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Product Details of [ 417716-92-8 ]

CAS No. :417716-92-8 MDL No. :MFCD16038644
Formula : C21H19ClN4O4 Boiling Point : -
Linear Structure Formula :- InChI Key :WOSKHXYHFSIKNG-UHFFFAOYSA-N
M.W : 426.85 Pubchem ID :9823820
Synonyms :
E7080;ER-203492-00

Safety of [ 417716-92-8 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 417716-92-8 ]

* 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.

  • Upstream synthesis route of [ 417716-92-8 ]
  • Downstream synthetic route of [ 417716-92-8 ]

[ 417716-92-8 ] Synthesis Path-Upstream   1~15

  • 1
  • [ 417722-93-1 ]
  • [ 1033090-34-4 ]
  • [ 417716-92-8 ]
YieldReaction ConditionsOperation in experiment
88.6%
Stage #1: at 25℃;
Stage #2: With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 85℃;
A solution of 4- (4-amino-3-chlorophenoxy) -7-methoxyquinoline-6-carboxamide (compound g) (1 g, 2.9 mmol) and compound m (0.44 g, 2.9 mmol) followed by DMF (10 ml),Stirring at 25 dissolved,After completely dissolved, N, N'-diisopropylethylamine (0.75 g, 5.8 mmol) was added and the reaction solution was slowly warmed to 85 ° C. The reaction was completed by TLC. Add water (50ml), stir and filter. The filter cake is washed with water and dried to yield levigninib (1.1g) in a yield of 88.6percent. Purity: 98.7percent.
Reference: [1] Patent: CN105985289, 2016, A, . Location in patent: Paragraph 0038; 0039; 0040; 0041; 0042; 0043
  • 2
  • [ 417722-93-1 ]
  • [ 6558-73-2 ]
  • [ 417716-92-8 ]
YieldReaction ConditionsOperation in experiment
89.3% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25 - 80℃; Method 1: Compound D (1.03 g, 3 mmol) was added to the reaction vessel.Compound E1 (0.39 g, 3 mmol),Then DMF (10 ml) was added and stirred to dissolve at 25 ° C.After complete dissolution, N,N'-diisopropylethylamine (0.78 g, 6 mmol) was added.The reaction was slowly warmed to 80 ° C and the reaction was monitored by TLC. Add water (50ml) and stir.Filter, filter cake washed with water, dried,Lenvatinib(1.14g),The yield was 89.3percent.
Reference: [1] Patent: CN108623521, 2018, A, . Location in patent: Paragraph 0064; 0065; 0066; 0068
  • 3
  • [ 765-30-0 ]
  • [ 417716-92-8 ]
YieldReaction ConditionsOperation in experiment
78% With N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole In tetrahydrofuran at 50℃; for 10 h; 4- [3-chloro-4- (benzyloxycarbonyl) amino phenoxy] -7-methoxy-quinoline-6-carboxamide (27.0g, 0.06mol)And N, N'- carbonyldiimidazole (11.5g, 0.07mol) was dissolved in tetrahydrofuran (60mL), with stirring, was added cyclopropylamine (4.0 g of,0.07mol), was added dropwise N, N- diisopropylethylamine (29.2g, 0.23mol), the reaction mixture was stirred for 10 hours at 50 deg.] C, TLC plates to determine the point of completion of the reaction, the reaction solution was concentrated by rotary evaporation to dryness, addition of dilute hydrochloric acid adjusted to neutral by adding ethyl acetate, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, recrystallized from methanol, Sidel cutting imatinib, a pale yellow solid (18.8g), 78.0percent yield.
Reference: [1] Patent: CN105801481, 2016, A, . Location in patent: Paragraph 0031; 0038; 0039; 0040
  • 4
  • [ 417722-93-1 ]
  • [ 1885-14-9 ]
  • [ 765-30-0 ]
  • [ 417716-92-8 ]
YieldReaction ConditionsOperation in experiment
90%
Stage #1: With pyridine In water; N,N-dimethyl-formamide at -20℃; for 3 h; Inert atmosphere
Stage #2: at 8℃; for 15 h; Inert atmosphere
Example 2 4-[3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline-carboxamide (0148) (0149) To a mixture of 26.0 kg of 4-(4-amino-3-chlorophenoxy)-7-methoxy-quinoline-6-carboxamide, 13.2 kg of pyridine, 1.36 kg of water and 196.0 L of N,N-dimethylformamide there was added 26.6 kg of phenyl chloroformate at −20° C. under a nitrogen atmosphere, and the mixture was stirred for 3 hours. Next, 19.4 kg of cyclopropylamine was further added at 8° C. and the mixture was stirred for 15 hours. After adding 13.0 L of water and 261.0 L of acetone to the reaction mixture, the deposited precipitate was filtered. The precipitate was rinsed with acetone, and the obtained solid was dried under reduced pressure to obtain 28.7 kg of a crude product of the title compound (89percent yield). This was crystallized from 359.6 L of 1,3-dimethyl-2-imidazolidinone and 575.0 L of 2-propanol, to obtain 25.7 kg of compound (IV) (90percent yield).
Reference: [1] Patent: US2017/233344, 2017, A1, . Location in patent: Paragraph 0148; 0149
  • 5
  • [ 530-62-1 ]
  • [ 765-30-0 ]
  • [ 417716-92-8 ]
YieldReaction ConditionsOperation in experiment
93.1% With carbon dioxide; triethylamine In dichloromethane at 50℃; for 6 h; To 600 ml of dichloromethane was added 60.0 g of 4- (4-amino-3-chlorophenoxy) -7-methoxyquinoline-6-carboxamide hydrochloride (E), 10.8 g of cyclopropylamine, 51.2 g N, N-carbonyldiimidazole and 47.8 g of triethylamine, CO2, and heated at 50 ° C under reflux for 6 hours.The reaction solution was washed with 900 ml of water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the methanol was recrystallized to give 62.1 g of the title compound (F) as white crystals.(Yield: 93.1percent)
Reference: [1] Patent: CN104876864, 2017, B, . Location in patent: Paragraph 0086; 0087; 0096; 0097
  • 6
  • [ 417721-36-9 ]
  • [ 417716-92-8 ]
YieldReaction ConditionsOperation in experiment
96.3% With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 20 - 65℃; for 22 h; In a reaction vessel were placed 7-methoxy-4-chloro-quinoline-6-carboxamide (5.00 kg, 21.13 mol), dimethylsulfoxide (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) in that order, under a nitrogen atmosphere. After stirring at 20°C for 30 minutes, the temperature was raised to 65°C over a period of 2.5 hours. After stirring at the same temperature for 19 hours, 33percent (v/v) acetone water (5.0 L) and water (10.0 L) were added dropwise over a period of 3.5 hours. Upon completion of the dropwise addition, the mixture was stirred at 60°C for 2 hours, and 33percent (v/v) acetone water (20.0 L) and water (40.0 L) were added dropwise at 55°C or higher over a period of 1 hour. After then stirring at 40°C for 16 hours, the precipitated crystals were collected by filtration using a nitrogen pressure filter, and the crystals were 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 drier to give 7.78 kg of the title compound (96.3percent yield).
96.3% With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 20 - 65℃; for 22 h; Preparation Example 3.; Preparation of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (3) ; 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 filtered off 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).1H-NMR chemical shift values for 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamides obtained in Preparation Examples 1 to 3 corresponded to those for 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide disclosed in WO 02/32872.
96.3% With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 20 - 65℃; for 22 h; Reference Example 3
Preparation of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide
In a reaction vessel were placed 7-methoxy-4-chloroquinoline-6-carboxamide (5.00 kg, 21.13 mol), dimethylsulfoxide (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) in that order, under a nitrogen atmosphere.
After stirring at 20° C. for 30 min, the temperature was raised to 65° C. over a period of 2.5 hours.
After stirring at the same temperature for 19 hours, 33percent (v/v) acetone water (5.0 L) and water (10.0 L) were added dropwise over a period of 3.5 hours.
Upon completion of the dropwise addition, the mixture was stirred at 60° C. for 2 hours, and 33percent (v/v) acetone water (20.0 L) and water (40.0 L) were added dropwise at 55° C. or higher over a period of 1 hour.
After then stirring at 40° C. for 16 hours, the precipitated crystals were collected by filtration using a nitrogen pressure filter, and the crystals were 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 (96.3percent yield).
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.

Reference: [1] Patent: EP1683785, 2006, A1, . Location in patent: Page/Page column 8
[2] Patent: EP1698623, 2006, A1, . Location in patent: Page/Page column 16
[3] Patent: US2007/4773, 2007, A1, . Location in patent: Page/Page column 5
[4] Patent: WO2006/137474, 2006, A1, . Location in patent: Page/Page column 11-12
[5] Patent: EP1797881, 2007, A1, . Location in patent: Page/Page column 13
[6] Patent: EP1683785, 2006, A1, . Location in patent: Page/Page column 8
[7] Patent: EP1698623, 2006, A1, . Location in patent: Page/Page column 15-16
[8] Patent: US2007/4773, 2007, A1, . Location in patent: Page/Page column 5
[9] Patent: WO2006/137474, 2006, A1, . Location in patent: Page/Page column 11
[10] Patent: US2007/117842, 2007, A1, . Location in patent: Page/Page column 7
[11] Patent: EP1797881, 2007, A1, . Location in patent: Page/Page column 13
[12] Patent: US2004/253205, 2004, A1,
[13] Patent: CN106632033, 2017, A, . Location in patent: Paragraph 0028
[14] Patent: CN108299294, 2018, A, . Location in patent: Paragraph 0059-0062
[15] Patent: US2007/117842, 2007, A1, . Location in patent: Page/Page column 7
[16] Patent: US2007/117842, 2007, A1, . Location in patent: Page/Page column 7
  • 7
  • [ 417722-93-1 ]
  • [ 79-22-1 ]
  • [ 765-30-0 ]
  • [ 417716-92-8 ]
YieldReaction ConditionsOperation in experiment
75.8%
Stage #1: With pyridine In N,N-dimethyl-formamide for 0.166667 h;
Stage #2: at 40℃; for 3 h;
Stage #3: at 40℃; for 5 h;
4-(3-Chloro-4-aminophenoxy)-7-methoxy-6-quinolinecarboxamide (5) 1.0 g, pyridine 0.86 g was dissolved in 40 mL of N,N-dimethylformamide, Stir for 10 minutes. To the above reaction liquid, 1.0 g of methyl chloroformate was added. After the addition was completed, the temperature was elevated to 40 ° C and stirred for 3 hours. The reaction solution was cooled to room temperature, and 0.60 g of cyclopropylamine was added. After the dropwise addition was completed, the mixture was heated to 40 ° C and stirred for 5 hours. The reaction solution was poured into 400 mL of water, filtered, and the filter cake was washed with water, and then dried white solid (1) (0.94 g, 75.8percent).
Reference: [1] Patent: CN108658859, 2018, A, . Location in patent: Paragraph 0009; 0034-0036; 0040; 0042
  • 8
  • [ 417722-95-3 ]
  • [ 765-30-0 ]
  • [ 417716-92-8 ]
YieldReaction ConditionsOperation in experiment
80.2% at 20℃; Preparation Example 1. Preparation of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-duinolinecarboxamide (1); Phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (17.5g, 37.7 mmol) disclosed in WO 02/32872 was dissolved in N,N-dimethylformamide (350 mL), and then cyclopropylamine (6.53 mL, 94.25 mmol) was added to the reaction mixture under a nitrogen atmosphere, followed by stirring overnight at room temperature. To the mixture was added water (1.75L), and the mixture was stirred. Precipitated crude crystals were filtered off, washed with water, and dried at 70 °C for 50 min. To the obtained crude crystals was added ethanol (300 mL), and then the mixture was heated under reflux for 30 min to dissolve, followed by stirring overnight to cool slowly down to room temperature. Precipitated crystals was filtered off and dried under vacuum, and then further dried at 70 °C for 8 hours to give the titled crystals (12.91 g; 80.2percent).
80.2% at 20℃; Reference Example 1
Preparation of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (1)
Phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (17.5 g, 37.7 mmol) disclosed in WO 02/32872 was dissolved in N,N-dimethylformamide (350 mL), and then cyclopropylamine (6.53 mL, 94.25 mmol) was added to the reaction mixture under a nitrogen atmosphere, followed by stirring overnight at room temperature.
To the mixture was added water (1.75 L), followed by stirring.
Precipitated crude crystals were collected by filtration, washed with water, and dried at 70° C. for 50 min.
To the obtained crude crystals was added ethanol (300 mL), and then the mixture was heated under reflux for 30 min to dissolve, followed by stirring overnight to cool slowly down to room temperature.
Precipitated crystals was collected by filtration and dried under vacuum, and then further dried at 70° C. for 8 hours to give the titled crystals (12.91 g, 80.2percent).
80.2% at 20℃; (Preparation Example 1) Preparation (1) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide
Phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (17.5g, 37.7 mmol) disclosed in
was dissolved in N,N-dimethylformamide (350 mL), and then cyclopropylamine (6.53 mL, 94.25 mmol) was added to the reaction mixture under a nitrogen atmosphere, followed by stirring overnight at room temperature.
To the mixture was added water (1.75L), and the mixture was stirred.
Precipitated crude crystals were collected by filtration, washed with water, and dried at 70 °C for 50 min.
To the obtained crude crystals was added ethanol (300 mL), and then the mixture was heated under reflux for 30 min to dissolve, followed by stirring overnight to cool slowly down to room temperature.
Precipitated crystals was collected by filtration and dried under vacuum, and then further dried at 70 °C for 8 hours to give the titled crystals (12.91 g; 80.2percent).
76% With N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole In tetrahydrofuran at 50℃; for 12 h; compound V (17.3g, 0.037mol) and N, N'- carbonyldiimidazole (7.1g, 0.044mol) was dissolved in tetrahydrofuran (40mL, 0.6mol), stirred was added cyclopropylamine (2.8g, 0.05mmol), was added dropwise N, N- diisopropylethylamine (16.8g, 0.130mol), i.e. the compound V, cyclopropylamine, a condensing agent (N, N'- carbonyl diimidazole), a base (N, N- diisopropylethylamine ), the molar ratio between the organic solvent (tetrahydrofuran) is (1.0: 1.3: 1.2: 3.5: 16), the reaction mixture was stirred for 50 deg.] C for 12 h, TLC confirmed completion of the reaction plate point, the reaction solution was concentrated by rotary evaporation to dryness, was added adjusted to neutral with dilute hydrochloric acid, extracted with ethyl acetate was added, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to dryness, recrystallized from methanol, to obtain music cutting erlotinib (Vl), as a pale yellow solid (13.04g), yield 76percent .

Reference: [1] Patent: EP1698623, 2006, A1, . Location in patent: Page/Page column 15
[2] Patent: US2007/4773, 2007, A1, . Location in patent: Page/Page column 4
[3] Patent: WO2006/137474, 2006, A1, . Location in patent: Page/Page column 10
[4] Patent: EP1797881, 2007, A1, . Location in patent: Page/Page column 12
[5] Patent: US2004/253205, 2004, A1,
[6] Patent: CN107739335, 2018, A, . Location in patent: Paragraph 0036-0038; 0042; 0046
[7] Patent: US2004/53908, 2004, A1,
  • 9
  • [ 417722-93-1 ]
  • [ 4747-72-2 ]
  • [ 417716-92-8 ]
YieldReaction ConditionsOperation in experiment
86.8% at 25℃; for 2 h; Method 2: Compound D (10.29 g, 30 mmol) was added to dichloromethane (100 mL).Compound E2 (2.49 g, 30 mmol) was added and stirred at 25 ° C for 2 days.Filtration yielded Lenvatinib(11.12g),The yield was 86.8percent.
Reference: [1] Patent: CN108623521, 2018, A, . Location in patent: Paragraph 0069; 0070; 0071; 0073
  • 10
  • [ 17609-80-2 ]
  • [ 417716-92-8 ]
Reference: [1] Patent: CN105801481, 2016, A,
[2] Patent: CN106632033, 2017, A,
[3] Patent: CN104876864, 2017, B,
  • 11
  • [ 417721-36-9 ]
  • [ 417716-92-8 ]
Reference: [1] Patent: CN108623521, 2018, A,
[2] Patent: CN108623521, 2018, A,
[3] Patent: CN108658859, 2018, A,
  • 12
  • [ 491-11-2 ]
  • [ 417716-92-8 ]
Reference: [1] Patent: CN108623521, 2018, A,
[2] Patent: CN108623521, 2018, A,
[3] Patent: CN108658859, 2018, A,
  • 13
  • [ 201811-58-7 ]
  • [ 417716-92-8 ]
Reference: [1] Patent: CN104876864, 2017, B,
  • 14
  • [ 417724-81-3 ]
  • [ 417716-92-8 ]
Reference: [1] Patent: CN107739335, 2018, A,
  • 15
  • [ 417716-92-8 ]
  • [ 75-75-2 ]
  • [ 857890-39-2 ]
YieldReaction ConditionsOperation in experiment
94% at 20 - 35℃; Example 3 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline-carboxamide methanesulfonate (0151) (0152) In a mixed solution of 20 methanesulfonic acid (5.44 kg) and 21 acetic acid (150 L) was dissolved 18 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline-carboxamide (23.0 kg) at 20° C. to 35° C. Methanesulfonic acid (777 g) was further added, the solution was filtered at a temperature of 35° C. or less, and the filter paper was washed with acetic acid (11.5 L). To the filtrate, 1-propanol (46.0 L) and seed crystals (230 g) were added at 25° C. to 45° C., and 22 1-propanol (161 L) and 23 isopropyl acetate (115 L) was further added dropwise at 25° C. to 45° C. The mixed solution was cooled to 15° C. to 25° C., and subsequently, the deposited crystals were filtered and washed with a mixed solution of 1-propanol and isopropyl acetate (1-propanol concentration: 33 v/v percent). To the resulting wet crystals, ethanol (173 L) was added and stirred at 20° C. to 60° C. for three hours. After the crystals were collected by filtration and washed with ethanol, the crystals were dried under reduced pressure at a temperature of 80° C. or less to thereby obtain 24 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline-carboxamide methanesulfonate (27.5 kg, yield: 94percent)
1.1 g at 60 - 65℃; for 5 h; Methanesulphonic acid (0.5 g) was added to a mixture of lenvatinib free base (1 g, obtained from lenvatinib hydrochloride) and isopropyl alcohol (30 mL) at 65 °C. The mixture was stirred at 60°C to 65°C for 5 hours, cooled to 25°C, and then stirred at 25°C to 26°C. The solid was filtered, washed with isopropyl alcohol (2x5 mL), and then dried in vacuum at 50°C to 55°C to obtain the title compound.
Reference: [1] Patent: US2017/233344, 2017, A1, . Location in patent: Paragraph 0151; 0152
[2] Patent: EP1698623, 2006, A1, . Location in patent: Page/Page column 17
[3] Patent: EP1698623, 2006, A1, . Location in patent: Page/Page column 18
[4] Patent: EP1698623, 2006, A1, . Location in patent: Page/Page column 17
[5] Patent: EP1698623, 2006, A1, . Location in patent: Page/Page column 18
[6] Patent: US2007/4773, 2007, A1, . Location in patent: Page/Page column 6
[7] Patent: US2007/4773, 2007, A1, . Location in patent: Page/Page column 8
[8] Patent: US2007/4773, 2007, A1, . Location in patent: Page/Page column 8
[9] Patent: US2007/4773, 2007, A1, . Location in patent: Page/Page column 7
[10] Patent: US2007/4773, 2007, A1, . Location in patent: Page/Page column 7
[11] Patent: US2007/4773, 2007, A1, . Location in patent: Page/Page column 7
[12] Patent: US2007/4773, 2007, A1, . Location in patent: Page/Page column 6
[13] Patent: WO2006/137474, 2006, A1, . Location in patent: Page/Page column 16
[14] Patent: WO2006/137474, 2006, A1, . Location in patent: Page/Page column 16
[15] Patent: US2007/4773, 2007, A1, . Location in patent: Page/Page column 7
[16] Patent: WO2006/137474, 2006, A1, . Location in patent: Page/Page column 14-15
[17] Patent: WO2006/137474, 2006, A1, . Location in patent: Page/Page column 14
[18] Patent: WO2017/221214, 2017, A1, . Location in patent: Page/Page column 12
[19] Patent: US2018/155291, 2018, A1, . Location in patent: Paragraph 0052; 0053; 0054; 0059; 0060
[20] Patent: WO2018/122780, 2018, A1, . Location in patent: Page/Page column 11
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