* 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.
A substitution reaction of AuCl (4.2g, 18mmol), 6- acetoxy-4-chloro-7-methoxy-quinazoline (12.6g, 50mmol), chloro-4-fluoroaniline (12.3g, 85mmol) in 50ml of methanol at 65°C. It was filtered after reaction completion. The filtrate was concentrated, washed with petroleum ether to give 16.9 g of Intermediate gefitinib, yield 93.4percent, purity 99.91percent.
92.5%
for 2 h; Reflux
Was added to the reactor4-Chloro-(3H) -quinazoline (2.52 g, 10 mmol) was dissolved in isopropanol (50 mL), m-phenylenediamine (1.6 g, 11 mmol) was added and the mixture was stirred well. The mixture was heated to reflux for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. The resulting solid was recrystallized from ethanol to give 3.34 g of 4- (3-chloro-4-fluoro) phenylamino-6-carbethoxy-7-methoxyquinazoline in a yield of 92.5percent.
91.2%
at 90℃; for 1 h;
Add 4-chloro-7-methoxyquinazolin-6-yl acetate prepared in step 2 to a 250 mL round bottom flask (1.1 g), 150 mL acetonitrile, 3-chloro-4-fluoroaniline (0.96 g, 1.2 eq). The reaction system was heated to 90 ° C and the reaction was continued for 1 h. The TLC assay was complete and a large amount of precipitate was observed. After the reaction system was cooled, suction filtration, washing the filter cake with acetonitrile, and drying in an oven, the obtained white solid was 4–((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline. -6-yl acetate, yield 91.2percent.
81%
at 88℃; for 5 h;
A suspension of 4-chloro-7-methoxyquinazolin-6-yl acetate (2.52 g),3-chloro-4-fluoroaniline (1.49 g) and isopropanol (60 mL) was stirred at 88 °C for 5 h. The reaction mixture was cooled to room temperature, filtered to afford the desired compound as a solid (2.51 g, 81.00 percent).
78%
for 3 h; Reflux
Into a 500-mL round-bottom flask, was placed 4-chloro-7-methoxyquinazolin-6-yl acetate (9.1 g, 36.02 mmol, 1.00 equiv), 3-chloro-4-fluoroaniline (5.23 g, 35.93 mmol, 1.00 equiv) in propan-2-ol (200 mL). The resulting solution was refluxed for 3 hours. The reaction mixture was cooled to room temperature. The solids were collected by filtration. This resulted in 10.1 g (78percent) of 4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl acetate as a brown solid. LC-MS: (ES, m/z): 362 [M+H]+ Retention time: 0.681min
2.51 g
at 88℃; for 5 h;
A suspension of 4-chloro-7-methoxyquinazolin-6-yl acetate (2.52 g), 3-chloro-4-fluoroaniline (1.49 g) and isopropanol (60 mL) was stirred at 88° C. for 5 h. The reaction mixture was cooled to room temperature, filtered to afford the desired compound as a solid (2.51 g, 81.00percent).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 2, p. 870 - 879
[2] Patent: CN105693630, 2016, A, . Location in patent: Paragraph 0033
[3] Patent: CN106045980, 2016, A, . Location in patent: Paragraph 0024; 0025; 0026
[4] Patent: CN108047209, 2018, A, . Location in patent: Paragraph 0041; 0047; 0048
[5] Patent: WO2013/71697, 2013, A1, . Location in patent: Paragraph 00195
[6] Dalton Transactions, 2015, vol. 44, # 29, p. 13100 - 13111
[7] Patent: WO2018/119441, 2018, A1, . Location in patent: Paragraph 00566; 00567
[8] Patent: US2010/143295, 2010, A1,
[9] Angewandte Chemie - International Edition, 2013, vol. 52, # 33, p. 8551 - 8556[10] Angew. Chem., 2013, vol. 125, # 33, p. 8713 - 8718,6
[11] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 14, p. 1911 - 1914
[12] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 18, p. 4908 - 4912
[13] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 14, p. 4745 - 4749
[14] Patent: US2014/206664, 2014, A1, . Location in patent: Paragraph 0225
[15] Patent: US2014/228361, 2014, A1, . Location in patent: Paragraph 0273-0274
[16] European Journal of Medicinal Chemistry, 2014, vol. 89, p. 826 - 834
[17] Patent: EP2796451, 2014, A1, . Location in patent: Paragraph 0079
[18] Patent: CN103570738, 2016, B, . Location in patent: Paragraph 0319; 0320; 0325
[19] Chinese Journal of Chemistry, 2017, vol. 35, # 11, p. 1693 - 1700
[20] Journal of Medicinal Chemistry, 2018, vol. 61, # 24, p. 11372 - 11383
2
[ 179688-53-0 ]
[ 367-21-5 ]
[ 788136-89-0 ]
Yield
Reaction Conditions
Operation in experiment
78%
Stage #1: With thionyl chloride In N,N-dimethyl-formamide for 6 h; Reflux Stage #2: With triethylamine In N,N-dimethyl-formamide; isopropyl alcohol at 20℃; for 9 h; Reflux
General procedure: A mixture of 4-hydroxyquinazolin-6-yl acetate (0.62 g, 3 mmol)and DMF (0.1 mL) in thionyl chloride (10 mL) was stirred underreflux for 6 h and then thionyl chloridewas removed under reducedpressure. To the residue was added isopropanol (20 mL), 3-bromoaniline (0.62 g, 3.6 mmol) and triethylamine (0.36 g,3.6 mmol). The resulting reaction mixture was stirred at roomtemperature for 6 h and then at reflux for another 3 h. After coolingto room temperature, the yellow solid was collected by suckfiltration, wash with isopropanol, water and ether sequentially, anddried at 50 °C to afford compound 12a as a yellow solid (0.74 g, 69percentyield).
Reference：
[1] European Journal of Medicinal Chemistry, 2017, vol. 127, p. 442 - 458
3
[ 948551-62-0 ]
[ 367-22-6 ]
[ 788136-89-0 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 110℃; for 3 h;
To a solution of 6-acetoxy-7-methoxy-quinazolin4-one (RO0505111-000) (1.0 g, 4.26 mmol) (from Example 15, Step A, supra) in SOCl2 (12.5 mL) (Aldrich) were added a few drops of DMF (0.1 mL). The reaction mixture was then heated with stirring at 100° C. for 3 hours. The solvents were evaporated and the residue was dried in vacuo. The residue was dissolved in 2-propanol (20 mL), followed by addition of 4-chloro-3-fluoroaniline (0.682 g, 4.69 mmol) (Aldrich). The reaction mixture was heated at 110° C. for 3 hours. The reaction mixture was cooled to room temperature and filtered. The precipitate was collected and dried in vacuo to give 6-acetoxy-4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazoline as a gray solid. (Yield 1.54 g, 100percent).
A substitution reaction of AuCl (4.2g, 18mmol), 6- acetoxy-4-chloro-7-methoxy-quinazoline (12.6g, 50mmol), chloro-4-fluoroaniline (12.3g, 85mmol) in 50ml of methanol at 65C. It was filtered after reaction completion. The filtrate was concentrated, washed with petroleum ether to give 16.9 g of Intermediate gefitinib, yield 93.4%, purity 99.91%.
92.5%
In isopropyl alcohol; for 2h;Reflux;
Was added to the reactor4-Chloro-(3H) -quinazoline (2.52 g, 10 mmol) was dissolved in isopropanol (50 mL), m-phenylenediamine (1.6 g, 11 mmol) was added and the mixture was stirred well. The mixture was heated to reflux for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. The resulting solid was recrystallized from ethanol to give 3.34 g of 4- (3-chloro-4-fluoro) phenylamino-6-carbethoxy-7-methoxyquinazoline in a yield of 92.5%.
91.2%
In acetonitrile; at 90℃; for 1h;
Add <strong>[230955-75-6]4-chloro-7-methoxyquinazolin-6-yl acetate</strong> prepared in step 2 to a 250 mL round bottom flask (1.1 g), 150 mL acetonitrile, 3-chloro-4-fluoroaniline (0.96 g, 1.2 eq). The reaction system was heated to 90 C and the reaction was continued for 1 h. The TLC assay was complete and a large amount of precipitate was observed. After the reaction system was cooled, suction filtration, washing the filter cake with acetonitrile, and drying in an oven, the obtained white solid was 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline. -6-yl acetate, yield 91.2%.
84%
In ethanol; for 1h;Reflux;
150 g (0.59 mol) of the compound of the formula VII was added to a 2 L three-necked flask, and 103 g (0.71 mol) of 3-chloro-4-fluoroaniline was added and dissolved in 1.2 L of ethanol, and the mixture was heated under reflux for 1 hour, and the reaction was monitored by HPLC. After cooling, filtration, the cake was rinsed with acetone, and the solid was collected, and dried at 50 C to obtain 200 g of a white compound of formula VIII with a molar yield of 84% and a purity of 99%.
81%
In isopropyl alcohol; at 88℃; for 5h;
A suspension of <strong>[230955-75-6]4-chloro-7-methoxyquinazolin-6-yl acetate</strong> (2.52 g),3-chloro-4-fluoroaniline (1.49 g) and isopropanol (60 mL) was stirred at 88 C for 5 h. The reaction mixture was cooled to room temperature, filtered to afford the desired compound as a solid (2.51 g, 81.00 %).
78%
In isopropyl alcohol; for 3h;Reflux;
Into a 500-mL round-bottom flask, was placed <strong>[230955-75-6]4-chloro-7-methoxyquinazolin-6-yl acetate</strong> (9.1 g, 36.02 mmol, 1.00 equiv), 3-chloro-4-fluoroaniline (5.23 g, 35.93 mmol, 1.00 equiv) in propan-2-ol (200 mL). The resulting solution was refluxed for 3 hours. The reaction mixture was cooled to room temperature. The solids were collected by filtration. This resulted in 10.1 g (78%) of 4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl acetate as a brown solid. LC-MS: (ES, m/z): 362 [M+H]+ Retention time: 0.681min
63%
In isopropyl alcohol;
Step 4 4-(3-Chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl acetate: 3-Chloro-4-fluorobenzenamine (1.7 g, 11.68 mmol, 1.02 equiv) was added to a solution of <strong>[230955-75-6]4-chloro-7-methoxyquinazolin-6-yl acetate</strong> (2.9 g, 11.48 mmol, 1.00 equiv) in isopropanol (60 mL). The resulting solution was stirred at about 85 C. for about 2 hours, and then was cooled to about 0 C. with a water/ice bath. The resulting precipitants were collected by filtration, and dried in an oven in vacuo to give the title product as a gray solid (2.6 g; yield=63%).
2.51 g
In isopropyl alcohol; at 88℃; for 5h;
A suspension of <strong>[230955-75-6]4-chloro-7-methoxyquinazolin-6-yl acetate</strong> (2.52 g), 3-chloro-4-fluoroaniline (1.49 g) and isopropanol (60 mL) was stirred at 88 C. for 5 h. The reaction mixture was cooled to room temperature, filtered to afford the desired compound as a solid (2.51 g, 81.00%).
In isopropyl alcohol; for 1h;Reflux;
General procedure: Compound 12 [18] (10.0 mmol) and substituted aniline(15.0 mmol) were mixed in isopropanol (10.0 mL) and refluxed for 1 h. After cooling to room temperature, the white solid was filtered to get compounds 13a-13d without further purification.
13 g
In 1,4-dioxane;
The 7.8g 3-chloro-4-fluoro aniline in dioxane (50ml) was added dropwise to the reaction solution to precipitate a solid, TLC monitored the reaction was completed, 40ml of water was added, the pH was adjusted to slightly alkaline solution with K0H, filtered, washed with water to give a yellow solid crude compound GG6. The solid was placed in a conical flask, adding an appropriate amount of tetrahydrofuran, ultrasonic washing the solid filtered to give 13g compound GG6
To a solution of 6-acetoxy-7-methoxy-quinazolin4-one (RO0505111-000) (1.0 g, 4.26 mmol) (from Example 15, Step A, supra) in SOCl2 (12.5 mL) (Aldrich) were added a few drops of DMF (0.1 mL). The reaction mixture was then heated with stirring at 100 C. for 3 hours. The solvents were evaporated and the residue was dried in vacuo. The residue was dissolved in 2-propanol (20 mL), followed by addition of 4-chloro-3-fluoroaniline (0.682 g, 4.69 mmol) (Aldrich). The reaction mixture was heated at 110 C. for 3 hours. The reaction mixture was cooled to room temperature and filtered. The precipitate was collected and dried in vacuo to give 6-acetoxy-4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazoline as a gray solid. (Yield 1.54 g, 100%).
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 80℃; for 6h;
To a mixture of 4-((3-chloro-4-fiuorophenyl)amino)-7- methoxyquinazolin-6-yl acetate (0.62 g) and K2CO3(0.35 g) in 10 mL of DMF was added 7-(3-chloropropyl)-3-(trifluoromethyl)-5,6,7,8- tetrahydro-[l ,2,4]triazolo[4,3-a]pyrazine (0.68 g) at rt. The reaction mixture was heated at 80 C for 6 h, diluted with water and extracted with CH2C12. The combined organic phases were dried over anhydrous Na2S0 for lh, and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 30: 1 (v/v) DCM/MeOH) to give the title compound as a white solid (0.43 g, 40.00 %), HPLC: 95.00 %. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 552.2 (M+l ); ? NMR (400 MHz, CDC13) ?: 1.80 (m, 2H), 2.46 (t, J = 4.2 Hz, 2H), 2.78 (t, J= 3.6 Hz, 2H), 3.58 (s, 2H), 4.03 (s, 3H), 4.10 (t, J = 4.2 Hz, 2H), 4.15 (t, = 3.6 Hz, 2H), 7.16 (s, 1 H), 7.26(s, 1 H), 7.45 (s, 1 H), 7.57 (m, 1H), 7.91 (m, 1 H), 8.64 (s, 1 H) ppm.
40%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 6h;
To a mixture of <strong>[788136-89-0]4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl acetate</strong> (0.62 g) and K2CO3 (0.35 g) in 10 mL of DMF was added 7-(3-chloropropyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (0.68 g) at rt. The reaction mixture was heated at 80 C. for 6 h, diluted with water and extracted with CH2Cl2. The combined organic phases were dried over anhydrous Na2SO4 for 1 h, and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 30:1 (v/v) DCM/MeOH) to give the title compound as a white solid (0.43 g, 40.00%), HPLC: 95.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 552.2 (M+1); 1H NMR (400 MHz, CDCl3) delta: 1.80 (m, 2H), 2.46 (t, J=4.2 Hz, 2H), 2.78 (t, J=3.6 Hz, 2H), 3.58 (s, 2H), 4.03 (s, 3H), 4.10 (t, J=4.2 Hz, 2H), 4.15 (t, J=3.6 Hz, 2H), 7.16 (s, 1H), 7.26 (s, 1H), 7.45 (s, 1H), 7.57 (m, 1H), 7.91 (m, 1H), 8.64 (s, 1H) ppm.
General procedure: A mixture of 4-hydroxyquinazolin-6-yl acetate (0.62 g, 3 mmol)and DMF (0.1 mL) in thionyl chloride (10 mL) was stirred underreflux for 6 h and then thionyl chloridewas removed under reducedpressure. To the residue was added isopropanol (20 mL), 3-bromoaniline (0.62 g, 3.6 mmol) and triethylamine (0.36 g,3.6 mmol). The resulting reaction mixture was stirred at roomtemperature for 6 h and then at reflux for another 3 h. After coolingto room temperature, the yellow solid was collected by suckfiltration, wash with isopropanol, water and ether sequentially, anddried at 50 C to afford compound 12a as a yellow solid (0.74 g, 69%yield).
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[(1-methyl-2-nitro-1H-imidazol-5-yl)methoxy]-N-[(1-methyl-2-nitro-1H-imidazol-5-yl)methyl]quinazolin-4-amine[ No CAS ]
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-((18,18,18-trifluoro-14,14-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)-17,17-bis(trifluoromethyl)-3,6,9,12,16-pentaoxaoctadecyl)oxy)quinazolin-4-amine[ No CAS ]
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