199327-61-2

Basic information

• Product Name: 7-Methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4(3H)-one
• Synonyms: 7-Methoxy-6-(3-Morpholin-4-ylpropoxy) Quinazolin- 4-(3H)-One Gefitinib HCL InterMediates G5;Getitinib interMediate;Gefitinib iMpurity F;Gefitinib Impurity 14;Gefitinib Impurity 8;7-methoxy-6-(3-morpholin-4-ylpropoxy)-1H-quinazolin-4-one;7-Methoxy-6-(3-morpholin-4-ylpropoxy)quainazolin-4(3H)-one;6-(3-morpholinopropoxy)-7-methoxyquinazolin-4(3H)-one
• CAS NO: 199327-61-2
• Molecular Formula: C₁₆H₂₁N₃O₄
• Molecular Weight: 319.35564
• EINECS: 1308068-626-2
• Product Categories: Gefitinib INTERMEDIATES;Heterocycles;Intermediates;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 199327-61-2.mol

Chemical Properties

• Melting Point: 233-236 °C
• Boiling Point: 519.53 °C at 760 mmHg
• Flash Point: 268.002 °C
• Appearance: /
• Density: 1.327 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.611
• Storage Temp.: 2-8°C
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 7.10±0.10(Predicted)
• CAS DataBase Reference: 7-Methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4(3H)-one(CAS DataBase Reference)
• NIST Chemistry Reference: 7-Methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4(3H)-one(199327-61-2)
• EPA Substance Registry System: 7-Methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4(3H)-one(199327-61-2)

Safety Data

• Hazardous Substances Data: 199327-61-2(Hazardous Substances Data)

Usage

Chemical Properties

White Solid

InChI:InChI=1/C16H21N3O4/c1-21-14-10-13-12(16(20)18-11-17-13)9-15(14)23-6-2-3-19-4-7-22-8-5-19/h9-11H,2-8H2,1H3,(H,17,18,20)

Synthetic route

C9H6N2O3(2-)*2Na(1+) + 4 (3-bromopropyl)-morpholine (125422-83-5) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
With 1-butyl-3-methylimidazolium Tetrafluoroborate In tetrahydrofuran at 65 - 70℃; for 5h;	93.8%

4-(3-chloropropyl)morpholine (7357-67-7) + C9H6N2O3(2-)*2K(1+) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
With 1-butyl-3-methylimidazolium Tetrafluoroborate In N,N-dimethyl-formamide at 55 - 60℃; for 5h;	93.7%

4-(3-iodopropyl)morpholine (1417436-51-1) + C9H6N2O3(2-)*2K(1+) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
With 1-butyl-3-methylimidazolium Tetrafluoroborate In N,N-dimethyl-formamide at 75 - 80℃; for 5h;	91.2%

formamidine acetic acid (3473-63-0) + methyl 5-(3-morpholinopropoxy)-2-amino-4-methoxy-benzoate (214472-41-0) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
In ethanol for 4h; Reflux;	88%
In methanol at 50 - 60℃; for 6h;	81.73%
In 2-methoxy-ethanol at 115℃; for 2h;	78%
In methanol at 50 - 60℃; for 6h;

2-amino-4-methoxy-5-[3-(morpholin-4-yl)propoxy]benzamide (246512-44-7) + formaldehyd (50-00-0) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
In water at 130℃; for 48h;	88%

7-methoxy-6-(3'-N-morpholino)propoxyquinazoline (1208902-96-8) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
Stage #1: 7-methoxy-6-(3'-N-morpholino)propoxyquinazoline With ammonium cerium (IV) nitrate; acetic acid In water Stage #2: With sodium hydroxide In water	87%
With peracetic acid; sulfuric acid In ethanol at 60℃; for 12h;	85%

2-nitro-4-methoxy-5-[3-(morpholin-4-yl)propoxy]benzonitrile (675126-26-8) + formic acid (64-18-6) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
Stage #1: 2-nitro-4-methoxy-5-[3-(morpholin-4-yl)propoxy]benzonitrile With iron(III) chloride; hydrazine hydrate In methanol; water for 3h; Heating; Stage #2: formic acid With hydrogenchloride In water at 90 - 130℃; Further stages.;	86%
Stage #1: 2-nitro-4-methoxy-5-[3-(morpholin-4-yl)propoxy]benzonitrile With iron(III) chloride; hydrazine hydrate In methanol; water at 80℃; for 3.5h; Stage #2: formic acid With hydrogenchloride In water at 130℃; for 4h;	68.65%
Stage #1: 2-nitro-4-methoxy-5-[3-(morpholin-4-yl)propoxy]benzonitrile With iron(III) chloride; hydrazine hydrate In methanol; water for 3h; Reflux; Stage #2: formic acid With hydrogenchloride In water at 130℃; for 3.5h;	58%

C16H20N2O6 → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
With formamidine acetic acid	82%

2-amino-4-methoxy-5-[3-(morpholin-4-yl)propoxy]benzamide (246512-44-7) + formic acid (64-18-6) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
Stage #1: 2-amino-4-methoxy-5-[3-(morpholin-4-yl)propoxy]benzamide; formic acid With formamide at 20 - 100℃; Stage #2: at 100℃; for 7h;	78%
Stage #1: 2-amino-4-methoxy-5-[3-(morpholin-4-yl)propoxy]benzamide; formic acid In dichloromethane at 100℃; for 5h; Acidic conditions; Stage #2: With hydrogenchloride In water at 70℃; for 3h; Acidic aqueous solution; Stage #3: With sodium hydroxide In water at 20 - 25℃; Alkaline aqueous solution;
With formamide at 20℃; for 8h; Reflux;	3.3 g

ammonium formate (16712-16-6, 64165-14-6, 65387-22-6, 70179-79-2, 540-69-2) + formamide (77287-34-4, 77287-35-5, 60100-09-6) + methyl 5-(3-morpholinopropoxy)-2-amino-4-methoxy-benzoate (214472-41-0) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
at 170℃; for 3h;	71.1%

ethyl 2-amino-4-methoxy-5-(3-morpholin-4-ylpropoxy)benzoate (1040264-49-0) + formamidine acetic acid (3473-63-0) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
In 2-methoxy-ethanol for 8h; Heating;	69.2%
In methanol for 6h; Reflux;

C16H23N3O5 → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
With trichlorophosphate In toluene for 2h; Reflux;	40%

4-(3-chloropropyl)morpholine (7357-67-7) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: 391.5 g / potassium carbonate / dimethylformamide / 3 h / 100 °C 2.1: 391 g / hydroxylamine hydrochloride; pyridine / methanol / 1 h / Heating 3.1: 349 g / acetic anhydride / 3 h / 110 °C 4.1: 329 g / aq. nitric acid / acetic acid / 8 h / 45 - 50 °C 5.1: FeCl3; hydrazine hydrate / H2O; methanol / 3 h / Heating 5.2: 86 percent / HCl / H2O / 90 - 130 °C View Scheme
Multi-step reaction with 5 steps 1.1: 95 percent / K2CO3 / dimethylformamide / 10 h / 85 °C 2.1: 95 percent / aq. H2SO4; HNO3; AcOH / 50 h / 20 °C 3.1: 75 percent / sodium dithionite / H2O / 20 - 50 °C 4.1: 38 percent / KOH / 2-methyl-butan-2-ol / 82 °C 5.1: formamide / 20 - 100 °C 5.2: 78 percent / 7 h / 100 °C View Scheme

4-methoxy-3-[3-(morpholin-4-yl)propoxy]benzonitrile (675126-28-0) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 329 g / aq. nitric acid / acetic acid / 8 h / 45 - 50 °C 2.1: FeCl3; hydrazine hydrate / H2O; methanol / 3 h / Heating 2.2: 86 percent / HCl / H2O / 90 - 130 °C View Scheme
Multi-step reaction with 4 steps 1.1: 95 percent / aq. H2SO4; HNO3; AcOH / 50 h / 20 °C 2.1: 75 percent / sodium dithionite / H2O / 20 - 50 °C 3.1: 38 percent / KOH / 2-methyl-butan-2-ol / 82 °C 4.1: formamide / 20 - 100 °C 4.2: 78 percent / 7 h / 100 °C View Scheme
Multi-step reaction with 4 steps 1: nitric acid; sulfuric acid; acetic acid / 37 h / 0 - 20 °C 2: dihydrogen peroxide; potassium carbonate / dimethyl sulfoxide / 1.5 h / 50 °C 3: palladium on activated charcoal / ethyl acetate; dichloromethane / 1.8 h / Reflux 4: formamide / 8 h / 20 °C / Reflux View Scheme

isovanillin (621-59-0) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: 391.5 g / potassium carbonate / dimethylformamide / 3 h / 100 °C 2.1: 391 g / hydroxylamine hydrochloride; pyridine / methanol / 1 h / Heating 3.1: 349 g / acetic anhydride / 3 h / 110 °C 4.1: 329 g / aq. nitric acid / acetic acid / 8 h / 45 - 50 °C 5.1: FeCl3; hydrazine hydrate / H2O; methanol / 3 h / Heating 5.2: 86 percent / HCl / H2O / 90 - 130 °C View Scheme
Multi-step reaction with 6 steps 1.1: 88 percent / sodium formate; formic acid; hydroxylamine sulfate / 8 h / 85 °C 2.1: 95 percent / K2CO3 / dimethylformamide / 10 h / 85 °C 3.1: 95 percent / aq. H2SO4; HNO3; AcOH / 50 h / 20 °C 4.1: 75 percent / sodium dithionite / H2O / 20 - 50 °C 5.1: 38 percent / KOH / 2-methyl-butan-2-ol / 82 °C 6.1: formamide / 20 - 100 °C 6.2: 78 percent / 7 h / 100 °C View Scheme
Multi-step reaction with 4 steps 1.1: formic acid; dihydrogen peroxide / 0 - 4 °C 1.2: Reflux 2.1: sodium carbonate / N,N-dimethyl-formamide / 10 h / 85 °C 3.1: trimethylaluminum / hexane; dichloromethane / 5 h / 0 °C / Inert atmosphere; Reflux 4.1: trichlorophosphate / toluene / 2 h / Reflux View Scheme

4-methoxy-3-[3-(4-morpholinyl)propoxy]benzaldoxime (934191-95-4) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 349 g / acetic anhydride / 3 h / 110 °C 2.1: 329 g / aq. nitric acid / acetic acid / 8 h / 45 - 50 °C 3.1: FeCl3; hydrazine hydrate / H2O; methanol / 3 h / Heating 3.2: 86 percent / HCl / H2O / 90 - 130 °C View Scheme

4-methoxy-3-[3-(4-morpholinyl)propoxy]benzaldehyde (861453-11-4) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 391 g / hydroxylamine hydrochloride; pyridine / methanol / 1 h / Heating 2.1: 349 g / acetic anhydride / 3 h / 110 °C 3.1: 329 g / aq. nitric acid / acetic acid / 8 h / 45 - 50 °C 4.1: FeCl3; hydrazine hydrate / H2O; methanol / 3 h / Heating 4.2: 86 percent / HCl / H2O / 90 - 130 °C View Scheme

2-amino-4-methoxy-5-[(3-morpholin-4-yl)propoxy]benzonitrile (675126-27-9) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 38 percent / KOH / 2-methyl-butan-2-ol / 82 °C 2.1: formamide / 20 - 100 °C 2.2: 78 percent / 7 h / 100 °C View Scheme

2-nitro-4-methoxy-5-[3-(morpholin-4-yl)propoxy]benzonitrile (675126-26-8) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 75 percent / sodium dithionite / H2O / 20 - 50 °C 2.1: 38 percent / KOH / 2-methyl-butan-2-ol / 82 °C 3.1: formamide / 20 - 100 °C 3.2: 78 percent / 7 h / 100 °C View Scheme
Multi-step reaction with 3 steps 1: dihydrogen peroxide; potassium carbonate / dimethyl sulfoxide / 1.5 h / 50 °C 2: palladium on activated charcoal / ethyl acetate; dichloromethane / 1.8 h / Reflux 3: formamide / 8 h / 20 °C / Reflux View Scheme

2-methoxy-5-cyanophenol (52805-46-6) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: 95 percent / K2CO3 / dimethylformamide / 10 h / 85 °C 2.1: 95 percent / aq. H2SO4; HNO3; AcOH / 50 h / 20 °C 3.1: 75 percent / sodium dithionite / H2O / 20 - 50 °C 4.1: 38 percent / KOH / 2-methyl-butan-2-ol / 82 °C 5.1: formamide / 20 - 100 °C 5.2: 78 percent / 7 h / 100 °C View Scheme
Multi-step reaction with 5 steps 1: potassium carbonate / N,N-dimethyl-formamide / 10 h / 85 °C 2: nitric acid; sulfuric acid; acetic acid / 37 h / 0 - 20 °C 3: dihydrogen peroxide; potassium carbonate / dimethyl sulfoxide / 1.5 h / 50 °C 4: palladium on activated charcoal / ethyl acetate; dichloromethane / 1.8 h / Reflux 5: formamide / 8 h / 20 °C / Reflux View Scheme

3-hydroxy-4-methoxybenzoate (6702-50-7) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: 76 percent / potassium carbonate / acetone / 24 h / Heating 2: 82 percent / nitric acid; trifluoroacetic acid / CH2Cl2 / 2 h / 20 °C 3: 60 percent / 1 h / 100 °C 4: hydrogen / palladium on activated carbon / methanol 5: 78 percent / 2-methoxy-ethanol / 2 h / 115 °C View Scheme
Multi-step reaction with 3 steps 1: sodium carbonate / N,N-dimethyl-formamide / 10 h / 85 °C 2: trimethylaluminum / hexane; dichloromethane / 5 h / 0 °C / Inert atmosphere; Reflux 3: trichlorophosphate / toluene / 2 h / Reflux View Scheme

methyl 3-(3-chloropropoxy)-4-methoxybenzoate (380844-22-4) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 82 percent / nitric acid; trifluoroacetic acid / CH2Cl2 / 2 h / 20 °C 2: 60 percent / 1 h / 100 °C 3: hydrogen / palladium on activated carbon / methanol 4: 78 percent / 2-methoxy-ethanol / 2 h / 115 °C View Scheme

methyl 4-methoxy-5-(3-chloropropoxy)-2-nitrobenzoate (380844-24-6) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 60 percent / 1 h / 100 °C 2: hydrogen / palladium on activated carbon / methanol 3: 78 percent / 2-methoxy-ethanol / 2 h / 115 °C View Scheme

4-methoxy-5-(3-morpholinylpropoxy)-2-nitrobenzoic acid methyl ester (214472-37-4) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogen / palladium on activated carbon / methanol 2: 78 percent / 2-methoxy-ethanol / 2 h / 115 °C View Scheme

gefitinib (184475-35-2) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
With ammonia In hydrogenchloride
With ammonia In hydrogenchloride
Stage #1: gefitinib With hydrogenchloride In water for 6h; Heating / reflux; Stage #2: With ammonia In water at 0℃;
Stage #1: gefitinib With hydrogenchloride In water for 6h; Heating / reflux; Stage #2: With ammonium hydroxide In water

C16H14N2O2 (1494468-50-6) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogen; palladium on activated charcoal 2: potassium carbonate / N,N-dimethyl-formamide 3: peracetic acid; sulfuric acid / ethanol / 12 h / 60 °C View Scheme

6-hydroxy-7-methoxyquinazoline (884344-38-1) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide 2: peracetic acid; sulfuric acid / ethanol / 12 h / 60 °C View Scheme

3-benzyloxy-4-methoxybenzaldehyde (6346-05-0) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
Multi-step reaction with 6 steps 1: nitric acid / water 2: hydrogenchloride; iron / ethanol 3: ethanol / Reflux 4: hydrogen; palladium on activated charcoal 5: potassium carbonate / N,N-dimethyl-formamide 6: peracetic acid; sulfuric acid / ethanol / 12 h / 60 °C View Scheme

2-aldehyde-4-benzyloxy-5-methoxy nitrobenzene (58662-50-3) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: hydrogenchloride; iron / ethanol 2: ethanol / Reflux 3: hydrogen; palladium on activated charcoal 4: potassium carbonate / N,N-dimethyl-formamide 5: peracetic acid; sulfuric acid / ethanol / 12 h / 60 °C View Scheme

5-benzyloxy-4-methoxy-2-aminobenzaldehyde (1042978-66-4) → 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: ethanol / Reflux 2: hydrogen; palladium on activated charcoal 3: potassium carbonate / N,N-dimethyl-formamide 4: peracetic acid; sulfuric acid / ethanol / 12 h / 60 °C View Scheme

7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2) → 4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline (199327-59-8)

Conditions	Yield
With thionyl chloride; N,N-dimethyl-formamide for 4h; Heating;	99.3%
With thionyl chloride In N,N-dimethyl-formamide at 84℃; for 1.5h;	96.85%
With thionyl chloride; N,N-dimethyl-formamide at 84℃;	94%

7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2) → 6-acetoxy-4-chloro-7-methoxyquinazoline (230955-75-6)

Conditions	Yield
With sulfuryl dichloride In acetonitrile at 55℃; Temperature; Concentration;	93.7%

7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2) → 4-(3-(4-chloro-7-methoxyquinazolin-6-yloxy)propyl)morpholine hydrochloride (1383952-42-8)

Conditions	Yield
With triethylamine; trichlorophosphate In acetonitrile at 80 - 90℃; for 1h; Temperature; Reagent/catalyst; Solvent;	84.1%

7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2) + 3-chloro-4-fluorophenylamine (367-21-5) → gefitinib (184475-35-2)

Conditions	Yield
Stage #1: 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one With thionyl chloride; N,N-dimethyl-formamide for 1h; Reflux; Stage #2: 3-chloro-4-fluorophenylamine In isopropyl alcohol for 1h; Reflux;	84%
With potassium carbonate In isopropyl alcohol at 80 - 85℃; for 1h;	82%
Stage #1: 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one With thionyl chloride In N,N-dimethyl-formamide for 2h; Heating; Stage #2: 3-chloro-4-fluorophenylamine In N,N-dimethyl-formamide at 100℃; for 1h; Further stages.;	73%
Stage #1: 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one With triethylamine; trichlorophosphate In toluene at 5 - 70℃; Stage #2: 3-chloro-4-fluorophenylamine In isopropyl alcohol; toluene at 70℃; for 1h;	62.86%
Stage #1: 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one With thionyl chloride for 4h; Reflux; Stage #2: 3-chloro-4-fluorophenylamine In i-Amyl alcohol for 6h; Reflux;

7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2) + propargyl bromide (106-96-7) → 7-methoxy-6-[3-(morpholin-4-yl)propoxy]-3-(prop-2-yn-1-yl)quinazolin-4(3H)-one

Conditions	Yield
With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃;	54%

7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2) + 2-fluoroethyl tosylate (383-50-6) → 4-(3-((4-(2-fluoroethoxy)-7-methoxyquinazolin-6-yl)oxy)propyl)-morpholine

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 90 - 100℃; for 2h;	27%

7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2) → 7-methoxy-6-[3-(4-morpholinyl)propoxy]quinazolin-4(3H)-thione (958669-54-0)

Conditions	Yield
With tetraphosphorus decasulfide In pyridine for 24h; Heating;

7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2) → 4-(methylthio)-7-methoxy-6-[3-(4-morpholinyl)propoxy]quinazoline (958669-55-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: P2S5 / pyridine / 24 h / Heating 2.1: aq. NaOH / methanol / 15 - 20 °C 2.2: 8.3 g / methanol; H2O / 5 h / 20 °C View Scheme

7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2) → gefitinib (184475-35-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: P2S5 / pyridine / 24 h / Heating 2.1: aq. NaOH / methanol / 15 - 20 °C 2.2: 8.3 g / methanol; H2O / 5 h / 20 °C 3.1: 85 percent / 3-chloro-4-fluoroaniline hydrochloride / propan-2-ol / 24 h / Heating View Scheme
Multi-step reaction with 2 steps 1: 90 percent / POCl3; triethylamine / toluene / 24 h / 58 °C 2: 91 percent / triethylamine / propan-2-ol / 288 h / Heating View Scheme
Multi-step reaction with 2 steps 1: oxalyl chloride / CHCl3; dimethylformamide / Heating 2: 70 percent / dimethylformamide / 1 h / 145 °C View Scheme
Multi-step reaction with 3 steps 1: trichlorophosphate / dichloromethane; N,N-dimethyl-formamide; acetonitrile / 3 h / 40 - 45 °C 2: hydrogenchloride / methanol; water / 1 h / 20 °C 3: sodium hydroxide / water / 1.5 h / 30 - 70 °C / pH 11 - 13 View Scheme

7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (199327-61-2) → O-Demethyl-Gefitinib (847949-49-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 90 percent / POCl3; triethylamine / toluene / 24 h / 58 °C 2: 91 percent / triethylamine / propan-2-ol / 288 h / Heating 3: 54 percent / LiCl / dimethylformamide / 15 h / Heating View Scheme

Upstream product

• 184475-35-2 gefitinib 
• 3473-63-0 formamidine acetic acid 
• 214472-41-0 methyl 5-(3-morpholinopropoxy)-2-amino-4-methoxy-benzoate 
• 246512-44-7 2-amino-4-methoxy-5-[3-(morpholin-4-yl)propoxy]benzamide 
• 64-18-6 formic acid 
• 675126-26-8 2-nitro-4-methoxy-5-[3-(morpholin-4-yl)propoxy]benzonitrile 
• 7357-67-7 4-(3-chloropropyl)morpholine 
• 675126-28-0 4-methoxy-3-[3-(morpholin-4-yl)propoxy]benzonitrile 
• 621-59-0 isovanillin 
• 934191-95-4 4-methoxy-3-[3-(4-morpholinyl)propoxy]benzaldoxime 
• 861453-11-4 4-methoxy-3-[3-(4-morpholinyl)propoxy]benzaldehyde 
• 675126-27-9 2-amino-4-methoxy-5-[(3-morpholin-4-yl)propoxy]benzonitrile 
• 52805-46-6 2-methoxy-5-cyanophenol 
• 6702-50-7 3-hydroxy-4-methoxybenzoate 

Downstream Products

• 199327-59-8 4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline 
• 184475-35-2 gefitinib 
• 936446-61-6 NRC-2694 
• 1172626-99-1 NRC-2694 A 
• 230955-75-6 6-acetoxy-4-chloro-7-methoxyquinazoline 
• 847949-49-9 O-Demethyl-Gefitinib 

Relevant articles and documents

A new heterocyclic compound initiates ROS accumulation and cause apoptotic cell death in human bone cancer cells

A new heterocyclic compound 7-methoxy-6-(3-morpholinopropoxy)quinazolin-4(3H)-one (1), designed using methyl 5-hydroxy-4-methoxy-2-nitrobenzoate (2) as the starting material, was successfully obtained via multiple synthesis route and finally characterized by fourier transform infrared (FT-IR) spectroscopy, 1H nuclear magnetic resonance (NMR), and single crystal X-ray crystallography. We investigated its effect on cell viability and proliferation with Cell Counting Kit-8 (CCK8) assay. The results revealed that compound 1 could block the proliferation of Saos-2 bone cancer cells. In addition, Annexin V-FITC/PI assay and Western blot analysis were performed to detect whether compound 1 could induce cell apoptosis. The results indicated that compound 1 could increase the number of apoptotic cells remarkably. Moreover, we examined the impact of compound 1 on ROS generation. Results revealed that compound 1 up-regulated the reactive oxygen species (ROS) genes expression and promoted the accumulation of ROS in Saos-2 cells. Finally, molecular docking has been utilized to study the binding mode of compound 1 with tubulin.

Isolation, identification and characterization of gefitinib novel degradation products by nmr and hrms, method development and validation by uplc

Gefitinib (GFT) sold under the brand name Iressa, is a medication used to treat certain type of breast, lung and other cancers, Gefitinib was subject to stress degradation under acidic, basic, peroxide mediated oxidation, photolytic and thermal degradation. The stress degradation was performed according to ICH guidelines Q1A(R2) and the drug was inert under thermal and photolytic conditions. One degradant is identified in acid hydrolysis referred as 7-methoxy-6-(3-morpholinopropoxy) quinazolin-4(3H)-one (GFT-DP1) and two degradants were formed in peroxide mediated hydrolysis referred as 4-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxy-1-oxidoquinazolin-6-yl)oxy)- propyl)morpholine-4-oxide (GFT-DP2) and 4-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-propyl)- morpholine-4-oxide (GFT-DP3). In present study, all the novel three degradation product structures were confirmed by HRMS and 1D (1H, 13C) and 2D (COSY, HSQC and HMBC) based on 1D and 2D NMR data proton and carbon chemical shift values assigned exactly for all degradation products. A stability indicating RP-UPLC method was developed and validated with shorter run time and this method was validated in terms of linearity, specificity, accuracy, LOD and LOQ.

4-heterocycle substituted quinazoline derivative and preparation method and application thereof

The invention discloses a 4-heterocycle substituted quinazoline derivative and a preparation method and application thereof. The compound has a structure expressed by a general formula (I): (please see the specification for the formula), in the formula, R1 and R2 are independently selected from hydrogen, a saturated or unsaturated five-membered heterocycle, or a saturated or unsaturated six-membered heterocycle, and n is an integer from 1 to 6; X is NH, O or S; and a heterocycle A is independently selected from pyridine or substituted pyridine, pyrimidine or substituted pyrimidine, pyrazol orsubstituted pyrazol, pyrazine or substituted pyrazine, thiazole or substituted thiazole, or benzothiazole or substituted benzothiazole. The compound or pharmaceutically formable salts thereof have aninhibitory effect on proliferation of tumor cells and can be used for preparing drugs for treatment of glioma, non-small cell lung cancer, breast cancer, colon cancer, stomach cancer, liver cancer andcervical cancer diseases.

Design, synthesis, and biological evaluation of quinazoline derivatives containing piperazine moieties as antitumor agents

A series of novel quinazoline derivatives containing piperazine analogs are synthesized via substitution reactions with 6,7-disubstituted 4-chloroquinazoline and benzyl piperazine (amido piperazine). Potent antiproliferative activities are observed against A549, HepG2, K562, and PC-3 with N-(3-chlorophenyl)-2-(4-(7-methoxy-6-(3-morpholino-propoxy)quinazoline-4-yl)piperazine-1-yl)acetamidename C9 showing excellent activity. This active derivative was screened for cell migration ability, proliferation effects, and apoptosis against A549 and PC-3 cells, with the result showing biological activity almost equal to that of the control gefitinib.

Preparing method of gefitinib intermediate

The invention discloses a preparing method of a gefitinib intermediate. The method includes the following steps of firstly, making a compound 1 react in the presence of sodium formate, formic acid andhydroxylamine sulphate to obtain a compound 2; secondly, making the compound 2 and a compound 3 react in the presence of potassium carbonate in a first solvent to obtain a compound 4; thirdly, makingthe compound 4 react in the presence of sulfuric acid and nitric acid in a second solvent to obtain a compound 5; fourthly, making the compound 5 react in the presence of alkaline and hydrogen peroxide in a third solvent to obtain a compound 6; fifthly, making the compound 6 react in the presence of ammonium formate and palladium/carbon in a fourth solvent to obtain a compound 7; sixthly, makingthe compound 7 react in the presence of formic acid and formamide to obtain a compound 8.

4 - (3 - chloro - 4 - fluoro benzyl amidogen) - 7 - methoxy - 6 - (3 - morpholino-propoxy) quinazoline preparation method

The invention provides a preparation method of 4-(3-chloro-4-fluorophenyl amido)-7-methoxy-6-(3-morpholine propoxy) quinazoline. Specifically, according to the method, 3-hydroxy-4-methoxybenzaldehyde (isovanillin) serves as raw materials, and the target product (I) is synthesized through the steps of oxidation, esterification, amidation, cyclization and the like. The method has the advantages of being short in synthetic route, low in cost, environmentally friendly, short in reaction step, easy to operate, high in yield and product purity and the like, and therefore the preparation method is suitable for industrial production.

Method for preparing compound

The invention provides a method for preparing a compound as shown in a formula I which is described in the specification. The method comprises a step of contacting a compound as shown in a formula III which is described in the specification or a derivative thereof with a compound as shown in a formula II which is described in the specification so as to obtain the compound as shown in the formula I. In the formulas, R1 and R2 are hydrogen, alkoxy groups or heteroaromatic rings, preferably alkoxy groups; and R is hydrogen, an alkyl group, a phenyl group, a substituted phenyl group or a naphthyl group. The compound as shown in the formula I is a tinib drug intermediate 6,7-disubstituted quinazolinone. According to the method provided in embodiments in the invention, aldoketones are used as cyclization raw materials in replacement of carboxylic acids for preparation of tinib drug intermediate, and since the aldoketones are not corrosive, the method has low requirements on reaction equipment and is more favorable for industrial production.

Preparation method of medicine for treating lung cancer

The invention provides a preparation method of a medicine for treating a lung cancer. Specifically, according to the method, 5-(3-morpholinyl propoxy)-6-methoxyisatin (II) is used as a raw material, and oxidation, substitution, chlorination and substitution are performed to synthesize a target product (I). The method has the advantages of short synthetic route, simplicity in experiment operation, environmental friendliness, high atom economy, good yield and effect and the like, and therefore, the method is suitable for industrial production.

Gefitinib and its derivatives of the new method for microwave synthesis

The invention discloses a new method for performing microwave synthesis on gefitinib and a derivative thereof. The method comprises the following steps of: at first, synthesizing 6-methoxyl-7-hydroxyl quinazoline-4-one from 2-iodo (bromo)-4-methoxyl-5-hydroxyl cyanophenyl used as an initial raw material and formamidine hydrochloride in a microwave mode; then performing reaction with 4-(3-bromo propyl) morpholine to introduce an alkyl side chain so as to obtain 7-methoxyl-6-[3-(4-morpholinyl) propoxy] quinazoline-4-ketone; in the presence of a catalyst, performing reaction on the obtained product and a chlorination reagent to obtain 4-chloro-7-methoxyl-6-[3-(4-morpholinyl) propoxy] quinazoline; finally, performing reaction on 4-chloro-7-methoxyl-6-[3-(4-morpholinyl) propoxy] quinazoline and 3-chloro-4-fluoroaniline to obtain a final product 4-(3-chloro-4-fluoroanilino)-7-methoxyl-6-(3-morpholinyl propoxy) quinazoline (gefitinib). The whole route steps are simplified into four steps, the yield is high, the method is convenient to carry out, the dangerousness is low, and the application of high-pollution reagents is reduced; moreover, the whole route is high in economy and suitable for industrial production, and the product cost is reduced. The reaction formula is as shown in the specification.

7-methoxy-6 - (3-morpholin-4- base third oxygen radical ) quinazolin -4 (3H)-ketone preparation method

The invention discloses a method for preparing 7-methoxy -6-(3-morpholine-4-propoxy) quinazoline-4(3H)-ketone. The method comprises steps of (1) reacting the 6-hydroxy-7-methoxy quinazoline-4-ketone with inorganic base, so as to obtain a compound shown in a formula III; (2) reacting the compound shown in the formula III with a compound shown in a formula IV in the presence of ionic liquid, after the reaction, and post-processing so as to obtain the 7-methoxy-6-(3-morpholine-4-propoxy) quinazoline-4(3H)-ketone. The preparation method is simple to operate, has high reaction selectivity, and is applicable to industrial production.