Name: 612501-80-1|4-((3-Chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl acetate hydrochloride|97%
Brand: Ambeed
SKU: A914838
Price: 14.0 USD
Availability: InStock
Rating: 90 (40 reviews)

1
[ 2106-04-9 ]
[ 230955-75-6 ]
[ 612501-80-1 ]

Yield	Reaction Conditions	Operation in experiment
92%	In isopropyl alcohol; at 80℃; for 3h;Heating / reflux;	6-Acetoxy-4-chloro-7-methoxyquinazoline (prepared as described in Example 25- 5 of in WO01/66099, 6.00 g, 23. 8 mmol) and 3-chloro-2-fluoroaniline (3.46 g, 23. 8 mmol) were suspended in iso-propanol (200 ml). The mixture was heated to 80C under reflux for 3 hours. The solvent was evaporated; the residue was crystallised from acetonitrile, giving 6-ACETOXY-4- (3-CHLORO-2-FLUOROANILINO)-7-METHOXYQUINAZOLINE hydrochloride as a pale pink crystalline solid (8.16 g, 92%) ; 1H NMR : 2.37 (s, 3H), 4. 00 (s, 3H), 7.34 (ddd, 1H), 7. 48 (s, 1H), 7.52 (ddd, 1H), 7.61 (ddd, 1H), 8. 62 (s, 1H), 8. 86 (s, 1H) ; Mass Spectrum : 362.4, 364.4.
92%	In isopropyl alcohol; at 80℃; for 3h;	Reference Example 1; 6-Acetoxy-4- (3-chloro-2-fluoroanilino)-7-methoxyquinazoline hydrochloride; 6-Acetoxy-4-chloro-7-methoxyquinazoline (prepared as described in Example 25-5 of in WO01/66099, 6.00 g, 23.8 mmol) and 3-chloro-2-fluoroaniline (3.46 g, 23.8 mmol) were suspended in iso-propanol (200 ml). The mixture was heated to 80C under reflux for 3 hours. The solvent was evaporated; the residue was crystallised from acetonitrile, giving the product hydrochloride as a pale pink crystalline solid (8.16 g, 92%) ; 1H NMR : 2.37 (s, 3H), 4.00 (s, 3H), 7.34 (ddd, 1H), 7.48 (s, 1H), 7.52 (ddd, 1H), 7.61 (ddd, 1H), 8.62 (s, 1H), 8.86 (s, 1H) ; Mass Spectrum: 362.4, 364.4.
	In toluene; at 70℃; for 1.16667h;	Step 1: Preparation OF4- (3-CHLORO-2-FLUOROANILINO)-6-HVDROXV-7-METHOXYQUINAZOLINE; 6-Acetoxy-7-methoxy-4 (1H)-quinazolinone (150 g; prepared as described in W096/15118, Example 39 thereof), N, N-diisopropylethylamine (123 ml) and toluene (1275 ml) were stirred at 70C, under nitrogen. Phosphorus oxychloride (150 ml) was added over 15 minutes to the slurry at 70C. The mixture was held at 70C for 2 hours to complete the chlorination. A dark brown solution formed after 30 minutes following addition of the phosphorus oxychloride. Toluene (680 ml) was added to the reaction mixture, followed by addition of 3-chloro-2-fluoroaniline (78 ml) over 10 minutes at 70C. On completion of the addition, a solid precipitated resulting in a beige slurry. The slurry was held at 70C for 1 hour and then cooled to ambient temperature. The reaction mixture was filtered and washed with toluene (2 x 300 ml), aqueous IMS (2 x 450 ml and IMS (2 x 450 ML). The solid was left to pull dry on the filter overnight to give 6-ACETOXY-4- (3-CHLORO-2-FLUOROANILINO)-7- methoxyquinazoline. HCl salt; NMR Spectrum: (DMSO d6) 2.39 (s, 3H); 4.02 (s, 3H); 7.36 (t, 1H) ; 7.58 (s, 1H); 7.64 (t, 1H) ; 8.79 (s, 1H) 8.91 (s, 1H); 11.93 (bs 1H); Mass Spectrum : M+H 362. 6-ACETOXY-4- (3-CHLORO-2-FLUOROANILINO)-7-METHOXYQUINAZOLINE. HCL salt (about 253 g), methanol (1900 ml) and water (632.5 ml) were stirred at ambient temperature. Sodium hydroxide solution (47% w/w; 108 ml) was added dropwise and the reaction mixture heated to 60C to form a dark solution. The solution was held at 60C for 1 hour and then screened to a clean vessel. The mixture was cooled to ambient temperature before acetic acid (72. 8 ml) was charged. The precipitated solid was filtered, washed with 50% aqueous methanol (500 ml) and methanol (500 ml), and then dried in a vacuum oven at 45C to give 4- (3-CHLORO-2- fluoroanilino) -6-hydroxy-7-methoxyquinazoline; (204.8 g; 75.7% yield); Melting point 265- 268C ; NMR Spectrum : (DMSO d6) 4.01 (s, 3H); 7.24 (s, 2H); 7.32 (t, 1H); 7.51-7. 56 (m, 2H); 7.78 (s, 1H); 8.58 (s, 1H); Mass Spectrum: (M+H) + 320.

In acetonitrile; at 80℃;

The intermediate <strong>[230955-75-6]6-acetoxy-4-chloro-7-methoxyquinazoline</strong> (50g, 0.198mol) was added to acetonitrile, followed by dropwise addition of 2-fluoro-3-chloroaniline (30.2g, 0.208mol) After the dropwise addition, the temperature was raised to 80 C, and the reaction was carried out at this temperature overnight.The reaction solution was cooled to room temperature, and filtered to obtain a solid. The solid was washed twice with a small amount of acetonitrile and dried under reduced pressure at 50 C to obtain the hydrochloride salt of intermediate A (81 g, purity 87%). The intermediate was used without further purification. Next reaction.

Reference： [1]Patent: WO2005/26156,2005,A1 .Location in patent: Page/Page column 91-92
[2]Patent: WO2003/82831,2003,A1 .Location in patent: Page/Page column 161
[3]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 742 - 746
[4]Journal of Medicinal Chemistry,2015,vol. 58,p. 8200 - 8215
[5]Patent: WO2005/12290,2005,A1 .Location in patent: Page/Page column 40
[6]Patent: CN110903283,2020,A .Location in patent: Paragraph 0084-0087

2
[ 612501-80-1 ]
[ 612501-52-7 ]

Yield	Reaction Conditions	Operation in experiment
77%	With ammonia; In methanol; water; at 50℃; for 2h;	6-ACETOXY-4- (3-CHLORO-2-FLUOROANILINO)-7-METHOXYQUINAZOLINE hydrochloride (8.72 g, 21.9 mmol) was dissolved in methanol (200 ml). Concentrated aqueous ammonia (15 ML) was added, and the solution heated to 50C with stirring for 2 hours, causing precipitation of a cream coloured solid. The solid was collected by filtration, washed with diethyl ether (3x 200 ml), and dried III VACUO at 60C over diphosphorous pentoxide, giving 4- (3-CHLORO-2-FLUOROANILINO)-6-HYDROXY-7-METHOXYQUINAZOLINE as an off white solid (5.40 g, 77%) ; 1H NMR : 3.95 (s, 3H), 7.19 (s, 1H), 7.23 (dd, 1H), 7.42 (dd, 1H), 7.50 (dd, 1H), 7.64 (s, 1H), 8. 32 (s, 1H), 9.43 (s, 1H), 9.67 (br. s, 1H); Mass Spectrum : 320.4, 322.4.
77%	With methanol; ammonia; water; at 50℃; for 2h;Product distribution / selectivity;	Reference Example 1; 6-Acetoxy-4- (3-chloro-2-fluoroanilino)-7-methoxyquinazoline hydrochloride; 6-Acetoxy-4-chloro-7-methoxyquinazoline (prepared as described in Example 25-5 of in WO01/66099, 6.00 g, 23.8 mmol) and 3-chloro-2-fluoroaniline (3.46 g, 23.8 mmol) were suspended in iso-propanol (200 ml). The mixture was heated to 80C under reflux for 3 hours. The solvent was evaporated; the residue was crystallised from acetonitrile, giving the product hydrochloride as a pale pink crystalline solid (8.16 g, 92%) ; 1H NMR : 2.37 (s, 3H), 4.00 (s, 3H), 7.34 (ddd, 1H), 7.48 (s, 1H), 7.52 (ddd, 1H), 7.61 (ddd, 1H), 8.62 (s, 1H), 8.86 (s, 1H) ; Mass Spectrum: 362.4, 364.4.
75.7%		Step 1: Preparation OF4- (3-CHLORO-2-FLUOROANILINO)-6-HVDROXV-7-METHOXYQUINAZOLINE; 6-Acetoxy-7-methoxy-4 (1H)-quinazolinone (150 g; prepared as described in W096/15118, Example 39 thereof), N, N-diisopropylethylamine (123 ml) and toluene (1275 ml) were stirred at 70C, under nitrogen. Phosphorus oxychloride (150 ml) was added over 15 minutes to the slurry at 70C. The mixture was held at 70C for 2 hours to complete the chlorination. A dark brown solution formed after 30 minutes following addition of the phosphorus oxychloride. Toluene (680 ml) was added to the reaction mixture, followed by addition of 3-chloro-2-fluoroaniline (78 ml) over 10 minutes at 70C. On completion of the addition, a solid precipitated resulting in a beige slurry. The slurry was held at 70C for 1 hour and then cooled to ambient temperature. The reaction mixture was filtered and washed with toluene (2 x 300 ml), aqueous IMS (2 x 450 ml and IMS (2 x 450 ML). The solid was left to pull dry on the filter overnight to give 6-ACETOXY-4- (3-CHLORO-2-FLUOROANILINO)-7- methoxyquinazoline. HCl salt; NMR Spectrum: (DMSO d6) 2.39 (s, 3H); 4.02 (s, 3H); 7.36 (t, 1H) ; 7.58 (s, 1H); 7.64 (t, 1H) ; 8.79 (s, 1H) 8.91 (s, 1H); 11.93 (bs 1H); Mass Spectrum : M+H 362. 6-ACETOXY-4- (3-CHLORO-2-FLUOROANILINO)-7-METHOXYQUINAZOLINE. HCL salt (about 253 g), methanol (1900 ml) and water (632.5 ml) were stirred at ambient temperature. Sodium hydroxide solution (47% w/w; 108 ml) was added dropwise and the reaction mixture heated to 60C to form a dark solution. The solution was held at 60C for 1 hour and then screened to a clean vessel. The mixture was cooled to ambient temperature before acetic acid (72. 8 ml) was charged. The precipitated solid was filtered, washed with 50% aqueous methanol (500 ml) and methanol (500 ml), and then dried in a vacuum oven at 45C to give 4- (3-CHLORO-2- fluoroanilino) -6-hydroxy-7-methoxyquinazoline; (204.8 g; 75.7% yield); Melting point 265- 268C ; NMR Spectrum : (DMSO d6) 4.01 (s, 3H); 7.24 (s, 2H); 7.32 (t, 1H); 7.51-7. 56 (m, 2H); 7.78 (s, 1H); 8.58 (s, 1H); Mass Spectrum: (M+H) + 320.

76.2 g

With methanol; potassium carbonate; at 20℃; for 8h;

The hydrochloride salt of intermediate A (90 g, 0.226 mol) was dissolved in methanol (1 L), potassium carbonate (69 g, 0.5 mol) was added, and the reaction was stirred at room temperature for 8 hours.After the reaction was completed, the reaction liquid was filtered, and the solid was washed with a small amount of methanol.The filtrate was concentrated under reduced pressure, and the solid was added to water (60 mL), slurried at 70 C for 1 hour, cooled and filtered, washed with a small amount of methanol, and dried under vacuum at 50 C to obtain intermediate C (76.2 g, 94%).

Reference： [1]Patent: WO2005/26156,2005,A1 .Location in patent: Page/Page column 92
[2]Patent: WO2003/82831,2003,A1 .Location in patent: Page/Page column 161
[3]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 742 - 746
[4]Patent: WO2005/12290,2005,A1 .Location in patent: Page/Page column 40
[5]Patent: CN110903283,2020,A .Location in patent: Paragraph 0092-0095

3
[ 612501-80-1 ]
2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: ammonium hydroxide / methanol / 2 h / 50 °C / Inert atmosphere 2: cesium fluoride / N,N-dimethyl acetamide / 12 h / 85 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 2 h / 20 °C / Inert atmosphere 4: N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / 20 °C / Inert atmosphere

Reference： [1]Barlaam, Bernard; Anderton, Judith; Ballard, Peter; Bradbury, Robert H.; Hennequin, Laurent F. A.; Hickinson, D. Mark; Kettle, Jason G.; Kirk, George; Klinowska, Teresa; Lambert-Van Der Brempt, Christine; Trigwell, Cath; Vincent, John; Ogilvie, Donald [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 8, p. 742 - 746]

4
[ 612501-80-1 ]
[ 1441145-46-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: ammonium hydroxide / methanol / 2 h / 50 °C / Inert atmosphere 2: cesium fluoride / N,N-dimethyl acetamide / 12 h / 85 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 2 h / 20 °C / Inert atmosphere 4: methanol / 18 h / 20 °C / Inert atmosphere 5: hydrogenchloride / 1,4-dioxane / 3 h / 20 °C / Inert atmosphere 6: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane; tetrahydrofuran / 2 h / 20 °C / Inert atmosphere

Reference： [1]Barlaam, Bernard; Anderton, Judith; Ballard, Peter; Bradbury, Robert H.; Hennequin, Laurent F. A.; Hickinson, D. Mark; Kettle, Jason G.; Kirk, George; Klinowska, Teresa; Lambert-Van Der Brempt, Christine; Trigwell, Cath; Vincent, John; Ogilvie, Donald [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 8, p. 742 - 746]

5
[ 612501-80-1 ]
[ 1441145-65-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: ammonium hydroxide / methanol / 2 h / 50 °C / Inert atmosphere 2.1: triphenylphosphine; di-tert-butyl-diazodicarboxylate / tetrahydrofuran / 0.25 h / -20 °C / Inert atmosphere 2.2: 24 h / -20 - 70 °C / Inert atmosphere 3.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C / Inert atmosphere 4.1: potassium iodide; potassium carbonate / N,N-dimethyl acetamide / 1 h / 70 °C / Inert atmosphere

Reference： [1]Barlaam, Bernard; Anderton, Judith; Ballard, Peter; Bradbury, Robert H.; Hennequin, Laurent F. A.; Hickinson, D. Mark; Kettle, Jason G.; Kirk, George; Klinowska, Teresa; Lambert-Van Der Brempt, Christine; Trigwell, Cath; Vincent, John; Ogilvie, Donald [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 8, p. 742 - 746]

6
[ 612501-80-1 ]
[ 612501-81-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: ammonium hydroxide / methanol / 2 h / 50 °C / Inert atmosphere 2: cesium fluoride / N,N-dimethyl acetamide / 12 h / 85 °C / Inert atmosphere

Reference： [1]Barlaam, Bernard; Anderton, Judith; Ballard, Peter; Bradbury, Robert H.; Hennequin, Laurent F. A.; Hickinson, D. Mark; Kettle, Jason G.; Kirk, George; Klinowska, Teresa; Lambert-Van Der Brempt, Christine; Trigwell, Cath; Vincent, John; Ogilvie, Donald [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 8, p. 742 - 746]

7
[ 612501-80-1 ]
Sapitinib [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: ammonium hydroxide / methanol / 2 h / 50 °C / Inert atmosphere 2: cesium fluoride / N,N-dimethyl acetamide / 12 h / 85 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 2 h / 20 °C / Inert atmosphere 4: potassium iodide; potassium carbonate / acetonitrile / 1 h / Reflux; Inert atmosphere

Reference： [1]Barlaam, Bernard; Anderton, Judith; Ballard, Peter; Bradbury, Robert H.; Hennequin, Laurent F. A.; Hickinson, D. Mark; Kettle, Jason G.; Kirk, George; Klinowska, Teresa; Lambert-Van Der Brempt, Christine; Trigwell, Cath; Vincent, John; Ogilvie, Donald [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 8, p. 742 - 746]

8
[ 612501-80-1 ]
[ 612500-78-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: ammonium hydroxide / methanol / 2 h / 50 °C / Inert atmosphere 2: cesium fluoride / N,N-dimethyl acetamide / 12 h / 85 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 2 h / 20 °C / Inert atmosphere

Reference： [1]Barlaam, Bernard; Anderton, Judith; Ballard, Peter; Bradbury, Robert H.; Hennequin, Laurent F. A.; Hickinson, D. Mark; Kettle, Jason G.; Kirk, George; Klinowska, Teresa; Lambert-Van Der Brempt, Christine; Trigwell, Cath; Vincent, John; Ogilvie, Donald [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 8, p. 742 - 746]

9
[ 612501-80-1 ]
tert-butyl [4-({4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl}oxy)piperidin-1-yl]acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: ammonium hydroxide / methanol / 2 h / 50 °C / Inert atmosphere 2: cesium fluoride / N,N-dimethyl acetamide / 12 h / 85 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 2 h / 20 °C / Inert atmosphere 4: potassium iodide; potassium carbonate / N,N-dimethyl acetamide / 1 h / 70 °C / Inert atmosphere

Reference： [1]Barlaam, Bernard; Anderton, Judith; Ballard, Peter; Bradbury, Robert H.; Hennequin, Laurent F. A.; Hickinson, D. Mark; Kettle, Jason G.; Kirk, George; Klinowska, Teresa; Lambert-Van Der Brempt, Christine; Trigwell, Cath; Vincent, John; Ogilvie, Donald [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 8, p. 742 - 746]

10
[ 612501-80-1 ]
[4-({4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl}oxy)piperidin-1-yl]acetic acid dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: ammonium hydroxide / methanol / 2 h / 50 °C / Inert atmosphere 2: cesium fluoride / N,N-dimethyl acetamide / 12 h / 85 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 2 h / 20 °C / Inert atmosphere 4: potassium iodide; potassium carbonate / N,N-dimethyl acetamide / 1 h / 70 °C / Inert atmosphere 5: hydrogenchloride / 1,4-dioxane / 3 h / 20 °C / Inert atmosphere

Reference： [1]Barlaam, Bernard; Anderton, Judith; Ballard, Peter; Bradbury, Robert H.; Hennequin, Laurent F. A.; Hickinson, D. Mark; Kettle, Jason G.; Kirk, George; Klinowska, Teresa; Lambert-Van Der Brempt, Christine; Trigwell, Cath; Vincent, John; Ogilvie, Donald [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 8, p. 742 - 746]

11
[ 612501-80-1 ]
[ 1441146-12-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: ammonium hydroxide / methanol / 2 h / 50 °C / Inert atmosphere 2: cesium fluoride / N,N-dimethyl acetamide / 12 h / 85 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 2 h / 20 °C / Inert atmosphere 4: methanol / 18 h / 20 °C / Inert atmosphere

Reference： [1]Barlaam, Bernard; Anderton, Judith; Ballard, Peter; Bradbury, Robert H.; Hennequin, Laurent F. A.; Hickinson, D. Mark; Kettle, Jason G.; Kirk, George; Klinowska, Teresa; Lambert-Van Der Brempt, Christine; Trigwell, Cath; Vincent, John; Ogilvie, Donald [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 8, p. 742 - 746]

12
[ 612501-80-1 ]
3-[4-({4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl}oxy)piperidin-1-yl]propionic acid dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: ammonium hydroxide / methanol / 2 h / 50 °C / Inert atmosphere 2: cesium fluoride / N,N-dimethyl acetamide / 12 h / 85 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 2 h / 20 °C / Inert atmosphere 4: methanol / 18 h / 20 °C / Inert atmosphere 5: hydrogenchloride / 1,4-dioxane / 3 h / 20 °C / Inert atmosphere

Reference： [1]Barlaam, Bernard; Anderton, Judith; Ballard, Peter; Bradbury, Robert H.; Hennequin, Laurent F. A.; Hickinson, D. Mark; Kettle, Jason G.; Kirk, George; Klinowska, Teresa; Lambert-Van Der Brempt, Christine; Trigwell, Cath; Vincent, John; Ogilvie, Donald [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 8, p. 742 - 746]

13
[ 612501-80-1 ]
4-(3-chloro-2-fluoroanilino)-6-[1-(N-ethylcarbamoylmethyl)piperidin-4-yl]oxy}-7-methoxyquinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: ammonium hydroxide / methanol / 2 h / 50 °C / Inert atmosphere 2: cesium fluoride / N,N-dimethyl acetamide / 12 h / 85 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 2 h / 20 °C / Inert atmosphere 4: potassium iodide; potassium carbonate / N,N-dimethyl acetamide / 1 h / 70 °C / Inert atmosphere 5: hydrogenchloride / 1,4-dioxane / 3 h / 20 °C / Inert atmosphere 6: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane; tetrahydrofuran / 2 h / 20 °C / Inert atmosphere

Reference： [1]Barlaam, Bernard; Anderton, Judith; Ballard, Peter; Bradbury, Robert H.; Hennequin, Laurent F. A.; Hickinson, D. Mark; Kettle, Jason G.; Kirk, George; Klinowska, Teresa; Lambert-Van Der Brempt, Christine; Trigwell, Cath; Vincent, John; Ogilvie, Donald [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 8, p. 742 - 746]

14
[ 612501-80-1 ]
[ 1441146-93-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: ammonium hydroxide / methanol / 2 h / 50 °C / Inert atmosphere 2.1: triphenylphosphine; di-tert-butyl-diazodicarboxylate / tetrahydrofuran / 0.25 h / -20 °C / Inert atmosphere 2.2: 24 h / -20 - 70 °C / Inert atmosphere

Reference： [1]Barlaam, Bernard; Anderton, Judith; Ballard, Peter; Bradbury, Robert H.; Hennequin, Laurent F. A.; Hickinson, D. Mark; Kettle, Jason G.; Kirk, George; Klinowska, Teresa; Lambert-Van Der Brempt, Christine; Trigwell, Cath; Vincent, John; Ogilvie, Donald [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 8, p. 742 - 746]

15
[ 612501-80-1 ]
[ 1441146-99-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: ammonium hydroxide / methanol / 2 h / 50 °C / Inert atmosphere 2.1: triphenylphosphine; di-tert-butyl-diazodicarboxylate / tetrahydrofuran / 0.25 h / -20 °C / Inert atmosphere 2.2: 24 h / -20 - 70 °C / Inert atmosphere 3.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C / Inert atmosphere

Reference： [1]Barlaam, Bernard; Anderton, Judith; Ballard, Peter; Bradbury, Robert H.; Hennequin, Laurent F. A.; Hickinson, D. Mark; Kettle, Jason G.; Kirk, George; Klinowska, Teresa; Lambert-Van Der Brempt, Christine; Trigwell, Cath; Vincent, John; Ogilvie, Donald [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 8, p. 742 - 746]

16
[ 612501-80-1 ]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[1-(N-(2-methoxyethyl)carbamoylmethyl)piperidin-4-yl]oxy}quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: ammonium hydroxide / methanol / 2 h / 50 °C / Inert atmosphere 2: cesium fluoride / N,N-dimethyl acetamide / 12 h / 85 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 2 h / 20 °C / Inert atmosphere 4: potassium iodide; potassium carbonate / N,N-dimethyl acetamide / 1 h / 70 °C / Inert atmosphere 5: hydrogenchloride / 1,4-dioxane / 3 h / 20 °C / Inert atmosphere 6: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane; tetrahydrofuran / 2 h / 20 °C / Inert atmosphere

Reference： [1]Barlaam, Bernard; Anderton, Judith; Ballard, Peter; Bradbury, Robert H.; Hennequin, Laurent F. A.; Hickinson, D. Mark; Kettle, Jason G.; Kirk, George; Klinowska, Teresa; Lambert-Van Der Brempt, Christine; Trigwell, Cath; Vincent, John; Ogilvie, Donald [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 8, p. 742 - 746]

17
[ 612501-80-1 ]
[ 1441145-10-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: ammonium hydroxide / methanol / 2 h / 50 °C / Inert atmosphere 2: cesium fluoride / N,N-dimethyl acetamide / 12 h / 85 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 2 h / 20 °C / Inert atmosphere 4: potassium iodide; potassium carbonate / N,N-dimethyl acetamide / 1 h / 70 °C / Inert atmosphere 5: hydrogenchloride / 1,4-dioxane / 3 h / 20 °C / Inert atmosphere 6: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane; tetrahydrofuran / 2 h / 20 °C / Inert atmosphere

Reference： [1]Barlaam, Bernard; Anderton, Judith; Ballard, Peter; Bradbury, Robert H.; Hennequin, Laurent F. A.; Hickinson, D. Mark; Kettle, Jason G.; Kirk, George; Klinowska, Teresa; Lambert-Van Der Brempt, Christine; Trigwell, Cath; Vincent, John; Ogilvie, Donald [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 8, p. 742 - 746]

18
[ 612501-80-1 ]
[ 848942-78-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: ammonium hydroxide / methanol / 2 h / 50 °C / Inert atmosphere 2: cesium fluoride / N,N-dimethyl acetamide / 12 h / 85 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 2 h / 20 °C / Inert atmosphere 4: potassium iodide; potassium carbonate / acetonitrile / 1 h / Reflux; Inert atmosphere

Reference： [1]Barlaam, Bernard; Anderton, Judith; Ballard, Peter; Bradbury, Robert H.; Hennequin, Laurent F. A.; Hickinson, D. Mark; Kettle, Jason G.; Kirk, George; Klinowska, Teresa; Lambert-Van Der Brempt, Christine; Trigwell, Cath; Vincent, John; Ogilvie, Donald [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 8, p. 742 - 746]

19
[ 612501-80-1 ]
[ 848488-66-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / methanol / 2 h / 10 - 15 °C 2: pyridine / dichloromethane / 5 - 25 °C

Reference： [1]Zeng, Qingbei; Wang, Jiabing; Cheng, Ziqiang; Chen, Kan; Johnström, Peter; Varnäs, Katarina; Li, David Yunzhi; Yang, Zhen Fan; Zhang, Xiaolin [Journal of Medicinal Chemistry, 2015, vol. 58, # 20, p. 8200 - 8215]

20
[ 612501-80-1 ]
(E)-methyl 3-(4-(3-chloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium carbonate / methanol / 2 h / 10 - 15 °C 2: pyridine / dichloromethane / 5 - 25 °C 3: palladium diacetate; triethylamine; 1,1'-bis-(diphenylphosphino)ferrocene; tetrabutylammomium bromide / N,N-dimethyl-formamide / 80 °C / Inert atmosphere

Reference： [1]Zeng, Qingbei; Wang, Jiabing; Cheng, Ziqiang; Chen, Kan; Johnström, Peter; Varnäs, Katarina; Li, David Yunzhi; Yang, Zhen Fan; Zhang, Xiaolin [Journal of Medicinal Chemistry, 2015, vol. 58, # 20, p. 8200 - 8215]

21
[ 612501-80-1 ]
[ 848488-65-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: potassium carbonate / methanol / 2 h / 10 - 15 °C 2.1: pyridine / dichloromethane / 5 - 25 °C 3.1: palladium diacetate; triethylamine; 1,1'-bis-(diphenylphosphino)ferrocene; tetrabutylammomium bromide / N,N-dimethyl-formamide / 80 °C / Inert atmosphere 4.1: ozone / dichloromethane / 0.25 h / -78 °C 4.2: 0.5 h / -78 - 25 °C / Inert atmosphere

Reference： [1]Zeng, Qingbei; Wang, Jiabing; Cheng, Ziqiang; Chen, Kan; Johnström, Peter; Varnäs, Katarina; Li, David Yunzhi; Yang, Zhen Fan; Zhang, Xiaolin [Journal of Medicinal Chemistry, 2015, vol. 58, # 20, p. 8200 - 8215]

22
[ 612501-80-1 ]
N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(morpholinomethyl)quinazolin-4-amine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: potassium carbonate / methanol / 2 h / 10 - 15 °C 2.1: pyridine / dichloromethane / 5 - 25 °C 3.1: palladium diacetate; triethylamine; 1,1'-bis-(diphenylphosphino)ferrocene; tetrabutylammomium bromide / N,N-dimethyl-formamide / 80 °C / Inert atmosphere 4.1: ozone / dichloromethane / 0.25 h / -78 °C 4.2: 0.5 h / -78 - 25 °C / Inert atmosphere 5.1: acetic acid / methanol / 0.5 h / 25 °C 5.2: 1 h / 25 °C

Reference： [1]Zeng, Qingbei; Wang, Jiabing; Cheng, Ziqiang; Chen, Kan; Johnström, Peter; Varnäs, Katarina; Li, David Yunzhi; Yang, Zhen Fan; Zhang, Xiaolin [Journal of Medicinal Chemistry, 2015, vol. 58, # 20, p. 8200 - 8215]

23
[ 612501-80-1 ]
(R)-4-(3-chloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yl 3-(dimethylamino)pyrrolidine-1-carboxylate hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / methanol / 2 h / 10 - 15 °C 2: potassium carbonate / N,N-dimethyl-formamide / 25 °C

Reference： [1]Zeng, Qingbei; Wang, Jiabing; Cheng, Ziqiang; Chen, Kan; Johnström, Peter; Varnäs, Katarina; Li, David Yunzhi; Yang, Zhen Fan; Zhang, Xiaolin [Journal of Medicinal Chemistry, 2015, vol. 58, # 20, p. 8200 - 8215]

24
[ 612501-80-1 ]
4-(3-chloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yl morpholine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / methanol / 2 h / 10 - 15 °C 2: triethylamine / dichloromethane / 25 °C

Reference： [1]Zeng, Qingbei; Wang, Jiabing; Cheng, Ziqiang; Chen, Kan; Johnström, Peter; Varnäs, Katarina; Li, David Yunzhi; Yang, Zhen Fan; Zhang, Xiaolin [Journal of Medicinal Chemistry, 2015, vol. 58, # 20, p. 8200 - 8215]

25
[ 612501-80-1 ]
(4-(3-chloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yl)(morpholino)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium carbonate / methanol / 2 h / 10 - 15 °C 2: pyridine / dichloromethane / 5 - 25 °C 3: palladium diacetate; 1,1'-bis-(diphenylphosphino)ferrocene / 70 °C / 2327.23 Torr

Reference： [1]Zeng, Qingbei; Wang, Jiabing; Cheng, Ziqiang; Chen, Kan; Johnström, Peter; Varnäs, Katarina; Li, David Yunzhi; Yang, Zhen Fan; Zhang, Xiaolin [Journal of Medicinal Chemistry, 2015, vol. 58, # 20, p. 8200 - 8215]

26
[ 612501-80-1 ]
(S)-4-(3-chloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yl 3-(dimethylamino)pyrrolidine-1-carboxylate hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / methanol / 2 h / 10 - 15 °C 2: potassium carbonate / N,N-dimethyl-formamide / 25 °C

Reference： [1]Zeng, Qingbei; Wang, Jiabing; Cheng, Ziqiang; Chen, Kan; Johnström, Peter; Varnäs, Katarina; Li, David Yunzhi; Yang, Zhen Fan; Zhang, Xiaolin [Journal of Medicinal Chemistry, 2015, vol. 58, # 20, p. 8200 - 8215]

27
[ 612501-80-1 ]
(1S,4S)-4-(3-chloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yl 5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / methanol / 2 h / 10 - 15 °C 2: triethylamine / dichloromethane / 25 °C

Reference： [1]Zeng, Qingbei; Wang, Jiabing; Cheng, Ziqiang; Chen, Kan; Johnström, Peter; Varnäs, Katarina; Li, David Yunzhi; Yang, Zhen Fan; Zhang, Xiaolin [Journal of Medicinal Chemistry, 2015, vol. 58, # 20, p. 8200 - 8215]

28
[ 612501-80-1 ]
4-(3-chloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yl 5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: potassium carbonate / methanol / 2 h / 10 - 15 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 25 °C 3.1: hydrogenchloride / water; ethyl acetate; 1,4-dioxane / 1 h / 25 °C 4.1: triethylamine; acetic acid / methanol / 25 °C 4.2: 24 h / 25 °C 5.1: ammonia / methanol / Resolution of racemate

Reference： [1]Zeng, Qingbei; Wang, Jiabing; Cheng, Ziqiang; Chen, Kan; Johnström, Peter; Varnäs, Katarina; Li, David Yunzhi; Yang, Zhen Fan; Zhang, Xiaolin [Journal of Medicinal Chemistry, 2015, vol. 58, # 20, p. 8200 - 8215]

29
[ 612501-80-1 ]
(S)-4-(3-chloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yl 3,4-dimethylpiperazine-1-carboxylate hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / methanol / 2 h / 10 - 15 °C 2: potassium carbonate / N,N-dimethyl-formamide / 16 h / 25 °C

Reference： [1]Zeng, Qingbei; Wang, Jiabing; Cheng, Ziqiang; Chen, Kan; Johnström, Peter; Varnäs, Katarina; Li, David Yunzhi; Yang, Zhen Fan; Zhang, Xiaolin [Journal of Medicinal Chemistry, 2015, vol. 58, # 20, p. 8200 - 8215]

30
[ 612501-80-1 ]
4-(3-chloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yl 4-methylpiperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / methanol / 2 h / 10 - 15 °C 2: potassium carbonate / N,N-dimethyl-formamide / 60 h / 25 °C

Reference： [1]Zeng, Qingbei; Wang, Jiabing; Cheng, Ziqiang; Chen, Kan; Johnström, Peter; Varnäs, Katarina; Li, David Yunzhi; Yang, Zhen Fan; Zhang, Xiaolin [Journal of Medicinal Chemistry, 2015, vol. 58, # 20, p. 8200 - 8215]

31
[ 612501-80-1 ]
(R)-4-(3-chloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yl 3,4-dimethylpiperazine-1-carboxylate hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / methanol / 2 h / 10 - 15 °C 2: potassium carbonate / N,N-dimethyl-formamide / 16 h / 25 °C

Reference： [1]Zeng, Qingbei; Wang, Jiabing; Cheng, Ziqiang; Chen, Kan; Johnström, Peter; Varnäs, Katarina; Li, David Yunzhi; Yang, Zhen Fan; Zhang, Xiaolin [Journal of Medicinal Chemistry, 2015, vol. 58, # 20, p. 8200 - 8215]

32
[ 612501-80-1 ]
(R)-4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl-2,4-dimethylpiperazinyl-1-carboxylic acid ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: potassium carbonate / methanol / 2 h / 10 - 15 °C 2: potassium carbonate / N,N-dimethyl-formamide / 25 °C 3: hydrogenchloride / methanol; water; 1,4-dioxane / 1 h / 25 °C 4: sodium cyanoborohydride / methanol / 25 °C

Reference： [1]Zeng, Qingbei; Wang, Jiabing; Cheng, Ziqiang; Chen, Kan; Johnström, Peter; Varnäs, Katarina; Li, David Yunzhi; Yang, Zhen Fan; Zhang, Xiaolin [Journal of Medicinal Chemistry, 2015, vol. 58, # 20, p. 8200 - 8215]

33
[ 612501-80-1 ]
4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl (2S)-2,4-dimethylpiperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / methanol / 2 h / 10 - 15 °C 2: potassium carbonate / N,N-dimethyl-formamide / 30 °C

Reference： [1]Zeng, Qingbei; Wang, Jiabing; Cheng, Ziqiang; Chen, Kan; Johnström, Peter; Varnäs, Katarina; Li, David Yunzhi; Yang, Zhen Fan; Zhang, Xiaolin [Journal of Medicinal Chemistry, 2015, vol. 58, # 20, p. 8200 - 8215]

34
[ 612501-80-1 ]
2-tert-butyl 5-(4-(3-chloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yl) 2,5-diazabicyclo[4.1.0]heptane-2,5-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / methanol / 2 h / 10 - 15 °C 2: potassium carbonate / N,N-dimethyl-formamide / 25 °C

Reference： [1]Zeng, Qingbei; Wang, Jiabing; Cheng, Ziqiang; Chen, Kan; Johnström, Peter; Varnäs, Katarina; Li, David Yunzhi; Yang, Zhen Fan; Zhang, Xiaolin [Journal of Medicinal Chemistry, 2015, vol. 58, # 20, p. 8200 - 8215]

35
[ 612501-80-1 ]
4-(3-chloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yl 2,5-diazabicyclo[4.1.0]heptane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium carbonate / methanol / 2 h / 10 - 15 °C 2: potassium carbonate / N,N-dimethyl-formamide / 25 °C 3: hydrogenchloride / water; ethyl acetate; 1,4-dioxane / 1 h / 25 °C

Reference： [1]Zeng, Qingbei; Wang, Jiabing; Cheng, Ziqiang; Chen, Kan; Johnström, Peter; Varnäs, Katarina; Li, David Yunzhi; Yang, Zhen Fan; Zhang, Xiaolin [Journal of Medicinal Chemistry, 2015, vol. 58, # 20, p. 8200 - 8215]

36
[ 612501-80-1 ]
4-(3-chloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yl 5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: potassium carbonate / methanol / 2 h / 10 - 15 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 25 °C 3.1: hydrogenchloride / water; ethyl acetate; 1,4-dioxane / 1 h / 25 °C 4.1: triethylamine; acetic acid / methanol / 25 °C 4.2: 24 h / 25 °C

Reference： [1]Zeng, Qingbei; Wang, Jiabing; Cheng, Ziqiang; Chen, Kan; Johnström, Peter; Varnäs, Katarina; Li, David Yunzhi; Yang, Zhen Fan; Zhang, Xiaolin [Journal of Medicinal Chemistry, 2015, vol. 58, # 20, p. 8200 - 8215]

37
[ 612501-80-1 ]
4‐tert‐butyl 1‐{4‐[(3‐chloro‐2‐fluorophenyl)amino]‐7‐methoxyquinazolin‐6‐yl} (2R)‐2‐methylpiperazine‐1,4‐dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / methanol / 2 h / 10 - 15 °C 2: potassium carbonate / N,N-dimethyl-formamide / 25 °C
	Multi-step reaction with 2 steps 1: potassium carbonate; methanol / 8 h / 20 °C 2: potassium carbonate / N,N-dimethyl-formamide / 10 h / 20 °C

Reference： [1]Zeng, Qingbei; Wang, Jiabing; Cheng, Ziqiang; Chen, Kan; Johnström, Peter; Varnäs, Katarina; Li, David Yunzhi; Yang, Zhen Fan; Zhang, Xiaolin [Journal of Medicinal Chemistry, 2015, vol. 58, # 20, p. 8200 - 8215]
[2]Current Patent Assignee: NANJING LEIZHENG PHARMACEUTICAL TECH - CN110903283, 2020, A

38
[ 612501-80-1 ]
4-tert-butyl-1-4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl (2R)-2-methylpiperazine-1,4-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium carbonate / methanol / 2 h / 10 - 15 °C 2: potassium carbonate / N,N-dimethyl-formamide / 25 °C 3: hydrogenchloride / methanol; water; 1,4-dioxane / 1 h / 25 °C
	Multi-step reaction with 3 steps 1: potassium carbonate; methanol / 8 h / 20 °C 2: potassium carbonate / N,N-dimethyl-formamide / 10 h / 20 °C 3: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C

Reference： [1]Zeng, Qingbei; Wang, Jiabing; Cheng, Ziqiang; Chen, Kan; Johnström, Peter; Varnäs, Katarina; Li, David Yunzhi; Yang, Zhen Fan; Zhang, Xiaolin [Journal of Medicinal Chemistry, 2015, vol. 58, # 20, p. 8200 - 8215]
[2]Current Patent Assignee: NANJING LEIZHENG PHARMACEUTICAL TECH - CN110903283, 2020, A

39
[ 612501-80-1 ]
potassium 4-(3-chloro-2-fluorophenylamino)-7-methoxyquinazolin-6-olate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium carbonate In methanol at 10 - 15℃; for 2h;

Reference： [1]Zeng, Qingbei; Wang, Jiabing; Cheng, Ziqiang; Chen, Kan; Johnström, Peter; Varnäs, Katarina; Li, David Yunzhi; Yang, Zhen Fan; Zhang, Xiaolin [Journal of Medicinal Chemistry, 2015, vol. 58, # 20, p. 8200 - 8215]

40
[ 612501-80-1 ]
C₂₂H₂₀⁽²⁾H₃ClFN₅O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: potassium carbonate; methanol / 8 h / 20 °C 2: potassium carbonate / N,N-dimethyl-formamide / 10 h / 20 °C 3: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 4: sodium hydride / tetrahydrofuran / 0 - 5 °C

Reference： [1]Current Patent Assignee: NANJING LEIZHENG PHARMACEUTICAL TECH - CN110903283, 2020, A

41
[ 612501-80-1 ]
C₂₂H₂₀⁽²⁾H₃ClFN₅O₃*ClH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: potassium carbonate; methanol / 8 h / 20 °C 2: potassium carbonate / N,N-dimethyl-formamide / 10 h / 20 °C 3: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 4: sodium hydride / tetrahydrofuran / 0 - 5 °C 5: hydrogenchloride / acetonitrile; water

Reference： [1]Current Patent Assignee: NANJING LEIZHENG PHARMACEUTICAL TECH - CN110903283, 2020, A

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	612501-80-1	MDL No. :	N/A
Formula :	C₁₇H₁₄Cl₂FN₃O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	RLTHSYZYTIYDTK-UHFFFAOYSA-N
M.W :	398.22	Pubchem ID :	57476866
Synonyms :

Num. heavy atoms :	26
Num. arom. heavy atoms :	16
Fraction Csp3 :	0.12
Num. rotatable bonds :	5
Num. H-bond acceptors :	6.0
Num. H-bond donors :	1.0
Molar Refractivity :	99.01
TPSA :	73.34 Å²

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.41 cm/s

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	4.67
Log Po/w (WLOGP) :	5.32
Log Po/w (MLOGP) :	3.48
Log Po/w (SILICOS-IT) :	3.67
Consensus Log Po/w :	3.43

[ CAS No. 612501-80-1 ] {[proInfo.proName]}

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Calculated chemistry of [ 612501-80-1 ]

Physicochemical Properties

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Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 612501-80-1 ]

Application In Synthesis of [ 612501-80-1 ]

[ 612501-80-1 ] Synthesis Path-Upstream 1~1

[ 612501-80-1 ] Synthesis Path-Downstream 1~41

Similar Product of
[ 612501-80-1 ]

Related Functional Groups of
[ 612501-80-1 ]

Fluorinated Building Blocks

Aryls

Chlorides

Ethers

Esters

Amines

Related Parent Nucleus of
[ 612501-80-1 ]

Quinazolines

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Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Log S (ESOL) :	-5.38
Solubility :	0.00167 mg/ml ; 0.0000042 mol/l
Class :	Moderately soluble
Log S (Ali) :	-5.94
Solubility :	0.00046 mg/ml ; 0.00000116 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-6.95
Solubility :	0.0000448 mg/ml ; 0.000000112 mol/l
Class :	Poorly soluble

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	2.84

Signal Word:	Warning	Class:
Precautionary Statements:	P261-P280-P301+P312-P302+P352-P305+P351+P338	UN#:
Hazard Statements:	H302-H315-H319-H335	Packing Group:
GHS Pictogram:

Yield	Reaction Conditions	Operation in experiment
77%	With ammonia In methanol; water at 50℃; for 2 h;	6-ACETOXY-4- (3-CHLORO-2-FLUOROANILINO)-7-METHOXYQUINAZOLINE hydrochloride (8.72 g, 21.9 mmol) was dissolved in methanol (200 ml). Concentrated aqueous ammonia (15 ML) was added, and the solution heated to 50°C with stirring for 2 hours, causing precipitation of a cream coloured solid. The solid was collected by filtration, washed with diethyl ether (3x 200 ml), and dried III VACUO at 60°C over diphosphorous pentoxide, giving 4- (3-CHLORO-2-FLUOROANILINO)-6-HYDROXY-7-METHOXYQUINAZOLINE as an off white solid (5.40 g, 77percent) ; 1H NMR : 3.95 (s, 3H), 7.19 (s, 1H), 7.23 (dd, 1H), 7.42 (dd, 1H), 7.50 (dd, 1H), 7.64 (s, 1H), 8. 32 (s, 1H), 9.43 (s, 1H), 9.67 (br. s, 1H); Mass Spectrum : 320.4, 322.4.
77%	at 50℃; for 2 h;	Reference Example 1; 6-Acetoxy-4- (3-chloro-2-fluoroanilino)-7-methoxyquinazoline hydrochloride; 6-Acetoxy-4-chloro-7-methoxyquinazoline (prepared as described in Example 25-5 of in WO01/66099, 6.00 g, 23.8 mmol) and 3-chloro-2-fluoroaniline (3.46 g, 23.8 mmol) were suspended in iso-propanol (200 ml). The mixture was heated to 80°C under reflux for 3 hours. The solvent was evaporated; the residue was crystallised from acetonitrile, giving the product hydrochloride as a pale pink crystalline solid (8.16 g, 92percent) ; 1H NMR : 2.37 (s, 3H), 4.00 (s, 3H), 7.34 (ddd, 1H), 7.48 (s, 1H), 7.52 (ddd, 1H), 7.61 (ddd, 1H), 8.62 (s, 1H), 8.86 (s, 1H) ; Mass Spectrum: 362.4, 364.4.
75.7%	Stage #1: With sodium hydroxide; water In methanol at 20 - 60℃; for 1 h;	Step 1: Preparation OF4- (3-CHLORO-2-FLUOROANILINO)-6-HVDROXV-7-METHOXYQUINAZOLINE; 6-Acetoxy-7-methoxy-4 (1H)-quinazolinone (150 g; prepared as described in W096/15118, Example 39 thereof), N, N-diisopropylethylamine (123 ml) and toluene (1275 ml) were stirred at 70°C, under nitrogen. Phosphorus oxychloride (150 ml) was added over 15 minutes to the slurry at 70°C. The mixture was held at 70°C for 2 hours to complete the chlorination. A dark brown solution formed after 30 minutes following addition of the phosphorus oxychloride. Toluene (680 ml) was added to the reaction mixture, followed by addition of 3-chloro-2-fluoroaniline (78 ml) over 10 minutes at 70°C. On completion of the addition, a solid precipitated resulting in a beige slurry. The slurry was held at 70°C for 1 hour and then cooled to ambient temperature. The reaction mixture was filtered and washed with toluene (2 x 300 ml), aqueous IMS (2 x 450 ml and IMS (2 x 450 ML). The solid was left to pull dry on the filter overnight to give 6-ACETOXY-4- (3-CHLORO-2-FLUOROANILINO)-7- methoxyquinazoline. HCl salt; NMR Spectrum: (DMSO d6) 2.39 (s, 3H); 4.02 (s, 3H); 7.36 (t, 1H) ; 7.58 (s, 1H); 7.64 (t, 1H) ; 8.79 (s, 1H) 8.91 (s, 1H); 11.93 (bs 1H); Mass Spectrum : M+H 362. 6-ACETOXY-4- (3-CHLORO-2-FLUOROANILINO)-7-METHOXYQUINAZOLINE. HCL salt (about 253 g), methanol (1900 ml) and water (632.5 ml) were stirred at ambient temperature. Sodium hydroxide solution (47percent w/w; 108 ml) was added dropwise and the reaction mixture heated to 60°C to form a dark solution. The solution was held at 60°C for 1 hour and then screened to a clean vessel. The mixture was cooled to ambient temperature before acetic acid (72. 8 ml) was charged. The precipitated solid was filtered, washed with 50percent aqueous methanol (500 ml) and methanol (500 ml), and then dried in a vacuum oven at 45°C to give 4- (3-CHLORO-2- fluoroanilino) -6-hydroxy-7-methoxyquinazoline; (204.8 g; 75.7percent yield); Melting point 265- 268°C ; NMR Spectrum : (DMSO d6) 4.01 (s, 3H); 7.24 (s, 2H); 7.32 (t, 1H); 7.51-7. 56 (m, 2H); 7.78 (s, 1H); 8.58 (s, 1H); Mass Spectrum: (M+H) + 320.

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

[ CAS No. 612501-80-1 ] {[proInfo.proName]}

Quality Control of [ 612501-80-1 ]

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Calculated chemistry of [ 612501-80-1 ]

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Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

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[ 612501-80-1 ] Synthesis Path-Upstream 1~1

[ 612501-80-1 ] Synthesis Path-Downstream 1~41

Similar Product of [ 612501-80-1 ]

Related Functional Groups of [ 612501-80-1 ]

Fluorinated Building Blocks

Aryls

Chlorides

Ethers

Esters

Amines

Related Parent Nucleus of [ 612501-80-1 ]

Quinazolines

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[ 612501-80-1 ]

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[ 612501-80-1 ]