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CAS No. : | 3945-69-5 | MDL No. : | MFCD03613550 |
Formula : | C10H17ClN4O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | BMTZEAOGFDXDAD-UHFFFAOYSA-M |
M.W : | 276.72 | Pubchem ID : | 2734059 |
Synonyms : |
|
Num. heavy atoms : | 18 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.7 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 7.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 70.25 |
TPSA : | 66.36 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.09 cm/s |
Log Po/w (iLOGP) : | -3.17 |
Log Po/w (XLOGP3) : | 1.26 |
Log Po/w (WLOGP) : | -3.52 |
Log Po/w (MLOGP) : | -3.56 |
Log Po/w (SILICOS-IT) : | 0.37 |
Consensus Log Po/w : | -1.72 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.4 |
Solubility : | 1.11 mg/ml ; 0.004 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.25 |
Solubility : | 1.55 mg/ml ; 0.00559 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.83 |
Solubility : | 0.406 mg/ml ; 0.00147 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 3.0 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P264-P270-P271-P280-P303+P361+P353-P304+P340-P305+P351+P338-P310-P330-P363-P403+P233-P501 | UN#: | 3261 |
Hazard Statements: | H314-H302 | Packing Group: | Ⅱ |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | at 20℃; | 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. |
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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In dichloromethane; at 20℃; | 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 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; In 1,4-dioxane; water; at 20℃; for 0.25h; | General procedure: To a solution of benzoic acid 1a (2.2 g, 18.0 mmol) and N-methylmorpholine (396 muL, 3.60 mmol) in 1,4-dioxane/H2O(100 mL:50 mL) was added DMT-MM (5.23 g, 18.9 mmol) at room temperature. After stirring for 15 min, a solution ofalanine 2a (1.76 g, 19.8 mmol) and aq 1 M NaOH (19.8 mL, 19.8 mmol) was added. After the reaction was completed(monitored by TLC), N-methylmorpholine (3.96 mL, 36.0 mmol) and DMT-MM (14.9 g, 54 mmol) were added in order.After stirring for 3 h, the reaction mixture was diluted in EtOAc (100 mL) and washed with aq 1 M HCl (40 mL), sat. aqNaHCO3 (40 mL), and brine (30 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reducedpressure. The residue was purified by column chromatography (EtOAc:hexane = 7:3) to give oxazole 3aa in 78% yield.5-((4,6-Dimethoxy-1,3,5-triazin-2-yl)oxy)-4-methyl-2-phenyloxazole (3aa) Yield: 78%. White solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate; at 23 - 29℃; for 0.5h;Conversion of starting material; | 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). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; In 1,4-dioxane; water; at 20℃; for 0.25h; | To a solution of benzoic acid 1a (2.2 g, 18.0 mmol) and N-methylmorpholine (396 muL, 3.60 mmol) in 1,4-dioxane/H2O(100 mL:50 mL) was added DMT-MM (5.23 g, 18.9 mmol) at room temperature. After stirring for 15 min, a solution ofalanine 2a (1.76 g, 19.8 mmol) and aq 1 M NaOH (19.8 mL, 19.8 mmol) was added. After the reaction was completed(monitored by TLC), N-methylmorpholine (3.96 mL, 36.0 mmol) and DMT-MM (14.9 g, 54 mmol) were added in order.After stirring for 3 h, the reaction mixture was diluted in EtOAc (100 mL) and washed with aq 1 M HCl (40 mL), sat. aqNaHCO3 (40 mL), and brine (30 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reducedpressure. The residue was purified by column chromatography (EtOAc:hexane = 7:3) to give oxazole 3aa in 78% yield.5-((4,6-Dimethoxy-1,3,5-triazin-2-yl)oxy)-4-methyl-2-phenyloxazole (3aa) Yield: 78%. White solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; In 1,4-dioxane; water; at 20℃; for 0.25h; | General procedure: To a solution of benzoic acid 1a (2.2 g, 18.0 mmol) and N-methylmorpholine (396 muL, 3.60 mmol) in 1,4-dioxane/H2O(100 mL:50 mL) was added DMT-MM (5.23 g, 18.9 mmol) at room temperature. After stirring for 15 min, a solution ofalanine 2a (1.76 g, 19.8 mmol) and aq 1 M NaOH (19.8 mL, 19.8 mmol) was added. After the reaction was completed(monitored by TLC), N-methylmorpholine (3.96 mL, 36.0 mmol) and DMT-MM (14.9 g, 54 mmol) were added in order.After stirring for 3 h, the reaction mixture was diluted in EtOAc (100 mL) and washed with aq 1 M HCl (40 mL), sat. aqNaHCO3 (40 mL), and brine (30 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reducedpressure. The residue was purified by column chromatography (EtOAc:hexane = 7:3) to give oxazole 3aa in 78% yield.5-((4,6-Dimethoxy-1,3,5-triazin-2-yl)oxy)-4-methyl-2-phenyloxazole (3aa) Yield: 78%. White solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In chloroform; at 0 - 5℃; for 12h; | N- (4, 6-dimethoxy-1, 3, 5-TRIAZIN-2-YLO)-N-METHYLMORPHOLINE CHLORIDE (0.278 g, 1 mmole), cooled down to temperature of 0-5C in 5 mi chloroform was connected with mixture of epimerides of the 4b acid, where R3=H and R4=3, 4-dimethoxyphenyl (0. 433 g, 1 mmole) and mixed for 12 hours. N-METHYLMORPHOLINE chloride was washed off with ice water, and organic phase was dried with MGS04, the drying agent was filtered off and the filtrate was evaporated under reduced pressure until dry. 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 CHC13, RRO. 55 1H-NMR (250 MHz, CDCI3) : B= 3.54 (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) : 1750 [cm-1] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87 - 90%; 12 - 15% | With sodium hydroxide; sodium dihydrogenphosphate; ammonium chloride; at 20℃; for 4h;pH 6.2;Conversion of starting material; | 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). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | In acetonitrile; at 5℃; for 3h;Product distribution / selectivity; | Mixture of 17.8 g (100 mmol) of lithium p-toluenosulfonate and 27.6 g (100 mmol) of N-methyl-N-(3,5-dimethoxy -2,4,6-triazinylo-1)morpholine chloride in 100 ml acetonitrile was cooled down to a temperature approximating to 5C and intensively stirred for 3 hours, next the precipitate was separated by filtration. The precipitate was two times washed with acetonitrile and the collected filtrates were evaporated to dryness under reduced pressure. Dry residue was washed with 50 ml tetrahydrofurane and crystallized from acetonitrile. It was obtained 31.7 g p-toluenosulfonate of N-methyl-N-(3,5-dimethoxy-2,4,6--triazinyl-1-)-morpholine, what equals to 77% yield. The new compound was characterized with the following data: melting point =59-60 C, [] Results of elementary analysis of the formula : C17H24N4O6S (412.47) calculated:%C 49.50,%H 5.87,%N 13.58,%S 7.77found:%C 48.67,%H 5.54,%N 13.61,%S 7.63. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.9% | In acetonitrile; at 20℃; | Step 112.1 : 4,6-Dimethoxy-1 ,3,5-triazin-2-yl 6-hydroxy-1-naphthoate; Add 21.4 g (0.11 mol) of 6-hydroxy-1 -naphthoic acid in to 450 ml_ of acetonitrile, then added33.2 g (0.12 mol) of 4-(4,6-Dimethoxy-[1 ,3,5]triazin-2-yl)-4-methyl-morpholin-4-ium chloride, and stir at room temperature overnight. Add 165 ml_ of water, stir for 5 min, filter, and rinse the cake with 150 mL of water. Dry at room temperature in a vacuum oven to obtain 4,6- dimethoxy-1 ,3r5-triazin-2-yl 6-hydroxy-1-naphthoate 27.22 g (72.9%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.0% | In dichloromethane; water; | Example 100 Into a 100-ml egg plant-type flask were added 2.65 g (0.01 mol) of an N-tert-butoxycarbonylphenylalanine, 1.79 g (0.01 mmol) of a Phenylalaninemethyl ester and 25 ml of a dichloromethane, which were then stirred at room temperature for 10 minutes. Next, into a 200-ml egg plant-type flask were added 27.3 g of the same <strong>[3945-69-5]4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride</strong> (water content of 8.4% by weight and purity of 99.5%) as the one obtained in Example 1 and 72.7 g of water, which were stirred and dissolved at 20 C. to separately prepare the condensing agent of the invention. 11.08 Grams (0.01 mol) of the thus prepared condensing agent of the invention was slowly added to the above 100-ml egg plant-type flask to effect the reaction at room temperature for 3 hours. After the reaction, 25 ml of a dichloromethane was added thereto, and the mixture was washed with 50 ml of water to separate the organic layer which was then dried on magnesium sulfate, condensed and was isolated and refined by using a silica gel column chromatography to obtain 4.05 g of an N-tert-butoxycarbonyl-L-phenylalanyl-L-phenylalaninemethyl ester (yield, 95.0%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With 4-methyl-morpholine; hydrogenchloride; sodium hydroxide; In methanol; diethyl ether; water; | Example 263 Into the 100-ml eggplant-type flask, there were introduced 2.65 g (0.01 mol) of an N-tert-butoxycarbonyl-L-phenylalanine, 1.01 g (0.01 mol) of an N-methylmorpholine and 45 ml of a methanol (water content of 100 ppm), which were, then, stirred for 10 minutes, followed by the addition of 2.77 g (0.01 mol) of a <strong>[3945-69-5]4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride</strong> to conduct the reaction at room temperature for 4 hours. After the reaction, the methanol was distilled off. To the residue was added 50 ml of a diethyl ether, and the mixture was washed with 30 ml of water, 30 ml of 1N hydrochloric acid and 30 ml of an 1N sodium hydroxide aqueous solution. Thereafter, the diethyl ether was distilled off under a reduced pressure, and the residue was isolated and refined through the silica gel column chromatography to obtain 2.60 g of an N-tert-butoxycarbonyl-L-phenylalaninemethyl ester (yield, 93%). |
With 4-methyl-morpholine; hydrogenchloride; In methanol; dichloromethane; water; | Example 84 Into a 100-ml egg plant-type flask were added 5.30 g (0.02 mols) of an N-tert-butoxycarbonyl-L-phenylalanine as a carboxylic acid compound, 2.42 g (0.024 mols) of a 4-methylmorpholine as a tertiary amine compound and 100 ml of methanol as an alcohol compound, which were then stirred at room temperature for 10 minutes. Then, 6.85 g (0.02 mols) of the same <strong>[3945-69-5]4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride</strong> having a water content of 19.1% by weight as the one prepared in Example 5 was added thereto as a condensing agent to effect the reaction at room temperature for 3 hours. After the reaction, methanol was distilled off, 100 ml of water was added thereto, and the extraction operation was conducted twice with 30 ml of a methylene chloride. The separated methylene chloride solution was collected, and the organic layer was washed with 20 ml of a saturated sodium carbonate aqueous solution, 20 ml of a 1N hydrochloric acid and 20 ml of water. The obtained organic layer was dried on magnesium sulfate, condensed and the residue was isolated and refined by using a silica gel column chromatography to obtain 5.36 g of an N-tert-butoxycarbonyl-L-phenylalaninemethyl ester (yield, 96%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In dichloromethane; water; | Example 54 Into a 100-ml egg plant-type flask were added 5.30 g (0.02 mols) of an N-tert-butoxycarbonyl-L-phenylalanine as a carboxylic acid compound, 3.58 g (0.02 mols) of an L-phenylalaninemethyl ester as an amine compound and 50 ml of a methylene chloride as a solvent, which were then stirred at room temperature for 10 minutes. Then, 6.85 g (0.02 mols) of the same <strong>[3945-69-5]4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride</strong> having a water content of 19.1% by weight as the one prepared in Example 5 was slowly added thereto as a condensing agent to effect the reaction at room temperature for 3 hours. After the reaction, 100 ml of water was added thereto to separate the solution. Thereafter, the extraction operation was conducted twice with 30 ml of a methylene chloride. The separated methylene chloride solution was collected, and the organic layer was washed with 30 ml of a saturated sodium carbonate aqueous solution, 30 ml of a 1N hydrochloric acid and 30 ml of water. The obtained organic layer was dried on magnesium sulfate, condensed and was isolated and refined by using a silica gel column chromatography to obtain 8.18 g of an N-tert-butoxycarbonyl-L-phenylalanyl-L-phenylalaninemethyl ester (yield, 96%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; hydrogenchloride; In methanol; dichloromethane; water; | Example 68 Into a 100-ml egg plant-type flask were added 3.00 g (0.02 mols) of a 3-phenylpropionic acid as a carboxylic acid compound, 2.22 g (0.022 mols) of a 4-methylmorpholine as a tertiary amine compound and 50 ml of methanol as an alcohol compound, which were then stirred at room temperature for 10 minutes. Then, 6.35 g (0.02 mols) of the same <strong>[3945-69-5]4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride</strong> having a water content of 12.8% by weight as the one prepared in Example 4 was added thereto as a condensing agent to effect the reaction at room temperature for 4 hours. After the reaction, methanol was distilled off, 100 ml of water was added thereto, and the extraction operation was conducted twice with 30 ml of a methylene chloride. The separated methylene chloride solution was collected, and the organic layer was washed with 20 ml of a saturated sodium carbonate aqueous solution, 20 ml of a 1N hydrochloric acid and 20 ml of water. The obtained organic phase was dried on magnesium sulfate, the methylene chloride was distilled off, and the residue was isolated and refined by using a silica gel column chromatography to obtain 3.05 g of a methyl 3-phenylpropionate (yield, 93%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; benzyl alcohol; In tetrahydrofuran; hydrogenchloride; dichloromethane; water; | Example 98 Into a 100-ml egg plant-type flask were added 3.00 g (0.02 mols) of a 3-phenylpropionic acid as a carboxylic acid compound, 6.06 g (0.06 mols) of a 4-methylmorpholine as a tertiary amine compound, 2.38 g (0.022 mols) of a benzyl alcohol as an alcohol compound and 50 ml of a tetrahydrofurane as a solvent, which were then stirred at room temperature for 10 minutes. Then, 6.85 g (0.02 mols) of the same <strong>[3945-69-5]4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride</strong> having a water content of 19.1% by weight as the one prepared in Example 5 was added thereto as a condensing agent to effect the reaction at room temperature for 24 hours. After the reaction, tetrahydrofurane was distilled off, 100 ml of water was added thereto, and the extraction operation was conducted twice with 30 ml of a methylene chloride. The separated methylene chloride solution was collected, and the organic layer was washed with 20 ml of a saturated sodium carbonate aqueous solution, 20 ml of a IN hydrochloric acid and 20 ml of water. The obtained organic phase was dried on magnesium sulfate, the methylene chloride was distilled off, and the residue was isolated and refined by using a silica gel column chromatography to obtain 4.51 g of a benzyl 3-phenylpropionate (yield, 94%). |
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 0.3% 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). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With hydrogenchloride; In ethanol; water; ethyl acetate; | 3-[(Methoxycarbonyl)amino]-N-para-[4-(trifluoromethyl)phenoxy]phenyl-isoxazole-5-carboxamide (44) A mixture of 0.162g (0.75mmol) of 3-(methoxycarbonyl)amino-4-methoxy-isoxazole-5-carboxylic acid, 0.172g (0.68mmol) of 4-[4-(trifluoromethyl) phenoxy]aniline and 0.212g (0.75mmol) of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride in 5ml of ethanol is heated at 70C for 6 hours, and then stirred at room temperature for 16 hours. After evaporation of the ethanol, the residue is taken up in ethyl acetate and the resulting solution is washed successively with a saturated solution of sodium hydrogenocarbonate, water, 2% solution of hydrochloric acid, and water. After drying and concentrating, the residue is chromatographed (ethyl acetate/heptane, 2:8) to give 0,122g (37% yield) of a cream solid (M+1 = 452). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N-methyl-acetamide; di-isopropyl ether; acetonitrile; | EXAMPLE 7 Preparation of N,N'-bis(4-dimethylamino-2-methylquinolin-6-yl)-terephthalamide 4-(4,6-Dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (177 mg) is added to a solution of 48 mg (0.29 mmol) of terephthalic acid and 128 mg (0.64 mmol) of 4-dimethylamino-6-aminoquinaldine in 6 mL of dimethylformamide, at a temperature in the region of 20 C. The mixture obtained is stirred at a temperature in the region of 20 C. for about 12 hours. The reaction mixture is successively taken up in 2 mL of acetonitrile and 2 mL of diisopropyl ether, and the precipitate thus obtained is slowly filtered on a 6 mL BOND-ELUT cartridge filled with sintered material. The insoluble matter obtained is washed with diisopropyl ether and then dried under argon. 154 mg of N,N'-bis(4-dimethylamino-2-methylquinolin-6-yl)-terephthalamide are thus obtained in the form of a beige powder of whose characteristics are the following: 1H NMR spectrum (400 MHz, (CD3)2SO d6, at a temperature of 373K, delta in ppm): 2.70 (s: 6H); 3.44 (s: 12H); 6.87 (s: 2H); 7.98 (d, J=9 Hz: 2H); 8.23 (s: 4H); 8.27 (dd, J=9 and 1.5 Hz: 2H); 8.94 (broad s: 2H); 10.64 (broad s: 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N-methyl-acetamide; di-isopropyl ether; | EXAMPLE 18 Preparation of N,N'-bis(4-dimethylamino-2-methylquinolin-6-yl)but-2-enediamide 4-(4,6-Dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (61 mg, 0.22 mmol) and then 44.3 mg (0.22 mmol) of 4-dimethylamino-6-amino-quinaldine are successively added to a solution of 11.6 mg (0.1 mmol) of fumaric acid in 2 mL of dimethylformamide, at a temperature in the region of 20 C. The mixture obtained is stirred at a temperature in the region of 20 C. for about 19 hours. The reaction mixture is filtered on sintered glass with a No. 3 porosity, and then washed with 2 mL of diisopropyl ether. The crude material thus obtained is solubilized in a (dichloromethane/2M ammoniacal methanol) (90-10 by volume) mixture and then deposited on a 20*20 MERCK preparative plate with the reference 1.05744 having a thickness of 0.5 mm. After elution in the (dichloromethane/2M ammoniacal methanol) (90-10 by volume) mixture, the product is isolated by taking up the silica with a (dichloromethane/methanol) (80-20 by volume) mixture. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at 40 C.; 19 mg of N,N'-bis(4-dimethylamino-2-methylquinolin-6-yl)but-2-enediamide are Thus Obtained in the Form of an Orange-Colored Solid Whose Characteristics are the Following: 1H NMR spectrum (400 MHz, (CD3)2SO d6, delta in ppm): 2.56 (s: 6H); 3.00 (s: 12H); 6.81 (s: 2H); 7.31 (s: 2H); 7.82 (d, J=9 Hz: 2H); 7.85 (dd, J=9 and 1.5 Hz: 2H); 8.61 (broad s: 2H); 10.79 (broad s: 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; at 20 - 25℃; for 0.166667h; | Into a round bottom flask, tetrahydrofuran (25 ml), N-I(S)- carboxyethylbutyl-(S)-alanine (1.Og) and 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4- methylmorpholinium chloride (1.274 g) were added. The reaction mass was stirred for about 10 minutes at a temperature ranging from about 200C to about 25C under nitrogen. The resulting solution contained the complex of Formula II. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N-methyl-acetamide; toluene; | EXAMPLE 21 Preparation of N,N'-bis(4-dimethylamino-2-methylquinolin-6-yl)-1,4-phenylenediacetamide 4-(4,6-Dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (91.3 mg, 0.33 mmol) and then 66.4 mg (0.33 mmol) of 4-dimethylamino-6-amino-quinaldine are successively added to a solution of 29.1 mg (0.15 mmol) of 1,4-phenylenediacetic acid in 2 mL of dimethylformamide, at a temperature in the region of 20 C. The mixture obtained is stirred at a temperature in the region of 20 C. for about 18 hours. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at 40 C. The residue obtained is taken up in 5 mL of toluene and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 C. The yellowish solid thus obtained is purified by FLASH chromatography on a BOND-ELUT cartridge (27 mm in diameter) filled with 25 g of conditioned silica (15-35 mum) and then eluted with a (dichloromethane/2M ammoniacal methanol) (90-10 by volume) mixture at a flow rate of 10 mL per minute. The fractions between 180 and 250 mL are combined and concentrated to dryness under reduced pressure (2.7 kPa) to 40 C. 40 mg of N,N'-bis-(4-dimethylamino-2-methylquinolin-6-yl)-1,4-phenylenediacetamide are thus obtained in the form of a foam whose characteristics are the following: 1H NMR spectrum (300 MHz, (CD3)2SO d6, delta in ppm): 2.51 (s: 6H); 2.93 (s: 12H); 3.69 (s: 4H); 6.76 (s: 2H); 7.04 (s: 4H); 7.71 (dd, J=9 and 2.5 Hz: 2H); 7.77 (d, J=9 Hz: 2H); 8.49 (d, J=2.5 Hz: 2H); 10.40 (broad s: 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | In N,N-dimethyl-formamide; | Example 394 Production of N-[3-({2-[(3-hydroxypropanoyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide To a solution of N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.362 mmol) and 3-hydroxypropanoic acid (131 mg, 0.435 mmol) in N,N-dimethylformamide (5 mL) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (160 mg, 0.544 mmol), and the mixture was stirred at room temperature for 16 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70?100/0) and precipitated from ethanol to give the title compound (30 mg, 17%) as a pale-green powder. 1H-NMR (CDCl3, 300 MHz) delta 2.63-2.70 (2H, m), 3.73 (1H, brs), 3.96-4.03 (2H, m), 6.89 (1H, d, J=9.4 Hz), 7.01-7.07 (1H, m), 7.42-7.48 (2H, m), 7.59-7.86 (4H, m), 7.95 (1H, s), 8.07 (1H, d, J=7.9 Hz), 8.11-8.17 (2H, m), 8.54 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; for 0.166667h;Product distribution / selectivity; | 5 g of 4-(4-methylpiperazinyl-methyl) benzoic acid dihydrochloride hemihydrate were added to the reaction mixture. All solid material was completely dissolved after10 minutes forming slightly yellow clear solution.; | |
In water; acetonitrile; at 20 - 25℃; for 0.75h;Product distribution / selectivity; | 1O g of 4-(4-methylpiperazinyl-methyl) benzoic acid dihydrochloride hemihydrate dissolved in50 ml of water were subsequently added to the reaction mixture at 20-25 0C. Suspension turned to a clear homogeneous solution after 15 minutes of vigorous stirring. Reaction mixture was stirred for 0.5 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium nitrate; | Example 10 Preparation of HA Derivative Modified with 2-Aminoethyl Cholesteryl Disulfide An anhydrous DMSO solution (10 mg/mL) of HA-TBA prepared by the same procedure as in Example 2-2 using HA-Na (Shiseido Co., Ltd.) having a molecular weight of 10 kDa as a raw material was prepared. Then, 2-aminoethyl 2-pyridyl disulfide hydrochloride (Py-SS-AM, Toronto) was added to each solution at the ratio relative to HA-TBA units indicated in Table 9 below. Thereafter, <strong>[3945-69-5]4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride</strong> (DMT-MM) was added at the ratio relative to HA-TBA units indicated in Table 9 below and stirred overnight at room temperature. Then, thiocholesterol (Chol-SH, Sigma Aldrich) was added at the ratio indicated in Table 9 below and stirred overnight at room temperature. Sodium nitrate was added to the reaction solution to 0.3 M, and isopropyl alcohol (IPA) was added. The resulting precipitate was recovered, washed with IPA, and then dried under reduced pressure to give an intended product (HA-SS-Chol) as a white solid. The 1H-NMR spectrum as measured under the same conditions as those in Example 2-3-1 is shown in . The introduction ratio of cholesteryl groups relative to HA units calculated according to the formula indicated in Example 2-3-1 is shown in Table 9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | In tetrahydrofuran; | Example (Ik-233) N-[4-Chloro-3-(cyclopropylcarbamoyl)phenyl]-3-[cyclopropyl(fluoro)methyl]-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 515 mg (1.86 mmol) of <strong>[3945-69-5]4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride</strong> are added to a solution of 410 mg (1.55 mmol) of 3-[cyclopropyl(hydroxy)methyl]-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid and 327 mg (1.55 mmol) of 5-amino-2-chloro-N-cyclopropylbenzamide in tetrahydrofuran (10 ml) and the mixture is stirred for six hours at room temperature. The reaction mixture is concentrated by evaporation, admixed with water, extracted with dichloromethane and the combined organic phases are dried over sodium sulphate. Following concentration by evaporation in vacuo, the solid is washed with dichloromethane to give 308 mg of (N-[4-chloro-3-(cyclopropylcarbamoyl)phenyl]-3-[cyclopropyl(hydroxy)methyl]-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (44%). 1H-NMR (400 MHz, d6-DMSO): delta=11.10 (s, 1H), 8.30 (d, 1H), 7.67 (m, 2H), 7.45 (d, 1H), 5.12 (br. s, 1H), 4.02 (br. d, 1H), 3.84 (s, 3H), 2.83 (m, 1H), 1.36 (m, 1H), 0.77 (m, 2H), 0.51 (m, 3H), 0.44 (m, 2H), 0.20 (m, 1H) ppm. HPLC-MSa): log P=2.00; mass (m/z) 439 [M-H2O+H]+. |
Tags: 3945-69-5 synthesis path| 3945-69-5 SDS| 3945-69-5 COA| 3945-69-5 purity| 3945-69-5 application| 3945-69-5 NMR| 3945-69-5 COA| 3945-69-5 structure
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