5 mols) and the mixture was stirred for 10 minutes. The conversion of the triazine compound at this moment was nearly 100%. The precipitated crystals were filtrated by means of suction, washed with 400 ml of the ethyl acetate and was dried at room temperature under a reduced pressure for 4 hours to obtain 159.4 g of a white solid of a 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride. The amount of water was 19.1% by weight and the yield was 93.2%. Analysis by using a high-performance liquid chromatography indicated the purity of the product to be 99.5% in terms of area %. The product was, then, preserved at 20 to 25 C. for 3 weeks and was measured for its purity to be 98.7%.
91.2%
With 4-methyl-morpholine; In water; ethyl acetate;
Example 6 Into a 2000-ml four neck distillation flask were added 87.8 g (0.5 mols) of a 2-chloro-4,6-dimethoxy-1,3,5-triazine, 1000 ml of an ethyl acetate and 27 g (1.5 mols) of water, which were then stirred at 5 to 10 C. for 10 minutes. Next, 53.1 g (0.525 mols) of a 4-methylmorpholine was added thereto, and the mixture was stirred at 5 to 10 C. for 6 hours. Further, water was added thereto in an amount of 54 g (3.0 mols) and the mixture was stirred for 10 minutes. The conversion of the triazine compound at this moment was nearly 100%. The precipitated crystals were filtrated by means of suction, washed with 400 ml of the ethyl acetate and was dried at room temperature under a reduced pressure for 7 hours to obtain 176.7 g of a white solid of a 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride. The amount of water was 28.6% by weight and the yield was 91.2%. Analysis by using a high-performance liquid chromatography indicated the purity of the product to be 99.2% in terms of area %. The product was, then, preserved at 20 to 25 C. for 3 weeks and was measured for its purity to be 98.5%.
With 4-methyl-morpholine; In water; ethyl acetate;
To the ethyl acetate solution of the 2-chloro-4,6-dimethoxy-1,3,5-triazine, 200 ml of ethyl acetate and 5.4 g of water were added, followed by stirring at 5 to 10 C. for 10 minutes. Then, 23.9 g (0.236 mol) of 4-methylmorpholine was added, and the reaction was conducted at 5to 10 C. for 5hours. The crystals precipitated were suction filtered, then washed with 100 ml of ethyl acetate and vacuum dried at room temperature for 6 hours to obtain 61.1 g of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride as a white solid. The water content in the white solid was 0.4% by weight, and the yield was 88.0%. From the high performance liquid chromatography analysis, the purity proved to be 99.3% (% by area).
With 4-methyl-morpholine; In water; ethyl acetate;
To the ethyl acetate solution of the 2-chloro-4,6-dimethoxy-1,3,5-triazine, 200 ml of ethyl acetate and 5.4 g of water were added, followed by stirring at 5 to 10 C. for 10 minutes. Then, 23.9 g (0.236 mol) of 4-methylmorpholine was added, and the reaction was conducted at 5 to 10 C. for 5 hours. Then, 8.1 g of water was added, followed by stirring for 10 minutes. The crystals precipitated were suction filtered, then washed with 100 ml of ethyl acetate and vacuum dried at room temperature for 3 hours to obtain 69.8 g of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride as a white solid. The water content in the white solid was 13.7% by weight, and the yield was 87.1%. From the high performance liquid chromatography analysis, the purity proved to be 99.5% (% by area).
1 Example 1
Example 1 In a 500-ml four-necked flask equipped with a stirrer and a thermometer, 44.1 g (0.525 mol) of sodium hydrogencarbonate and 160.2 g (water content: 650 ppm, 5.0 mol) of methanol were placed. With stirring at a temperature of not higher than 10° C., 46.1 g (0.25 mol) of cyanuric chloride was added, followed by stirring at 20° C. for 1 hour. Then, the reaction was conducted at 60° C. for 3.5 hours. The weight of the reaction solution from which a salt formed had been removed was 192 g, and the water content was 49,500 ppm. After cooling, methanol was distilled off. To the residue, 200 ml of water was added, and the objective product was extracted with 250 ml of ethyl acetate. The organic layer was washed with 100 ml of water and then vacuum concentrated to obtain 39.2 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine as a white solid. The yield was 89.2%. From the gas chromatography analysis, the purity proved to be 96.3% (% by area).
88.3%
With potassium hydrogencarbonate In methanol; water
2 Example 2
Example 2 In a 500-ml four-necked flask equipped with a stirrer and a thermometer, 52.6 g (0.525 mol) of potassium hydrogencarbonate and 160.2 g (water content: 340 ppm, 5.0 mol) of methanol were placed. With stirring at a temperature of not higher than 10° C., 46.1 g (0.25 mol) of cyanuric chloride was added, followed by stirring at 20° C. for 1 hour. Then, the reaction was conducted at 50° C. for 2.5 hours. The weight of the reaction solution from which a salt formed had been removed was 193 g, and the water content was 49,600 ppm. After cooling, methanol was distilled off. To the residue, 200 ml of water was added, and the objective product was extracted with 250 ml of ethyl acetate. The organic layer was washed with 100 ml of water and then vacuum concentrated to obtain 38.8 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine as a white solid. The yield was 88.3%. From the gas chromatography analysis, the purity proved to be 96.0% (% by area).
87.5%
With potassium hydrogencarbonate In methanol; water; ethyl acetate
6 Example 6
Example 6 In a 1-liter (1000-ml) four-necked flask equipped with a stirrer and a thermometer, 52.6 g (0.525 mol) of potassium hydrogencarbonate, 80.1 g (5.0 mol, water content: 530 ppm) of methanol and 100 ml of ethyl acetate were placed. With stirring at a temperature of not higher than 10° C., 46.1 g (0.25 mol) of cyanuric chloride was added, followed by stirring at 20° C. for 1 hour. Then, the reaction solution was refluxed at 62° C. for 6 hours. The weight of the reaction solution from which a salt formed had been removed was 202 g, and the water content was 46,300 ppm. Then, 150 ml of ethyl acetate and 200 ml of water were added, followed by liquid separation. The organic layer was washed with 200 ml of water and then vacuum concentrated to obtain 38.4 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine as a white solid. The yield was 87.5%. From the gas chromatography analysis, the purity proved to be 93.8% (% by area).
84.3%
With sodium hydrogencarbonate In methanol; water; ethyl acetate
5 Example 5
Example 5 In a 1-liter (1000-ml) four-necked flask equipped with a stirrer and a thermometer, 44.1 g (0.525 mol) of sodium hydrogencarbonate, 80.1 g (2.5 mol, water content: 560 ppm) of methanol and 100 ml of ethyl acetate were placed. With stirring at a temperature of not higher than 10° C., 46.1 g (0.25 mol) of cyanuric chloride was added, followed by stirring at 20° C. for 1 hour. Then, the reaction solution was refluxed at 62° C. for 10 hours. The weight of the reaction solution from which a salt formed had been removed was 205 g, and the water content was 46,000 ppm. Then, 150 ml of ethyl acetate and 200 ml of water were added, followed by liquid separation. The organic layer was washed with 200 ml of water and then vacuum concentrated to obtain 37.0 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine as a white solid. The yield was 84.3%. From the gas chromatography analysis, the purity proved to be 96.1% (% by area).
84.8%
With sodium hydrogencarbonate In methanol; water
3 Example 3
Example 3 In a 1-liter (1000-ml) four-necked flask equipped with a stirrer and a thermometer, 88.2 g (1.05 mol) of sodium hydrogencarbonate and 160.2 g (water content: 460 ppm, 5.0 mol) of methanol were placed. With stirring at a temperature of not higher than 10° C., 92.2 g (0.5 mol) of cyanuric chloride was added, followed by stirring at 20° C. for 1 hour. Then, the reaction was conducted at 60° C. for 3.5 hours. The weight of the reaction solution from which a salt formed had been removed was 233 g, and the water content was 80,300 ppm. After cooling, methanol was distilled off. To the residue, 400 ml of water was added, and the objective product was extracted with 500 ml of ethyl acetate. The organic layer was washed with 400 ml of water and then vacuum concentrated to obtain 74.4 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine as a white solid. The yield was 84.8%. From the gas chromatography analysis, the purity proved to be 97.4% (% by area).
82.8%
With potassium hydrogencarbonate In methanol; water
4 Example 4
Example 4 In a 1-liter (1000-ml) four-necked flask equipped with a stirrer and a thermometer, 105.1 g (1.05 mol) of potassium hydrogencarbonate and 160.2 g (5.0 mol, water content: 530 ppm) of methanol were placed. With stirring at a temperature of not higher than 10° C., 92.2 g (0.5 mol) of cyanuric chloride was added, followed by stirring at 20° C. for 1 hour. Then, the reaction was conducted at 50° C. for 4 hours. The weight of the reaction solution from which a salt formed had been removed was 230 g, and the water content was 79,800 ppm. After *cooling, methanol was distilled off. To the residue, 400 ml of water was added, and the objective product was extracted with 500 ml of ethyl acetate. The organic layer was washed with 400 ml of water and then vacuum concentrated to obtain 72.7 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine as a white solid. The yield was 82.8%. From the gas chromatography analysis, the purity proved to be 94.9% (% by area).
67.2%
With sodium hydrogencarbonate In methanol; water
C.1 Comparative Example 1
Comparative Example 1 In a 500-ml four-necked flask equipped with a stirrer and a thermometer, 63.0 g (0.75 mol) of sodium hydrogencarbonate, 98.5 g (3.08 mol, water content: 187 ppm) of methanol and 12.1 g (0.675 mol) of water were placed. With stirring at a temperature of not higher than 10° C., 46.1 g (0.25 mol) of cyanuric chloride was added, followed by stirring for 30 minutes. Then, the reaction was conducted at 35° C. for 15 hours. The weight of the reaction solution from which a salt formed had been removed was 158 g, and the water content was 143,000 ppm. After cooling, methanol was distilled off. To the residue, 400 ml of water was added, and the objective product was extracted with 300 ml of ethyl acetate. The organic layer was washed with 100 ml of water and then vacuum concentrated to obtain 29.5 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine. The yield was 67.2%. From the gas chromatography analysis, the purity proved to be 94.0% (% by area).
With sodium hydrogencarbonate In methanol; water
3.E Step E
Step E Synthesis of 2-chloro-4,6-dimethoxy-1,3,5-triazine as an intermediate To a stirred mixture of 45.0 grams of methanol and 5.0 grams of water was added 16.8 grams (0.2 mole) of sodium bicarbonate and 18.5 grams (0.1 mole) of cyanuric chloride. The addition caused the reaction mixture temperature to rise to 35° C. and the liberation of carbon dioxide gas. After the gas evolution slowed, the reaction mixture was heated to reflux where it stirred for 30 minutes. The reaction mixture was cooled, diluted with water, and the resultant solid was collected by filtration. The solid was washed repeatedly with water and dried to yield 13.0 grams of 2-chloro-4,6-dimethoxy-1,3,5-triazine, m.p. 74°-76° C. Recrystallization of the solid from heptane raised the melting point to 75°-76° C.
With sodium hydrogencarbonate In methanol; ice-water; water
1 2-Chloro-4,6-dimethoxy-1,3,5-triazine
EXAMPLE 1 2-Chloro-4,6-dimethoxy-1,3,5-triazine To a vigorously-stirred suspension of 54.6 g of sodium bicarbonate in 146 g of methanol and 16 ml water was added 60.0 g of cyanuric chloride in portions over a period of 30 minutes. The temperature rose to 30°-35° C. and, following the addition, was allowed to drop to 25° C. and the mixture was then heated to 50°+-2° C. for 21/2 hours. The solution was allowed to cool and 600 ml ice-water was added and stirred for 15 minutes. Filtration of the thick reaction mixture followed by crystallization from hot hexanes gave 31.3 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine as a colorless crystalline solid, m.p. 76°-78° C. NMR(CDCl3): δ 4.1 (singlet, OCH3 's).
With 4-methyl-morpholine; In N,N-dimethyl-formamide;
A. Diethyl N-[4-{2-(2-Amino-4(3H)-oxo-7-H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl}-benzoyl]-L-glutamate To a suspension of 185 mg (0.62 mmol) of 4-[2-(2-amino-4(3H)-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid in 15 mL of dry dimethyl formamide were added 0.08 mL (0.74 mmol) of 4-methylmorpholine and 130 mg (0.74 mmol) of 2-chloro-4,6-dimethoxy-1,3,5-triazine. The resulting mixture was stirred at room temperature for 2 hours, an additional 0.08 mL of 4-methylmorpholine and 221 mg (0.93 mmol) of diethyl L-glutamate hydrochloride were added, and the reaction mixture was stirred for 3.5 hours at room temperature. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, eluding with 9:1 ethyl acetate:methanol, to give 186 mg (62%) of diethyl N-[4-{2-(2-amino-4(3H)-oxo-7-H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl}-benzoyl]-L-glutamate as an off-white solid: IR (KBr) 3340, 3216, 2979, 1728, 1635, 1538, 1499, 1437, 1371, 1204, 1095, 1021, 785, 668 cm-1, 1 H NMR (DMSO-d6) delta 10.64 (1H, s), 10.21 (1H, s), 8.64 (1H, d, J=5.0 Hz), 7.79 (2H, d, J=7.5 Hz), 7.30 (2H, d, J=8.0 Hz), 6.32 (1H, s), 6.07 (2H, br s), 4.44 (1H, q, J=5.0 Hz), 4.11 (2H, q, J=7.0 Hz), 4.05 (2H, q, J=7.0 Hz), 2.99 (2H, t, J=8.0 Hz), 2.87 (2H, t, J=8.0 Hz), 2.44 (2H, t, J=7.5 Hz), 2.15-2.08 (1H, m), 2.05-1.97 (1H, m), 1.19 (3H, t, J=6.5 Hz), 1.17 (3H, t, J=6.5 Hz); 13 C NMR (DMSO-d6) delta 172.24, 171.86, 166.68, 159.25, 152.18, 151.02, 146.31, 131.11, 128.19, 127.42, 117.66, 113.48, 98.75, 60.54, 59.93, 51.98, 36.14, 30.19, 27.99, 25.71, 14.07 (two carbons); EIMS m/z 483 (M+), 321, 281, 252, 191, 163, 141, 129, 119, 100, 91, 84; HRMS calc+d for C24 H29 N5 O6 483.2118, found 483.2119.
2-{4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoylamino}bicyclo[2.2.1]heptane-2-carboxylic acid ammonium salt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.025 g (9%)
With 4-methyl-morpholine In methanol; N,N-dimethyl-formamide
14 2-{4-[2-(2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoylamino}bicyclo[2.2.1]heptane-2-carboxylic Acid Ammonium Salt
Example 14 2-{4-[2-(2-Amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoylamino}bicyclo[2.2.1]heptane-2-carboxylic Acid Ammonium Salt After flame drying a 15-mL two-neck round bottom flask under argon, 0.20 g (0.57 mmol) of 4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoic acid hydrochloride was suspended in 2 mL of anhydrous N,N-dimethylformamide, followed by the addition of 0.19 mL (1.7 mmol) of 4-methylmorpholine. After stirring the reaction at room temperature for 15 minutes, 0.15 g (0.86 mmol) of 2-chloro-4,6-dimethoxy-1,3,5-triazine was added. The reaction was stirred at room temperature for 30 minutes and 0.134 g (0.86 mmol) of 2-aminonorbornane-2-carboxylic acid was added. The reaction mixture was stirred at room temperature for 3 hours. The volatiles were concentrated in vacuo, and the residue was treated with 50 mL of H20, and the white solid was filtered and dried in a vacuum oven at 60°C. The crude solid was purified using rotor chromatography on a 2 mm Chromatotron silica gel plate, and eluted with a gradient of 20% CH3OH/CHCl3to 75:25:1 CHCl3/CH3OH/NH4OH. The correct fractions were combined and removed in vacuoto give 0.025 g (9%) of 2-{4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoylamino}bicyclo[2.2.1]heptane-2-carboxylic acid ammonium salt as a white solid. Rf =0.30 (6/3.2/0.8) (CHCl3/CH3OH/NH4OH); m.p. 241°C (foam); IR (KBr, cm-1) = 615, 647, 772, 1019, 1121, 1218, 1307, 1370, 1477, 1538, 1641, 2952, 3344; UV (0.1 N NaOH) λmax= 273, 241, 218 (ε = 9839, 14408, 21458); Exact mass: Calcd= 452.2298; Found= 452.2338 5; 1H NMR (300 MHz, DMSOd6) δ 1.26-1.37 (m, 2H), 1.48-1.81 (m, 7H), 1.84-1.88 (m, 4H), 2.63-2.83 (m, 4H), 3.19-3.27 (m, 2H), 5.97 (s, 2H), 6.27 (S, 1H), 7.31 (d, J=8.1 Hz, 2H), 7.78 (d, J=7.9 Hz, 2H), 8.53 (s, 1H).
2-(4-aminoimidazolyl)-2-phenyl-1-pyrrolidinylethan-1-one, hydrochloride[ No CAS ]
[ 159634-94-3 ]
[ 220540-73-8 ]
Yield
Reaction Conditions
Operation in experiment
84%
In water
1 N-((1R)-2-indol-3-yl-1-{N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]carbamoyl}ethyl)-2-[(tert-butoxy)carbonylamino]-2-methylpropanamide
Example 1 N-((1R)-2-indol-3-yl-1-{N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]carbamoyl}ethyl)-2-[(tert-butoxy)carbonylamino]-2-methylpropanamide N-Methyl morpholine (0.28 mL, 8.32 mm, 1 eq) was added to a stirred slurry of 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.46 g, 2.57 mm, 1 eq) and (2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-indol-3-ylpropanoic acid (1 g, 2.57 mm) in 10 mL of anhydrous tetrahydrofuran cooled to less than 0° C. After 1.5 hours, 2-(4-aminoimidazolyl)-2-phenyl-1-pyrrolidinylethan-1-one, hydrochloride (0.97 g, 2.82 mm, 1.1 eq) was added and stirring was continued at ice bath temperatures. The reaction was stirred for 4 hours and quenched by the addition of 15 mL of deionized water and ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution, dried over magnesium sulfate and the volatiles were removed under vacuum to give the crude product as a light purple foam (1.4 g, 84%) The crude product was purified by preparative chromatography to provide 0.52 g (31.5%) of the product as a foam. 1H nmr (CDCl3): δ1.10-1.40 (m, 15H), 1.67-1.92 (m, 3H), 2.92-3.60 (m, % H), 4.90 (s, broad, 1H), 5.33 (s, broad, 1H), 5.85 (d, 1H), 6.80-7.05 (m, 3H), 7.13-7.39 (m, 10H), 7.44-7.80 (m, 2H), 8.96 (s, broad, 1H), 10.20 (s, broad, 1H).
2-(4-nitroimidazolyl)-2-phenylacetic acid[ No CAS ]
[ 3140-73-6 ]
[ 2133-40-6 ]
methyl (2S)-1-[2-(4-nitroimidazolyl)-2-phenylacetyl]pyrrolidine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17.45 g (60%)
With hydrogenchloride; In tetrahydrofuran; methyl t-butyl ether, methylene chloride; water;
Preparation 4 Methyl (2S)-1-[2-(4-nitroimidazolyl)-2-phenylacetyl]pyrrolidine-2-carboxylate N-Methyl morpholine (17.79 ml, 2 eq) was added to a stirred solution of 2-(4-nitroimidazolyl)-2-phenylacetic acid (1) (20 g, 80.9 mm) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (14.45 g,80.1 mm, 1.0 eq) in 175 ml of anhydrous tetrahydrofuran at 25 C. After stirring the reaction mixture at ambient temperature for 1.5 h, 14.45g (80.9 mm, 1.0 eq) of proline methyl ester hydrochloride was added. The reaction was stirred overnight at room temperature and the solvent was evaporated under a stream of nitrogen. The residue was partitioned between 200 Ml of 1M HCl and 200 mL of deionized water. The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution. A quantity of water sufficient to dissolve the resulting solids was added. The organic layer was washed with brine, dried over magnesium sulfate, filtered and the volatiles were removed under vacuum to give a brown foam. The foam was dissolved in methyl t-butyl ether, methylene chloride and methanol to effect crystallization. The resulting slurry was filtered and dried under vacuum to give 17.45 g (60%) of a cream colored product MS: 358 (M+) IR (cm-1): 1744, 1668; H1 nmr d (d6 DMSO): 1.42-1.46 (m, 3H), 1.6-1.9 (m, 1H), 2.42-2.63 (m,1H), 3.21 (s, 1.5H), 3.25 (s, 1.5H), 3.30-3.36 (m, 1H), 4.01-4.06 (m, 1H), 6.36 (s, 0.5H), 6.43 (s, 0.5h), 7.0-7.2 (m, 5H), 7.38 (s, 0.5H), 7.41 (s, 0.5H), 7.75 (s, 0.5H), 7.83 (s, 0.5H)
With potassium hydrogencarbonate In acetonitrile at 0℃; for 15h;
VII
A vigorously stirred suspension of N-methylmorpholinium methanosulphonate (1 ,97 g, l O mmol) and finely powdered potassium bicarbonate (1.10 g; 1 1 mmol) in acetonitrile (30 ml_) was cooled to 0 0C and 2-chloro-4,6-dimethoxy-1 ,3,5-triazine (CDMT) (1.75 g; 10 mmol) was added. The stirring was continued until all CDMT was consumed (usually 15 hrs). Then, the precipitate was filtered off, the filtrate was concentrated to VA of the volume and left to crystallization. The product was filtered, washed and dried, yielding 1.85 g (60 %) N-methyl-N-(4,6-dimethoxy- 2,4,6-triazin-2-yl)-morpholinium methanosulphonate, mp =96-98°C. 1H-NMR (CD3CN): 2.44 (s, 3H, CH3-S-)3.39 (s, 3H, CH3-N-); 3.72 (AB system, 4H, -N-CH2-CH2-O-); 3.85 (d, 2H, -N-CH2-CJH2-O-); 4.06 (s, 6H, CJH3-O-); 4.65 (d, 2H, - N-CH2-CH2-O-) [ppm]. Analysis for: C11H20N4O6S:Calculated: %C 39,28 %H 5,99 %N 16,66 %S 9,53,Found: %C 39;45 %H 6;14 %N 16;20 %S 8,61.
55%
With sodium hydrogencarbonate In acetonitrile at 5℃; for 20h;
With potassium hydrogencarbonate; caesium carbonate In acetonitrile at 5℃; for 10h;
IV
A vigorously stirred suspension of 1 ,4-diazabicyclo-[2,2,2]-octanium tetrafluoroborate (1 ,99 g, 10 mmol), finely powdered potassium bicarbonate (1.50 g; 15 mmol) and cesium carbonate (100 mg) in acetonitrile (30 ml_) was cooled to 5 0C and 2-chloro-4,6-dimethoxy-1 ,3,5-triazine (CDMT) (1.75 g; 10 mmol) was added. The stirring was continued until all CDMT was consumed (usually 10 hrs). Then, the precipitate was filtered off, the filtrate was concentrated to VA of the volume and left to crystallization. The product was filtered, washed and dried, yielding 2.61 g (77 %) N-(4,6-dimethoxy-2,4,6-triazin-2-yl)-1 ,4- diazabicyclooctanium tetrafluoroborate, mp =262 - 265 °C, 1H-NMR (D2O): 3.88 (AB system, 6H, -N-(CH2)3-); 3.99 (AB system, 6H, C-N+- (CH2)3-); 4.08 (s, 3H, CH3-O-); 4.15 (s, 3H, CH3-O-) [ppm]. Analysis for:: Cu Hi8BF4 N5O2 Calculated: 38,96 % C, 5,35 % H, 20,65 % N; Found: 38.61 % C , 5.28 % H, 20.35% N.
With sodium hydrogencarbonate In acetonitrile at 5℃; for 14h;
XII
A vigorously stirred suspension of quinuclidinium 10-camhorsulphonate (3,44 g, 10 mmol) and finely powdered sodium bicarbonate (1 ,26 g; 15 mmol) in acetonitrile (30 ml_) was cooled to 5 0C and 2-chloro-4,6-dimethoxy-1 ,3,5-triazine (CDMT) (1.75 g; 10 mmol) was added. The stirring was continued until all CDMT was consumed (usually 14 hrs). Then, the precipitate was filtered off, the filtrate was concentrated to VA of the volume and left to crystallization. The product was filtered, washed and dried, yielding 4.35 g (90 %) N-(4,6-dimethoxy-2,4,6-triazin-2- yl)-quinuclidinium 10-camphorsulphonate, mp =128-130°C.1H-NMR (CD3CN): 0.78 (s, 3H, CH3-C-); 1.08 (s, 3H, CH3-C-);1.26-1.45 (m, 2H, - CiH2-); 1.76 (m, 1 H, -CH2-CH-CH2-); 1.96 (q, 6H, -CH2-CiH2-CH-); 1.99 (m, 1 H, - CH2-CH2-CH-); 2.20-2.30 (m, -CH2-); 2.51 (m, 1 H, -CH2-S-) 2.98 (m, 1 H, -CH2-S-); 3.25 (q, 6H, -N-CH2-CH2-CH-); 4.12 (s, 6H, CH3-O-) [ppm]. Analysis for: C22H34N4OeSCalculated: % C 54,75 % H 7,10 % N 1 1 ,61 % S 6,64 Found: % C 65.60 % H 6.91 % N 1 1.89 % S 6.20.
With N-ethyl-N,N-diisopropylamine In acetonitrile at 130℃; for 1h; microwave irradiation;
4.1
Example 4; Preparation of Compound 4: N-(4,6-dimethoxy-1,3,5-triazin-2-yl)valyl-(4R)-N-((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-4-((6-methoxy-1-isoquinolinyl)oxy)-L-prolinamide; Step 1:; To a mixture of valine tert-butyl ester hydrochloride (0.367 g, 1.75 mmol) and DIEA (0.567 g, 4.38 mmol) in acetonitrile (5 mL) was added 2-chloro-4,6-dimethoxy-1,3,5-triazene (0.476 g, 2.63 mmol). The mixture was heated to 130° C. in a microwave reactor for 1 hours. Solvent was removed and the viscous brown residue was dissolved in ethyl acetate (75 mL) and the solution was washed with 1.0M aqueous HCl (2×10 mL). The aqueous extracts were combined and back-extracted with ethyl acetate (50 mL), and the organic phases were combined and washed with 10% aqueous sodium carbonate (15 mL) and then with brine. The organic phase was dried over anhydrous MgSO4, filtered and concentrated to a brown oil which was purified by flash silica gel chromatography (97:3 dichloromethane:methanol) to give the product as a light brown viscous oil (0.521 g, 95% yield).
76%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 100℃; for 0.166667h; Microwave irradiation;
A solution of 2-amino-3-methylbutanoate hydrochloride (0.5 g, 2.8 mmol), DIPEA (1.16 ml, 6.7 mmol) and 2-chloro-4,6-dimethoxy-l ,3,5-triazine (0.4 g, 1.9 mmol) in ACN (10 ml) was sealed in a microwave tube and heated to 100°C for 10 min by microwave irradiation. The reaction mixture was concentrated to dryness and dried well under vacuum to give the crude product, which was purified by column chromatography on silica gel to get the pure product 2-((4,6-dimethoxy- l ,3,5-triazin-2-yl)amino)-3-methylbutanoate as an off-white solid, 0.45 g (76%). NMR (400 MHz, CDC13) δ 0.96-1.00 (6H, t, , J=8 Hz), 1.45 (9H, s), 2.19-2.27 (1 H, m), 3.94 (3H, s), 3.95 (3H, s), 4.58-4.61 (1H, q, J=4H), 5.76-5.78 (1H, d, J=8 Hz). MS (LC/MS) m/z observed 313.06, expected 313.18 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
Intermediate 11 S-Ethyl 3-(4-hydroxyphenyl)-2-[(4,6-dimethoxy-1,3,5-triazin-2-yl)amino]propionate A mixture of <strong>[4089-07-0]L-<strong>[4089-07-0]tyrosine ethyl ester hydrochloride</strong></strong> (0.50 g, 2.0 mmol) and DIPEA (0.74 ml, 4.4 mmol) in CH3CN (8 ml) was stirred at room temperature for 15 minutes and then 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.43 g, 2.2 mmol) was added, and the reaction stirred overnight then concentrated in vacuo.. The residue was partitioned between EtOAc (50 ml) and NaHCO3 solution (50 ml).. The organic layer was washed with 10percent citric acid solution (50 ml), NaHCO3 solution (50 ml) and water (50 ml), dried (MgSO4) and concentrated in vacuo to give the title compound as a colourless gum (0.48 g, 68percent): deltaH (DMSO d6) 6.90 (2H, d), 6.65 (2H, d), 5.90 (1H, m), 4.90 (1H, m), 4.10 (2H, m), 3.95 (3H, s), 3.90 (3H, s), 3.10 (2H, m), 1.20 (3H, t, J 7.1 Hz); m/z (EI+, 70V) 349.
Stage #1: 4-methyl-morpholine; 2-chloro-4,6-dimethoxy-1 ,3,5-triazine In tetrahydrofuran at 0 - 5℃; for 0.5h;
Stage #2: (4S,5R)-2,4-diphenyl-4,5-dihydrooxazole-5-carboxylic acid In tetrahydrofuran at 0 - 20℃; for 12h;
14 14. Example
Solution of 2-CHLOR-4, 6-dimethoxy-1,3, 5-triazine (0.175 g, 1 MMOLE) in 5 mi THF was mixed with N-METHYLMORPHOLINE (0.11 ml, 1 MMOLE) for 30 minutes at temperature of 0- 5C, to form respective quaternary triazinilammonium salt. Then, phenyl isoserine of the formula 4c (0.267 g, 1 MMOL) was added and mixed for 12 hours, first at temperature of 0- 5C, next at room temperature. N-methylmorpholine hydrochloride was filtered off and solvent was removed from the filtrate. It gave respective triazine ester of the formula 6c, where R5=R6=OCH3, with the quantitative yield. TLC: ELUENT CHCI3, Rf=0.50 H-NMR (CDCI3) : #=3, 76 (s, 6H) ; 5.31 (d, J=7.5 Hz, 1H); 5.56 (d, J=7.5 Hz, 1H); 7.35- 7.48 (m, 6H) ; 7. 75-7.77 (m, 2H) ; 8.04 (d, J=8.0 Hz; 2H) [ppm] IR (KBr): 1785 [CM~11 The triazine ester, in the presence of DMAP, was coupled with protected Baccatin III of the generalized formula 3, where R2=SI (C2H5) 3. It gave 0.885 G of the final product (yield 91. 5%) with the formula 2, where Ri is defined by the formula 9, R2 = Si (C2H5) 3. TLC: eluent (acetone: benzene 1: 4), RF=0. 75 'H-NMR (CDCI3) : B= 0.57 (M, 6H); 0.95 (t, J= 8.0 Hz, 9H) ; 1.21 (s, 3H); 1.23 (s, 3H) ; 1.67 (s, 3H) ; 1.75 (s, 1H) ; 1.86-1. 89 (m, 1H); 1.99 (s, 3H); 2.08 (s, 3H) ; 2.17 (s, 3H); 2.23-2. 26 (m, 1H) ; 2.35-2. 37 (m, 1H) ; 2.54-2. 57 (m, 1H) ; 3.84 (d, J=7.5 Hz, 1H) ; 4.16 (d, J=8.5 Hz, 1 H) ; 4.31 (d, J=8.5 Hz, 1 H) ; 4.47-4. 50 (m, 1 H) ; 4.93-4. 96 (m, 2H); 5.60 (d, J=6.5 Hz, 1 H) ; 5.67 (d, J=7.5 Hz, 1H) ; 6.15-6. 19 (m, 1H) ; 6.43 (s, 1H) ; 7.35-7. 39 (m, 5H); 7.47-7. 51 (m, 4H); 7.59 (t, J=7.5 Hz, 1 H) ; 7.64 (t, J= 7.5 Hz, 1H) ; 8.08 (d. J=7.5 Hz, 2H); 8.25 (d, J= 7.5 Hz, 2H) [ppm] The product of condensation was treated with 0.1 N HCI in methanol, and the final product was chromatographically purified on silica gel with the system of hexane: ethyl acetate 1.5 : 1. It gave 0. 594 g (i. e. yield 76%) of a product SPECTROSCOPICALLY and CHROMATOGRAPHICALLY identical to Paclitaxel.
Solution of 2-CHLOR-4, 6-dimethoxy-1,3, 5-triazine (0.175 g, 1 mmole) in 5 ML THF was mixed with N-METHYLMORPHOLINE (D ML, 1 mmole) for 30 minutes at temperature of 0- 5C, to form respective quaternary TRIAZINILAMMONIUM salt. Then, phenyl isoserine of the formula 4b, where R3= R4=CH3 (0 325 g, 1 MMOL) was added and mixed for 12 hours, first at temperature of 0-5C, next at room temperature. N-METHYLMORPHOLINE was filtered off and solvent was removed from the filtrate. It gave respective triazine ester of the formula 6b, where R3=R4=CH3, R5=R6=OCH3, with the quantitative yield. TLC : ELUENT CHCI3, RF=0. 50 'H-NMR (COCI3) : 5= 1.76 (s, 3H); 1.79 (s, 3H); 3.76 (s, 6H); 5.20 (d, J= 7.5 Hz, 1H) ; 5.59, (d, J= 7.5 Hz, 1 H) ; 7.43-7. 56 (m, 8H) ; 7.70-7. 43 (m, 2H) [ppm]. IR (KBr): 1790 [CM~1] The triazine ester was coupled with protected Baccatin (it of generalized formula 3, where R2=Si (C2HS) 3, in the presence of magnesium bromide and diazobicycloundekane. It gave 0.945 g of the final product (93.8%) with the melting temperature of 171-173C. TLC: eluent (acetone: benzene 1: 4), RF=0. 85 1H-NMR (CDCI3) : 6=0. 55 (q, J=8. 5 Hz, 6H); 0.94 (t, J=8.5 Hz, 9H); 1.17 (s, 3H) ; 1.22 (s, 3H); 1.67 (s, 3H); 1.77 (s, 1H) ; 1.83-1. 85 (m, 1H) ; 1.87 (s, 3H); 1.94 (s, 3H); 2.02 (s, 3H); 2.07 (s, 3H); 2.02-2. 18 (m, 2H); 2.19 (s, 3H); 2.07-2. 20 (m, 2H); 2.48-2. 50 (m, 2H); 3.77 (d, J=7.5 Hz, 1H) ; 4.07 (d, J=8.5 Hz, 1H) ; 4.25 (d, J=8.5 Hz, 1H) ; 4.42-4. 46 (m, 1H) ; 4.58 (d, J=7.5 HZ, 1H) ; 4.88-4. 93 (m, 1H) ; 5.28 (d, J=6. 5 Hz, 1H) ; 5.68 (d, J=7.5 Hz, 1H) ; 6.21- 6.25 (m, 1H) ; 6.49 (s, 1H) ; 6.91-6. 96 (m, 1H) ; 7.07-7. 22 (m, 8H); 7.44-7. 48 (m, 2H) ; 7.61- 7.65 (m, 1 H) ; 8.02 (d, J=7.5 Hz, 2H) [ppm] The product of condensation was treated with formic acid in THF, and the final product was CHROMATOGRAPHICALLY PURIFIED on silica gel with the system of hexane: ethyl acetate 2: 1. It gave 0.621 G (yield 76%) of a product spectroscopically and CHROMATOGRAPHICALLY identical to Paclitaxel.
With 4-methyl-morpholine; In N,N-dimethyl-formamide; at 25℃; for 1.5h;
To a solution of 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl]benzoic acid (38.4 mg, 0.129 mmol) in 5 mL of DMF was added N-methylmorpholine (40.4 mg, 0.399 mmol), followed by the addition of 2-chloro-4,6-dimethoxy-1,3,5-triazine (22.64 mg, 0.129 mmol). The resulting mixture was stirred for 1.5 hours at 25 !C, at which time HPLC showed that the reaction was complete. L-glutamic acid gamma-benzyl ester (30.6 mg, 0.129 mmol) was added, and stirring was continued at 25 !C until complete conversion of precursor was determined by HPLC (around two hours). To the reaction mixture was added 10 mL of methylene chloride and 10 ml of deionized water, and the mixture was stirred for 15 minutes. The layers were separated. The aqueous layer was extracted with DCM (10 ml*2). The organic phases were combined. The solution was concentrated on rotary-evaporator under reduced pressure. The resulting residue was subjected to flash chromatography on a Biotage system. Yield: 55 mg, 82%. 1HNMR in d6-DMSO, delta ppm: 10.61 (1H, s), 10.20 (1H, s), 8.72 (1H, d, J=10 Hz), 7.78 (2H, d, J=5 Hz), 7.35 (5H, m), 7.30 (2H, m), 6.30 (1H, s), 6.07 (2H, s), 5.14 (2H, s), 3.86 (1H, m), 2.97 (2H, t), 2.84 (2H, t), 2.20 (2H, s), 2.02 (1H, m), 1.95 (1H, m). ESI-MS: 518 [M+H]+.
Part A Phenylmethyl (3S)-2-[(2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)heptanoyl]-3-[(3-pyridazinylamino)carbonyl]-1-pyrazolidinecarboxylate To a solution of (3S)-2-[(2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)heptanoyl]-1-[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (590 mg, 0.95 mmol), <strong>[5469-70-5]3-pyridazinamine</strong> (100 mg, 1.05 mmol) and 2-chloro-4,6-bis(methyloxy)-1,3,5-triazine (183 mg, 1.05 mmol) in acetonitrile (30 mL) under N2 was added 4-methylmorpholine (212 mg, 2.1 mmol) dropwise. The mixture was stirred at rt overnight. TLC showed that the reaction was complete. The mixture was diluted with ethyl acetate and washed with 5% citric acid, followed by brine. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (2:1) to provide the titled compound (460 mg, 79%)
With potassium carbonate; potassium hydroxide; In N,N-dimethyl acetamide; water; at 0 - 30℃; for 18h;Cooling with ice;
Example 1 Preparation of 3-(4,6-dimethoxy-1,3,5-triazin-2-yl)-<strong>[71294-03-6]7-fluoro-1,3-dihydro-2H-indol-2-one</strong> Variant A: 7-Fluoro-1,3-dihydro-2H-indol-2-one (100 g) is introduced as initial charge in 600 ml of N,N-dimethylacetamide and cooled to ca. 0 C. with ice/methanol cooling. A solution of potassium hydroxide (43.2 g) and potassium carbonate (143 g) in 600 ml of water is added and the mixture is briefly after-stirred. Then, 2-chloro-4,6-dimethoxy-1,3,5-triazine (140.8 g) is added and in each case 100 ml of water and N,N-dimethylacetamide are used for after-rinsing. The cooling bath is removed, the mixture heats up to ca. 30 C. It is stirred for 18 hours at room temperature. After adding 150 ml of toluene, dilute hydrochloric acid (ca. 700 ml) is used to adjust the pH to 3-4 and at the same time some antifoam (Fluowet PL 80) is added. The solid is filtered off with suction, washed three times with in each case 250 ml of water and twice with in each case 250 ml of heptane and dried in vacuo at 55 C. This gives the title compound as solid in a purity of 96.6% (187.5 g, 95% of theory). LC-MS: M+H=291 (100%). 1H NMR (400 MHz, DMSO-D6): delta (ppm)=11.37 (s, 1H), 7.64 (d, 1H), 6.97 (dt, 1H), 6.86 (dd, 1H), 4.05 (s, 6H).
With lanthanide(III)chloride heptahydrate In neat (no solvent) at 50℃; for 3.5h; Inert atmosphere;
With lanthanide(III)chloride heptahydrate In neat (no solvent) at 50℃; for 3.5h; Inert atmosphere;
General procedure for synthesis of the titlecompounds (3a-l)
General procedure: 3-Bromoquinoline (1a) (0.20 mL, 0.001 mol), dimethyl phenylphosphonite (0.23 mL, 0.001 mol) and Lewisacid catalyst, LaCl3.7H2O (20 mol%) were taken into around bottom flask (50 mL) flushed with nitrogen. Thereaction mixture was stirred for 2 h at 50C under N2atmosphere. The progress of the reaction was checkedby TLC using ethyl acetate: n-hexane (1:1) as an eluent.After completion of the reaction, the reaction mixturewas dissolved in 10 mL of ethyl acetate and thenfiltered-off to remove the catalyst. The residue i.e., catalyst was further washed with ethyl acetate (3 ×5 mL) and the combined organic layer was concentrated under reduced pressure to obtain the crude product,methyl phenyl (quinolin-3-yl)phosphinate (3a). The crude product was purified by column chromatography using ethyl acetate: hexane (1:3) as an eluent. The same procedure was employed to synthesize further title compounds 3(a-l) (table 4)
With 4-methyl-morpholine In tetrahydrofuran at 20℃; Cooling with ice;
5 Example 5 Synthesis of Compound Fc-D5
Ferrocenecarboxylic acid (0.46 g, 2 mmol), 2,6-dimethoxy-4-chloro-triazine (CDMT, 0.438 g, 2.5mmol) was added to a 100 mL round bottom flask and 20 mL dry tetrahydrofuran was added.The mixture was stirred in an ice bath and 10 mL contained NMM (0.253 g, 2.5 mmol)The dry tetrahydrofuran solution was slowly added dropwise to the reaction system.After stirring in an ice bath for 30 minutes, the reaction was naturally warmed to room temperature. After the TLC reaction was completed,The reaction solution was concentrated under reduced pressure, and the residue was separated by direct column. (V petroleum ether: V ethyl acetate, 5:1-2:1)Elution of the mobile phase yielded compound Fc-D1 0.638 g, yield: 92%. Light yellow solid
With 4-methyl-morpholine In tetrahydrofuran at 25℃; for 1h;
With hydrazine hydrate In acetonitrile at 60℃; for 1h; Sonication;
3.5. General Method for the Synthesis of Hydrazine-1,3,5-triazine Derivatives
General procedure: Solution of hydrazine hydrate (20 mL, 80%) in acetonitrile (20 mL) was added to a solution of thechloro derivatives (20 mmol, CC 1, DCMeT 2, or DMeCT 4) in 50 mL acetonitrile at room temperature.The reaction mixture was sonicated at 60 C for 1 h. The excess solvent and hydrazine hydrate wasremoved under reduced pressure, and excess of diethyl ether was added to give a slightly pink coloredsolid which on drying converted to white solid. The solid was collected by filtration, washed withdiethyl ether (2 50 mL), and finally dried under vacuum to give a pure product in yield 95%-98%.
900 mg
With hydrazine hydrate In acetonitrile at 20℃; for 0.5h;
Synthesis of 2
Hydrazine hydrate (80 %, 1.1 ml, 22.8 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (1 g, 5.7 mmol) in CH3CN (20 ml) were stirred for 0.5 h at room temperature. The product was collected by filtration and washed twice with 10 ml of cold CH3CN. The residue was dried at 40 C in vacuo to give 2 (900 mg) as a pale pink powder solid, which was unstable and used for the next step without further purification.
With hydrazine hydrate In ethanol at 60℃; for 1h; Sonication;
3 2.2.3. General method for the synthesis of 2-hydrazino-4,6-disubstituted-1,3,5-triazineusing ultrasonic irradiation (3, 5 and 8)
General procedure: To a solution of 2-chloro-4,6-disubstituted-1,3,5-triazine(20 mmol) in 50 mL ethanol, 10 mL of hydrazine hydrate (80%)was added dropwise and then the reaction mixture was sonicatedfor 60 min at 60 C. The solvent was removed under vacuum andexcess ether was added to afford the product as a white solid inhigher yield (>90%)than the reported yield for the synthesis of 2-hydrazino-4,6-dipiperidino-1,3,5-triazine (3a) [48,49], 2-hydrazino-4,6-dimorpholino-1,3,5-triazine (3b) [46,50] and 2-hydrazino-4,6-dimethoxy-1,3,5-triazine (5) [50,51]and useddirectly in the next step.
With hydrazine hydrate In ethanol at 60℃; for 1h; Sonication;
(i) General Method for the Synthesis of 2-Hydrazino-4,6-dimorpholinio or Dimethoxy-1,3,5-triazine (3 and 5)
General procedure: Hydrazine hydrate (10 mL, 80%) was added dropwise to a solution of 2-chloro-4,6-dimorpholino or dimethoxy-1,3,5-triazine 2 or 4 (20 mmol) in 50 mL ethanol at room temperature and then the reaction mixture was sonicated for 60 min at 60 °C. Ethanol and excess hydrazine were removed under vacuum and then excess diethyl ether was added to afford the product as a white solid in yield >90%. The spectral data of the two products 3 and 5 were in good agreement with the reported data [40, 42] and were used directly without further purification.
Stage #1: tetrafluoroboric acid; N-methyl-D-proline methyl ester In diethyl ether; dichloromethane
Stage #2: 2-chloro-4,6-dimethoxy-1 ,3,5-triazine With sodium hydrogencarbonate In acetonitrile at 20℃;
Synthesis of L-5b (DMT/L-N-MePro-OMe/BF4-)from L-N-methylproline methyl ester tetrafluoroborateand CDMT
General procedure: To the solution of L-N-methylproline methyl ester (5.50 g; 39 mmol) in dichloromethane (50 mL)equimolar amount of HBF4 in ether (4.02 mL; 39mmol) was added. Solvent was removed under reduced pressure yielding quantitatively L-Nmethylprolinemethyl ester tetrafluoroborate as white solid. Solid residue was dissolved in acetonitrile(100 mL), anhydrous NaHCO3 (6.10 g; 72mmol) and CDMT (6.30 g; 39 mmol) were addedand suspension was vigorously stirred at room temperature until all CDMT was consumed as monitoredby TLC. The suspension was filtered. The filtercake was washed several times with acetonitrile and combined filtrates were evaporated under reduced pressure affording 5b (DMT/L-N-MePro-OMe/BF4-) (12.0 g, yield 83%) as pale oil.
With potassium carbonate; In tetrahydrofuran; at 70℃; for 4h;
General procedure: 2-Chloro-4,6-dimethoxy-1,3,5-triazine (1 mmol) (2), substituted aniline (1 mmol)/heterocyclic amines (3) (1 mmol), anhydrous K2CO3 (2 mmol) were added in dry THF (5 mL) taken in a round bottom flask. The reaction mixture was refluxed at 70 C for 4 h. After completion of the reaction the product is confirmed on thin-layer chromatography (TLC) using eluent (2:8 mL,ethyl acetate-hexane). The reaction mixture was quenched with water and the crude product was extracted with ethyl acetate (3 times) and organic layer was separated and dried over anhydrous Na2SO4. The solvent evaporated on rotavapour. The Crude material was purified by column chromatography (ethylacetate-n-hexane) and product 4(a-x) with good yield (70-75 %) were obtained (Scheme-II).
With potassium carbonate; In tetrahydrofuran; at 70℃; for 4h;
General procedure: 2-Chloro-4,6-dimethoxy-1,3,5-triazine (1 mmol) (2), substituted aniline (1 mmol)/heterocyclic amines (3) (1 mmol), anhydrous K2CO3 (2 mmol) were added in dry THF (5 mL) taken in a round bottom flask. The reaction mixture was refluxed at 70 °C for 4 h. After completion of the reaction the product is confirmed on thin-layer chromatography (TLC) using eluent (2:8 mL,ethyl acetate-hexane). The reaction mixture was quenched with water and the crude product was extracted with ethyl acetate (3 times) and organic layer was separated and dried over anhydrous Na2SO4. The solvent evaporated on rotavapour. The Crude material was purified by column chromatography (ethylacetate-n-hexane) and product 4(a-x) with good yield (70-75 percent) were obtained (Scheme-II).
With potassium carbonate; In tetrahydrofuran; at 70℃; for 4.0h;
General procedure: 2-Chloro-4,6-dimethoxy-1,3,5-triazine (1 mmol) (2), substituted aniline (1 mmol)/heterocyclic amines (3) (1 mmol), anhydrous K2CO3 (2 mmol) were added in dry THF (5 mL) taken in a round bottom flask. The reaction mixture was refluxed at 70 C for 4 h. After completion of the reaction the product is confirmed on thin-layer chromatography (TLC) using eluent (2:8 mL,ethyl acetate-hexane). The reaction mixture was quenched with water and the crude product was extracted with ethyl acetate (3 times) and organic layer was separated and dried over anhydrous Na2SO4. The solvent evaporated on rotavapour. The Crude material was purified by column chromatography (ethylacetate-n-hexane) and product 4(a-x) with good yield (70-75 %) were obtained (Scheme-II).
With potassium carbonate; In tetrahydrofuran; at 70℃; for 4h;
General procedure: 2-Chloro-4,6-dimethoxy-1,3,5-triazine (1 mmol) (2), substituted aniline (1 mmol)/heterocyclic amines (3) (1 mmol), anhydrous K2CO3 (2 mmol) were added in dry THF (5 mL) taken in a round bottom flask. The reaction mixture was refluxed at 70 C for 4 h. After completion of the reaction the product is confirmed on thin-layer chromatography (TLC) using eluent (2:8 mL,ethyl acetate-hexane). The reaction mixture was quenched with water and the crude product was extracted with ethyl acetate (3 times) and organic layer was separated and dried over anhydrous Na2SO4. The solvent evaporated on rotavapour. The Crude material was purified by column chromatography (ethylacetate-n-hexane) and product 4(a-x) with good yield (70-75 %) were obtained (Scheme-II).
With potassium carbonate In tetrahydrofuran at 70℃; for 4h;
General procedure for the synthesis of substituted 4,6-dimethoxy-N-phenyl-1,3,5-triazin-2-amines (4a-x)
General procedure: 2-Chloro-4,6-dimethoxy-1,3,5-triazine (1 mmol) (2), substituted aniline (1 mmol)/heterocyclic amines (3) (1 mmol), anhydrous K2CO3 (2 mmol) were added in dry THF (5 mL) taken in a round bottom flask. The reaction mixture was refluxed at 70 °C for 4 h. After completion of the reaction the product is confirmed on thin-layer chromatography (TLC) using eluent (2:8 mL,ethyl acetate-hexane). The reaction mixture was quenched with water and the crude product was extracted with ethyl acetate (3 times) and organic layer was separated and dried over anhydrous Na2SO4. The solvent evaporated on rotavapour. The Crude material was purified by column chromatography (ethylacetate-n-hexane) and product 4(a-x) with good yield (70-75 %) were obtained (Scheme-II).
With potassium carbonate; In tetrahydrofuran; at 70℃; for 4h;
General procedure: 2-Chloro-4,6-dimethoxy-1,3,5-triazine (1 mmol) (2), substituted aniline (1 mmol)/heterocyclic amines (3) (1 mmol), anhydrous K2CO3 (2 mmol) were added in dry THF (5 mL) taken in a round bottom flask. The reaction mixture was refluxed at 70 C for 4 h. After completion of the reaction the product is confirmed on thin-layer chromatography (TLC) using eluent (2:8 mL,ethyl acetate-hexane). The reaction mixture was quenched with water and the crude product was extracted with ethyl acetate (3 times) and organic layer was separated and dried over anhydrous Na2SO4. The solvent evaporated on rotavapour. The Crude material was purified by column chromatography (ethylacetate-n-hexane) and product 4(a-x) with good yield (70-75 %) were obtained (Scheme-II).
With O4P(3-)*3K(1+)*5H2O; tris(1-adamantyl)phosphine; C28H26N2O8Pd2S2 In tetrahydrofuran at 20℃; for 1.5h; Inert atmosphere; Schlenk technique;
90%
With O4P(3-)*3K(1+)*5H2O; tris(1-adamantyl)phosphine; {2-[((acetyl-κO)amino)phenyl-κC](tri-1-adamantylphosphine)palladium}(p-toluenesulfonate) In tetrahydrofuran at 20℃; for 1.5h;
To a mixture of 2-chloro-4,6-dimethoxyl,3,5-triazine (88 mg, 0.50 mmol, 1 equiv), furan-2-ylboronic acid (84 mg, 0.75 mmol, 1.5 equiv), and K3P045H20 (0.45 mg, 1.5 mmol, 3 equiv) was added THF (400 jiL) then a THF stock solution of 3 and PAd3 (100 iL, 0.25 imol of Pd/PAd3). The mixture was stirred at room temperature for 1.5 h. The reaction mixture was diluted with ethyl acetate then extracted with water. The combine organic layers were evaporatedand the crude product was purified by flash chromatography. After drying, 93 mg (90%) of 38 was obtained as a white solid.‘H NMR (501 MHz, CDC13) 7.64 - 7.59 (m, 1H), 7.44 (d, J 3.5 Hz, 1H), 6.53 (dd, J= 3.4, 1.7 Hz, 1H), 4.03 (s, 6H).13C{’H} NMR (126 MHz, CDC13) ö 172.6, 166.5, 150.1, 146.6, 117.4, 112.5, 55.2.HRMS (ESI) m/z calculated for C9H9N303 (M+1) 208.0717, found 208.0706.
With potassium carbonate sesquihydrate; tris(1-adamantyl)phosphine; C28H26N2O8Pd2S2 In tetrahydrofuran at 20℃; for 5h; Inert atmosphere; Schlenk technique;
93%
With potassium carbonate sesquihydrate; tris(1-adamantyl)phosphine; {2-[((acetyl-κO)amino)phenyl-κC](tri-1-adamantylphosphine)palladium}(p-toluenesulfonate) In tetrahydrofuran at 20℃; for 5h; Inert atmosphere;
To a mixture of 2-chloro-4,6-dimethoxy-l,3,5-triazine (88 mg, 0.50 mmol, 1 equiv), 2,6- difluorophenylboronic acid (118 mg, 0.75 mmol, 1.5 equiv), and K2C031.5H20 (0.25 g, 1.5 mmol, 3 equiv) was added THF (300 tL) then a THF stock solution of 3and PAd3 (200 tL inTHF,0.5 imol) and the mixture was stirred at room teperature for 5 h. The reaction mixture was diluted with ethyl acetate then extracted with water. The combine organic layers were evaporatedand the crude product was purified by flash chromatography. After drying, 118 mg (93 %) of 11 was obtained as a white solid.1H NMR (501 MHz, CDC13) ö 7.39 (tt, J 8.4, 6.2 Hz, 1H), 7.02 - 6.93 (m, 2H), 4.07 (s, 6H). ‘3C{’H}{’H} NMR (126 MHz, CDC13) 172.5, 170.6 (t, J 1.6 Hz), 160.6 (dd, J 255.1, 6.0Hz), 131.9 (t,J 11.3 Hz), 115.4 (t,J 16.4 Hz), 111.9 (dd,J 20.2, 5.0 Hz), 55.5. HRMS (ESI) m/z calculated for C11H9F2N302 (M+1) 254.0736, found254.0722.
With 4-methyl-morpholine In N,N-dimethyl-formamide at 20℃; Inert atmosphere;
5 [0052] Example 5: Preparation of Micafungin
[0052] Example 5: Preparation of MicafunginTo a stirred solution of PPIB (1 gm, 2.84 mmol), CDMT (0.6 gm, 3.41 mmole) and FR 179642 (2.66 g, 2.84 mmol) in DMF (20 mL) was charged NMM ( 0.96mL, 8.5 mmol, 3 eq.) at room temperature. The mixture was allowed to stir for overnight at room temperature. The reaction mixture was filtered, the filtrate was charged slowly in diisopropyl ether. The precipitated white solid was filtered and washed successively with ether and suck dried. Obtained solid stirred with acetonitrile (5 vol.) for 15 mm. at RT and filtered and dried under vacuum.
bis(4,6-dimethoxy-1,3,5-triazine-2-yl)isophthalate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34%
With 4-methyl-morpholine In 1-methyl-pyrrolidin-2-one at 0℃; for 0.25h; Inert atmosphere;
Synthesis of triazine-based active ester 2
The isophthalic acid 2.08g (12.5mmol), 4.83g (27.5mmol) of 2-chloro-4,6-dimethoxy- 1,3,5-triazine, and 50 mL of N-methyl-2-pyrrolidone were added to the flask furnished with a thermometer, a nitrogen introducing pipe, and a stirrer, and it cooled at 0 degree C. Then, it was dropped under stirring of 3.79 g (37.5mmol) of N-methyl morpholines, and was made to react for 15 minutes, and the reaction mixture of the bis(4,6 dimethoxy- 1,3,5-triazine 2-yl)isophthalate (IPBT) denoted by a following formula (17) was obtained.This reaction mixture was fed into 500 mL of distilled water, and a depositing output was filtered. Ethyl acetate and the mixed solvent of n-hexane performed recrystallization, and it performed reduced pressure drying at the room temperature. The colorless powdered crystal of IPBT was obtained (34% of yield).
23%
With 4-methyl-morpholine; 1-methyl-pyrrolidin-2-one In water at 0℃; for 0.25h; Inert atmosphere;
A thermometer, and a nitrogen inlet tube, an agitator is installed in a flask, 4. 2 part of isophthalic acid and 9.7 part of 2-chloro -4, 6-dimethoxy -1, 3, 5-triazine and 100 part of N-methyl-2-pyrrolidone at 0 °C cooling is added. Thereafter,7. 6 parts of N-methyl morpholine along with water under agitation, reacting the 15 minutes, following eq. (3) Triazine active ester of a dicarboxylic acid represented by reaction is obtained. The reaction liquid is thrown in 1000 parts of ion-exchanged water, filtered product is precipitated, and n-hexane solvent mixture of ethyl acetate is re-crystallization, drying, white powder of activated ester of a dicarboxylic acid having a triazine resin powder 1 (yield 23%)is obtained.
bis(4,6-dimethoxy-1,3,5-triazin-2-yl)-4,4'-oxybisbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
With 4-methyl-morpholine In 1-methyl-pyrrolidin-2-one at 0℃; for 0.25h; Inert atmosphere;
Synthesis of triazine-based active ester 1
In a flask equipped with a thermometer, a nitrogen inlet tube and a stirrer, 6.45 g (25 mmol) of oxydibenzoic acid (diphenyl ether-4,4'-dicarboxylic acid), 9.69 g (55 mmol) of 2-chloro-4,6- dimethoxy-1,3,5-triazine and N -methyl-2-pyrrolidone was added, and the mixture was cooled to 0 ° C. Thereafter, 7.6 g (75 mmol) of N-methylmorpholine was added dropwise with stirring and reacted for 15 minutes to obtain bis (4,6-dimethoxy-1,3,5-triazin- -yl) 4,4'-oxybisbenzoate (OBBT) was obtained.This reaction mixture was fed into 500 mL of distilled water, and a depositing output was filtered. Ethyl acetate and the mixed solvent of n-hexane performed recrystallization, and it performed reduced pressure drying at the room temperature. The colorless powdered crystal of OBBT was obtained (48% of yield).
43%
With 4-methyl-morpholine; 1-methyl-pyrrolidin-2-one In water at 0℃; for 0.25h; Inert atmosphere;
A thermometer, and a nitrogen inlet tube, an agitator is installed in a flask, 6.5 part of 4,4'-diphenyl ether dicarboxylic acid and 9.7 part of 2-chloro -4, 6-dimethoxy -1, 3, 5-triazine and 100 part of N-methyl-2-pyrrolidone at 0 °C cooling is added. Thereafter,7. 6 parts of N-methyl morpholine along with water under agitation, reacting the 15 minutes, following eq. (4) Triazine active ester of a dicarboxylic acid represented by reaction is obtained. The reaction liquid is thrown in 1000 parts of ion-exchanged water, filtered product is deposited, a mixture of ethyl acetate and n-hexane is a solvent, drying the white powder of activated ester of a dicarboxylic triazine resin powder 2 (yield 43%)is obtained.
2-(acetamido)-4-chloro-6-methoxy-1,3,5-triazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31%; 28%; 4%
Acetamide (27 mg, 0.46 mmol) in THF (600 muL) was added to a suspension of sodium hydride (20 mg, 0.51 mmol) in THF (300 muL) at 0 C. After stirring for 45 min at 50 C, the reaction mixture was cooled to 0 C. A THF (200 muL) solution of <strong>[3638-04-8]2,4-dichloro-6-methoxy-1,3,5-triazine</strong> (6, 100 mg, 0.56 mmol) was added dropwise to the resulting suspension, and the mixture was stirred for 2 h at 0 C. To the mixture was added CH2Cl2 and 1 M KHSO4at 0 C. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane/EtOAc 9:1 to 1:1) to afford I (4 mg, 4%), 2-acetamido-4,6-dichloro-1,3,5-triazine (7a) (27 mg, 28%), CDMT (25 mg, 31%), and 6 (18 mg, 18% recovery).
With 4-methyl-morpholine In tetrahydrofuran at 0 - 25℃; for 2.5h;
1.1 Example 1(1R, 3aR, 4aR, 6R, 8aR, 9S, 9aS) -9 - [(4,6-dimethoxy-1,3,5-triazin-2-yl) oxyCarbonyl] -1-methyl-3-oxododecaphthalene [2,3-c] furan-6-yl] urethane 8
2.69 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine was weighedWas dissolved in 25 mL of tetrahydrofuran,Cooled to 0 ° C with stirring,1.55 g of N-methylmorpholine was added,Slowly dropping oxaliplatin sulfate intermediate carboxylic acid 2Tetrahydrofuran solution (30 mL)(Containing 4.95 g of wolapramine sulfate intermediate carboxylic acid 2),Drop finished,Slowly returned to 25 ° C reaction,After 2.5 h reaction,Filter,And use100 mL of tetrahydrofuran,Collecting filtrate and washing liquid,Concentrated under reduced pressure to dry,After dissolving with 50 mL of ethyl acetate10% citric acid washed 3 times,Each time 25mL,And then washed once with 25 mL of sodium bicarbonate,Washed once again with purified water,The organic layer was collected and dried over anhydrous sodium sulphate overnight,The next day,Filter,And washed with ethyl acetate,Collecting filtrate and washing liquid,Concentrated under reduced pressure and dried to constant weight,To give the target compound 8,6.85 g of a white solid, yield: 98.1%
N-(4,6-diphenylpyrimidin-2-yl)-4,6-dimethoxy-1,3,5-triazin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In acetone; for 8h;Reflux;
4,6-Diphenylpyrimidin-2-amine (0.01 mol) and 2-chloro-4,6- dimethoxy-1,3,5-triazine (0.01 mol) were taken in round bottom flask and dissolved in dry acetone (50 mL). The reaction mixture was refluxed for 8 h. After checking the TLC, the reaction mixture was poured into ice-cold water. Neutralization of HCl was done by sodium carbonate solution (0.005 N, 10 mL water). The solid was filtered, washed and dried. Spectral data for compound 3: The IR of compound 3 exhibited nu(N-H) = 3500-3300 cm-1 (N-H str. due to 2 amines), nu(C=C) =1633.76 cm-1 (-C=C- str. in aromatic ring), nu(C-O-C)stretching = 1222.91 cm-1 (C-O-C in ether), nu(C-N) stretching= 802.41 cm-1, nu(C-H)(sp2) stretching = 3150-2950; 1H NMR (400 MHz, DMSO-d6) delta ppm: 3.33 (s, 6H, -2OCH3), 6.5 (s,1H (C-H), pyrimidine ring), 7.38-7.42 (m, 10H, Ar-H).
Method One: Compound of formula (1) (0.1 mol), base (0.1-0.2 mol),Compound (5) (0.1-0.15 mol) and solvent (150 mL) were stirred for 2-8 hours. filter,Wash and dry to give the compound of formula (I) in 70-95% yield;_Prepared according to general method I using triethylamine in dichloromethane to give (I-2) as a white solid.Yield 95%
3-chloro-4-((4,6-dimethoxy-1,3,5-triazin-2-yl)thio)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28%
With sodium methylate In methanol for 5h; Reflux;
General procedure: For the synthesis of 6-14 to 6-21, intermediate 4 (2.4 mmol),intermediate 3 (1.6 mmol) and sodium methoxide (4.8 mmol) were added to 40 mL methanol. The reaction proceeded for 5 h under reflux and the mixture was then vacuumed to get rid of the solvent.The crude product was further extracted three times by using sodium hydroxide solution and ethyl acetate. The aqueous layer was then adjusted by hydrochloric acid to a pH value of 3-4. The product was extracted by ethyl acetate and finally purified by flash column chromatography using dichloromethane/methanol (80:1)and the yields were in the range of 10%-28%.
With caesium carbonate In water; N,N-dimethyl-formamide at 80℃; for 18h; Reflux;
3.23. 4,6-dimethoxy-1,3,5-triazine-2-carbonitrile (2x)
A round-bottomed flask (10 mL) was charged with 2-Chloro-4,6-dimethoxy-1,3,5-triazine (1.5 mmol, 0.263 g), Cs2CO3 (1.5mmol, 0.488 g), the catalyst (0.0075 g, 1.7 mol%) and 1:1 (V/V)DMF/H2O(5 mL). The reaction mixture was refluxed and then K4[Fe(CN)6] (0.60mmol, 0.253 g) was then added. The final mixture was stirred for 18 h at 80 °C. After cooling and filtering the reaction mixture on short package of celite, solvent were removed at reduced pressure and the crude product was purified by column chromatography on silica gel using dichloromethane-ethanol 60:2 (v/v) as the eluents to afford the pure product. Yield: 73%. Light yellow solid. M.p. 143-146oC.1H-NMR (250 MHz, DMSO-d6/TMS) δ (ppm): 3.95 (s, 6H, OCH3).13C-NMR (100 MHz, CDCl3/TMS) δ (ppm): 55.9, 60.4, 171.1, 171.2, 174.1. IR (KBr, cm-1): 3016, 2962, 2723, 2245, 1612, 1573, 1465, 1365, 1296, 1203, 1141, 995, 948, 810, 740, 640, 586, 470.Anal.Calcd.for C6H6N4O2 (166.19): C, 43.38; H, 3.64; N, 33.72. Found: C, 43.31; H, 3.58; N, 33.64.
Stage #1: 2-chloro-4,6-dimethoxy-1 ,3,5-triazine; 2-(2-Aminoethoxy)ethanol In acetonitrile at 0℃; for 1h;
Stage #2: With sodium hydrogencarbonate In acetonitrile at 83℃; for 16.5h;
3.3.1. Synthesis of 2-(2-((4,6-Dimethoxy-1,3,5-triazin-2-yl)amino)ethoxy)ethan-1-ol
To a round-bottomed ask containing 2-chloro-4,6-dimethoxy-1,3,5-triazine 4 (435 mg, 3.28 mmol)in acetonitrile (10 mL) at 0 °C was added dropwise a solution of 2-(2-aminoethoxy)ethanol 1 (240 mg,2.28 mmol) in acetonitrile (5 mL) for a period of 1 h. The reaction solution was then mixed withNaHCO3 (210 mg, 2.51 mmol). The progress of this nucleophilic aromatic substitution reaction couldbe readily monitored by TLC and was proceeded at 83 C for a total of 16.5 h.After the reaction, salts formed were filtered and the solution was concentrated in vacuo for30 min. The crude product was then mixed with dichloromethane (30 mL), and the resulting solutionwas extracted with 10 wt% sodium bicarbonate (15 mL 3). The organic layer collected was dried overanhydrous Na2SO4, filtered and concentrated under reduced pressure and in vacuo for another 3 h.Purication was done by silica gel column chromatography (ethyl acetate /hexane = 1:3 to 1:0, v/v) andthe desired compound, 2-(2-((4,6-dimethoxy-1,3,5-triazin-2-yl)amino)ethoxy)ethan-1-ol was isolated asa white solid (438 mg, 80% yield).
With lithium perchlorate In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere;
4.1.15. Representative procedure for synthesis of ammonium salts 11: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium perchlorate (11a)
To a THF solution (20 mL) of CDMT (878 mg, 5.0 mmol) and LiClO4 (585 mg, 5.5 mmol), NMM (605 mL, 5.5 mmol) was added dropwise under a N2 atmosphere at rt. After stirring for 30 min, the solvent was removed by decantation and the residue was washed with THF. Repetition of this washing process afforded the title compound (1.57 g, 92% yield) as a white solid. 1H NMR (400 MHz,CD3CN/TMS): d 4.46 (d, J 9.6 Hz, 2H), 4.13 (s, 6H), 4.04e3.98 (m,2H), 3.79-3.70 (m, 4H), 3.41 (s, 3H); 13C NMR (100 MHz, CD3CN):174.99, 171.20, 62.76, 61.09, 57.82, 56.94; HRMS (DART) m/z:[M ClO4] Calcd for C10H17N4O3 241.1301; Found: 241.1246.
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 24.1h;
In a 1000ml three-necked round bottom flask equipped with a mechanical stirrer, thermometer and condenser, add <strong>[610-66-2]2-nitrophenylacetonitrile</strong> (32g, 0.2mol), 2-chloro-4,6-dimethoxy-1,3 5-Triazine (53 g, 0.3 mol), N, N-dimethylformamide (400 mL), stirred for 10 minutes, after the reaction material is dissolved, potassium carbonate (41 g, 0.3 mol) is added, and then the temperature is raised to 90 degrees to react 24 hours.After monitoring the reaction, the system was naturally cooled to room temperature, and the next oxidation operation was directly performed. Under mechanical agitation, 30% hydrogen peroxide (91 g, 0.8 mol) was slowly added dropwise to the system cooled down to room temperature to control the system temperature not to exceed 70 degrees.After the dropwise addition, the mixture was stirred at room temperature for 10 hours. Pour into 500mL of water and stir, the solid is precipitated and filtered directly,Wash the filter cake with a small amount of water to obtain 40 g of solid product (4,6-dimethoxy-1,3,5-triazin-2-yl) (2-nitrophenyl) methanoneThe yield is 70%.
With sodium perchlorate In tetrahydrofuran at 25℃; for 1h;
3.1. Synthesis of DMTTMA(ClO4)
TMA (75 mg, 1.27 mmol) was added to a solution of CDMT (200 mg, 1.14 mmol)and NaClO4 (155 mg, 1.27 mmol) in THF (4 mL) at 25 °C. After stirring for 1 h, the precipitate was collected, washed with THF, and dried under reduced pressure to give DMTTMA(ClO4) as a white solid (340 mg, yield 99%). m.p. 163-168 °C; 1H NMR(300 MHz, D2O, 25 °C): δ= 4.21 (s, 6H), 3.65 ppm (s, 9H); 13C NMR (75 MHz, D2O, 25 °C): δ= 175.2, 173.6, 58.6, 55.7 ppm; IR (KBr): v = 1606, 1531, 1485, 1375, 1052, 825, 624 cm-1.
With potassium carbonate In acetonitrile at 80℃; for 3h; Inert atmosphere;
18.2 Step 2: Preparation of 2-(3-(2-chloro-5-fluoro-4-nitrophenoxy)-1 H-pyrazol-1 -yl)-4,6-dimethoxy- 1 ,3,5-triazine
To a solution of 3-(2-chloro-5-fluoro-4-nitrophenoxy)-1 H-pyrazole (250 mg, 0.97 mmol) in MeCN (8 mL) was added 2-chloro-4,6-dimethoxy-1 ,3,5-triazine (170 mg, 0.97 mmol) and K2CO3 (268 mg, 1 .94 mmol). The reaction mixture was stirred at 80 °C for 3 hours under N2 atmosphere. The mixture was concentrated and purified by Combi-Flash (eluted by EA/PE= 1/2) to give product (160 mg, 41 .14%) as a white solid. LC/MS: 396.9 [M+H]+.
41.14%
With potassium carbonate In acetonitrile at 80℃; for 3h; Inert atmosphere;
18.2 Step 2: Preparation of 2-(3-(2-chloro-5-fluoro-4-nitrophenoxy)-1 H-pyrazol-1 -yl)-4,6-dimethoxy- 1 ,3,5-triazine
To a solution of 3-(2-chloro-5-fluoro-4-nitrophenoxy)-1 H-pyrazole (250 mg, 0.97 mmol) in MeCN (8 mL) was added 2-chloro-4,6-dimethoxy-1 ,3,5-triazine (170 mg, 0.97 mmol) and K2CO3 (268 mg, 1 .94 mmol). The reaction mixture was stirred at 80 °C for 3 hours under N2 atmosphere. The mixture was concentrated and purified by Combi-Flash (eluted by EA/PE= 1/2) to give product (160 mg, 41 .14%) as a white solid. LC/MS: 396.9 [M+H]+.
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