183322-18-1

Basic information

• Product Name: 4-Chloro-6,7-bis(2-methoxyethoxy)quinazoline
• Synonyms: 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline;4-Chloro-6,7-(2-methoxyethoxy)quinazoline;4-Chloro-6,7-bis(2-methoxyethoxy)quinazolin;6,7-Bis(2-methoxyethoxy)-4-chloroquinazoline;Erlotinib Intermediate 1;4-chloro-6,7-di(2-methoxyethoxy)quinazoline;CP-335963;PF-508367
• CAS NO: 183322-18-1
• Molecular Formula: C₁₄H₁₇ClN₂O₄
• Molecular Weight: 312.74878
• EINECS: 1308068-626-2
• Product Categories: intermidiate of Erlotinib hydrochloride;API intermediates;Intermediate of erlotinib hydrochloride
• Mol File: 183322-18-1.mol
• Article Data: 51

Chemical Properties

• Melting Point: 105-107 °C
• Boiling Point: 446.7 °C at 760 mmHg
• Flash Point: 224 °C
• Appearance: white to off-white/
• Density: 1.257
• Vapor Pressure: 9.41E-08mmHg at 25°C
• Refractive Index: 1.561
• Storage Temp.: room temp
• Solubility: DMSO: ≥20mg/mL
• PKA: 0.54±0.30(Predicted)
• CAS DataBase Reference: 4-Chloro-6,7-bis(2-methoxyethoxy)quinazoline(CAS DataBase Reference)
• NIST Chemistry Reference: 4-Chloro-6,7-bis(2-methoxyethoxy)quinazoline(183322-18-1)
• EPA Substance Registry System: 4-Chloro-6,7-bis(2-methoxyethoxy)quinazoline(183322-18-1)

Safety Data

• Hazard Codes: Xn
• Statements: 22-41
• Safety Statements: 26-39
• WGK Germany: 3
• Hazardous Substances Data: 183322-18-1(Hazardous Substances Data)

Usage

Uses

4-Chloro-6,7-bis(2-methoxyethoxy)quinazoline is an aurora 2 kinase inhibitor, PDGF inhibitor, useful in the treatment of cancer.

InChI:InChI=1/C14H17ClN2O4/c1-18-3-5-20-12-7-10-11(16-9-17-14(10)15)8-13(12)21-6-4-19-2/h7-9H,3-6H2,1-2H3

Synthetic route

6,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one (179688-29-0) → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; trichlorophosphate In toluene Heating;	100%
With triethylamine; trichlorophosphate In toluene at 70 - 80℃; for 3h;	90%
Stage #1: 6,7-bis-(2-methoxyethoxy)-4(3H)quinazolinone With thionyl chloride; N,N-dimethyl-formamide In dichloromethane for 6h; Reflux; Stage #2: With sodium hydroxide In dichloromethane at 20℃; for 0.5h; pH=7 - 8;	89.5%
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane for 6h; Reflux;	89.5%

6,7-bis(2-methoxyethoxy)quinazolin-4-one hydrochloride → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions	Yield
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 50℃; for 3h;	99.3%

6,7-bis(2-methoxyethoxy)-3,4-dihydroquinazolin-4-one (179688-29-0) → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions	Yield
With oxalyl dichloride In chloroform; N,N-dimethyl-formamide for 1.5h; Heating;	98%
With oxalyl dichloride In dichloromethane Solvent; Reagent/catalyst; Temperature; Reflux; Large scale;	97%
With thionyl chloride In N,N-dimethyl-formamide at 60℃; Temperature; Concentration;	95.6%

C14H18N2O5 (179688-29-0) → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions	Yield
With trichlorophosphate In dichloromethane; N,N-dimethyl-formamide at 20℃; for 6h; Reagent/catalyst;	97.1%
With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 30℃; for 5 - 13h; Product distribution / selectivity; Heating / reflux;
Stage #1: C14H18N2O5 With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 30℃; for 5h; Heating / reflux; Stage #2: With sodium hydroxide In dichloromethane; water; N,N-dimethyl-formamide at 25℃; for 0.25 - 0.333333h; pH=7 - 8;
Stage #1: C14H18N2O5 With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 30℃; for 5h; Heating / reflux; Stage #2: With sodium hydroxide In dichloromethane; water; N,N-dimethyl-formamide at 25℃; for 0.25 - 0.333333h; pH=7 - 8;
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane for 5 - 13h; Product distribution / selectivity; Heating / reflux;

6,7-bis(2-methoxyethoxy)quinazolone → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions	Yield
	92%
	92%
With oxalyl dichloride; N,N-dimethyl-formamide In methanol for 1.5h; Reflux;	92%
With oxalyl dichloride In chloroform; N,N-dimethyl-formamide for 1.5h; Heating / reflux;

C13H19NO5 (1006377-63-4) → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: acetic anhydride / 110 °C 2.1: 85 percent / aq. nitric acid / acetic acid / 8 h / 45 - 50 °C 3.1: FeCl3; hydrazine hydrate / H2O; methanol / 3 h / Heating 3.2: 81 percent / HCl / H2O / 90 - 130 °C 4.1: 94 percent / thionyl chloride / dimethylformamide / 2 h / Heating View Scheme

3,4-bis(2-methoxyethoxy) benzonitrile (80407-68-7) → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 85 percent / aq. nitric acid / acetic acid / 8 h / 45 - 50 °C 2.1: FeCl3; hydrazine hydrate / H2O; methanol / 3 h / Heating 2.2: 81 percent / HCl / H2O / 90 - 130 °C 3.1: 94 percent / thionyl chloride / dimethylformamide / 2 h / Heating View Scheme
Multi-step reaction with 5 steps 1: nitric acid 2: dihydrogen peroxide 3: palladium on activated charcoal; ammonium formate 4: water / 24 h / 130 °C 5: trichlorophosphate; triethylamine View Scheme

2-nitro-4,5-bis(2-methoxyethoxy)benzonitrile (236750-65-5) → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: FeCl3; hydrazine hydrate / H2O; methanol / 3 h / Heating 1.2: 81 percent / HCl / H2O / 90 - 130 °C 2.1: 94 percent / thionyl chloride / dimethylformamide / 2 h / Heating View Scheme
Multi-step reaction with 3 steps 1: hydrazine hydrate / water / 3 h / 20 - 30 °C 2: trifluoroacetic acid / ethyl acetate / 4 h / Reflux 3: trichlorophosphate; N,N-dimethyl-formamide / ethyl acetate / 2 h / 70 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1: dihydrogen peroxide 2: palladium on activated charcoal; ammonium formate 3: water / 24 h / 130 °C 4: trichlorophosphate; triethylamine View Scheme

3,4-bis(2-methoxyethoxy)benzaldehyde (80407-64-3) → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: hydroxylamine hydrochloride; pyridine / methanol / Heating 2.1: acetic anhydride / 110 °C 3.1: 85 percent / aq. nitric acid / acetic acid / 8 h / 45 - 50 °C 4.1: FeCl3; hydrazine hydrate / H2O; methanol / 3 h / Heating 4.2: 81 percent / HCl / H2O / 90 - 130 °C 5.1: 94 percent / thionyl chloride / dimethylformamide / 2 h / Heating View Scheme
Multi-step reaction with 6 steps 1: hydroxylamine hydrochloride; acetic anhydride 2: nitric acid 3: dihydrogen peroxide 4: palladium on activated charcoal; ammonium formate 5: water / 24 h / 130 °C 6: trichlorophosphate; triethylamine View Scheme

3,4-dihydroxybenzaldehyde (139-85-5) → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: 98 percent / potassium carbonate / dimethylformamide / 100 °C 2.1: hydroxylamine hydrochloride; pyridine / methanol / Heating 3.1: acetic anhydride / 110 °C 4.1: 85 percent / aq. nitric acid / acetic acid / 8 h / 45 - 50 °C 5.1: FeCl3; hydrazine hydrate / H2O; methanol / 3 h / Heating 5.2: 81 percent / HCl / H2O / 90 - 130 °C 6.1: 94 percent / thionyl chloride / dimethylformamide / 2 h / Heating View Scheme

Ethyl protocatechuate (3943-89-3) → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: potassium carbonate; tetrabutylammonium iodide / acetone / 120 h / Heating 2: acetic acid; nitric acid / 24 h / 20 °C 3: hydrogen / PtO2*H2O / methanol / 20 °C / 2585.74 Torr 4: 84 percent / 12 h / 165 - 170 °C 5: phosphoryl choride; N,N-diethylaniline / 0.67 h / 70 - 90 °C View Scheme
Multi-step reaction with 5 steps 1: potassium carbonate; tetrabutylammonium iodide / acetone 2: acetic acid; nitric acid / 24 h / 20 °C 3: hydrogen / PtO2*H2O / methanol / 20 °C / 2585.74 Torr 4: 84 percent / 12 h / 165 - 170 °C 5: phosphoryl choride; N,N-diethylaniline / 0.67 h / 70 - 90 °C View Scheme
Multi-step reaction with 5 steps 1: 68 percent / potassium carbonate; tetrabutylammonium iodide / acetone / 72 h / Heating 2: nitric acid; trifluoroacetic acid / CH2Cl2 / 20 °C 3: 94 percent / hydrogen / palladium on activated carbon / methanol 4: 62 percent / formamide / 3 h / 160 °C 5: 98 percent / oxalyl chloride / CHCl3; dimethylformamide / 1.5 h / Heating View Scheme

3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9) → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: acetic acid; nitric acid / 24 h / 20 °C 2: hydrogen / PtO2*H2O / methanol / 20 °C / 2585.74 Torr 3: 84 percent / 12 h / 165 - 170 °C 4: phosphoryl choride; N,N-diethylaniline / 0.67 h / 70 - 90 °C View Scheme
Multi-step reaction with 4 steps 1: nitric acid; trifluoroacetic acid / CH2Cl2 / 20 °C 2: 94 percent / hydrogen / palladium on activated carbon / methanol 3: 62 percent / formamide / 3 h / 160 °C 4: 98 percent / oxalyl chloride / CHCl3; dimethylformamide / 1.5 h / Heating View Scheme
Multi-step reaction with 3 steps 1.1: nitric acid / acetic acid / 24 h / 20 °C / cooling with ice-water 2.1: ammonium formate / 5%-palladium/activated carbon / 7 h / 150 °C 3.1: thionyl chloride / N,N-dimethyl-formamide / dichloromethane / 6 h / Reflux 3.2: 0.5 h / 20 °C / pH 7 - 8 View Scheme

ethyl 2-amino-4,5-bis(2-methoxyethoxy)-benzoate (179688-27-8) → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 84 percent / 12 h / 165 - 170 °C 2: phosphoryl choride; N,N-diethylaniline / 0.67 h / 70 - 90 °C View Scheme
Multi-step reaction with 2 steps 1: 62 percent / formamide / 3 h / 160 °C 2: 98 percent / oxalyl chloride / CHCl3; dimethylformamide / 1.5 h / Heating View Scheme
Multi-step reaction with 2 steps 1.1: N,N-dimethyl-formamide / 10 h / 130 - 140 °C 1.2: 65 - 80 °C 2.1: trichlorophosphate; triethylamine / toluene / 3 h / 70 - 80 °C View Scheme

2-nitro-4,5-bis(2-methoxyethoxy)benzoic acid ethyl ester (179688-26-7) → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogen / PtO2*H2O / methanol / 20 °C / 2585.74 Torr 2: 84 percent / 12 h / 165 - 170 °C 3: phosphoryl choride; N,N-diethylaniline / 0.67 h / 70 - 90 °C View Scheme
Multi-step reaction with 3 steps 1: 94 percent / hydrogen / palladium on activated carbon / methanol 2: 62 percent / formamide / 3 h / 160 °C 3: 98 percent / oxalyl chloride / CHCl3; dimethylformamide / 1.5 h / Heating View Scheme
Multi-step reaction with 2 steps 1.1: ammonium formate / 5%-palladium/activated carbon / 7 h / 150 °C 2.1: thionyl chloride / N,N-dimethyl-formamide / dichloromethane / 6 h / Reflux 2.2: 0.5 h / 20 °C / pH 7 - 8 View Scheme

3,4-Dihydroxybenzoic acid (99-50-3) → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions	Yield
Multi-step reaction with 6 steps 1: 98 percent / H2SO4 / Heating 2: 99 percent / K2CO3; TBAI / acetone / Heating 3: 85 percent / HNO3; Ac2O / 20 °C 4: 100 percent / H2 / Pd/C / ethanol 5: 90 percent / 160 °C 6: 100 percent / POCl3; diisopropylethylamine / toluene / Heating View Scheme
Multi-step reaction with 6 steps 1.1: sulfuric acid / 10 h / 40 - 80 °C 2.1: potassium tert-butylate; potassium iodide / N,N-dimethyl-formamide / 12 h / 100 °C 3.1: sulfuric acid; nitric acid / 1 h / 20 °C / Darkness 4.1: palladium 10% on activated carbon / ethanol / 10 h / 20 °C 4.2: 20 °C 5.1: ammonium formate; triethylamine / 6 h / 160 °C 6.1: oxalyl dichloride / N,N-dimethyl-formamide; dichloromethane / 3 h / 50 °C View Scheme

3,4-dihydroxybenzoic acid methyl ester (2150-43-8) → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: 99 percent / K2CO3; TBAI / acetone / Heating 2: 85 percent / HNO3; Ac2O / 20 °C 3: 100 percent / H2 / Pd/C / ethanol 4: 90 percent / 160 °C 5: 100 percent / POCl3; diisopropylethylamine / toluene / Heating View Scheme

methyl 3,4-bis{[2-(methyloxy)ethyl]oxy}benzoate (179688-14-3) → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: 85 percent / HNO3; Ac2O / 20 °C 2: 100 percent / H2 / Pd/C / ethanol 3: 90 percent / 160 °C 4: 100 percent / POCl3; diisopropylethylamine / toluene / Heating View Scheme
Multi-step reaction with 4 steps 1: nitric acid; acetic anhydride; acetic acid / acetic acid / 0 - 5 °C 2: hydrogen / ethanol 3: ethanol / Reflux 4: thionyl chloride / N,N-dimethyl-formamide / Reflux View Scheme

2-amino-4,5-bis-(2-methoxyethoxy)-benzoic acid methyl ester (476168-17-9) → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 90 percent / 160 °C 2: 100 percent / POCl3; diisopropylethylamine / toluene / Heating View Scheme
Multi-step reaction with 2 steps 1: ethanol / Reflux 2: thionyl chloride / N,N-dimethyl-formamide / Reflux View Scheme
Multi-step reaction with 2 steps 1: formamide / 160 - 165 °C 2: thionyl chloride / N,N-dimethyl-formamide / 0.67 h / 85 °C View Scheme

methyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate (501684-22-6) → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 100 percent / H2 / Pd/C / ethanol 2: 90 percent / 160 °C 3: 100 percent / POCl3; diisopropylethylamine / toluene / Heating View Scheme
Multi-step reaction with 3 steps 1: hydrogen / ethanol 2: ethanol / Reflux 3: thionyl chloride / N,N-dimethyl-formamide / Reflux View Scheme

2-methoxy-ethanol (109-86-4) + 4-chloro-6,7-dihydroxyquinazoline (1145671-36-8) → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions	Yield
With PS-triphenylphosphine; di-tert-butyl-diazodicarboxylate In dichloromethane at 0 - 20℃; Mitsunobu reaction;

ethyl 2-amino-4,5-bis-(2-methoxyethoxy)benzoate hydrochloride → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 25 - 145 °C 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / Reflux View Scheme
Multi-step reaction with 2 steps 1: ammonium formate / 3 h / 160 - 165 °C / Inert atmosphere 2: oxalyl dichloride; N,N-dimethyl-formamide / methanol / 1.5 h / Reflux View Scheme
Multi-step reaction with 2 steps 1: ammonium formate / 3 h / 160 - 165 °C / Inert atmosphere 2: pyridine; trichlorophosphate / 2.5 h / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: formic acid / 160 °C / Large scale 2: oxalyl dichloride / dichloromethane / Reflux; Large scale View Scheme
Multi-step reaction with 2 steps 1: ammonium formate; triethylamine / 6 h / 160 °C 2: oxalyl dichloride / N,N-dimethyl-formamide; dichloromethane / 3 h / 50 °C View Scheme

C22H29NO8S → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions

Yield

Multi-step reaction with 6 steps 1: sodium hydroxide / methanol / 2 h / 20 °C 2: dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; silver hexafluoroantimonate; [bis(acetoxy)iodo]benzene / dichloromethane / 16 h / 40 °C / Inert atmosphere 3: sodium hydroxide / ethanol / 20 °C 4: ethanol / 1 h / Reflux 5: hydrogenchloride / water / 2 h / 100 - 105 °C 6: trichlorophosphate / toluene / 4 h / Reflux View Scheme

3,4-bis(2-methoxyethoxy)-benzoic acid (819813-71-3) → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions	Yield
Multi-step reaction with 9 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 3 h / 0 - 20 °C 2: triethylamine / dichloromethane / 0 - 20 °C 3: triethylamine; dmap / dichloromethane / 24 h / 20 °C 4: sodium hydroxide / methanol / 2 h / 20 °C 5: dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; silver hexafluoroantimonate; [bis(acetoxy)iodo]benzene / dichloromethane / 16 h / 40 °C / Inert atmosphere 6: sodium hydroxide / ethanol / 20 °C 7: ethanol / 1 h / Reflux 8: hydrogenchloride / water / 2 h / 100 - 105 °C 9: trichlorophosphate / toluene / 4 h / Reflux View Scheme
Multi-step reaction with 5 steps 1: sulfuric acid / Cooling with ice; Reflux 2: nitric acid; acetic acid / 24.5 h / 0 - 20 °C 3: palladium 10% on activated carbon; hydrogen / methanol / 12 h 4: 12 h / 165 - 170 °C / Inert atmosphere 5: trichlorophosphate / 6 h / Reflux View Scheme

C13H17ClO5 → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions

Yield

Multi-step reaction with 8 steps 1: triethylamine / dichloromethane / 0 - 20 °C 2: triethylamine; dmap / dichloromethane / 24 h / 20 °C 3: sodium hydroxide / methanol / 2 h / 20 °C 4: dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; silver hexafluoroantimonate; [bis(acetoxy)iodo]benzene / dichloromethane / 16 h / 40 °C / Inert atmosphere 5: sodium hydroxide / ethanol / 20 °C 6: ethanol / 1 h / Reflux 7: hydrogenchloride / water / 2 h / 100 - 105 °C 8: trichlorophosphate / toluene / 4 h / Reflux View Scheme

C15H23NO6 → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions

Yield

Multi-step reaction with 7 steps 1: triethylamine; dmap / dichloromethane / 24 h / 20 °C 2: sodium hydroxide / methanol / 2 h / 20 °C 3: dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; silver hexafluoroantimonate; [bis(acetoxy)iodo]benzene / dichloromethane / 16 h / 40 °C / Inert atmosphere 4: sodium hydroxide / ethanol / 20 °C 5: ethanol / 1 h / Reflux 6: hydrogenchloride / water / 2 h / 100 - 105 °C 7: trichlorophosphate / toluene / 4 h / Reflux View Scheme

2-(3,4-bis(2-methoxyethoxy)phenyl)-4,5-dihydro-oxazole → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; silver hexafluoroantimonate; [bis(acetoxy)iodo]benzene / dichloromethane / 16 h / 40 °C / Inert atmosphere 2: sodium hydroxide / ethanol / 20 °C 3: ethanol / 1 h / Reflux 4: hydrogenchloride / water / 2 h / 100 - 105 °C 5: trichlorophosphate / toluene / 4 h / Reflux View Scheme

C17H21F3N2O6 → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium hydroxide / ethanol / 20 °C 2: ethanol / 1 h / Reflux 3: hydrogenchloride / water / 2 h / 100 - 105 °C 4: trichlorophosphate / toluene / 4 h / Reflux View Scheme

2-(4,5-dihydro-1,3-oxazol-2-yl)-4,5-bis(2-methoxyethoxy)aniline → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: ethanol / 1 h / Reflux 2: hydrogenchloride / water / 2 h / 100 - 105 °C 3: trichlorophosphate / toluene / 4 h / Reflux View Scheme

2-((6,7-bis(2-methoxyethoxy))-4-quinazolinylamino)-ethanol → 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride / water / 2 h / 100 - 105 °C 2: trichlorophosphate / toluene / 4 h / Reflux View Scheme

4-Iodophenol (540-38-5) + 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → 4-(4-iodo-phenoxy)-6,7-bis-(2-methoxy-ethoxy)-quinazoline (882511-67-3)

Conditions	Yield
With potassium carbonate In isopropyl alcohol Heating;	100%

3-Iodoaniline (626-01-7) + 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → [6,7-bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-iodo-phenyl)-amine (882511-64-0)

Conditions	Yield
With isopropyl alcohol Heating;	100%

p-aminoiodobenzene (540-37-4) + 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → [6,7-bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(4-iodo-phenyl)-amine (882511-65-1)

Conditions	Yield
With isopropyl alcohol Heating;	100%

2-methyl-4-(3-aminophenyl)-3-butyn-2-ol (69088-96-6) + 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → 3-butyn-2-ol, 4-[3-[[6,7-bis(2-methoxyethoxy)-4-quinazolinyl]amine]phenyl]-2-methyl, hydrochloride (299912-59-7)

Conditions	Yield
In acetonitrile at 25℃; for 5h; Inert atmosphere; Reflux;	100%
In acetonitrile for 5h; Inert atmosphere; Reflux;	100%

1-tert-butyloxycarbonyl-4-(4-amino-2-methylphenyloxy)piperidine (138227-69-7) + 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → [6,7-Bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-[3-methyl-4-(piperidin-4-yloxy)-phenyl]-amine hydrochloride

Conditions	Yield
Stage #1: 1-tert-butyloxycarbonyl-4-(4-amino-2-methylphenyloxy)piperidine; 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline In 1,2-dichloro-ethane; tert-butyl alcohol at 90℃; for 1h; Stage #2: With hydrogenchloride In 1,2-dichloro-ethane; tert-butyl alcohol at 20℃; for 0.166667h;	99%

3-acetylenephenylamine (54060-30-9) + 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
In isopropyl alcohol for 18h; Heating;	98%
In iso-propanol (IPA) for 0.5h; Product distribution / selectivity; Heating / reflux;	97%
Stage #1: 3-acetylenephenylamine; 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline In N,N-dimethyl-formamide; acetonitrile at 90℃; for 7h; Darkness; Stage #2: With hydrogenchloride In water at 15 - 30℃; Temperature; Solvent;	97.6%

1,2-dimethylindole (875-79-6) + 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → 4-(1,2-dimethyl-1H-indol-3-yl)-6,7-bis(2-methoxyethoxy)quinazoline

Conditions	Yield
With 1,1,1,3',3',3'-hexafluoro-propanol; bis(trifluoromethanesulfonyl)amide at 100℃; for 6h; Sealed tube;	98%

1-ethyl-2-phenyl-1H-indole (13228-39-2) + 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → 4-(1-ethyl-2-phenyl-1H-indol-3-yl)-6,7-bis(2-methoxyethoxy)quinazoline

Conditions	Yield
With 1,1,1,3',3',3'-hexafluoro-propanol; bis(trifluoromethanesulfonyl)amide at 100℃; for 6h; Sealed tube;	98%

4-methoxy-aniline (104-94-9) + 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → 6,7-bis(2-methoxyethoxy)-N-(4-methoxyphenyl)quinazolin-4-amine (299912-64-4)

Conditions	Yield
In isopropyl alcohol at 80℃; for 0.666667h; Temperature;	97.21%
In water; isopropyl alcohol

3-acetylenephenylamine (54060-30-9) + 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → erlotinib (183321-74-6)

Conditions	Yield
In isopropyl alcohol Concentration; Reflux;	96.6%
In isopropyl alcohol Temperature; Reflux;	96.6%
In isopropyl alcohol at 20℃; Concentration; Temperature; Reflux;	96.6%

2-(3-aminophenyl)ethan-1-ol (52273-77-5) + 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → 2-(3-((6,7-bis(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)ethan-1-ol

Conditions	Yield
With pyridine In isopropyl alcohol for 4h; Reflux; Inert atmosphere;	96%

ethyl (E)-3-(3-aminophenyl)acrylate (125872-97-1) + 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → ethyl (E)-3-(3-((6,7-bis(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)acrylate (1453173-53-9)

Conditions	Yield
In isopropyl alcohol for 5h; Reflux;	93.6%

3-biphenyl amine (2243-47-2) + 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → [6,7-di(2-methoxyethoxy)quinazolin-4-yl]-(biphenyl-3'-yl)amine hydrochloride (1456819-76-3)

Conditions	Yield
In isopropyl alcohol at 80℃; for 0.25h; Microwave irradiation;	93%

m-ethylaniline (587-02-0) + 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → N-(3-ethylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine (299912-61-1)

Conditions	Yield
In water; ethyl acetate; isopropyl alcohol	90%

3-chloro-4-(3-(2-nitro-1H-imidazol-1-yl)propoxy)aniline + 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → N-(3-chloro-4-(3-(2-nitro-1H-imidazol-1-yl)propoxy)phenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine

Conditions	Yield
In isopropyl alcohol for 2h; Reflux;	89%

(2-amino-6-bromophenyl)methanol (861106-92-5) + 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → C21H24BrN3O5 (1347720-73-3)

Conditions	Yield
With pyridine In acetonitrile for 4h; Reflux;	88.89%
With pyridine In acetonitrile for 4h; Reflux;	88.89%

4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → 6,7-bis(2-methoxyethoxy)-N-[3-[(trimethylsilyl)ethynyl]phenyl]-4-quinazolinamine, monohydrochloride (299912-58-6)

Conditions	Yield
With aniline In isopropyl alcohol	88%

(2-amino-6-chlorophenyl)methanol (39885-08-0) + 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → C21H24ClN3O5 (1347720-70-0)

Conditions	Yield
In isopropyl alcohol for 4h; Reflux;	87.63%
In isopropyl alcohol for 4h; Reflux;	87.63%

methyl 3-amino-1H-pyrrole-2-carboxylate (1326566-41-9) + 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → methyl 3-(6,7-bis(2-methoxyethoxy)quinazolin-4-ylamino)-1H-pyrrole-2-carboxylate (1326566-33-9)

Conditions	Yield
In isopropyl alcohol for 4h; Reflux;	87%

1-(2-amino-4-chlorophenyl)pentyl-1-alcohol (1347720-50-6) + 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → C25H32ClN3O5 (1347721-31-6)

Conditions	Yield
With sulfuric acid In isopropyl alcohol at 20℃;	86.67%

2-amino-6-nitrobenzyl alcohol (98451-51-5) + 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → C21H24N4O7 (1347720-82-4)

Conditions	Yield
With hydrogenchloride In 1,4-dioxane; water at 20℃; for 7h;	86.46%
With hydrogenchloride In 1,4-dioxane; water at 20℃; for 7h;	86.46%

2-amino-6-cyanobenzyl alcohol (1347720-24-4) + 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → C22H24N4O5 (1347720-85-7)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 20℃;	86.3%

(2-amino-6-methoxyphenyl)methanol (177531-95-2) + 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → C22H27N3O6 (1347720-91-5)

Conditions	Yield
In acetonitrile at 20℃;	86.24%

1-methylindole (603-76-9) + 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (183322-18-1) → 6,7-bis(2-methoxyethoxy)-4-(1-methyl-1H-indol-3-yl)quinazoline

Conditions	Yield
With 1,1,1,3',3',3'-hexafluoro-propanol; bis(trifluoromethanesulfonyl)amide at 100℃; for 6h; Sealed tube;	86%

Upstream product

• 1172625-04-5 4,5-bis(2-methoxyethoxy)-2-nitrobenzamide 
• 236750-62-2 2-amino-4,5-bis[(2-methoxy)ethoxy]benzamide 
• 819813-71-3 3,4-bis(2-methoxyethoxy)-benzoic acid 
• 183322-17-0 ethyl 2-amino-4,5-bis-(2-methoxyethoxy)benzoate hydrochloride 
• 109-86-4 2-methoxy-ethanol 
• 1145671-36-8 4-chloro-6,7-dihydroxyquinazoline 
• 179688-29-0 C₁₄H₁₈N₂O₅ 
• 139-85-5 3,4-dihydroxybenzaldehyde 
• 80407-64-3 3,4-bis(2-methoxyethoxy)benzaldehyde 
• 236750-65-5 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile 
• 80407-68-7 3,4-bis(2-methoxyethoxy)-benzonitrile 
• 1006377-63-4 C₁₃H₁₉NO₅ 

Downstream Products

• 882511-67-3 4-(4-iodo-phenoxy)-6,7-bis-(2-methoxy-ethoxy)-quinazoline 
• 882511-65-1 [6,7-bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(4-iodo-phenyl)-amine 
• 1145671-52-8 6,7-bis(2-methoxyethoxy)-N-phenylquinazolin-4-amine 
• 1234579-30-6 1-{5-[6,7-bis(2-methoxyethoxy)quinazolin-4-ylthio][1,3,4]thiadiazol-2-yl}-3-(3-chlorophenyl)urea 
• 1370256-71-5 1-{5-[6,7-bis(2-methoxyethoxy)quinazolin-4-ylthio][1,3,4]thiadiazol-2-yl}-3-(3-fluorophenyl)urea 
• 1370256-72-6 1-{5-[6,7-bis(2-methoxyethoxy)quinazolin-4-ylthio][1,3,4]thiadiazol-2-yl}-3-(3-bromophenyl)urea 
• 1370256-73-7 1-{5-[6,7-bis(2-methoxyethoxy)quinazolin-4-ylthio][1,3,4]thiadiazol-2-yl}-3-(3-ethynylphenyl)urea 
• 1234579-28-2 2-{2-[6,7-bis(2-methoxyethoxy)quinazolin-4-ylthio]-4-methylthiazol-5-yl}-N-(3-chlorophenyl)acetamide 
• 1234579-26-0 2-{2-[6,7-bis(2-methoxyethoxy)quinazolin-4-ylthio]-4-methylthiazol-5-yl}-N-[3-(trifluoromethyl)phenyl]acetamide 
• 1234579-27-1 2-{2-[6,7-bis(2-methoxyethoxy)quinazolin-4-ylthio]-4-methylthiazol-5-yl}-N-[4-(trifluoromethyl)phenyl]acetamide 
• 1234579-29-3 2-{2-[6,7-bis(2-methoxyethoxy)quinazolin-4-ylthio]-4-methylthiazol-5-yl}-N-(3,5-dimethylphenyl)acetamide 
• 1370256-65-7 2-{2-[6,7-bis(2-methoxyethoxy)quinazolin-4-ylthio]thiazol-4-yl}-N-(3-chlorophenyl)acetamide 
• 1370256-66-8 2-{2-[6,7-bis(2-methoxyethoxy)quinazolin-4-ylthio]thiazol-4-yl}-N-[3-(trifluoromethyl)phenyl]acetamide 
• 1370256-68-0 2-{2-[6,7-bis(2-methoxyethoxy)quinazolin-4-ylthio]thiazol-4-yl}-N-(3,5-dimethylphenyl)acetamide 

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