Gefitinib impurity 5 | Morpholines

Structure of Gefitinib impurity 5
CAS No.: 199327-61-2

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Quality Control of [ 199327-61-2 ] Purity: 97% SDS Specification

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Product Details of [ 199327-61-2 ]

CAS No. :	199327-61-2
Formula :	C₁₆H₂₁N₃O₄
M.W :	319.36
SMILES Code :	O=C1NC=NC2=C1C=C(OCCCN3CCOCC3)C(OC)=C2
MDL No. :	MFCD12760130
InChI Key :	WFUBWLXSYCFZEH-UHFFFAOYSA-N
Pubchem ID :	135399673

Safety of [ 199327-61-2 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 199327-61-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	23
Num. arom. heavy atoms	10
Fraction Csp3	0.5
Num. rotatable bonds	6
Num. H-bond acceptors	6.0
Num. H-bond donors	1.0
Molar Refractivity	89.97
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	76.68 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.72
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	0.67
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.65
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.6
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	2.6
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.45

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.17
Solubility	2.17 mg/ml ; 0.00679 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.86
Solubility	4.44 mg/ml ; 0.0139 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-4.48
Solubility	0.0105 mg/ml ; 0.0000329 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	Yes
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-7.77 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<0.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.58

Application In Synthesis of [ 199327-61-2 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 199327-61-2 ]

[ 199327-61-2 ] Synthesis Path-Downstream 1~54

1
[ 246512-44-7 ]
[ 64-18-6 ]
[ 199327-61-2 ]

Yield	Reaction Conditions	Operation in experiment
		The solution so obtained was acidified with formic acid (45.8 kg) and the resultant mixture was concentrated by distillation under reduced pressure (0.12 bar) to remove 460 litres of solvent. Formamide (438 kg) was added and distillation at reduced pressure (0.12 bar) was continued until the distillation temperature reached [95°C.] The mixture was heated for a further 5 hours at approximately [100°C.] The mixture was cooled to [20°C] and the resulting solid was collected by filtration, washed in turn with water, isopropanol and tert-butyl methyl ether and dried. There was thus obtained 7-methoxy- [6- (3-MORPHOLINOPROPOXY)-3,] 4-dihydroquinazolin-4-one (63 kg); NMR Spectrum: [(DMSOD6)] 1.93 (m, 2H), 2.37 (t, 4H), 2.43 (t, 2H), 3.58 (t, 4H), 3.91 (s, 3H), 4.11 (t, 2H), 7.13 (s, 1H), 7.44 (s, 1H), 7.98 (s, 1H), 12.05 (broad s, 1H); Mass Spectrum: M+H+ 320.
3.3 g	With formamide; at 20℃; for 8h;Reflux;	Compound 7 (3.6 g, 11.6 mmol) and formic acid (14.5 mL),The formamide (14.5 mL) was mixed, stirred at room temperature for 15 min, then heated to reflux for 8 h.After the reaction is completed, the mixture is distilled under reduced pressure, and the residue is suction filtered.The acetone was rinsed and recrystallized from ethyl acetate.Compound 8 (3.3 g) was obtained.

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4102 - 4106.
[2]Patent: WO2004/24703,2004,A1 .Location in patent: Page 10-11.
[3]Patent: CN109627222,2019,A .Location in patent: Paragraph 0036; 0037; 0038.

2
[ 675126-26-8 ]
[ 64-18-6 ]
[ 199327-61-2 ]

References: [1]Heterocycles,2007,vol. 71,p. 39 - 48.

3
[ 199327-61-2 ]
[ 367-21-5 ]
[ 184475-35-2 ]

Yield	Reaction Conditions	Operation in experiment
84%		7 - methoxy -6 - [3 - (4 - morpholinyl) propoxy] quinazoline -4 (3H) - ketone (V) (7.5g, 23mmol), thionyl chloride (105 ml) and DMF (1.5g) after mixing the heating to reflux 1 hour, evaporate the solvent. The residue is added toluene (35 ml), concentrated under reduced pressure, repeated 3 times. The residue by adding isopropanol (35 ml), stirring at room temperature for 1 hour, filtered, filters cake Canada to 3 - chloro -4 - fluoro aniline (7.5g, 52mmol) isopropyl alcohol (80 ml) solution, stirring under heating to reflux 1 hour. Cooling to 30 °C, filtering, drying filter cake. The resulting solid re-dissolved in water (100 ml) and heating to the 60 °C PH add saturated sodium hydroxide solution adjusted to 9.5 - 10.0, after cooling crystallization, filtration, the filter cake is recrystallized with ethyl acetate, to obtain 4 - (3 - chloro -4 - fluoro benzyl amidogen) -7 - methoxy -6 - (3 - morpholino-propoxy) quinazoline (I) (8.8g), yield 84percent.
82%	With potassium carbonate; In isopropyl alcohol; at 80 - 85℃; for 1h;	To the reaction tank, 121.3 g of 3-chloro-4-fluoroaniline and 1.8 L of isopropanol were added to the whole solution,219.6 g of potassium carbonate was added, 268.2 g of intermediate 1 was added, and the mixture was heated to 80 to 85 ° C for 1 hour.TLC monitoring (MeOH: DCM = 1: 5, ZJ1 Rf = 0.6, product Rf = 0.8), the feed point disappeared.Hot filter, the filtrate cooled to room temperature, get solid, filter, filter cake with leaching of isopropyl alcohol 1.5L after drying,Dried at 50-60 ° C for 6 h under reduced pressure to give crude gefitinib, pale yellow solid 333.5 g, yield: 94percent, HPLC purity 99.3percent Purification of crude gefitinibTo the reaction tank was added gefitinib crude 333.5 g, methyl isobutyl ketone 2L and ethyl acetate 6L, stir, literWarm reflux 3 hours, dissolved, hot filter, the filtrate naturally cooled to 20 ~ 25 ,The crystallization was carried out for 24 hours. The filter cake was dried at a temperature of 88 to 93 ° C under reduced pressure (-0.08 MPa) for 6 hours to obtain 273.5 g of white crystalline powder, which was gefitinib. mp: 193-195 ° C, yield: 82percent. HPLC showed that the single product was less than 0.1percent.
62.86%		(XII) One-Pot Reaction; (1) Preparation of Gefitinib <strong>[199327-61-2]7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one</strong> (29.12 g, 0.0913 mol) is dissolved in toluene, Et3N (19 ml, 0.1366 mol) is added at 5° C., and after POCl3 (17.8 ml, 0.1824 mol) is added, reaction is carried out for 3 hours at 70° C. 3-chloro-4-fluoroaniline (15.9 g, 0.1093 mol) mixed into the isopropyl alcohol (10 ml) is added to the above reaction solution, and then stirring is carried out for 1 hour at 70° C. Wheat solid compound is obtained by filter, water (380 ml) is added to dissolve the solid compound entirely, NaOH (30 ml, 20percent) is added, and after stirred for 1 hour, filter is carried out. After dissolved solid and filtered, Gefitinib (25.65 g, 62.86percent) that is white solid compound is obtained, whose purity determined by HPLC is greater than 99.9percent. 1H-NMR (DMSO) spectrum: 2.21 (brs, 2H), 2.84 (brs, 4H), 2.92 (brs, 2H), 3.80 (brs, 4H), 3.99 (s, 3H), 4.28 (brs, 2H), 7.15 (s, 1H), 7.24 (t, 1H, J=8.9 Hz), 7.71 (m, 2H) 8.00 (m, 1H), 8.44 (s, 1H)

Example 11: Preparation of gefitinib; A mixture of 7-methox^ -6-(3-mophiholin-4-ylpropoxy)-3H-quinazolin-4-one (3.5 g) and thionyl chloride (10.5 ml) was refluxe lor 4 hours. The reaction mass was distilled under reduced pressure to remove excess of thionyl chloride. To the resulting reaction mass, isoamyl alcoho' ("i2.5 ml) was added, followed by addition of 3-chloro-4-fluoro-aniline (1.82 g) and refluxed for 6 houis. Thereafter, reaction mixture was cooled to room temperature, filtered, and distilled to obtain title compound which was further purified with methanol.

References: [1]Patent: CN105153065,2017,B .Location in patent: Paragraph 0166; 0167; 0168; 0169.
[2]Patent: CN107098863,2017,A .Location in patent: Paragraph 0053-0054.
[3]Heterocycles,2007,vol. 71,p. 39 - 48.
[4]Patent: US2010/267949,2010,A1 .Location in patent: Page/Page column 7.
[5]Patent: WO2010/76810,2010,A2 .Location in patent: Page/Page column 17.

4
[ 199327-61-2 ]
[ 958669-54-0 ]

References: [1]Synthetic Communications,2007,vol. 37,p. 3409 - 3415.

5
[ 199327-61-2 ]
[ 958669-55-1 ]

References: [1]Synthetic Communications,2007,vol. 37,p. 3409 - 3415.

6
[ 199327-61-2 ]
[ 184475-35-2 ]

References: [1]Synthetic Communications,2007,vol. 37,p. 3409 - 3415.
[2]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4102 - 4106.
[3]Journal of labelled compounds and radiopharmaceuticals,2005,vol. 48,p. 829 - 843.
[4]Patent: KR2015/1936,2015,A .

7
[ 7357-67-7 ]
[ 199327-61-2 ]

References: [1]Heterocycles,2007,vol. 71,p. 39 - 48.
[2]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4102 - 4106.

8
[ 675126-28-0 ]
[ 199327-61-2 ]

References: [1]Heterocycles,2007,vol. 71,p. 39 - 48.
[2]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4102 - 4106.
[3]Patent: CN109627222,2019,A .

9
[ 621-59-0 ]
[ 199327-61-2 ]

References: [1]Heterocycles,2007,vol. 71,p. 39 - 48.
[2]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4102 - 4106.
[3]Patent: CN105153065,2017,B .
[4]Patent: CN109627222,2019,A .

10
[ 934191-95-4 ]
[ 199327-61-2 ]

References: [1]Heterocycles,2007,vol. 71,p. 39 - 48.

11
[ 861453-11-4 ]
[ 199327-61-2 ]

References: [1]Heterocycles,2007,vol. 71,p. 39 - 48.

12
[ 199327-61-2 ]
[ 847949-49-9 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4102 - 4106.

13
[ 675126-27-9 ]
[ 199327-61-2 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4102 - 4106.

14
[ 675126-26-8 ]
[ 199327-61-2 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4102 - 4106.
[2]Patent: CN109627222,2019,A .

15
[ 52805-46-6 ]
[ 199327-61-2 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4102 - 4106.
[2]Patent: CN109627222,2019,A .

16
[ 6702-50-7 ]
[ 199327-61-2 ]

References: [1]Journal of labelled compounds and radiopharmaceuticals,2005,vol. 48,p. 829 - 843.
[2]Patent: CN105153065,2017,B .

17
[ 380844-22-4 ]
[ 199327-61-2 ]

References: [1]Journal of labelled compounds and radiopharmaceuticals,2005,vol. 48,p. 829 - 843.

18
[ 380844-24-6 ]
[ 199327-61-2 ]

References: [1]Journal of labelled compounds and radiopharmaceuticals,2005,vol. 48,p. 829 - 843.

19
[ 214472-37-4 ]
[ 199327-61-2 ]

References: [1]Journal of labelled compounds and radiopharmaceuticals,2005,vol. 48,p. 829 - 843.

20
[ 184475-35-2 ]
[ 199327-61-2 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonia; In hydrogenchloride;	The starting material was prepared as follows: A suspension of 4-(3-chloro-4-fluoroanilino)-6-(3-morpholinopropoxy)-7-methoxyquinazoline (6.0 g 13.4 mmol), (WO 96 33980), in 6M hydrochloric acid (120 ml) was heated at reflux for 6 hours. The mixture was cooled to 0° C. and carefully neutralised with cooling by addition of concentrated aqueous ammonia. The resulting precipitate was collected by filtration, washed with dilute aqueous ammonia and water and dried under vacuum to give 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (4.2 g). 1H NMR Spectrum: (DMSOd6) 2.4(m, 6H); 3.59(t, 4H); 3.75(t, 2H); 3.90(s, 3H); 4.12(t, 2H); 7.12(s, 1H); 7.43(s, 1H); 7.98(s, 1H); 12.0(br s, 1H). MS-ESI: 320 [MH]+
	With ammonia; In hydrogenchloride;	The starting material was prepared as follows: A suspension of 4-(3-chloro-4-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline (6.0 g, 13.4 mmol), (WO 96/33980), in 6M hydrochloric acid (120 ml) was heated at reflux for 6 hours. The mixture was cooled to 0° C. and carefully, with cooling, was neutralised by addition of concentrated aqueous ammonia. The resulting precipitate was collected by filtration, washed with dilute aqueous ammonia and water and dried under vacuum to give 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (4.2 g, 98percentyield). 1H NMR Spectrum: (DMSOd6) 2.4(m, 6H); 3.59(t, 4H); 3.75(t, 2H); 3.90(s, 3H); 4.12(t, 2H); 7.12(s, 1H); 7.43 (s, 1H); 7.98 (s, 1H); 12.0(br s, 1H) MS-ESI: 320 [MH]+
		The 4-amino-7-methoxy-6-(3-morpholinopropoxy)quinazolile used as a starting material was prepared as follows :- A mixture of 4-(3-chloro-4-fluoroanhino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline (International Patent Application WO 96/33 980, Example 1 therein; 6 g) and 6N aqueous hydrochloric acid solution (120 ml) was stirred and heated to reflux for 6 hours. The mixture was cooled to 0° C. and carefully, with cooling, was neutralised by the addition of concentrated aqueous ammonium hydroxide solution. The No. resultant precipitate was isolated, washed in turn with a dilute aqueous ammonium hydroxide solution and with water and dried under vacuum. There was thus obtained 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (4.2 g); NMR Spectrum: (DMSOd6) 2.4 (m, 6H), 3.59 (t, 4H), 3.75 (t, 2H), 3.9 (s, 3H), 4.12 (t, 2H), 7.12 (s, 1H), 7.43 (s, 1H), 7.98 (s, 1H), 12.0 (br s, 1H); Mass Spectrum: M + H+ 320. A mixture of a portion (0.99 g) of the material so obtained, thionyl chloride (10 ml) and DMF (0.1 ml) was stirred and heated to 80° C. for 1.5 hours. The mixture was cooled to ambient temperature, toluene (10 ml) was added and the mixture was evaporated. The residue was partitioned between ethyl acetate and water (the acidity of the aqueous layer being adjusted to pH 7.5 by the addition of 2N aqueous sodium hydroxide solution). The organic layer was washed No. with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 9:1 mixture of methylene chloride and methanol as eluent. The solid so obtained was triturated under hexane, reisolated and washed with diethyl ether. There was thus obtained 4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline (0.614 g); NMR Spectrum: (CDCl3) 2.12 (m, 2H), 2.5 (br s, 4H), No. 2.59 (t, 2H), 3.73 (t, 4H), 4.05 (s, 3H), 4.27 (t, 2H), 7.33 (s, 1H), 7.4 (s, 1H), 8.86 (s, 1H). A mixture of 4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline (1.6 g) and isopropanol (50 ml) was placed in a Carius tube which was cooled to -78° C. prior to the addition of liquid ammonia (10 ml). The Carius tube was sealed and heated to 130° C. for 20 hours. The Carius tube was cooled to ambient temperature, opened and the mixture was evaporated. The residue was triturated under diethyl ether. There was thus obtained 4- No.amino-7-methoxy-6-(3-morpholinopropoxy)quinazoline (containing 2.9 equivalents of ammoniuin chloride; 1.54 g) which was used without further purification. A portion of the material was purified by column chromatography on silica using a 19:1 mixture of methylene chloride and methanol as eluent. The purified product gave the following data :- NMR Spectrum: (DMSOd6) 1.95 (m, 2H), 2.5 (m, 6H), 3.6 (m, 4H), 3.9 (s, 3H), 4.1 (m, 2H), 7.05 (s, 1H), 7.4 (br s, 2H), No. 7.6 (s, 1H), 8.25 (s, 1H); Mass Spectrum: M + H+ 319.

A mixture of 4-(3-chloro-4-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline (International Patent Application WO 96/33980, Example 1 therein; 6 g) and 6N aqueous hydrochloric acid solution (120 ml) was stirred and heated to reflux for 6 hours.. The mixture was cooled to 0° C. and carefully, with cooling, was neutralised by the addition of concentrated aqueous ammonium hydroxide solution.. The resultant precipitate was isolated, washed in turn with a dilute aqueous ammonium hydroxide solution and with water and dried under vacuum.. There was thus obtained 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (4.2 g); NMR Spectrum: (DMSOd6) 2.4 (m, 6H), 3.59 (t, 4H), 3.75 (t, 2H), 3.9 (s, 3H), 4.12 (t, 2H), 7.12 (s, 1H), 7.43 (s, 1H), 7.98 (s, 1H), 12.0 (br s, 1H); Mass Spectrum: M+H+ 320.

References: [1]Patent: US6265411,2001,B1 .
[2]Patent: US6294532,2001,B1 .
[3]Patent: US2003/225111,2003,A1 .Location in patent: Page 55.
[4]Patent: US6806274,2004,B1 .Location in patent: Page column 96.

21
[ 199327-61-2 ]
[ 1020109-17-4 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; trichlorophosphate; In toluene; at 50℃; for 5h;	Whilst maintaining the temperature of the reaction mixture at about [50°C,] phosphorus oxychloride (365 kg) was added to a stirred slurry of [7-METHOXY-6- (3-MORPHOLINOPROPOXY)-] 3,4-dihydroquinazolin-4-one (220 kg), triethylamine (105 kg) and toluene (1790 litres). The resultant mixture was stirred at about [50°C] for 5 hours to complete the formation of 4-chloro- [7-METHOXY-6- (3-MORPHOLINOPROPOXY)] quinazoline.

References: [1]Patent: WO2004/24703,2004,A1 .Location in patent: Page 11-12.

22
[ 1040264-49-0 ]
[ 3473-63-0 ]
[ 199327-61-2 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; for 6h;Reflux;	Example 10: Preparation of 7-methoxy-6-(3-morpholin-4-ylpropoxy)-3/f-quinazolin-4-one; 4-Methoxy-5-(3-mophiholin-4-ylpropoxy)-2-nitrobenzoic acid ethyl ester (50g) was hydrogenated using 10percent palladium on carbon (50percent wet, 5g) in methanol (250ml) at" 3.0-3.5 kg/cm2 for 3 hours. After completion of reaction, catalyst was removed by filtration. Formamidine acetate (22g) in methanol was added to resulting filtrate and refluxed for 6 hours. After completion of reaction, the reaction mass was cooled to room temperature, stirred for 2 hours. The resulting product was filtered, washed with methanol (50 ml) and dried to betaive 33g (73percent) of the title compound.

References: [1]Journal of Heterocyclic Chemistry,2008,vol. 45,p. 703 - 708.
[2]Patent: WO2010/76810,2010,A2 .Location in patent: Page/Page column 17.

23
[ 1208902-96-8 ]
[ 199327-61-2 ]

Yield	Reaction Conditions	Operation in experiment
85%	With peracetic acid; sulfuric acid; In ethanol; at 60℃; for 12h;	General procedure: To a solution of 6,7-dimethoxyquinazoline 1a (200.0 mg, 1.05 mmol) in ethanol (20 mL) were added 40percent peracetic acid (1.0mL, 5.26 mmol) and 0.01 mL sulfuric acid (1.8 mmol). After the reaction was stirred at 60°C for 4?12 h (see Table 2) and then cooled to room temperature, excess sodium bisulfite (541.8 mg, 5.26 mmol) was added to get rid of the peroxide. The solid was filtered off after stirring for 20 min, and the filtrate was concentrated under reduced pressure to give the crude product, which was washed by ethanol and petroleum ether to give 2a as a light yellow solid (179.7 mg, 83percent), mp>300°C.

References: [1]Tetrahedron,2010,vol. 66,p. 962 - 968.
[2]Synthetic Communications,2014,vol. 44,p. 346 - 351.

24
[ 16712-16-6 ]
[ 77287-34-4 ]
[ 214472-41-0 ]
[ 199327-61-2 ]

Yield	Reaction Conditions	Operation in experiment
71.1%	at 170℃; for 3h;	(XI) Cyclizing Step; (1) Preparation of 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one Methyl 2-amino-5-methoxy-4-(3-morpholinopropoxy)benzoate 5 (41.6 g, 0.1284 mol) is placed in a bottle with a rounded bottom, HCONH2 (108 ml) and HCO2NH4 (9.8 g, 0.0762 mmol) are added to react for 3 hours at 170° C. After cooled to normal temperature, filter and dried, ice water (83.2 ml) is used to wash to obtain yellowish-white solid compound 6 (14.8 g, 71.1percent). 1H-NMR (DMSO) spectrum: 2.07 (m, 2H), 2.58 (brs, 4H), 2.61 (t, 2H, J=6.8 Hz), 3.71 (m, 4H), 3.98 (s, 3H), 4.18 (t, 2H, J=6.8 Hz), 7.15 (s, 1H), 7.59 (s, 1H), 8.00 (s, 1H).

References: [1]Patent: US2010/267949,2010,A1 .Location in patent: Page/Page column 7.

25
[ 199327-61-2 ]
[ 936446-61-6 ]

References: [1]Patent: US2011/39844,2011,A1 .

26
[ 199327-61-2 ]
[ 1172626-99-1 ]

References: [1]Patent: US2011/39844,2011,A1 .

27
[ 199327-61-2 ]
N-(3-ethynylphenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine dihydrochloride [ No CAS ]

References: [1]Patent: US2011/39844,2011,A1 .

28
[ 1494468-50-6 ]
[ 199327-61-2 ]

References: [1]Synthetic Communications,2014,vol. 44,p. 346 - 351.

29
[ 884344-38-1 ]
[ 199327-61-2 ]

References: [1]Synthetic Communications,2014,vol. 44,p. 346 - 351.

30
[ 6346-05-0 ]
[ 199327-61-2 ]

References: [1]Synthetic Communications,2014,vol. 44,p. 346 - 351.

31
[ 58662-50-3 ]
[ 199327-61-2 ]

References: [1]Synthetic Communications,2014,vol. 44,p. 346 - 351.

32
[ 1042978-66-4 ]
[ 199327-61-2 ]

References: [1]Synthetic Communications,2014,vol. 44,p. 346 - 351.

33
[ 7357-67-7 ]
C₉H₆N₂O₃^(2-)*2K⁽¹⁺⁾ [ No CAS ]
[ 199327-61-2 ]

Yield	Reaction Conditions	Operation in experiment
93.7%	With 1-butyl-3-methylimidazolium Tetrafluoroborate; In N,N-dimethyl-formamide; at 55 - 60℃; for 5h;	The compound of Formula III dipotassium salt (10.7g, 40mmol) in 20mL DMF was followed by the addition fo 5percent [Bmim]BF4 and the addition of Formula IV (X=Cl) (7.9g, 48mmol) and was heated to about 55-60°C for 5.0 hours. The reaction mixture was suction filtered to remove the resulting white solid KCl. The solvent was distilled DMF and was added with 20mL distilled water. 0.5M hydrochloric acid was added to adjust to pH to 6-7 and stirred at room temperature. The water vapor was distilled off and Formula 1 was obtained (12.0g, 93.7percent yield).

References: [1]Patent: CN103910689,2016,B .Location in patent: Paragraph 0041.

34
C₉H₆N₂O₃^(2-)*2Na⁽¹⁺⁾ [ No CAS ]
[ 125422-83-5 ]
[ 199327-61-2 ]

Yield	Reaction Conditions	Operation in experiment
93.8%	With 1-butyl-3-methylimidazolium Tetrafluoroborate; In tetrahydrofuran; at 65 - 70℃; for 5h;	The compound of Formula III disodium salt (7.1g, 30mmol) in 20mL THF was followed by the addition fo 5percent [Bmim]BF4 and the addition of Formula IV (X=Br) (7.5g, 36mmol) and was heated to about 65-70°C for 5.0 hours. The reaction mixture was suction filtered to remove the resulting white solid NaBr. The solvent was distilled THF and was added with 20mL distilled water. 0.5M hydrochloric acid was added to adjust to pH to 6-7 and stirred at room temperature. The water vapor was distilled off and Formula 1 was obtained (9.0g, 93.8percent yield).

References: [1]Patent: CN103910689,2016,B .Location in patent: Paragraph 0044.

35
[ 1417436-51-1 ]
C₉H₆N₂O₃^(2-)*2K⁽¹⁺⁾ [ No CAS ]
[ 199327-61-2 ]

Yield	Reaction Conditions	Operation in experiment
91.2%	With 1-butyl-3-methylimidazolium Tetrafluoroborate; In N,N-dimethyl-formamide; at 75 - 80℃; for 5h;	The compound of Formula III dipotassium salt (13.4g, 50mmol) in 40mL DMF was followed by the addition fo 5percent [Bmim]BF4 and the addition of Formula IV (X=I) (15.3g, 60mmol) and was heated to about 75-80°C for 5.0 hours. The reaction mixture was suction filtered to remove the resulting white solid KI. The solvent was distilled DMF and was added with 20mL distilled water. 0.5M hydrochloric acid was added to adjust to pH to 6-7 and stirred at room temperature. The water vapor was distilled off and Formula 1 was obtained (14.6g, 91.2percent yield).

References: [1]Patent: CN103910689,2016,B .Location in patent: Paragraph 0047.

36
[ 179688-52-9 ]
[ 199327-61-2 ]

References: [1]Patent: CN103910689,2016,B .
[2]Patent: CN103910689,2016,B .

37
[ 199327-61-2 ]
[ 230955-75-6 ]

Yield	Reaction Conditions	Operation in experiment
93.7%	With sulfuryl dichloride; In acetonitrile; at 55℃;	1) exchange resin 12.8g in D301 macroporous weakly basic styrene anion, 6- (2-morpholino-ethoxy) -7-methoxy-3,4-dihydro-quinazolin-4 ketone (31.9g, 100mol), sulfuryl chloride (16.2g, 120mmol) in 100ml acetonitrile were contact reaction, the contact reaction temperature was 55 , after the reaction was quenched with ice-water, extracted with methylene chloride, concentrated under reduced pressure to give 6-acetoxy-4-chloro-7-methoxy-quinazoline of 31.7g, a yield of 93.7percent, a purity of 99.05percent.

References: [1]Patent: CN105541737,2016,A .Location in patent: Paragraph 0026; 0034.

38
[ 199327-61-2 ]
4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline dihydrochloride [ No CAS ]

References: [1]Patent: KR2015/1936,2015,A .

39
[ 162012-72-8 ]
4-(3-halopropyl)morpholine [ No CAS ]
[ 199327-61-2 ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) iodide; potassium carbonate; In water; at 90℃; for 0.5h;Microwave irradiation;	1 mmol of 7-methoxy-7-hydroxyquinazolin-4-one and 1.2 mmol of 4- (3-bromopropyl) morpholine were weighed in waterPhase, Cul catalyst 0. lmmol, alkali K2C03 3mmol, 90 ° C microwave heating reflux 0.5h, microwave power 150W. After completion of the reaction, the mixture was cooled to room temperature and filtered to obtain a solid powder.

References: [1]Patent: CN103923023,2016,B .Location in patent: Paragraph 0037-0039.

40
C₁₆H₂₀N₂O₆ [ No CAS ]
[ 199327-61-2 ]

Yield	Reaction Conditions	Operation in experiment
82%	With formamidine acetic acid;	The compound (III) (15.Og, 44.60 mmol) and formamidine acetate(9.29 g, 89.22 mmol) was dispersed in 1-methoxy-2-propanol (300 mL). The 1-methoxy-2-propanol was removed under reduced pressure, and the residue was recrystallized from ethyl acetate.(11.8 g, 82percent) of the title compound as white object

References: [1]Patent: CN105218476,2016,A .Location in patent: Paragraph 0106; 0123; 0124.

41
5-(3-morpholinopropoxy)-6-methoxyisatin [ No CAS ]
[ 199327-61-2 ]

References: [1]Patent: CN105218476,2016,A .

42
[ 214472-17-0 ]
[ 199327-61-2 ]

References: [1]Patent: CN105153065,2017,B .

43
C₁₆H₂₃N₃O₅ [ No CAS ]
[ 199327-61-2 ]

Yield	Reaction Conditions	Operation in experiment
40%	With trichlorophosphate; In toluene; for 2h;Reflux;	N - a hydroxyimino -4 - methoxy -5 - [3 - (4 - morpholinyl) propoxy] benzoic acid amide (IV) (10g, 29.6mmol) dissolved in toluene (200 ml), added phosphorus oxychloride (17.6 ml, 192 . 4mmol) heating to reflux 2 hours, said technological solvent is distilled under reduced pressure, the residue is dissolved in dichloromethane (300 ml), water (100 ml), anhydrous magnesium sulfate drying, filtering, the filtrate off the solvent, the residue method for the chromatographic purification (mobile phase: hexane: ethyl acetate as 5:1), to obtain the product 7 - methoxy -6 - [3 - (4 - morpholinyl) propoxy] quinazoline -4 (3H) - ketone (V) (3.8g), yield 40percent.

References: [1]Patent: CN105153065,2017,B .Location in patent: Paragraph 0164; 0165.

44
[ 199327-61-2 ]
[ 1383952-42-8 ]

Yield	Reaction Conditions	Operation in experiment
84.1%	With triethylamine; trichlorophosphate; In acetonitrile; at 80 - 90℃; for 1h;	To the reaction tank into the acetonitrile 1.35L, phosphorus pentachloride 832g,After stirring, 109.3 g of 7-methoxy-6- (3-morpholin-4-ylpropoxy) quinazolin-4 (3H) -one was added, 5 ml of TEA was added,Heating to 80 ~ 90 reaction 1h,TLC monitoring (MeOH: DCM = 1: 5, starting material Rf = 0.4, product Rf = 0.6)The basic material disappeared, 55 ~ 60 vacuum distillation, steaming most of the solvent, distillation finished cooling,Temperature control 20 ~ 25 by adding 3L isopropyl alcohol beating 1h, room temperature filtration, filter cake drying,Dried at 50-60 ° C for 8 h under reduced pressure to give 284.0 g of pale yellow solid, which was gefitinib intermediate 1, the yield was 84.1percent and the HPLC purity was 98.3percent.

References: [1]Patent: CN107098863,2017,A .Location in patent: Paragraph 0059-0060; 0062.

45
[ 199327-61-2 ]
[ 383-50-6 ]
4-(3-((4-(2-fluoroethoxy)-7-methoxyquinazolin-6-yl)oxy)propyl)-morpholine [ No CAS ]

References: [1]Journal of labelled compounds and radiopharmaceuticals,2018,vol. 61,p. 42 - 53.

46
[ 199327-61-2 ]
[ 113426-12-3 ]
[¹⁸F]4-(3-((4-(2-fluoroethoxy)-7-methoxyquinazolin-6-yl)oxy)propyl)-morpholine [ No CAS ]

References: [1]Journal of labelled compounds and radiopharmaceuticals,2018,vol. 61,p. 42 - 53.

47
[ 246512-44-7 ]
[ 50-00-0 ]
[ 199327-61-2 ]

Yield	Reaction Conditions	Operation in experiment
88%	In water; at 130℃; for 48h;	2-Amino-4-methoxy-5-[(3-morpholinyl)-propoxy-]-benzamide (cas:246512-44-7, 3.09 g, 10 mmol) and paraformaldehydeA mixture of (600 mg, 20 mmol monomer) [monomer molar ratio: 1:2] was added to the reaction flask, then 10 ml of water was added, and the temperature was raised to 130°C by sealing. The reaction was carried out for 48 hours, and then allowed to stand and the solid was filtered off.This was recrystallized from ethyl acetate to give 2.70 g of 7-methoxy-6-[(3-morpholinyl)-propoxy-]-quinazolinone in 88percent yield.

References: [1]Patent: CN107445907,2017,A .Location in patent: Paragraph 0025; 0026; 0059; 0060.

48
[ 199327-61-2 ]
[ 909863-33-8 ]