[ CAS No. 184475-71-6 ] {[proInfo.proName]}

Name: 184475-71-6|4-((3-Chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol|98%
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Quality Control of [ 184475-71-6 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 184475-71-6 ]

SDS Specification

Alternatived Products of [ 184475-71-6 ]

Product Details of [ 184475-71-6 ]

CAS No. :	184475-71-6	MDL No. :	MFCD09908046
Formula :	C₁₅H₁₁ClFN₃O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JLVTVCRXFMLUIF-UHFFFAOYSA-N
M.W :	319.72	Pubchem ID :	10471217
Synonyms :		Chemical Name :	4-((3-Chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol

Calculated chemistry of [ 184475-71-6 ]

Physicochemical Properties

Num. heavy atoms :	22
Num. arom. heavy atoms :	16
Fraction Csp3 :	0.07
Num. rotatable bonds :	3
Num. H-bond acceptors :	5.0
Num. H-bond donors :	2.0
Molar Refractivity :	82.56
TPSA :	67.27 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-5.58 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.78
Log Po/w (XLOGP3) :	3.76
Log Po/w (WLOGP) :	4.3
Log Po/w (MLOGP) :	2.85
Log Po/w (SILICOS-IT) :	3.22
Consensus Log Po/w :	3.38

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-4.53
Solubility :	0.00941 mg/ml ; 0.0000294 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.87
Solubility :	0.00436 mg/ml ; 0.0000136 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-6.32
Solubility :	0.000152 mg/ml ; 0.000000474 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.41

Safety of [ 184475-71-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 184475-71-6 ]

* 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.

Upstream synthesis route of [ 184475-71-6 ]
Downstream synthetic route of [ 184475-71-6 ]

[ 184475-71-6 ] Synthesis Path-Upstream 1~2

1
[ 63-68-3 ]
[ 184475-71-6 ]
[ 179688-52-9 ]

Reference： [1] Patent: US5866572, 1999, A,
[2] Patent: US5770599, 1998, A,
[3] Patent: US5770603, 1998, A,

2
[ 109-70-6 ]
[ 184475-71-6 ]
[ 912556-91-3 ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 40℃; for 6 h;	A suspension of 4-((3-chloro-4-fluorophenyl)amino)-7- methoxyquinazolin-6-ol (20.00 g), K₂CO₃(10.37 g), KI (1.04 g), l-bromo-3-chloropropane (7.50 mL) and DMF (150 mL) was stirred at 40 °C for 6 h. The reaction mixture was poured into water and filtered. The filter residue was purified by a silica gel column chromatography (eluting agent: EA) to give the title compound as pale yellow liquid (22.05 g, 89.00 percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 396.1 (M+l); ? NMR (400 MHz, CDC1₃) ?: 2.01 (m, 2H), 3.68 (t, J = 4.2 Hz, 2H), 4.00 (s, 3H), 4.10(t, J = 4.2 Hz, 2H), 6.80 (s, 1H), 7.16 (s, 1 H), 7.26 (s, 1H), 7.30 (s, 1 H), 7.47 (s, 1 H), 8.64 (s, 1H) ppm.
89%	With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 40℃; for 6 h;	A suspension of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (20.00 g), K₂CO₃(10.37 g), KI (1.04 g), 1-bromo-3-chloropropane (7.50 mL) and DMF (150 mL) was stirred at 40° C. for 6 h. The reaction mixture was poured into water and filtered. The filter residue was purified by a silica gel column chromatography (eluting agent: EA) to give the title compound as pale yellow liquid (22.05 g, 89.00percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 396.1 (M+1); ¹H NMR (400 MHz, CDCl₃) δ: 2.01 (m, 2H), 3.68 (t, J=4.2 Hz, 2H), 4.00 (s, 3H), 4.10 (t, J=4.2 Hz, 2H), 6.80 (s, 1H), 7.16 (s, 1H), 7.26 (s, 1H), 7.30 (s, 1H), 7.47 (s, 1H), 8.64 (s, 1H) ppm.
Ca. 330 mg	With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 4 h; Heating	The steps for the synthesis of intermediate compound 8: Refering to the formula IV, and according to the formula VI, compound 7 (478mg, 1.5mmol), 1-bromo-3-chloropropane (1.18g, 7.5mmol) and K₂CO₃ (1.05g, 7.5mmol) were added in into the flask prefilled with 3ml of DMF, heating it up to 90°C and keeping for 4 hours, and then cooling down to the room temperature. 15ml of water was added in, and the organic phases, extracted by ethyl acetate (20ml × 3), were combined. The combined organic phase was washed by water and saturated aqueous solution of Na₂CO₃ respectively. MgSO₄, used as desiccant, was added. The solvent was removed by rotary evaporator after the desiccant was removed by filtration. Using silica gel column (gradient elution using petroleum ether containing 20v/vpercent-80v/vpercent ethyl acetate as eluent) to separate the residue, and about 330mg of product 8 was obtained.

Reference： [1] Patent: WO2013/71697, 2013, A1, . Location in patent: Paragraph 00197
[2] Patent: US2014/228361, 2014, A1, . Location in patent: Paragraph 0277-0278
[3] Patent: US2014/206664, 2014, A1, . Location in patent: Paragraph 0225; 0229
[4] Patent: EP2796451, 2014, A1, . Location in patent: Paragraph 0082

[ 184475-71-6 ] Synthesis Path-Downstream 1~32

1
[ 788136-89-0 ]
[ 184475-71-6 ]

Yield	Reaction Conditions	Operation in experiment
95.3%	With sodium methylate; In methanol; for 3h;Reflux;	To the reaction vessel was added 4- (3-chloro-4-fluoro) phenylamino-6-carbethoxy-7-methoxyquinazoline (3.61 g,10mmol), dissolved in 30mL methanol, added sodium methoxide (2.7g, 50mmol), stirred evenly, heated to reflux, reaction 3hour. After completion of the reaction, the solid was removed by filtration, and the solid was cooled to give 4- (3-chloro-4-fluoro) phenylamino-6-hydroxy-7-methoxy Ylquinazoline was obtained in a yield of 95.3%.
>95%	With methanol; ammonium hydroxide; at 20℃; for 3h;	Reference is made to the literature method (W. Cheng, et al., Eur. J. Med. Chem., 2015, 89, 826-834).As follows: 1.0 g of 4- (3-chloro-4-fluoroanilino) -6-acetoxy-7-methoxyquinazoline was added to 10 mL of methanol,Was added concentrated aqueous ammonia (25%) 0.5 mL,Room temperature reaction 3 h.Treatment: filter, filter cake with cold methanol leaching,Collected and dried to give a white solid. Yield:> 95%.
90%	With water; sodium hydroxide; In methanol; at 20℃; for 6h;	To a suspension of 4-((3-chloro-4-fluorophenyl)amino)-7- methoxyquinazolin-6-yl acetate (2.51 g) and methanol (50 mL) was added 5 mol/L NaOH (5.00 mL) at room temperature. The reaction mixture was stirred at room temperature for 6 h, and was adjusted to pH 5 with 0.1 N HC1 (aq). The mixture was filtered to give the title compound as a solid (1.99 g, 90.00 %).

90%	With methanol; sodium hydroxide; at 20℃; for 6h;	To a suspension of <strong>[788136-89-0]4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl acetate</strong> (2.51 g) and methanol (50 mL) was added 5 mol/L NaOH (5.00 mL) at room temperature. The reaction mixture was stirred at room temperature for 6 h, and was adjusted to pH 5 with 0.1 N HCl (aq). The mixture was filtered to give the title compound as a solid (1.99 g, 90.00%).
89%	With ammonia; In methanol; water; at 20 - 100℃; for 19.5h;	To a solution of 6-acetoxy-4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazoline (1.54 g, 4.26 mmol) (from Example 18, Step A, supra) in MeOH (30 mL) was added an aqueous solution of NH4OH (29%, 0.86 mL, 12.7 mmol). The reaction mixture was stirred at room temperature for 18 hours, then heated at 100 C. for 1.5 hours. The mixture was then cooled to room temperature and filtered. The precipitate was collected and dried in vacuo to give the desired 4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-ol as a gray solid. (Yield 1.21 g, 89%).
87%	With ammonium hydroxide; In methanol;	Step 5 4-(3-Chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol: Ammonium hydroxide (5 mL) was added to a solution of <strong>[788136-89-0]4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl acetate</strong> (2.6 g, 7.19 mmol, 1.00 equiv) in methanol (50 mL). The resulting solution was stirred at about 25 C. for about 18 hours. The solids were collected by filtration. After washing with methanol (10 mL), the solid was dried in vacuo to give the title product as a solid (2.0 g; yield=87%). 1H NMR (300 MHz, DMSO) delta: 9.70 (s, 1H), 9.48 (s, 1H), 8.49 (s, 1H), 8.21-8.24 (dd, J=6.9, 2.7 Hz 1H), 7.82-7.87 (m, 1H), 7.37-7.44 (q, 1H), 7.23, (s, 1H), 3.99 (s, 3H); LC-MS: m/z=320/322 (MH)+.
85%	With ammonium hydroxide; In methanol; at 20℃; for 2h;	General procedure: A mixture of compound 12a (1.40 g, 3.91 mmol) and ammoniumhydroxide (8 mL) in methanol (30 mL) was stirred at room temperaturefor 2 h. After removing the volatile under reduced pressure,the residue was diluted with water (30 mL), and stirred for10 min. The resulting solid was collected by suck filtration, washedwith water, and dried at 50 C to afford compound 13a as an offwhitesolid (1.16 g, 94% yield)
84%	With water; sodium hydroxide; In methanol; at 20℃;	Into a 500-mL round-bottom flask, was placed a solution of 4-[(3-chloro-4- fluorophenyl)amino]-7-methoxyquinazolin-6-yl acetate (10.1 g, 27.92 mmol, 1.00 equiv) in methanol (200 mL), a solution of NaOH (4 g, 100.01 mmol, 5.00 equiv) in water(20 mL). The resulting solution was stirred for overnight at room temperature. The pH value of the solution was adjusted to 5 with hydrogen chloride (1mol/L). The solids were collected by filtration. This resulted in 7.5 g (84%) of 4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-ol as a brown solid. LC-MS: (ES, m/z): 320 [M+H]+ Retention time: 0.904 min [00570] 1H-NMR: (DMSO, ppm): delta = 11.15-11.12 (s, 1H), 10.59-10.51 (s, 1H), 9.88-9.82 (s, 1H), 8.25-7.99(m, 2H), 7.86-7.69 (m, 1H), 7.58-7.47 (m, 1H), 7.37-7.33(s, 1H), 4.06-3.99(s, 3H).
82%	With ammonia; In methanol; at 20℃; for 2h;	Adding a compound of formula VIII to a 1L three-necked bottle180g (0.5mol),800 mL of a 20% ammonia methanol solution was added, and the reaction was stirred at room temperature for 2 hours, and the reaction was monitored by HPLC. The filter cake was rinsed with a small amount of methanol, and the solid was collected, and dried at 50 C to obtain 130 g of an off-white compound of formula IX with a molar yield of 82% and a purity of 99%.
72%	With methanol; ammonium hydroxide; at 75℃; for 2h;	Adding step 3 to a 100 mL round bottom flask <strong>[788136-89-0]4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl acetate</strong> (1 g), Methanol (40mL) and 2mL of 25% ammonia water, the reaction system is heated to 75 C The mixture was refluxed and refluxed for 2 hours, and a large amount of white solid precipitated in the reaction system. The TLC detection of the starting material was complete. The reaction system was slowly cooled to room temperature, the suspension was filtered, the filter cake was washed twice with methanol, and dried in an oven. That is, 4-((3-chloro-4-fluorophenyl)amino)-7-methoxy-6-ol was obtained in a yield of 72%.
	With ammonium hydroxide; In methanol; at 20℃; for 3h;	General procedure: Compounds 13a-13d was added to the mixture of methanol (15.0 mL) and 25% ammonia (2.0 mL) and stirred for 3-4 h at room temperature.The solid was filtered and washed with chilled methanol and dried in vacuum to obtain 14a-14d.
78 g	With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 4h;	10g of compound GG6 dissolved in 200ml of tetrahydrofuran, 30 mL water, 1 · 5eq of of NaOH, stirred at room temperature 4h, TLC After completion of the reaction was monitored, adjusted to pH 4 with hydrochloric acid, the reaction mixture was poured into 500ml of water, filtered, and the solid was collected and dried to obtain 78g compound GG

Reference： [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 870 - 879
[2]Patent: CN106045980,2016,A .Location in patent: Paragraph 0027; 0028; 0029
[3]Patent: CN106432202,2017,A .Location in patent: Paragraph 0012
[4]Patent: WO2013/71697,2013,A1 .Location in patent: Paragraph 00196
[5]Patent: US2014/228361,2014,A1 .Location in patent: Paragraph 0275-0276
[6]Patent: US2004/254205,2004,A1 .Location in patent: Page 19
[7]Dalton Transactions,2015,vol. 44,p. 13100 - 13111
[8]Patent: US2010/143295,2010,A1
[9]European Journal of Medicinal Chemistry,2017,vol. 127,p. 442 - 458
[10]Patent: WO2018/119441,2018,A1 .Location in patent: Paragraph 00568-00570
[11]Patent: CN109721552,2019,A .Location in patent: Paragraph 0116-0118
[12]Patent: CN108047209,2018,A .Location in patent: Paragraph 0041; 0049; 0050
[13]Journal of Medicinal Chemistry,2018,vol. 61,p. 11372 - 11383
[14]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1911 - 1914
[15]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4908 - 4912
[16]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4745 - 4749
[17]Patent: US2014/206664,2014,A1 .Location in patent: Paragraph 0225
[18]Patent: EP2796451,2014,A1 .Location in patent: Paragraph 0079
[19]European Journal of Medicinal Chemistry,2015,vol. 89,p. 826 - 834
[20]Patent: CN103570738,2016,B .Location in patent: Paragraph 0319; 0320; 0326
[21]Chinese Journal of Chemistry,2017,vol. 35,p. 1693 - 1700
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[23]Angewandte Chemie - International Edition,2013,vol. 52,p. 8551 - 8556
Angew. Chem.,2013,vol. 125,p. 8713 - 8718,6

2
[ 7357-67-7 ]
[ 184475-71-6 ]
[ 184475-35-2 ]

Yield	Reaction Conditions	Operation in experiment
92%	With 18-crown-6 ether; potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 60℃; for 3h;	30 ml of N, N-dimethylformamide 3 g (9.38 mmol) of 4- (3'-chloro-4'-fluoroanilino) -7-methoxyquinazolin- Was added 1.92 g (11.73 mmol) of 3-morpholinopropyl chloride, 7.50 g (54.23 mmol) of potassium carbonate, 1.27 g (8.44 mmol) of sodium iodide, And 0.25 g (0.94 mmol) of 18-crown-6 was added. The reaction was warmed to 60 DEG C and stirred for 3 hours. The reaction product was filtered, and 90 ml of water was added to the filtrate to precipitate crystals. After filtration and drying, 3.72 g of gefitinib was obtained (yield: 88.7%).3.0 g of gefitinib synthesized using Example 1 was suspended in 45 ml of ethanol in a three neck round bottom flask equipped with a reflux condenser, a thermometer and a stirrer. The mixture was refluxed and stirred for 1 hour, then slowly cooled to room temperature, Stir for about 15 hours. This was filtered and dried to obtain 2.76 g of high purity gefitinib (yield: 92.0%, purity: 99.94%).
90%	With tetrabutylammomium bromide; sodium carbonate; potassium iodide; In iso-butanol;Reflux;	4-(3-Chloro-4-fluorophenylaminofluorophenylamino)-6-hydroxy-7-methoxyquinazoline 2 (50 g, 0.1563 mol), KI (2.0 g), sodium carbonate (24 g) and TBAB (2 g) were added to 2-butanol (500 mL). N-morpholinopropyl chloride (28 g, 0.1711 mol) was added and heated to reflux for 8-10 hr. Reaction progress was monitored on TLC for completion. The mass was filtered to remove the inorganics and the filtrate distilled to get crude Gefitinib 63 g, (Yield 90%, purity 98%). Crude Gefitinib was refluxed with 315 mL methanol for 1 hr then cooled to 5-10C. The mass was filtered and washed with 60 mL chilled methanol. The isolated wet cake was suspended in 500 mL toluene and 50 mL methanol and heated to 85-90C to get a clear solution, 2.5 g activated charcoal was added to the clear solution and maintained further for 30 min. The reaction mass was filtered over celite bed and washed with 50 mL toluene and methanol mixture (50:50 ratio). Reaction mixture was distilled up to 200 mL volume, at this point material starts crystallizing. Reaction mass was cooled to 25-30C, filtered and washed with toluene 50 mL to get pure white color Gefitinib 1, 56 g (Yield 81%, purity >99%). m.p. 193-95C; 1H NMR (DMSO-d6, 300 MHz): delta 9.540 (s, 1H), 8.504 (s, 1H), 8.120-8.135 (d, J = 4.5 Hz, 1H), 7.788 (s, 2H), 7.412-7.471 (t, J = 8.7 Hz, 1H), 7.194 (s, 1H), 4.176 (s, 2H), 3.944 (s, 3H), 3.590 (s, 4H), 2.399-2.514 (m, 6H), 2.002 (s, 2H); MS (EI): m/z 448 (M+ 1).
88%	In N,N-dimethyl-formamide; at 80 - 90℃;	In 30L reaction bottle to add a step reactant N-(3-chloro-propyl) morpholine (493g), DMF (5L), stirring and heating, decompression concentrating; the concentrate by adding DMF (3L), the temperature is increased to 80 C -90 C reaction 6-8 hours stop the reaction. Reaction liquid cooling to 40 C -50 C, filtering, washing with DMF. The filtrate is distilled under reduced pressure; concentrating the water instillment purification, continue to stir 3 hours. Filtering, washing with purified water. The filter cake is added to the methanol reflux 6 hours, cooling and filtering, and washing with methanol. Get N-(3-chloro-4-fluoro phenyl) - 7-methoxy-6 - (3-morpholin-4-propoxy) quinazoline-4-amine, that is, crude product.3, crude product refiningThe resulting added to the methanol in crude, stirring reflux. Cooling the stirring 3 hours crystallization, cooling to 25 C -30 C, filtering, the filter cake is washed with methanol eluviation. Vacuum drying the filter cake 10 hours. Obtained product Geftinat 540g, yield: 88%. Gefitinib products by HPLC detection, as shown in Figure 2.Although the invention has been in a preferred embodiment of the above disclosed, but it is not used to limit the invention, any person familiar with this technology, without departing from the spirit of this invention and within the scope, can be various changes and modification, the scope of protection of the present invention should be defined by the rights of whichever is required.

87%	With potassium carbonate; In N,N-dimethyl-formamide; at 85℃; for 6h;Inert atmosphere;	Example 5Preparation ofN-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amme (I, gefitinib) [0035] Under N2, the mixture of 4-[(3-chloro-4-fluorophenyl) amino]-7- methoxyquinazolin-6-ol (VII, 30.0 g, 93.8 mmol, 1.0 eq.), 4-(3-chloropropyl) morpholine (VIII, 16.lg, 1.05 eq.), K2C03 (25.9 g, 2.0 eq.) and N,N-dimethylformamide DMF (360 mL) was heated to 85C for 6 h. After the reaction completion, the mixture was cooled to 20-25C. The mixture was filtered and washed with DMF (60 mL2). The conc. HCI (3.0 eq.) was added dropwise into filtrate. A lot of solid precipitated. The mixture was filtered, washed with DMF (60 mL2). The filter-cake was dissolved in water (360 mL) at 75C. The iN NaOH aq. was added to the mixture to adjust pH value about 12-13. The mixture was filtered, washed with H20 (60 mL*2) and dried in vacuo at 50C to afford gefitinib as off-white solid (38.0 g) with 96.7% purity in 87% yield.1H NMR (400 MHz, d6-DMSO) O 9.44 (5, 1H), 8.50 (5, 1H), 8.12 (dd, J= 6.9, 2.7 Hz,1H), 7.80 (m, 2H), 7.44 (t, 1H), 7.20 (5, 1H), 4.18 (t, J= 6.7 Hz, 2H), 3.94 (5, 3H), 3.59(t, J = 4.4 Hz, 4H), 2.49 (t, J = 6.9 Hz, 2H), 2.41 (bs, 4H), 2.00 (m, 2H). l3 NMR (100 MHz, d6-DMSO) O 156.48, 154.94, 153.57 (J = 241 Hz), 153.05,148.74, 147.43, 137.33 (J = 3 Hz), 123.91, 122.77 (J = 7 Hz), 119.19 (J = 19 Hz),116.90 (J=21 Hz), 109.26,107.72,103.14,67.59,66.43,56.31,55.35,53.73,26.13.
85.2%	With potassium carbonate; In N,N-dimethyl-formamide; at 80 - 85℃; for 4h;	100 g (0.31 mol) of the compound of the formula IX was added to a 2 L three-necked flask, and 141 g (1.02 mol) of potassium carbonate was added thereto.DMF 800 mL, warmed to 80-85 C, and added N-(3-chloropropyl)morpholine 53.3 g (0.32 mol) in 200 mL DMF solution.The reaction was carried out for 4 hours, and the reaction was monitored by HPLC. About 600 mL of DMF was distilled off under reduced pressure, poured into 3 L of water and stirred for 1 hour, and filtered.The solid was collected, dried at 50 C to obtain a white-like crude gefitinib 130 g, purity 96%.130 g of the crude gefitinib obtained above was added to 2.6 L of methanol, heated to reflux to dissolve, and cooled to 25 C.After crystallization for 3 hours, filtration, collecting solid, drying at 60 C to obtain white gefitinib 118 g, molar yield 85.2%, pureDegree 99.6%.
84%		Under N2 protection, 6.4 g (20 mmol) of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (compound 6)It was added to 300 mL of DMF, heated to 75 C., 5 g (24 mmol) of 4-(3-chloropropyl)morpholine was added dropwise over a period of about 1 h, and during the addition, 1.4 g (10 mmol) was added in portions.Potassium carbonate (in 6 batches, 1 h was added), and the reaction was continued for 6 h after the addition was complete. After the reaction was completed, the mixture was filtered, the filter cake was washed with a little DMF, and the filtrate was concentrated under reduced pressure. The concentrate was stirred with 100 g of ice water and filtered to give a crude product. After the crude product was added to methanol, the solution was concentrated with concentrated hydrochloric acid to obtain gefitinib salt. The acid salt, the hydrochloride salt was further added to water, and the pH was adjusted to 8 with aqueous ammonia to obtain a large amount of a white powder, ie, gefitinib (7.5 g) in a yield of 84%.
67%	With potassium carbonate; In N,N-dimethyl-formamide;	Step 6 N-(3-Chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine: Potassium carbonate (800 mg, 5.80 mmol, 5.79 equiv) was added to a solution of 4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol (320 mg, 1.00 mmol, 1.00 equiv), 4-(3-chloropropyl)-morpholine (190 mg, 1.16 mmol, 1.16 equiv), and N,N-dimethylformamide (10 mL). The resulting solution was stirred at about 80 C. for about 2 hours. The resulting crude product was purified by silica gel chromatography (ethyl acetate/methanol (6:1)) to give the title product as a white solid (0.3 g; yield=67%). 1H NMR (300 MHz, DMSO) delta: 9.57 (s, 1H), 8.51 (s, 1H), 8.11-8.14 (dd, J=6.6, 2.4 Hz 1H), 7.78-7.82 (m, 2H), 7.43-7.49, (t, 1H), 7.22 (s, 1H), 4.18-4.22 (t, 2H), 3.95 (s, 3H), 3.58-3.61 (t, 4H), 2.50-2.53 (m, 2H), 2.40-2.51 (t, 2H), 1.99-2.03 (t, 2H); LC-MS: m/z=447/449 (MH)+.
50%	With potassium carbonate; In N,N-dimethyl-formamide;	EXAMPLE 1 A mixture of 4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (1 g), 3-morpholinopropyl chloride (J. Amer. Chem. Soc., 1945, 67, 736; 0.62 g), potassium carbonate (2.5 g) and DMF (50 ml) was stirred and heated to 80 C. for 2 hours. A further portion (0.1 g) of 3-morpholinopropyl chloride was added and the mixture was heated to 80 C. for 1 hour. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography using a 4:1 mixture of ethyl acetate and methanol as eluent. The material so obtained was recrystallized from toluene. There was thus obtained 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline (0.69 g, 50% m.p. 119-120 C.; NMR Spectrum: 2.0 (m, 2H), 2.45 (m, 6H), 3.6 (m, 4H), 3.95 (s, 3H), 4.2 (t, 2H), 7.2 (s, 1H), 7.4 (t, 1H), 7.8 (m, 2H), 8.1 (m, 1H), 8.5 (s, 1H), 9.5 (s, 1H); Elemental Analysis: Found C, 58.7; H, 5.3; N, 12.2; C22 H24 ClFN4 O3 requires C, 59.1; H, 5.4; N, 12.5%.
40%	With tetrabutylammomium bromide; In acetonitrile; for 16h;Heating / reflux;Product distribution / selectivity;	Example 12 : Preparation of Gefitinib; Acetonitrile (500 ml), N-(4-fluoro-3-chloro phenyl)-6-hydroxy-7-methoxy quinazoline-4- amine (50 gm), 3-morpholinopropyl chloride (35 gm) and tetrabutyl ammonium bromide (5 gm) were refluxed for 16 hours. The reaction mass was distilled off to remove acetonitrile completely at 40-45C. To the residue, water (500 ml) was charged and stirred for 15 minutes at 25-300C. The solid obtained was filtered, washed with methanol (50 ml) and dried at 45-50C. The crude solid was dissolved in a mixture of toluene (1200 ml) and methanol (200 ml). The reaction mass was distilled off under reduced pressure at 40-450C to 400 ml volume, cooled to 10-150C, stirred for 30 minutes, the solid filtered, washed with toluene (40 ml) and dried to yield gefitinib (28 gm, 40% yield).
154.7 g		About 123.0 g of 4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol and about 1100.0 mL of N,N-dimethylformamide were placed in a flask. The resulting mixture was suspended with stirring while about 186.0 g of potassium carbonate and about 4.7 g of N,N-dimethylaminopyridine were added. The reaction mixture was cooled to about -10, slowly added with about 77.0 g of iodotrimethylsilane while paying attention to heat generation, and stirred at about 15 for about 1 hr. Then about 75.5 g of 4-(3-chloropropyl)morpholine was diluted with about 130.0 mL of N,N-dimethylformamide and then slowly added. The reaction mixture was heated to about 80 and stirred for about 2 hr. The termination of the reaction was confirmed using HPLC and TLC. The reaction product was cooled to about 20, slowly added with 2460.0 mL of purified water, and stirred for 30 min, and the produced solid was filtered. The obtained solid was washed with about 490.0 mL of purified water and then dried in a vacuum at about 50 for about 3 hr, yielding about 154.7 g of the title compound N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib) as pale yellow powder.[98]HPLC purity: 99.21% (N-alkylated impurity, that is, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine: 0.3%)[99]1H-NMR (400MHz, DMSO-d6): 2.0 (m,2H), 2.4 (m,6H), 3.7 (m,4H), 3.9 (s,3H), 4.2 (t,2H), 7.2 (s,1H), 7.4 (t,1H), 7.8 (m,2H), 8.2 (m,1H), 8.5 (s,1H), 9.6 (s,1H)

Reference： [1]Patent: KR101635724,2016,B1 .Location in patent: Paragraph 0064; 0075; 0076
[2]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2014,vol. 53B,p. 1269 - 1274
[3]Patent: CN105503748,2016,A .Location in patent: Paragraph 0067; 0068; 0069; 0070
[4]Patent: WO2015/188318,2015,A1 .Location in patent: Paragraph 0035; 0038; 0039
[5]Patent: CN109721552,2019,A .Location in patent: Paragraph 0119-0122
[6]Patent: CN107698523,2018,A .Location in patent: Paragraph 0096; 0097; 0098
[7]Molecules,2006,vol. 11,p. 286 - 297
[8]Patent: US2010/143295,2010,A1
[9]Patent: US5770599,1998,A
[10]Patent: WO2008/125867,2008,A2 .Location in patent: Page/Page column 27
[11]Patent: WO2013/180403,2013,A1 .Location in patent: Paragraph 96-99

3
[ 179688-53-0 ]
[ 184475-71-6 ]

Reference： [1]Molecules,2006,vol. 11,p. 286 - 297
[2]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1911 - 1914
[3]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4745 - 4749
[4]Patent: WO2013/71697,2013,A1
[5]Patent: WO2013/180403,2013,A1
[6]Patent: US2014/206664,2014,A1
[7]Patent: US2014/228361,2014,A1
[8]Patent: EP2796451,2014,A1
[9]Dalton Transactions,2015,vol. 44,p. 13100 - 13111
[10]Patent: CN103570738,2016,B
[11]Patent: CN106045980,2016,A
[12]Patent: US2009/111772,2009,A1
[13]Chinese Journal of Chemistry,2017,vol. 35,p. 1693 - 1700
[14]Patent: CN108047209,2018,A
[15]Journal of Medicinal Chemistry,2018,vol. 61,p. 11372 - 11383
[16]Patent: CN109721552,2019,A
[17]Angewandte Chemie - International Edition,2013,vol. 52,p. 8551 - 8556
Angew. Chem.,2013,vol. 125,p. 8713 - 8718,6
[18]European Journal of Medicinal Chemistry,2021,vol. 216

4
[ 13794-72-4 ]
[ 184475-71-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: L-methionine; methanesulfonic acid / 12 h / Heating 2: pyridine; 4-(dimethylamino)pyridine / 6 h / 100 °C 3: 92 percent / N,N-diethylaniline; phosphoryl chloride / 1 h / 80 - 100 °C 4: propan-2-ol / 5 h / 90 °C 5: 90 percent / ammonia / methanol; H₂O / 24 h / 20 °C
	Multi-step reaction with 5 steps 1: methionine; MeSO₃H / 3 h / 100 °C 2: pyridine 3: SOCl₂ 4: NH₄OH / methanol
	Multi-step reaction with 5 steps 1: methanesulfonic acid; L-methionine / 120 °C 2: pyridine; dmap / 100 °C 3: trichlorophosphate / toluene / Reflux 4: pyridine / isopropyl alcohol / Reflux 5: water; sodium hydroxide / methanol

	Multi-step reaction with 5 steps 1.1: methanesulfonic acid; DL-methionine / 3 h / 130 °C / Cooling with ice 1.2: pH 7 2.1: pyridine / 3 h / 20 - 100 °C 3.1: thionyl chloride / N,N-dimethyl-formamide / 3 h / 70 °C 4.1: isopropyl alcohol / 5 h / 88 °C 5.1: water; sodium hydroxide / methanol / 6 h / 20 °C
	Multi-step reaction with 5 steps 1: methanesulfonic acid; DL-methionine / 12 h / 120 °C 2: dmap; pyridine / 12 h / 0 - 20 °C 3: trichlorophosphate; N-ethyl-N,N-diisopropylamine / toluene / 14 h / 120 °C 4: isopropyl alcohol / 2 h / 90 °C 5: ammonia; methanol / 12 h / 20 °C
	Multi-step reaction with 5 steps 1: DL-methionine; methanesulfonic acid / 3 h / 130 °C 2: pyridine / 3 h / 100 °C 3: thionyl chloride / N,N-dimethyl-formamide / 3 h / 70 °C 4: isopropyl alcohol / 5 h / 88 °C 5: sodium hydroxide; methanol / 6 h / 20 °C
	Multi-step reaction with 5 steps 1: DL-methionine; methanesulfonic acid / 12 h / 120 °C 2: dmap; pyridine / 12 h / 0 - 20 °C 3: trichlorophosphate; N-ethyl-N,N-diisopropylamine / toluene / 14 h / 120 °C 4: isopropyl alcohol / 2 h / 90 °C 5: ammonium hydroxide / methanol / 12 h / 20 °C
	Multi-step reaction with 5 steps 1: magnesium sulfate; methanesulfonic acid 2: pyridine / 20 °C 3: triethylamine; trichlorophosphate / acetonitrile / 80 °C 4: 1,4-dioxane 5: sodium hydroxide / water; tetrahydrofuran / 4 h / 20 °C
	Multi-step reaction with 5 steps 1: methanesulfonic acid; L-methionine / 5 h / 150 - 160 °C 2: pyridine / 3 h / Heating / reflux 3: trichlorophosphate / 3 h / Heating / reflux 4: isopropyl alcohol / 3 h / Heating / reflux 5: methanol; lithium hydroxide; water / 0.5 h / 20 °C
	Multi-step reaction with 5 steps 1: L-methionine; methanesulfonic acid 2: pyridine / 100 °C 3: thionyl chloride; N,N-dimethyl-formamide / 90 °C 4: isopropyl alcohol / Reflux 5: ammonia / water; methanol / 24 h / 20 °C
	Multi-step reaction with 5 steps 1: methanesulfonic acid; DL-methionine / Inert atmosphere 2: pyridine / Inert atmosphere 3: thionyl chloride / N,N-dimethyl-formamide / Inert atmosphere 4: isopropyl alcohol / Inert atmosphere 5: ammonium hydroxide / 3 h / Inert atmosphere; Reflux
	Multi-step reaction with 3 steps 1: thionyl chloride / N,N-dimethyl-formamide / 6 h / 79 - 81 °C 2: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 8 h / 88 - 91 °C / Inert atmosphere 3: pyridine hydrochloride / dimethyl sulfoxide / 12 h / 135 °C / Inert atmosphere

Reference： [1]Knesl, Petr; Roeseling, Dirk; Jordis, Ulrich [Molecules, 2006, vol. 11, # 4, p. 286 - 297]
[2]Barker, Andrew J.; Gibson, Keith H.; Grundy, Walter; Godfrey, Andrew A.; Barlow, Jeffrey J.; Healy, Mark P.; Woodburn, James R.; Ashton, Susan E.; Curry, Brenda J.; Scarlett, Lynn; Henthorn, Lianne; Richards, Laura [Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 14, p. 1911 - 1914]
[3]Chen, Yurong; Feng, Man; Li, Shilei; Xu, Jingli; Ning, Hongyu; He, Yong; Wang, Xiao; Ding, Rui; Qi, Chuanmin [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 14, p. 4745 - 4749]
[4]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2013/71697, 2013, A1
[5]Current Patent Assignee: Qian, Wei - US2014/206664, 2014, A1
[6]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - US2014/228361, 2014, A1
[7]Current Patent Assignee: Qian, Wei - EP2796451, 2014, A1
[8]Current Patent Assignee: CHINESE ACADEMY OF SCIENCES; Shanghai Institute of Materia Medica (in: CAS) - CN103570738, 2016, B
[9]Current Patent Assignee: CURIS INC - US2009/111772, 2009, A1
[10]Shi, Huiping; Lai, Bonan; Chen, Shizhen; Zhou, Xin; Nie, Jing; Ma, Jun-An [Chinese Journal of Chemistry, 2017, vol. 35, # 11, p. 1693 - 1700]
[11]Li, Zhengqiu; Hao, Piliang; Li, Lin; Tan, Chelsea Y. J.; Cheng, Xiamin; Chen, Grace Y. J.; Sze, Siu Kwan; Shen, Han-Ming; Yao, Shao Q. [Angewandte Chemie - International Edition, 2013, vol. 52, # 33, p. 8551 - 8556][Angew. Chem., 2013, vol. 125, # 33, p. 8713 - 8718,6]
[12]Current Patent Assignee: GUANGXI NORMAL UNIVERSITY - CN113264889, 2021, A

5
[ 179688-52-9 ]
[ 184475-71-6 ]

Reference： [1]Molecules,2006,vol. 11,p. 286 - 297
[2]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1911 - 1914
[3]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4745 - 4749
[4]Patent: WO2013/71697,2013,A1
[5]Patent: US2014/206664,2014,A1
[6]Patent: US2014/228361,2014,A1
[7]Patent: EP2796451,2014,A1
[8]Patent: CN103570738,2016,B
[9]Patent: CN106045980,2016,A
[10]Patent: US2009/111772,2009,A1
[11]Chinese Journal of Chemistry,2017,vol. 35,p. 1693 - 1700
[12]Patent: CN108047209,2018,A
[13]Journal of Medicinal Chemistry,2018,vol. 61,p. 11372 - 11383
[14]Patent: CN109721552,2019,A
[15]Angewandte Chemie - International Edition,2013,vol. 52,p. 8551 - 8556
Angew. Chem.,2013,vol. 125,p. 8713 - 8718,6
[16]European Journal of Medicinal Chemistry,2021,vol. 216

6
[ 230955-75-6 ]
[ 184475-71-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1911 - 1914
[2]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4745 - 4749
[3]Patent: WO2013/71697,2013,A1
[4]Angewandte Chemie - International Edition,2013,vol. 52,p. 8551 - 8556
Angew. Chem.,2013,vol. 125,p. 8713 - 8718,6
[5]Patent: US2014/206664,2014,A1
[6]Patent: US2014/228361,2014,A1
[7]Patent: EP2796451,2014,A1
[8]European Journal of Medicinal Chemistry,2015,vol. 89,p. 826 - 834
[9]Dalton Transactions,2015,vol. 44,p. 13100 - 13111
[10]Patent: CN103570738,2016,B
[11]Patent: CN106045980,2016,A
[12]Patent: US2009/111772,2009,A1
[13]Chinese Journal of Chemistry,2017,vol. 35,p. 1693 - 1700
[14]Patent: CN108047209,2018,A
[15]Patent: WO2018/119441,2018,A1
[16]Journal of Medicinal Chemistry,2018,vol. 61,p. 11372 - 11383
[17]Patent: CN109721552,2019,A

7
[ 132710-90-8 ]
[ 295330-86-8 ]
[ 184475-71-6 ]
[ 295330-38-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;triethylamine; In N-methyl-acetamide;	EXAMPLE I 4-(3-chloro-4-fluorophenylamino)-6-[3-(4-tert-butyloxycarbonylpiperazino)propyloxy]-7-methoxyquinazoline 500 mg of 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline, 600 mg of 1-[3-(methanesulfonyloxy)propyl]-4-tert-butyloxycarbonylpiperazine (prepared by reacting <strong>[132710-90-8]1-(3-hydroxypropyl)-4-tert-butyloxycarbonylpiperazine</strong> with methanesulfonic acid anhydride in the presence of triethylamine) and 520 mg of potassium carbonate are stirred in 20 ml of dimethylformamide for 8 hours at 80 C. A further 300 mg of the piperazino compound is added and stirring is continued for another 4 hours at 80 C. The reaction mixture is concentrated by evaporation and the residue is divided between water and ethyl acetate. The organic phase is concentrated by evaporation and the residue is purified by chromatography on a silica gel column with ethyl acetate. Yield: 700 mg of (82% of theory); Rf value: 0.29 (silica gel; ethyl acetate/methanol=9:1); mass spectrum: (M-H)=544, 546.

Reference： [1]Patent: US2002/177601,2002,A1

8
[ 63-68-3 ]
[ 184475-71-6 ]
[ 179688-52-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; methanesulfonic acid;	The 4-(3-chloro-4-fluoroanilino)-6-hydroxy-7-methoxyquinazoline used as a starting material was obtained as follows: 6,7-Dimethoxy-3,4-dihydroquinazolin-4-one (European Patent Application No. 0566226, Example 1 thereof; 26.5 g) was added portionwise to stirred methanesulphonic acid (175 ml). L-Methionine (22 g) was added and the resultant mixture was stirred and heated to reflux for 5 hours. The mixture was cooled to ambient temperature and poured onto a mixture (750 ml) of ice and water. The mixture was neutralised by the addition of a concentrated (40%) aqueous sodium hydroxide solution. The precipitate was isolated, washed with water and dried. There was thus obtained 6-hydroxy-7-methoxy-3,4-dihydroquinazolin-4-one (11.5 g).
	With sodium hydroxide; methanesulfonic acid;	The 4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline used as a starting material was obtained as follows: 6,7-Dimethoxy-3,4-dihydroquinazolin-4-one (European Patent Application No. 0 566 226, Example 1 thereof; 26.5 g) was added portionwise to stirred methanesulphonic acid (175 ml). L-Methionine (22 g) was added and the resultant mixture was stirred and heated to reflux for 5 hours. The mixture was cooled to ambient temperature and poured onto a mixture (750 ml) of ice and water. The mixture was neutralised by the addition of a concentrated (40%) aqueous sodium hydroxide solution. The precipitate was isolated, washed with water and dried. There was thus obtained 6-hydroxy-7-methoxy-3,4-dihydroquinazolin-4-one (11.5 g).
	With sodium hydroxide; methanesulfonic acid;	The 4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline used as a starting material was obtained as follows: 6, 7-Dimethoxy-3, 4-dihydroquinazolin-4-one (European Patent Application No. 0 566 226, Example 1 thereof; 26.5 g) was added portionwise to stirred methanesulphonic acid (175 ml). L-Methionine (22 g) was added and the resultant mixture was stirred and heated to reflux for 5 hours. The mixture was cooled to ambient temperature and poured onto a mixture (750 ml) of ice and water. The mixture was neutralised by the addition of a concentrated (40%) aqueous sodium hydroxide solution. The precipitate was isolated, washed with water and dried. There was thus obtained 6-hydroxy-7-methoxy-3,4-dihydroquinazolin-4-one (11.5 g).

Reference： [1]Patent: US5866572,1999,A
[2]Patent: US5770599,1998,A
[3]Patent: US5770603,1998,A

9
[ 99314-44-0 ]
[ 184475-71-6 ]
4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-methyloxetan-3-ylmethoxy)quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24%		EXAMPLE 10 Using an analogous procedure to that described in Example 5 except that the reaction mixture was stirred at ambient temperature for 72 hours, 4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline was reacted with 3-methyl-3-(4-toluenesulphonyloxymethyl)-oxetane (Chem. Pharm. Bull., 1985, 33, 1707) to give 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-methyloxetan-3-ylmethoxy)quinazoline in 24% yield, m.p. 226-227 C. (recrystallized from ethanol); NMR Spectrum: 1.43 (s, 3H), 3.93 (s, 3H), 4.23 (s, 2H), 4.37 (d, 2H), 4.53 (d, 2H), 7.2 (s, 1H), 7.43 (t, 1H), 7.78 (m, 1H), 7.88 (s, 1H), 8.11 (m, 1H), 8.49 (s, 1H), 9.49 (s, 1H); Elemental Analysis: Found C, 59.5; H, 4.7; N, 10.2; C20 H19 ClFN3 O3 requires C, 59.5; H, 4.7; N, 10.4%.

Reference： [1]Patent: US5770603,1998,A

10
[ 57616-69-0 ]
[ 184475-71-6 ]
4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-pyrrolidin-1-ylpropoxy)-quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide;	EXAMPLE 13 A mixture of 4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (1.28 g), <strong>[57616-69-0]3-(pyrrolidin-1-yl)propyl chloride hydrochloride</strong> (Chem. Abs., 82, 57736; 1.5 g), potassium carbonate (2.8 g) and DMF (20 ml) was stirred and heated to 80 C. for 5 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 20:3 mixture of methylene chloride and methanol as eluent. The material so obtained (1.1 g) was triturated under ethyl acetate to give 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-pyrrolidin-1-ylpropoxy)quinazoline (0.094 g). The organic solution was evaporated and the residual solid was recrystallized from acetonitrile. There was thus obtained a second crop (0.85 g) of the same product. The material gave the following characterising data: m.p. 159-161 C.; NMR Spectrum: 1.95 (m, 4H), 3.3 (m, 6H), 3.95 (s, 3H), 4.3 (t, 2H), 7.2 (s, 1H), 7.4 (t, 1H), 7.9 (m, 1H), 8.1 (s, 1H), 8.2 (m, 1H), 8.5 (s, 1H), 9.8 (broad s, 1H); Elemental Analysis: Found C, 61.0; H, 5.7; N, 13.1; C22 H24 ClFN4 O2 requires C, 61.3; H, 5.6; N, 13.0%.

Reference： [1]Patent: US5770599,1998,A

11
[ 4286-55-9 ]
[ 184475-71-6 ]
[ 1012057-92-9 ]

Yield	Reaction Conditions	Operation in experiment
93%	Stage #1: 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 0.166667h; Stage #2: 1-bromo-6-hexanol In N,N-dimethyl-formamide at 60℃; for 6h;	53.53a A mixture of compound 0109 (1.1 g, 3.44 mmol) and K2CO3 (1.9 g, 13.76 mmol) in DMF (20 mL) was stirred at 4O0C for 10 min. 6-Bromohexan-l-ol (0.64 g, 3.44 mmol) was added and the mixture was stirred at 6O0C for 6 h. DMF was removed under reduced pressure and the residue was suspended in water. The resulting solid was collected and dried to give product 0901 (1.35 g, 93%). LC-MS: 420 [M+l]+.

Reference： [1]Current Patent Assignee: CURIS INC - WO2008/33747, 2008, A2 Location in patent: Page/Page column 154

12
[ 184475-71-6 ]
[ 159877-36-8 ]
[ 1438082-56-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 7h;	A mixture of N-(3-chloro-4-fluorophenyl)-6-(3- chloropropoxy)-7-methoxyquinazolin-4-amine (2.00 g), 2C03 (5.00 g) and te -butyl octahydro-l H-pyrrolo[3,4-b]pyridine-l -carboxylate (1.20 g) in 20 mL of DMF was stirred at 80 C for 7 h, then poured into 50 mL of ice-water and extracted with CH2C12 (50 mL*2). The combined organic phases were dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20: 1 (v/v) DCM/MeOH) to give the title compound as a pale yellow solid (1.10 g, 45.00 %), HPLC: 92.00 %. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 586.2 (?+1);? NMR (400 MHz, CDC13) ?: 1.38 (s, 9H), 1.34-1.82 (m, 6H), 2.09- 2.43 (m, 7H), 3.29 (m, 2H), 3.68 (m, 1 H), 3.83 (s, 3H), 4.06 (m, 2H), 6.93 (s, 1H), 7.06 (s, 1 H), 7.30 (s, 1 H), 7.44 (d, J = 4.0 ??, ? ?), 7.87 (d, J = 4.0 Hz, 1 H), 8.54 (s, 1 H) ppm.

Reference： [1]Patent: WO2013/71697,2013,A1 .Location in patent: Paragraph 00314

13
[ 184475-71-6 ]
[ 159877-36-8 ]
[ 1438073-26-7 ]

Reference： [1]Patent: WO2013/71697,2013,A1

14
[ 109-70-6 ]
[ 184475-71-6 ]
[ 912556-91-3 ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 40℃; for 6h;	A suspension of 4-((3-chloro-4-fluorophenyl)amino)-7- methoxyquinazolin-6-ol (20.00 g), K2CO3(10.37 g), KI (1.04 g), l-bromo-3-chloropropane (7.50 mL) and DMF (150 mL) was stirred at 40 C for 6 h. The reaction mixture was poured into water and filtered. The filter residue was purified by a silica gel column chromatography (eluting agent: EA) to give the title compound as pale yellow liquid (22.05 g, 89.00 %). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 396.1 (M+l); ? NMR (400 MHz, CDC13) ?: 2.01 (m, 2H), 3.68 (t, J = 4.2 Hz, 2H), 4.00 (s, 3H), 4.10(t, J = 4.2 Hz, 2H), 6.80 (s, 1H), 7.16 (s, 1 H), 7.26 (s, 1H), 7.30 (s, 1 H), 7.47 (s, 1 H), 8.64 (s, 1H) ppm.
89%	With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 40℃; for 6h;	A suspension of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (20.00 g), K2CO3 (10.37 g), KI (1.04 g), 1-bromo-3-chloropropane (7.50 mL) and DMF (150 mL) was stirred at 40 C. for 6 h. The reaction mixture was poured into water and filtered. The filter residue was purified by a silica gel column chromatography (eluting agent: EA) to give the title compound as pale yellow liquid (22.05 g, 89.00%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 396.1 (M+1); 1H NMR (400 MHz, CDCl3) delta: 2.01 (m, 2H), 3.68 (t, J=4.2 Hz, 2H), 4.00 (s, 3H), 4.10 (t, J=4.2 Hz, 2H), 6.80 (s, 1H), 7.16 (s, 1H), 7.26 (s, 1H), 7.30 (s, 1H), 7.47 (s, 1H), 8.64 (s, 1H) ppm.
	With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 4h;	Referring to the formula IV, and according to the formula VI, compound 7 (478 mg, 1.5 mmol), 1-bromo-3-chloropropane (1.18 g, 7.5 mmol) and K2CO3 (1.05 g, 7.5 mmol) were added in into the flask prefilled with 3 ml of DMF, heating it up to 90 C. and keeping for 4 hours, and then cooling down to the room temperature. 15 ml of water was added in, and the organic phases, extracted by ethyl acetate (20 ml×3), were combined. The combined organic phase was washed by water and saturated aqueous solution of Na2CO3 respectively. MgSO4, used as desiccant, was added. The solvent was removed by rotary evaporator after the desiccant was removed by filtration. Using silica gel column (gradient elution using petroleum ether containing 20 v/v %-80 v/v % ethyl acetate as eluent) to separate the residue, and about 330 mg of product 8 was obtained.

Ca. 330 mg

With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 4h;Heating;

The steps for the synthesis of intermediate compound 8: Refering to the formula IV, and according to the formula VI, compound 7 (478mg, 1.5mmol), 1-bromo-3-chloropropane (1.18g, 7.5mmol) and K2CO3 (1.05g, 7.5mmol) were added in into the flask prefilled with 3ml of DMF, heating it up to 90C and keeping for 4 hours, and then cooling down to the room temperature. 15ml of water was added in, and the organic phases, extracted by ethyl acetate (20ml × 3), were combined. The combined organic phase was washed by water and saturated aqueous solution of Na2CO3 respectively. MgSO4, used as desiccant, was added. The solvent was removed by rotary evaporator after the desiccant was removed by filtration. Using silica gel column (gradient elution using petroleum ether containing 20v/v%-80v/v% ethyl acetate as eluent) to separate the residue, and about 330mg of product 8 was obtained.

Reference： [1]Patent: WO2013/71697,2013,A1 .Location in patent: Paragraph 00197
[2]Patent: US2014/228361,2014,A1 .Location in patent: Paragraph 0277-0278
[3]Patent: US2014/206664,2014,A1 .Location in patent: Paragraph 0225; 0229
[4]Patent: EP2796451,2014,A1 .Location in patent: Paragraph 0082

15
[ 1450754-38-7 ]
[ 184475-71-6 ]
[ 1450754-57-0 ]

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 8551 - 8556
Angew. Chem.,2013,vol. 125,p. 8713 - 8718,6

16
[ 57535-57-6 ]
[ 184475-71-6 ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2014,vol. 53B,p. 1269 - 1274
[2]Medicinal Chemistry Research,2020,vol. 29,p. 2112 - 2122

17
[ 164161-49-3 ]
[ 184475-71-6 ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2014,vol. 53B,p. 1269 - 1274

18
[ 855793-63-4 ]
[ 184475-71-6 ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2014,vol. 53B,p. 1269 - 1274

19
[ 286371-64-0 ]
[ 184475-71-6 ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2014,vol. 53B,p. 1269 - 1274

20
[ 52805-46-6 ]
[ 184475-71-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 5247 - 5250
[2]Patent: WO2015/188318,2015,A1
[3]Patent: WO2015/188318,2015,A1
[4]Patent: CN107698523,2018,A

21
[ 52805-37-5 ]
[ 184475-71-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 5247 - 5250
[2]Patent: WO2015/188318,2015,A1
[3]Patent: WO2015/188318,2015,A1
[4]Patent: CN107698523,2018,A

22
[ 184475-71-6 ]
[ 655225-02-8 ]
[ 295330-38-0 ]

Yield	Reaction Conditions	Operation in experiment
5.5 g	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 3h;	3.5.2 5g of compound GG7 dispersed in 50ml DMF was added K2C03 (2.0eq), compound 59 (1.2eq), 80 ° C reaction 3h, tlc monitoring After completion of the reaction, poured into 400ml of water, filtered and dried to obtain 5.5g compound GG8

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF SCIENCES; Shanghai Institute of Materia Medica (in: CAS) - CN103570738, 2016, B Location in patent: Paragraph 0319; 0320; 0327

23
[ 1018895-28-7 ]
[ 184475-71-6 ]
[ 184475-35-2 ]

Yield	Reaction Conditions	Operation in experiment
89.2%	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 6h;	20.7 g of compound II and 30.4 g4- (3-chloro-4-fluoroanilino) -6-hydroxy-7-methoxy-quinazoline (Compound IV)Was added to 170 ml of N, N-dimethylformamide,Add 34gCesium carbonate,Heated to 80 C,The reaction was stirred for 6 hours,TLC point board monitoring reaction is complete,The reaction solution is poured into ice water,Precipitation of solids,Decompression filtration,The filter cake was recrystallized from absolute ethanol,To give 36.9 g of a white solid,Yield 89.2%.

Reference： [1]Patent: CN106854185,2017,A .Location in patent: Paragraph 0031; 0035-0037

24
[ 957621-67-9 ]
[ 184475-71-6 ]
[ 184475-35-2 ]

Yield	Reaction Conditions	Operation in experiment
89.5%	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 6h;	A mixture of 28.5 g of compound II and 30.4 g of 4- (3-chloro-4-fluoroanilino) -6-hydroxy-7-methoxy-quinazoline (Compound IV)Was added to 180 ml of N, N-dimethylformamide,36 g of cesium carbonate was added and heated to 80 C. The reaction was stirred for 6 hours. The TLC spotted plate was completely monitored. The reaction solution was poured into ice water, the solid was precipitated and filtered under reduced pressure. The filter cake was recrystallized from absolute ethanol to give 38 g of a white solid , The yield was 89.5%.

Reference： [1]Patent: CN106854184,2017,A .Location in patent: Paragraph 0035-0037

25
[ 39070-14-9 ]
[ 184475-71-6 ]
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[(1-methyl-2-nitro-1H-imidazol-5-yl)methoxy]quinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With N-ethyl-N,N-diisopropylamine; triphenylphosphine; In N,N-dimethyl-formamide; at 20℃; for 5h;Cooling with ice;	A mixture of 4- (3-chloro-4-fluoroanilino) -6-hydroxy-7-methoxyquinazoline (1) (64 mg, 0.2 mmol)<strong>[39070-14-9]1-methyl-2-nitro-5-hydroxymethylimidazole</strong> (7) (32 mg, 0.2 mmol) andTriphenylphosphine (105 mg, 0.4 mmol)Was dissolved in DMF (3 mL)N, N-diisopropylethylamine (DIEA, 52 mg, 0.4 mmol) was added under ice-To be completed, room temperature reaction 5h.Treatment: DMF was removed under reduced pressure and the residue was extracted with water and dichloromethane (1: 1 by volume)The organic phase was collected and separated by column chromatography to give a white solid59%

Reference： [1]Patent: CN106432202,2017,A .Location in patent: Paragraph 0020

26
[ 125422-83-5 ]
[ 184475-71-6 ]
[ 184475-35-2 ]

Yield	Reaction Conditions	Operation in experiment
78%	With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 12h;	Reference is made to the literature method (W. Cheng, et al., Eur. J. Med. Chem., 2015, 89, 826-834).Specifically, 64 mg (0.20 mmol) of 4- (3-chloro-4-fluoroanilino) -6-hydroxy-7-methoxyquinazoline (1)Was added with 50 mg (0.24 mmol) of 4- (3-bromopropyl) morpholine3 mL of dimethylformamide (DMF)Then, 14 mg (0.10 mmol) of K2CO3 was added,The reaction was carried out at 70 C for 12 h.Treatment: The concentrate was concentrated under reduced pressure and the concentrate was extracted with saturated brine and dichloromethane (1: 1 by volume). The organic phase was collected, dried over anhydrous sodium sulfate,Column chromatography (V dichloromethane: V methanol = 100: 3) to give a white solid. Yield: 78%.

Reference： [1]Patent: CN106432202,2017,A .Location in patent: Paragraph 0015

27
[ 184475-71-6 ]
[ 184475-35-2 ]

Reference： [1]Synthetic Communications,2017,vol. 47,p. 1990 - 1998

28
[ 7357-67-7 ]
[ 184475-71-6 ]
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)-quinazoline-4-amine [ No CAS ]
[ 184475-35-2 ]

Yield	Reaction Conditions	Operation in experiment
13.5%Chromat.; 64.5%		To a suspension of HCl salt of 2 (712 mg, 2.0 mmol) in dimethylsulfoxide (6.5 mL) were added potassium carbonate (967 mg, 7.0 mmol) and 4-(3-chloropropyl)morpholine (393 mg, 2.40 mol). The mixture was heated to 80 C and stirred for 2 hr (termination of the reaction was confirmed by HPLC and TLC analysis). The reaction mixture was cooled to 20 C and purified water (14.2 mL) was slowly added. The mixture was stirred for 30 min. The precipitate was collected by filtration, washed with purified water (14.2 mL), and dried at 50 C for 3 hr to give gefitinib as pale yellow powder (577 mg, 64.5%).

Reference： [1]Synthetic Communications,2017,vol. 47,p. 1990 - 1998

29
[ 31839-20-0 ]
[ 184475-71-6 ]

Reference： [1]Patent: WO2018/119441,2018,A1
[2]Patent: CN109721552,2019,A

30
[ 76-05-1 ]
[ 184475-71-6 ]
[ 655225-02-8 ]
C₂₇H₃₃ClFN₅O₄*C₂HF₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	Stage #1: 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline; tert-butyl 4-(3-bromopropyl)-piperazine-1-carboxylate With potassium carbonate In N,N-dimethyl-formamide at 80℃; Stage #2: trifluoroacetic acid In methanol; water

Reference： [1]Cheng, Meng; Yu, Xufen; Lu, Kaylene; Xie, Ling; Wang, Li; Meng, Fanye; Han, Xiaoran; Chen, Xian; Liu, Jing; Xiong, Yue; Jin, Jian [Journal of Medicinal Chemistry, 2020, vol. 63, # 3, p. 1216 - 1232]

31
[ 367-21-5 ]
[ 179688-53-0 ]
[ 184475-71-6 ]

Yield	Reaction Conditions	Operation in experiment
		Compound 40-1 (200.0 mg, 853.94 mmol) was dissolved in thionyl chloride (3 mL), and to the mixture wasadded N,N-dimethylformamide (6 mL 85.39 mmol). The reaction solution was heated to 80 C and stirred for 1 hour. Thereaction solution was concentrated under reduced pressure, and to the residue was added a solution of 3-chloro-4-fluoroaniline (130.0 mg, 893.09 mmol) in isopropanol (5 mL) at room temperature. The mixture was heated to 90 C andstirred for 3 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added ethylacetate (15 mL) at room temperature. The suspension was stirred at room temperature for 1 hour and then filtered. Thefilter cake was dried in vacuo to afford compound 40-2. LC-MS: m/z = 320.1 [M+H]+.

Reference： [1]Patent: EP3733663,2020,A1 .Location in patent: Paragraph 0338-0340

32
[ 36839-55-1 ]
[ 184475-71-6 ]
N-(3-chloro-4-fluorophenyl)-6-(2-(2-(2-iodoethoxy)ethoxy)ethoxy)-7-methoxyquinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: 1,2-bis-(2-iodoethoxy)ethane; 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.25h; Inert atmosphere; Stage #2: 1,2-bis-(2-iodoethoxy)ethane In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 4h;

Reference： [1]Abdelmalek, Carine M.; Hu, Zexi; Kronenberger, Thales; Küblbeck, Jenni; Kinnen, Franziska J. M.; Hesse, Salma S.; Malik, Afsin; Kudolo, Mark; Niess, Raimund; Gehringer, Matthias; Zender, Lars; Witt-Enderby, Paula A.; Zlotos, Darius P.; Laufer, Stefan A. [Journal of Medicinal Chemistry, 2022, vol. 65, # 6, p. 4616 - 4632]

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A840663[ 1228665-04-0 ]

4-((3-Chloro-4-fluorophenyl)amino)-7-(methoxy-D3)quinazolin-6-ol

Reason: Stable Isotope

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[ CAS No. 184475-71-6 ] {[proInfo.proName]}

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[ 184475-71-6 ] Synthesis Path-Upstream 1~2

[ 184475-71-6 ] Synthesis Path-Downstream 1~32

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