| 96.3% |
With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 20 - 65℃; for 22 h; |
(Preparation Example 3) Preparation (3) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide
7-Methoxy-4-chloroquinoline-6-carboxamide (5.00 kg, 21.13 mol), dimethyl sulfoxide (55.05 kg), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (5.75 kg, 25.35 mol) and potassium t-butoxide (2.85 kg, 25.35 mol) were introduced in this order into a reaction vessel under a nitrogen atmosphere.
The mixture was stirred for 30 min at 20 °C, and the temperature was raised to 65 °C over 2.5 hours.
The mixture was stirred at the same temperature for 19 hours. 33percent (v/v) acetone-water (5.0 L) and water (10.0 L) were added dropwise over 3.5 hours.
After the addition was completed, the mixture was stirred at 60 °C for 2 hours. 33percent (v/v) acetone-water (20.0 L) and water (40.0 L) were added dropwise at 55 °C or more over 1 hour.
After stirring at 40 °C for 16 hours, precipitated crystals were collected by filtration using a nitrogen pressure filter, and was washed with 33percent (v/v) acetone-water (33.3 L), water (66.7 L), and acetone (50.0 L) in that order.
The obtained crystals were dried at 60 °C for 22 hours using a conical vacuum dryer to give 7.78 kg of the titled compound (yield: 96.3percent).
Further, all of the 1H-NMR chemical sift values of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide prepared in Preparation Examples 1 to 3 described above agreed with those of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide described in.
|
| 88% |
With caesium carbonate In dimethyl sulfoxide at 70℃; for 23 h; |
To dimethylsulfoxide (20 mL) were added 7-methoxy-4-chloro-quinoline-6-carboxamide (0.983 g), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (1.13 g) and cesium carbonate (2.71 g), followed by heating and stirring at 70°C for 23 hours. After the reaction mixture was allowed to cool down to room temperature, water (50 mL) was added, and the produced crystals were collected by filtration to give 1.56 g of the title compound (88percent yield). 1H-NMR(d6-DMSO): 0.41(2H, m), 0.66(2H, m), 2.56(1H, m), 4.01(3H, s), 6.51(1H, d, J=5.6Hz), 7.18(1H, d, J=2.8Hz), 7.23(1H, dd, J=2.8, 8.8Hz), 7.48(1H, d, J=2.8Hz), 7.50(1H, s), 7.72(1H, s), 7.84(1H, s), 7.97(1H, s), 8.25(1H, d, J=8.8Hz), 8.64(1H, s), 8.65(1H, d, J=5.6Hz) |
| 88% |
With caesium carbonate In dimethyl sulfoxide at 70℃; for 23 h; |
(3) Preparation of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide ; To dimethyl sulfoxide (20 mL) were added 7-methoxy-4-chloroquinoline-6-carboxamide (0.983 g), ;1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (1.13 g) and cesium carbonate (2.71 g), and the mixture was heated and stirred at 70 °C for 23 hours. The reaction mixture was cooled to room temperature, and water (50 mL) was added, and the resultant crystals were then filtered off to give 1.56 g of the titled compound (yield: 88percent). |
| 88% |
With caesium carbonate In dimethyl sulfoxide at 70℃; for 23 h; |
(3)
Preparation of 4-(3-chloro-4-5 (cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide
To dimethylsulfoxide (20 mL) were added 7-methoxy-4-chloroquinoline-6-carboxamide (0.983 g), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (1.13 g) and cesium carbonate (2.71 g), followed by heating and stirring at 70° C. for 23 hours.
After the reaction mixture was allowed to cool down to room temperature, water (50 mL) was added, and the produced crystals were collected by filtration to give 1.56 g of the titled compound (88percent yield).
|
| 88% |
With caesium carbonate In dimethyl sulfoxide at 70℃; for 23 h; |
To DMSO (20 mL) were added 7-methoxy-4-chloro-quinoline-6-carboxamide (0.983 g), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (1.13 g) and cesium carbonate (2.71 g), and the mixture was heated and stirred at 70° C. for 23 hours. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the resultant solid was then filtered off to give 1.56 g of the titled compound (yield: 88percent). 1H-NMR (d6-DMSO): 0.41 (2H, m), 0.66 (2H, m), 2.56 (1H, m), 4.01 (3H, s), 6.51 (1H, d, J=5.6 Hz), 7.18 (1H, d, J=2.8 Hz), 7.23 (1H, dd, J=2.8, 8.8 Hz), 7.48 (1H, d, J=2.8 Hz), 7.50 (1H, s), 7.72 (1H, s), 7.84 (1H, s), 7.97 (1H, s), 8.25 (1H, d, J=8.8 Hz), 8.64 (1H, s), 8.65 (1H, d, J=5.6 Hz). |
| 88% |
With caesium carbonate In dimethyl sulfoxide at 70℃; for 23 h; |
(3)
Preparation of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide
To dimethyl sulfoxide (20 mL) were added 7-methoxy-4-chloroquinoline-6-carboxamide (0.983 g), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (1.13 g) and cesium carbonate (2.71 g), and the mixture was heated and stirred at 70 °C for 23 hours.
The reaction mixture was cooled to room temperature, and water (50 mL) was added, and the resultant crystals were then collected by filtration to give 1.56 g of the titled compound (yield: 88percent).
|
| 88% |
With caesium carbonate In dimethyl sulfoxide |
(2)
production of 4-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide
TO dimethylsulfoxide (20 mL) were added 7-methoxy-4-chloroquinoline-6-carboxamide (0.983 g), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (1.13 g) and cesium carbonate (2.71 g), and the mixture was stirred at 70° C. for 23 hours.
The mixture was cooled to room temperature, addition of water (50 mL) yielded crystals, and the crystals were filtered off to give the title compound (1.56 g, yield 88percent).
|
| 86.6% |
With caesium carbonate In dimethyl sulfoxide at 85℃; for 12 h; |
Into a 250 ml round bottom three-mouth flask, add 7-methoxy-4-chloroquinoline-6-carboxamide (2.0g, 8 . 4mmol), compound IV (1.9g, 8.4mmol), cesium carbonate (5.5g, 16.9mmol) and dimethylsulfoxide (40 ml). At 85 °C heating and stirring 12 hours. After cooling to room temperature the reaction solution, the addition of water (100 ml), filtering of the crystalline compound 3.1g, the yield of 86.6percent. |
| 51.9% |
With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 26 h; |
Add 15.0 L of N,N-dimethylformamide to the reaction kettle.730.0 g (3.08 mol) of 4-chloro-7-methoxyquinolin-6-carboxamide was added in sequence with stirring.837.0g (3.7mol)1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea and 2.0 kg (6.16 mol) of cesium carbonate,The reaction was stirred at 60 ° C for 26 h, and the reaction was completed by TLC. Stir and cool, and flush the reaction solution to an appropriate amount of water.The crude lenvatinib was filtered, and the content of the compound of the impurity formula I was determined by HPLC to be 0.32percent.27.0 L of methanol was added to the reaction vessel, heated to reflux, and then stirred,The upper step wet product was added to the kettle, dissolved under reflux, and stirred for crystallization. Filtration, the resulting solid was 1.85 g,The yield was 51.9percent, and the purity was 98.3percent, wherein the content of the compound of the impurity formula I was 0.04percent. |
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
