183322-16-9

Basic information

• Product Name: Ethyl 3,4-bis(2-methoxyethoxy)benzoate
• Synonyms: 3,4-Bis(2-methoxyethoxy)benzoic acid ethyl ester;Ethyl 3,4-bis(2-methoxyethoxy)benzoate;Thyl3,4-bis(2-methoxyethoxy)benzoate;Erlotinib interMediate II;Benzoic acid,3,4-bis(2-Methoxyethoxy)-, ethyl ester;183322-16-9;3,4-bis(2-methoxyethoxy)benzoate;Ethyl 3,4-bis(2-methoxyethoxy)
• CAS NO: 183322-16-9
• Molecular Formula: C₁₅H₂₂O₆
• Molecular Weight: 298.33158
• EINECS: 1312995-182-4
• Product Categories: Erlotinib
• Mol File: 183322-16-9.mol
• Article Data: 22

Chemical Properties

• Melting Point: 55-58 °C
• Boiling Point: 401.7 °C at 760 mmHg
• Flash Point: 175.5 °C
• Appearance: /
• Density: 1.102
• Vapor Pressure: 1.15E-06mmHg at 25°C
• Refractive Index: 1.488
• Storage Temp.: Sealed in dry,Room Temperature
• CAS DataBase Reference: Ethyl 3,4-bis(2-methoxyethoxy)benzoate(CAS DataBase Reference)
• NIST Chemistry Reference: Ethyl 3,4-bis(2-methoxyethoxy)benzoate(183322-16-9)
• EPA Substance Registry System: Ethyl 3,4-bis(2-methoxyethoxy)benzoate(183322-16-9)

Safety Data

• Hazardous Substances Data: 183322-16-9(Hazardous Substances Data)

Usage

Uses

3,4-bis(2-Methoxyethoxy)benzoic Acid Ethyl Ester is a compound used in the synthesis of Erlotinib (E625008), a cancer treatment medicine.

InChI:InChI=1/C15H22O6/c1-4-19-15(16)12-5-6-13(20-9-7-17-2)14(11-12)21-10-8-18-3/h5-6,11H,4,7-10H2,1-3H3

Synthetic route

Ethyl protocatechuate (3943-89-3) + 2-Bromoethyl methyl ether (6482-24-2) → 3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9)

Conditions	Yield
With potassium carbonate; potassium iodide In acetone at 60℃; for 19h; Inert atmosphere;	100%
With potassium carbonate In acetone at 20 - 70℃; for 24h;	93%
With tetra-(n-butyl)ammonium iodide; potassium carbonate In acetone for 64h; Inert atmosphere; Reflux;	93%

3,4-bis(2-methoxyethoxy)-benzoic acid (819813-71-3) + ethanol (64-17-5) → 3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9)

Conditions	Yield
With sulfuric acid Cooling with ice; Reflux;	98%

2-chloroethyl methyl ether (627-42-9) + Ethyl protocatechuate (3943-89-3) → 3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9)

Conditions	Yield
With 4-(Methylamino)pyridine; potassium carbonate at 90 - 95℃; Temperature; Reagent/catalyst;	95%
With carbon dioxide; ammonia at 50℃; for 0.5h; Temperature; Reagent/catalyst;	94.6%
With potassium tert-butylate; potassium iodide In N,N-dimethyl-formamide at 100℃; for 12h;	87%
With tetra-(n-butyl)ammonium iodide; potassium carbonate In acetone for 120h; Heating;
With potassium carbonate In N,N-dimethyl-formamide at 90 - 100℃; for 9h;	95 %Chromat.

2-methoxyethyl methanesulfonate (16427-44-4) + Ethyl protocatechuate (3943-89-3) → 3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9)

Conditions	Yield
With tetrabutylammomium bromide; potassium carbonate In toluene for 6h; Reflux;	95%
With potassium tert-butylate; tetrabutylammomium bromide In N,N-dimethyl-formamide at 30 - 40℃; for 10h;	90.5%

Ethyl protocatechuate (3943-89-3) + 2-methoxy-ethyl p-toluenesulfonyloxy ester (17178-10-8) → 3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9)

Conditions	Yield
With potassium carbonate In acetonitrile for 6h; Reflux;	89%
With potassium carbonate In acetonitrile for 6h; Reflux;	89%

4-chloro-6,7-di-(2-methoxyethoxy)quinazoline hydrochloride + Ethyl protocatechuate (3943-89-3) + 2-Bromoethyl methyl ether (6482-24-2) → 3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9)

Conditions	Yield
With potassium carbonate In acetone

3,4-Dihydroxybenzoic acid (99-50-3) → 3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: sulfuric acid / 10 h / 40 - 80 °C 2: potassium tert-butylate; potassium iodide / N,N-dimethyl-formamide / 12 h / 100 °C View Scheme

3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9) → 2-nitro-4,5-bis(2-methoxyethoxy)benzoic acid ethyl ester (179688-26-7)

Conditions	Yield
With sulfuric acid; nitric acid In acetic acid at 20 - 70℃; for 2h;	100%
With sulfuric acid; nitric acid In acetic acid at 15 - 35℃;	100%
With sulfuric acid; nitric acid; acetic anhydride; acetic acid at 40℃; for 2h; Concentration; Large scale;	98.3%

3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9) → C15H22O7

Conditions	Yield
Stage #1: 3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester In tetrahydrofuran for 0.5h; Reflux; Stage #2: With peracetic acid; dinitrogen monoxide In tetrahydrofuran at 50℃; under 22502.3 Torr; for 2h; Reagent/catalyst; Temperature; Autoclave;	95.2%

3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9) → 3,4-bis(2-methoxyethoxy)-benzoic acid (819813-71-3)

Conditions	Yield
With potassium hydroxide In ethanol; water at 20℃; for 3h;	90%

3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9) → 6,7-bis(2-methoxyethoxy)-3,4-dihydroquinazolin-4-one (179688-29-0)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 3 steps 1: acetic acid; nitric acid / 0 °C 2: hydrogen; palladium on activated charcoal / methanol 3: 165 - 170 °C 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

3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9) → erlotinib hydrochloride (183319-69-9)

Conditions	Yield
Multi-step reaction with 5 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 5: pyridine / propan-2-ol View Scheme
Multi-step reaction with 6 steps 1.1: sulfuric acid; nitric acid / 1 h / 20 °C / Darkness 2.1: palladium 10% on activated carbon / ethanol / 10 h / 20 °C 2.2: 20 °C 3.1: ammonium formate; triethylamine / 6 h / 160 °C 4.1: oxalyl dichloride / N,N-dimethyl-formamide; dichloromethane / 3 h / 50 °C 5.1: methanol / 3 h / 20 - 30 °C 5.2: 3 h / 50 °C 6.1: hydrogenchloride / water; dichloromethane; methanol / 3 h / 25 °C View Scheme

3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9) → ethyl 2-amino-4,5-bis(2-methoxyethoxy)-benzoate (179688-27-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: acetic acid; nitric acid / 24 h / 20 °C 2: hydrogen / PtO2*H2O / methanol / 20 °C / 2585.74 Torr View Scheme
Multi-step reaction with 2 steps 1: nitric acid; trifluoroacetic acid / CH2Cl2 / 20 °C 2: 94 percent / hydrogen / palladium on activated carbon / methanol View Scheme
Multi-step reaction with 2 steps 1: sulfuric acid; nitric acid / acetic acid / 15 - 35 °C 2: hydrogen; platinum on carbon / methanol / 20 - 40 °C / 760.05 Torr View Scheme

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

Conditions	Yield
Multi-step reaction with 5 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 5: 53 percent / pyridine / propan-2-ol / 2 h / Heating View Scheme

3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9) → 6,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one (179688-29-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: nitric acid / acetic acid / 24 h / 20 °C / cooling with ice-water 2: ammonium formate / 5%-palladium/activated carbon / 7 h / 150 °C View Scheme
Multi-step reaction with 2 steps 1: nitric acid; acetic acid / 24 h / 20 °C / Cooling with ice 2: ammonium formate; 5%-palladium/activated carbon / 7 h / 150 °C View Scheme
Multi-step reaction with 3 steps 1.1: sulfuric acid; nitric acid / acetic acid / 15 - 35 °C 2.1: hydrogen; platinum on carbon / methanol / 20 - 40 °C / 760.05 Torr 3.1: N,N-dimethyl-formamide / 10 h / 130 - 140 °C 3.2: 65 - 80 °C View Scheme

3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9) → 9-chloro-2,3-bis(2-methoxyethoxy)-8H-quinazolino[4,3-b]quinazoline (1347720-71-1)

Conditions	Yield
Multi-step reaction with 5 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 4.1: isopropyl alcohol / 4 h / Reflux 5.1: trichlorophosphate / 2 h / Reflux 5.2: pH 10 View Scheme
Multi-step reaction with 5 steps 1: nitric acid; acetic acid / 24 h / 20 °C / Cooling with ice 2: ammonium formate; 5%-palladium/activated carbon / 7 h / 150 °C 3: thionyl chloride; N,N-dimethyl-formamide / dichloromethane / 6 h / Reflux 4: isopropyl alcohol / 4 h / Reflux 5: trichlorophosphate / 2 h / Reflux View Scheme

3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9) → 9-bromo-2,3-bis(2-methoxyethoxy)-8H-quinazolino[4,3-b]quinazoline (1347720-74-4)

Conditions	Yield
Multi-step reaction with 5 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 4.1: pyridine / acetonitrile / 4 h / Reflux 5.1: trichlorophosphate / 2 h / Reflux 5.2: pH 9 View Scheme
Multi-step reaction with 5 steps 1: nitric acid; acetic acid / 24 h / 20 °C / Cooling with ice 2: ammonium formate; 5%-palladium/activated carbon / 7 h / 150 °C 3: thionyl chloride; N,N-dimethyl-formamide / dichloromethane / 6 h / Reflux 4: pyridine / acetonitrile / 4 h / Reflux 5: trichlorophosphate / 2 h / Reflux View Scheme

3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9) → 9-fluoro-2,3-bis(2-methoxyethoxy)-8H-quinazolino[4,3-b]quinazoline (1347719-30-5)

Conditions	Yield
Multi-step reaction with 5 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 4.1: hydrogenchloride / isopropyl alcohol; water 5.1: triethylamine; methanesulfonyl chloride / toluene / 7 h / 20 °C / cooling with ice View Scheme
Multi-step reaction with 5 steps 1: nitric acid; acetic acid / 24 h / 20 °C / Cooling with ice 2: ammonium formate; 5%-palladium/activated carbon / 7 h / 150 °C 3: thionyl chloride; N,N-dimethyl-formamide / dichloromethane / 6 h / Reflux 4: hydrogenchloride / isopropyl alcohol; water / 20 °C 5: triethylamine; methanesulfonyl chloride / toluene / 7 h / 20 °C / Cooling with ice View Scheme

3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9) → 9-ethynyl-2,3-bis(2-methoxyethoxy)-8H-quinazolino[4,3-b]quinazoline (1347720-79-9)

Conditions	Yield
Multi-step reaction with 8 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 4.1: pyridine / acetonitrile / 4 h / Reflux 5.1: trichlorophosphate / 2 h / Reflux 5.2: pH 9 6.1: hydrogenchloride / ethanol; water / Heating 7.1: triethylamine / triphenylphosphine; palladium diacetate; copper(l) iodide / 7 h / Inert atmosphere; Reflux 8.1: sodium hydroxide / toluene / 6 h / Inert atmosphere; Reflux View Scheme
Multi-step reaction with 8 steps 1: nitric acid; acetic acid / 24 h / 20 °C / Cooling with ice 2: ammonium formate; 5%-palladium/activated carbon / 7 h / 150 °C 3: thionyl chloride; N,N-dimethyl-formamide / dichloromethane / 6 h / Reflux 4: pyridine / acetonitrile / 4 h / Reflux 5: trichlorophosphate / 2 h / Reflux 6: hydrogenchloride / ethanol / Heating 7: triethylamine; triphenylphosphine; palladium diacetate; copper(l) iodide / 7 h / Inert atmosphere; Reflux 8: sodium hydroxide / toluene / 4 h / Resolution of racemate; Inert atmosphere View Scheme

3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9) → 9-nitro-2,3-bis(2-methoxyethoxy)-8H-quinazolino[4,3-b]quinazoline (1347719-34-9)

Conditions	Yield
Multi-step reaction with 5 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 4.1: hydrogenchloride / 1,4-dioxane; water / 7 h / 20 °C 5.1: triethylamine; methanesulfonyl chloride / chloroform / 20 °C / cooling with ice View Scheme
Multi-step reaction with 5 steps 1: nitric acid; acetic acid / 24 h / 20 °C / Cooling with ice 2: ammonium formate; 5%-palladium/activated carbon / 7 h / 150 °C 3: thionyl chloride; N,N-dimethyl-formamide / dichloromethane / 6 h / Reflux 4: hydrogenchloride / water; 1,4-dioxane / 7 h / 20 °C 5: triethylamine; methanesulfonyl chloride / chloroform / 20 °C View Scheme

3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9) → 9-amino-2,3-bis(2-methoxyethoxy)-8H-quinazolino[4,3-b]quinazoline (1347720-84-6)

Conditions	Yield
Multi-step reaction with 6 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 4.1: hydrogenchloride / 1,4-dioxane; water / 7 h / 20 °C 5.1: triethylamine; methanesulfonyl chloride / chloroform / 20 °C / cooling with ice 6.1: hydrogen / palladium 10% on activated carbon / methanol / 5 h / 760.05 Torr / Reflux View Scheme
Multi-step reaction with 6 steps 1: nitric acid; acetic acid / 24 h / 20 °C / Cooling with ice 2: ammonium formate; 5%-palladium/activated carbon / 7 h / 150 °C 3: thionyl chloride; N,N-dimethyl-formamide / dichloromethane / 6 h / Reflux 4: hydrogenchloride / water; 1,4-dioxane / 7 h / 20 °C 5: triethylamine; methanesulfonyl chloride / chloroform / 20 °C 6: hydrogen; palladium 10% on activated carbon / methanol / 5 h / 760.05 Torr / Reflux View Scheme

3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9) → 9-chloro-2,3-bis(2-methoxyethoxy)-8H-quinazolino[4,3-b]quinazoline hydrochloride

Conditions

Yield

Multi-step reaction with 6 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 4.1: isopropyl alcohol / 4 h / Reflux 5.1: trichlorophosphate / 2 h / Reflux 5.2: pH 10 6.1: hydrogenchloride / ethanol; water / Heating View Scheme

3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9) → 9-fluoro-2,3-bis(2-methoxyethoxy)-8H-quinazolino[4,3-b]quinazoline mesylate

Conditions

Yield

Multi-step reaction with 6 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 4.1: hydrogenchloride / isopropyl alcohol; water 5.1: triethylamine; methanesulfonyl chloride / toluene / 7 h / 20 °C / cooling with ice 6.1: ethanol / 0.5 h / Reflux View Scheme

3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9) → 9-ethynyl-2,3-bis(2-methoxyethoxy)-8H-quinazolino[4,3-b]quinazoline hydrochloride

Conditions

Yield

Multi-step reaction with 9 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 4.1: pyridine / acetonitrile / 4 h / Reflux 5.1: trichlorophosphate / 2 h / Reflux 5.2: pH 9 6.1: hydrogenchloride / ethanol; water / Heating 7.1: triethylamine / triphenylphosphine; palladium diacetate; copper(l) iodide / 7 h / Inert atmosphere; Reflux 8.1: sodium hydroxide / toluene / 6 h / Inert atmosphere; Reflux 9.1: hydrogenchloride / ethanol View Scheme

3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9) → 9-amino-2,3-bis(2-methoxyethoxy)-8H-quinazolino[4,3-b]quinazoline hydrobromide

Conditions

Yield

Multi-step reaction with 7 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 4.1: hydrogenchloride / 1,4-dioxane; water / 7 h / 20 °C 5.1: triethylamine; methanesulfonyl chloride / chloroform / 20 °C / cooling with ice 6.1: hydrogen / palladium 10% on activated carbon / methanol / 5 h / 760.05 Torr / Reflux 7.1: hydrogen bromide / ethyl acetate; ethanol View Scheme

3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9) → C21H24ClN3O5 (1347720-70-0)

Conditions	Yield
Multi-step reaction with 4 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 4.1: isopropyl alcohol / 4 h / Reflux View Scheme
Multi-step reaction with 4 steps 1: nitric acid; acetic acid / 24 h / 20 °C / Cooling with ice 2: ammonium formate; 5%-palladium/activated carbon / 7 h / 150 °C 3: thionyl chloride; N,N-dimethyl-formamide / dichloromethane / 6 h / Reflux 4: isopropyl alcohol / 4 h / Reflux View Scheme

3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9) → C21H24BrN3O5 (1347720-73-3)

Conditions	Yield
Multi-step reaction with 4 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 4.1: pyridine / acetonitrile / 4 h / Reflux View Scheme
Multi-step reaction with 4 steps 1: nitric acid; acetic acid / 24 h / 20 °C / Cooling with ice 2: ammonium formate; 5%-palladium/activated carbon / 7 h / 150 °C 3: thionyl chloride; N,N-dimethyl-formamide / dichloromethane / 6 h / Reflux 4: pyridine / acetonitrile / 4 h / Reflux View Scheme

3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9) → 9-bromo-2,3-bis(2-methoxyethoxy)-8H-quinazolino[4,3-b]quinazoline hydrochloride

Conditions

Yield

Multi-step reaction with 6 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 4.1: pyridine / acetonitrile / 4 h / Reflux 5.1: trichlorophosphate / 2 h / Reflux 5.2: pH 9 6.1: hydrogenchloride / ethanol; water / Heating View Scheme

3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (183322-16-9) → C21H24FN3O5 (1347720-76-6)

Conditions	Yield
Multi-step reaction with 4 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 4.1: hydrogenchloride / isopropyl alcohol; water View Scheme
Multi-step reaction with 4 steps 1: nitric acid; acetic acid / 24 h / 20 °C / Cooling with ice 2: ammonium formate; 5%-palladium/activated carbon / 7 h / 150 °C 3: thionyl chloride; N,N-dimethyl-formamide / dichloromethane / 6 h / Reflux 4: hydrogenchloride / isopropyl alcohol; water / 20 °C View Scheme

Upstream product

• 3943-89-3 Ethyl protocatechuate 
• 17178-10-8 2-methoxy-ethyl p-toluenesulfonyloxy ester 
• 16427-44-4 2-methoxyethyl methanesulfonate 
• 819813-71-3 3,4-bis(2-methoxyethoxy)-benzoic acid 
• 64-17-5 ethanol 
• 99-50-3 3,4-Dihydroxybenzoic acid 
• 6482-24-2 2-Bromoethyl methyl ether 
• 627-42-9 2-chloroethyl methyl ether 

Downstream Products

• 179688-26-7 2-nitro-4,5-bis(2-methoxyethoxy)benzoic acid ethyl ester 
• 179688-29-0 6,7-bis(2-methoxyethoxy)-3,4-dihydroquinazolin-4-one 
• 183322-18-1 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline 
• 183319-69-9 erlotinib hydrochloride 
• 179688-27-8 ethyl 2-amino-4,5-bis(2-methoxyethoxy)-benzoate 
• 179688-29-0 6,7-bis-(2-methoxyethoxy)-4(3H)quinazolinone 
• 1347720-70-0 C₂₁H₂₄ClN₃O₅ 
• 1347720-73-3 C₂₁H₂₄BrN₃O₅ 
• 1347720-76-6 C₂₁H₂₄FN₃O₅ 
• 1347720-82-4 C₂₁H₂₄N₄O₇ 
• 1347720-89-1 C₂₂H₂₄F₃N₃O₅ 
• 1347719-48-5 N-{2,3-bis(2-methoxyethoxy)-8H-quinazolino[4,3-b]quinazoline}benzamide 
• 1347720-93-7 C₂₁H₂₃ClFN₃O₅ 
• 1347721-06-5 C₂₂H₂₆ClN₃O₅ 

Relevant articles and documents

Synthetic method of erlotinib

The invention relates to a synthetic method of erlotinib, and belongs to the technical field of chemical synthesis. The preparation method comprises the following synthesis steps: (1) reacting a compound I with 2-chloroethyl methyl ether to generate a compound II; (2) oxidizing the compound II through peracetic acid to generate a compound III; (3) reacting the compound III with benzene sulfonyl chloride to generate a compound IV; (4) carrying out a ring closing reaction on the compound IV, ammonium chloride and formamide to generate a compound V; (5) reacting the compound V with phosphorus oxychloride to generate a compound VI; and (6) reacting the compound VI with m-aminophenylacetylene to generate a compound VII erlotinib. The invention provides a new synthetic route, and the used raw materials are common materials, are simple and easily available, can adapt to production of various scales, and the synthetic method has good industrial production prospects.

Preparation method of 3,4-di(2-methoxyl ethoxyl) ethyl benzoate

The invention belongs to the field of drug synthesis and relates to a preparation method of an anticancer drug intermediate, and in particular to a preparation method of 3,4-di(2-methoxyl ethoxyl) ethyl benzoate. The formula is as shown in the description. The preparation method is researched and reported in many literatures or patents, but organic solvents such as acetonitrile, acetone and DMF are needed to take part in. According to the preparation method provided by the invention, the solvents in the existing literatures or patents are not needed, but a product which is high in yield and purity can be obtained. The preparation method is a green and environmental-friendly preparation method and is suitable for industrial production.

Model quinazoline chlorethazine compound and its preparation method and application for treating tumor (by machine translation)

A novel quinazoline nitrogen mustard compound is characterized in that: one end is provided with a nitrogen mustard alkylating group; the other end is provided with a 6, 7-substituted quinazoline structure; a substituent R1 is located at a site 4 of a quinazoline matrix, and represents 2-, 3-, 4- nitrogen mustard substituent; and substituents R2, R3 are located at site 6 and 7 of a quinazoline matrix, and represent methoxyethoxy, methoxy, morpholine propoxy, 3-etrahydrofuran oxygen group and hydroxyl group. The compound has a structure shown as a formula A. Experiments show that the compound can cause cross-linking of DNA, and is a bifunctional alkylating agent. In vivo antitumor activity experiment show that the compound has good activity; furthermore, the compound has the advantage of low toxicity, which a nitrogen mustard drug is lack of. At the same time, the compound is easy for synthesis, has high total yield. Advantages of the compound show that it has great potential to become a drug for treatment of cancer.