Gefitinib impurity 5 | Morpholines

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Quality Control of Gefitinib impurity 5 Purity: 97% SDS Specification

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Product Details of Gefitinib impurity 5

CAS No. :	199327-61-2
Formula :	C₁₆H₂₁N₃O₄
M.W :	319.36
SMILES Code :	O=C1NC=NC2=C1C=C(OCCCN3CCOCC3)C(OC)=C2
Synonyms :	Gefitinib impurity 5
MDL No. :	MFCD12760130
InChI Key :	WFUBWLXSYCFZEH-UHFFFAOYSA-N
Pubchem ID :	135399673

Safety of Gefitinib impurity 5

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

Application In Synthesis of Gefitinib impurity 5

* 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 1~35

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 ]