Name: 850140-72-6|(S,E)-N-(4-((3-Chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide|99%
Brand: Ambeed
SKU: A149039
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Yield	Reaction Conditions	Operation in experiment
		(7) 4-[(3-chloro-4-fluorophenyl)amino]-6-[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]-amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline Mass spectrum (ESI): m/z=486, 488 [M+H]
		(10) 4-[(3-chloro-4-fluorophenyl)amino]-6-[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)quinazoline Mass spectrum (ESI+): m/z=486, 488 [M+H]+; Rf value: 0.45 (silica gel, methylene chloride/methanol=5:1).
		(7) 4-[(3-chloro-4-fluorophenyl)amino]-6-[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]-amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline Mass spectrum (ESI+): m/z=486, 488 [M+H]+

2
[ 850140-72-6 ]
[ 110-16-7 ]
2-butenamide, N-(4-((3-chloro-4-fluorophenyl)amino)-7-([(3S)-tetrahydro-3-furanyl]oxy)-6-quinazolinyl)-4-(dimethylamino)-, (2E)-, (2Z)-2-butenedioate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96.5%	In tetrahydrofuran; at 20℃;	Example 1: Preparation of <strong>[850140-72-6]Afatinib</strong> di-maleate Form C<strong>[850140-72-6]Afatinib</strong> free base (3 g) was dissolved in tetrahydrofuran (THF) (7.6 mL) and stirred at room temperature until a clear solution was obtained. While stirring the clear solution, a solution of maleic acid (1.48 g) in THF (7.6 mL) was added dropwise at roomtemperature. After completion of this addition, a suspension containing a sticky solid was obtained. THF (60mL) was added to the suspension and this mixture was stirred at room temperature overnight. A solid precipitate formed and was collected by filtration and washed with THF (30 mL) to yield a yellowish solid. The product was dried at 40C and 20mbar (yield: 4.28 g, 96.5%). XRPD peak data for the product is provided in the Table below.
91.5%	In ethanol; at 70℃;	Example 3 (E)-4-Dimethylamino-But-2-Enoic Acid-(4-(3-Chloro-4-Fluoro-Phenylamino)-7-((S)-Tetra-Hydrofuran-3-Yloxy)-Quinazolin-6Yl)-Amide Dimaleate 6.0 kg (12.35 mol) of (E)-4-dimethylamino-but-2-enoic acid-(4-(3-chloro-4-fluoro-phenylamino)-7-((S)-tetrahydrofuran-3-yloxy)-quinazolin-6yl)-amide are placed in 84 litres of ethanol and heated to 70 C. and combined with a solution of 2.94 kg (25.31 mol) of maleic acid in 36 litres of ethanol. After crystallisation has set in, first the mixture is cooled to 20 C. and stirred for 2 hours, then for 3 hours at 0 C. The precipitate is suction filtered, washed with 19 litres of ethanol and dried in vacuo at 40 C. Yield: 8.11 kg (91.5%) melting point: 178 C. 1H-NMR (CD3OD): delta=2.47+2.27 (m+m, 2H), 2.96 (s, 6H), 4.03 (m, 2H), 4.07+3.92 (m+m, 2H), 4.18+4.03 (m+m, 2H), 5.32 (m, 1H), 6.26 (s, 4H), 6.80 (m, 1H), 6.99 (m, 1H), 7.27(s, 1H), 7.30 (t, 1H), 7.66 (m,1H), 7.96 (dd,1H), 8.62 (s,1H), 9.07 (s, 1H) ppm
91%	In ethanol; at 0 - 50℃; for 5.5h;Large scale;	First, 16 kg of absolute ethanol and 2.15 kg of maleic acid were heated to 50 C in a 100 L reaction tank to be stirred to completely dissolve. Next, 46 kg of absolute ethanol and 3.79 kg of <strong>[850140-72-6]afatinib</strong> (purity 99.86%, impurity I content 0.01%, impurity II content 0.03%) were heated to 50 C in a 50 L reaction tank, and then dissolved and immediately introduced into the above. The mixture was stirred and mixed in a 100 L reaction tank, and after the majority of the solids were precipitated in the tank, stirring was continued at 50 C for 30 min. Then, the mixture was cooled to 20 C and stirred for 2 h, and finally cooled to 0 C and stirred for 3 h.After filtration, the filter cake was rinsed with 31 kg of absolute ethanol.After drying at 40 C for 2 h, a white solid of 5.08 kg was obtained.The purity is 99.84%, and the impurity I content is 0.01%.The impurity II content was 0.09%, and the yield was 91%.

86.5%	In ethanol; at 10 - 15℃;Inert atmosphere;	To the reactor was added anhydrous ethanol (450 g)A mixture of 72 g of Formula II,Nitrogen protection.Temperature control at 10 ~ 15 .Slowly dropping maleic acid ethanol solution (maleic acid 72g, anhydrous ethanol 0.54Kg),Control the temperature at 10 ~ 15 ,Time consuming 2 ~ 3hr.Control the temperature at 10 ~ 15 ,Stir for 2hr.Filtration gave a white to pale yellow solid,The wet product was washed with 90 g of absolute ethanol.45 ± 2 under reduced pressure drying (-0.09MPa, water bath temperature control)(Product evenly spread out, thin, every 6 hours re-material once)Formula I 93g.Yield 86.5%Purity 99.54%Less than 0.1%EE value of 99.65%,Cis-isomer is not detected,The X-ray powder diffraction pattern shows a single crystal form (melting point at 178 C).
83%	In tetrahydrofuran; at 20℃; for 1.03333h;	THF (0.5 ml) was added to 200 mg (0.41 mmol) <strong>[850140-72-6]afatinib</strong> free base and the mixture was stirred at room temperature to obtain a light yellow coloured solution. A solution of 100 mg (0.8 mmol) maleic acid in 0.5 ml THF was added over the course of 2 min. Another 4 ml THF were added and the mixture was stirred for 1 h. The solids were filtered off, rinsed with 2 ml THF and dried on a rotary evaporator at 48 C / 3 mbar for 6 h to give 0.245 g (83% yield) of a white solid.DSC shows an exotherm at 125.9C followed by a minor endotherm at 156.8 and a major endotherm at 173.9C.XRPD confirms crystalline nature. IR (cm"1): 3321.2, 3034.0, 1687.6, 1643.6, 1498, 1456.6, 1353.4, 1268.4, 1067.5, 869.0,780, 654.7and 576.4.Residual solvent: THF = 3390 ppm
26.5 g	In methanol; at 20 - 60℃; for 0.5h;	In a round bottom flask, <strong>[850140-72-6]afatinib</strong> (20 g) was dissolved in methanol (200 mL) by stirring at 20C to 35C to obtain a solution. Maleic acid (9.5 g) was added to the solution at the same temperature to obtain a reaction mixture. The reaction mixture was heated and stirred at 55C to 60C for 30 minutes. The reaction mixture was concentrated undervacuum at 45C to 46C to obtain a solid. Cyclohexane (100 mL) was added to the solid and the mixture was stirred at 45C to 46C for 5 minutes. The solution was cooled to 20C to 30C to obtain a solid. The solid obtained was filtered and dried under vacuum at40C to 45C to obtain the crystalline Form A of <strong>[850140-72-6]afatinib</strong> dimaleate.Yield: 26.5 g
18.8 g	In dimethyl sulfoxide; at 20 - 35℃;	A solution of <strong>[850140-72-6]Afatinib</strong> (15.Og) in acetonitrile (300 ml) was stirred at room temperature for 30 mm.. The clear solution was filtered through 5 micron filter paper. The filtrate was charged in the flask and 2/3 of maleic acid solution[prepared by dissolving maleic acid (9.lg) in dimethylsulfoxide (lOml) and acetonitrile (lOml] was added drop wise. The reaction mass was stirred for 15-20 mm followed by addition of rest of the maleic acid solution. After complete addition the reaction mass was stirred for 1-2h at 20-35C.The solid thus formed was filtered and washed with acetonitrile (15m1) and suck dried for 10-15mm.The product thus obtained was charged in the reactor and acetonitrilec(150m1) was added.The reaction mas was stirred for 15 mm and then filtered under nitrogen. The product was washed with acetonitrile (15m1x2). The product was suck dried for 1-2h and then dried under vacuum (NLT 700 mmHg) for 5-6 h. The resulting product wascharged in a flask and ethyl acetate (600m1) was added andreaction mass was stirred for 90 mm. The solid thus formed was filtered, washed with ethyl acetate (150m1) and suck dried for 20-30 mm. and finally under vacuum (NLT 700mmHg) at 45C for 20-22h. . 18.8 g of crystalline form M of <strong>[850140-72-6]Afatinib</strong> dimaleate was obtainedWater Content: 2.54%
30 g	In methanol; at 60 - 65℃;	<strong>[850140-72-6]Afatinib</strong> (25 g) base and maleic acid (12.5 g) were dissolved in methanol (1125 mL) at 60-65 C. The clear solution was filtered through Hyflo to remove any undissolved particulate, cooled to 25-30 C and subjected to spray drying in a laboratory spray dryer (Model Buchi-290) with a feed rate of the solution 5-10mL/min and an inlet temperature at 65 C to yield amorphous form of <strong>[850140-72-6]afatinib</strong> dimaleate (30 g).
30 g	In methanol; at 60 - 65℃;	<strong>[850140-72-6]Afatinib</strong> (25 g) base and maleic acid (12.5 g) were dissolved in methanol (1125 mL) at 60-65 C. The clear solution was filtered through Hyflo to remove any undissolved particulate, cooled to 25-30 C. and subjected to spray drying in a laboratory spray dryer (Model l3uchi-290) with a feed rate of the solution 5-lOmL/min and an inlet temperature at 65 C. to yield amorphous form of <strong>[850140-72-6]afatinib</strong> dimaleate (30 g).
27 g	In ethanol; water; at 0 - 5℃; for 3h;Inert atmosphere;	A mixture of N-[4-[(3-chloro-4-fluorophenyl) amino]-7-[[(3S)-tetrahydro-3-thranyl]oxy]-6-quinazolinyl]- 4-(dimethylamino)-(2E)-2-butenamide compound of formula-i 0 (25 gm) and ethanol (175 ml) was stirred for 15 minutes under nitrogen atmosphere. Cooled the reaction mixture to 0-5 C. 12.62 gm of Maleic acid in 75 ml ethanol was slowly added to the reaction mixture at 0-5 C. and stirred for 3 irs at the same temperature. The solid formed was filtered under nitrogen atmosphere, washed with ethanol and dried to get the title compound. Yield: 27 g; MR: 172-178 C.

Reference： [1]Patent: WO2013/52157,2013,A1 .Location in patent: Page/Page column 13; 14
[2]Patent: US2005/85495,2005,A1 .Location in patent: Page/Page column 6-7
[3]Patent: CN108358900,2018,A .Location in patent: Paragraph 0045-0050
[4]Patent: CN106243092,2016,A .Location in patent: Paragraph 0026; 0049-0052; 0061-0064; 0073-0076; 0085-0088
[5]Patent: WO2012/121764,2012,A1 .Location in patent: Page/Page column 52-53
[6]Patent: WO2016/51380,2016,A1 .Location in patent: Page/Page column 5; 6
[7]Patent: WO2017/33107,2017,A1 .Location in patent: Page/Page column 27; 28; 29; 30; 31
[8]Patent: WO2017/93789,2017,A1 .Location in patent: Page/Page column 19
[9]Patent: US2018/30038,2018,A1 .Location in patent: Paragraph 0212; 0213-0218; 0221-0228; 0231; 0232; 0234-0243
[10]Patent: US2018/297989,2018,A1 .Location in patent: Paragraph 0210; 0215; 0216; 0250; 0281; 0282; 0282; 0283

3
[ 1413945-87-5 ]
[ 850140-72-6 ]

Yield	Reaction Conditions	Operation in experiment
91%		10 g of diethyl [4-(3-chloro-4-fluoro-phenylamino)-7-((S)-tetrahydrofuran-3-yloxy)- quinazolin-6-ylcarbamoyl]-methyl}-phosphonate and 0.8 g lithium chloride are suspended in 60 ml of ethanol and cooled to -5C. 11 g of 45percent potassium hydroxidesolutio? is added dropwise first of all and then 4.8 g dimethylaminoacetaldehyde- hydrogen sulphite adduct in 48 ml of water is added. The reaction solution is stirred for 1 h and then 60 ml of water are added. The suspension is suction filtered, washed with 40 ml of water and dried in vacuo at 45C. Yield: 8 g (91 percent of theoretical) m.p.: 100 -1020C

Reference： [1]Patent: WO2007/85638,2007,A1 .Location in patent: Page/Page column 23

4
[ 618061-76-0 ]
[ 3616-56-6 ]
[ 850140-72-6 ]

Yield	Reaction Conditions	Operation in experiment
97.7%		To a 50 ml single-neck round-bottom flask equipped with magnetic needle and nitrogen balloon was charged 5.0 ml (46.9 mmol) concentrated HCl, 5.0 ml water and the mixture was stirred at 30 °C. After 15 min, 5.3 ml (27.1 mmol) (dimethylamino)- acetaldehyde-diethyl acetal was added over a period of 5 min at 30 °C. The mixture was stirred at room temperature in an inert atmosphere overnight. The solution thus obtained was designated as reagent "A".A 250 ml two-neck round-bottom flask equipped with magnetic needle, thermometer and nitrogen balloon was charged with 6.0 g (10.85 mmol) diethyl (4-(3-chloro-4- fluorophenylam o)-7-(S)-(tetrahyc ^methyl)-phosphonate, 0.47 g (10.85 mmol), lithium chloride anhydrous and 25 ml THF. The mixture was cooled to -8 °C in an ice-salt bath and a cold solution of potassium hydroxide (4.7 g, 82.7 mmol dissolved in 24 ml water kept at -18°C) was added over the period of 15 min. Reagent "A" was added dropwise over the course of 30 min to the reaction mixture which was maintained at -7 °C and stirred at the same temperature for 1 h. The reaction was slowly allowed to come to 20 °C and stirred at this temperature for 45 min. 20 ml water were added and the mixture was extracted with 3 x 50 ml ethyl acetate. The combined extract was dried on sodium sulphate, evaporated and the resulting residue dried at 45 °C under vacuum to give a yellow solid. 200 ml water were added to the solid, the mixture was stirred for 1 h, filtered, washed with 200 ml water, dried on a rotary evaporator at 45 °C for 2 h to give 5.1 g (97.7percent, 10.6 mmol) of an off- white solid. DSC shows two endothermic peaks at 95.9 °C and 138.6 °C.IR (cm"1): 3547.4, 2980.2, 2947.8, 2865.7, 2774, 1673.1, 1626.9, 1575.8, 1536.1,1500.1, 1455.7, 1430.5, 1397.0, 1233.4, 1147.1, 981.9, 852.1, 778.5 and 660.9.
78%		Example 2 (E)-4-Dimethylamino-But-2-Enoic acid-[4-(3-Chloro-4-Fluoro-Phenylamino)-7-((S)-Tetrahydrofuran-3-Yloxy)-Quinazolin-6yl]-Amide 5.6 litres of 30percent hydrochloric acid (53.17 mol) are added to 4.4 litres of water. Then 4.28 kg of 95percent (dimethylamino)-acetaldehyde-diethylacetal (26.59 mol) are added dropwise within 20 minutes at 30° C. The reaction solution is stirred for 8 hours at 35° C. stirred, cooled to 5° C. and stored under argon. This solution is referred to as solution B. 4.55 kg (68.06 mol) of potassium hydroxide are dissolved in 23.5 litres of water and cooled to -5° C. This solution is referred to as solution C. 5.88 kg (10.63 mol) of diethyl ((4-(3-chloro-4-fluoro-phenylamino)-7-(tetrahydrofuran-3-yloxy)-quinazoline-6-ylcarbamoyl)-methyl)-phosphonate and 0.45 kg of lithium chloride (10.63 mol) are placed in 23.5 litres of tetrahydrofuran and cooled to -7° C. The cold solution C is added within 10 minutes. Then solution B is added at -7° C. within 1 hour. After stirring for a further hour at -5° C. the reaction mixture is heated to 30° C. and combined with 15 litres of water. After cooling to 3° C. the suspension is suction filtered, the precipitate is washed with water and dried. Yield: 5.21 kg of crude product, 100percent, water content: 6.7percent The crystallisation of the crude product is carried out with butyl acetate/methylcyclohexane Yield: 78percent purity HPLC 99.4Fl percent, water content 5.4percent
		5.6 litres of 30percent hydrochloric acid (53.17 mol) was added to 4.4 liters of water. Then 4.28 kgof 95percent (dimethylamino)-acetaldehyde-diethyl-acetal (26.59 mol) was added dropwise within20 minutes at 30 deg C. The solution is stined for 8 hours at 35 deg C. stined, cooled to 5 deg C. and stored under argon. This solution is refened to as solution B.4.55 kg (68.06 mol) of Potassium hydroxide was dissolved in 23.5 liters of water and cooledto -5 deg C. This solution is referred to as solution C.5.88 kg (10.63 mol) of diethyl ((4-(3-Chloro-4-fluoro-phenylamino)-7-(tetrahydrofuran-3 - yloxy)-quinazoline-6-ylcarbamoyl)-methyl)-phosphonate and 0.45 kg of lithium chloride (10.63 mol) were placed in 23.5 liters of tetrahydrofuran and cooled to -7 deg C. The coldsolution C was added within 10 minutes. Then solution B was added at -7 deg. C within 1 hour. Stined for a further hour at -5 deg C, heated to 30 deg C. and combined with 15 litres of water. After cooling to 3deg C. the suspension was suction filtered, washed with water and dried. Yield: 5.21 kg of crude product, 100percent, water content: 6.7percentThe crystallisation of the crude product is canied out with butylacetate/methylcyclohexane Yield: 78percent purity HPLC 99.4F1 percent, water content 5.4percent.

Reference： [1]Patent: WO2012/121764,2012,A1 .Location in patent: Page/Page column 49-50
[2]Patent: US2005/85495,2005,A1 .Location in patent: Page/Page column 6
[3]Patent: WO2016/166720,2016,A2 .Location in patent: Page/Page column 16

5
[ 850140-72-6 ]
[ 97-67-6 ]
afatinib di-L-malate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80.7%	In ethyl acetate; at 20℃; for 1.03333h;	Ethyl acetate (2 ml) was added to 200 mg (0.41 mmol) <strong>[850140-72-6]afatinib</strong> free base and the light yellow solution was stirred at room temperature. A solution of 110 mg (0.8 mmol) L- malic acid in 3 ml ethyl acetate was added over the course of 2 min at room temperature. Precipitation was observed and ethyl acetate (5 ml) was added. The mixture was stirred at room temperature for 1 h. The solid was filtered off, washed with 2 ml ethyl acetate and dried at 48 C / 3 mbar for 6 h to give 251 mg (80.7%) of a light yellow solid.IR (cm ): 2983.9, 1719.3, 1535.8, 1498.4, 1263.8, 879.4 and 778.2.Residual solvent: ethyl acetate = 5.37%

Reference： [1]Patent: WO2012/121764,2012,A1 .Location in patent: Page/Page column 57-58

6
[ 850140-72-6 ]
[ 56-84-8 ]
afatinib di-L-aspartate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	In tetrahydrofuran; water; at 20 - 110℃;	Water (4 ml) was added to 110 mg (0.8 mmol) L-aspartic acid and the mixture was stirred at 110 C. A solution of 200 mg (0.41 mmol) <strong>[850140-72-6]afatinib</strong> free base in 1 ml THF was added. The mixture was stirred for 30 min. The heating was switched off and the mixture was allowed to cool to room temperature. Another 2 ml THF was added and stirring continued at room temperature. After one week the mixture was concentrated on a rotary evaporator to give 0.3 g (97% yield) of a light yellow solid.DSC shows endothermic peaks at 134.8 C, 158.8 C, 167.5 C, 222.1 C and 255.3 C. IR (cm"1): 3411.4, 2986.7, 1688, 1625.5, 1534.4, 1498.2, 1425.9, 1208.6, 1054, 899.9, 659.3 and 552.1.Residual solvent: THF = not detected

Reference： [1]Patent: WO2012/121764,2012,A1 .Location in patent: Page/Page column 59

7
[ 850140-72-6 ]
[ 110-17-8 ]
[ 1398312-22-5 ]

Yield	Reaction Conditions	Operation in experiment
67.7%	In ethanol; at 20 - 70℃;Product distribution / selectivity;	Ethanol (2 ml) was added to 200 mg (0.4 mmol) <strong>[850140-72-6]afatinib</strong> free base and the mixture was stirred at 70 C to obtain a light yellow coloured solution. A solution of 100 mg (0.8 mmol) fumaric acid in 2.5 ml ethanol was added at 70 C over the course of 2 min and the solution was stirred for 10 min. Heating was stopped and the mixture was allowed to cool to room temperature. 2.5 ml diethyl ether was added to obtain a turbid solution. The reaction mixture was stirred for 1 h, which resulted in a solid. The solid was filtered off, dried at 48 C at 5 mbar for 5 h to obtain 0.2 g (67.7%, 0.3 mmol) of an off-white solid.DSC shows two broad endothermic peaks at 67.3 C, 126.8 C and a broad exothermic peak at 169.0 C. IR (cm-1): 2982.5, 1679.7, 1530.5, 1499.8, 1428.4, 1214.1, 1144.5, 980.0, 672.8 and 540.2Residual solvent: ethanol = 3.26%, diethyl ether = 547 ppm.1H NMR indicates presence of a monofurnarate.

Reference： [1]Patent: WO2012/121764,2012,A1 .Location in patent: Page/Page column 53-54

8
[ 850140-72-6 ]
[ 144-62-7 ]
afatinib dioxalate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	In ethanol; at 40℃; for 0.833333h;Reflux;	Ethanol (3 ml) was added to 200 mg (0.41 mmol) afatimb free base and the mixture was heated to 40 C to get a light yellow solution. A solution of 70 mg (0.8 mmol) oxalic acid in 1 ml ethanol was added at 40 C and the reaction mixture was heated under reflux conditions for 50 min. The reaction temperature was allowed to cool to ambient temperature and 3 ml ethanol was added. The solid was filtered off and dried at 60 C / 3 mbar for 5.5 h to give 215 mg (78 %) of an off-white solid.DSC shows a sharp endotherm at 185.4C followed by an exotherm at 190.7C.IR (cm_1): 3041.5, 2867, 1776.2, 1702, 1640.3, 1522.9, 1500.1, 1454, 1402.6, 1329.1.

Reference： [1]Patent: WO2012/121764,2012,A1 .Location in patent: Page/Page column 55

9
[ 850140-72-6 ]
[ 75-75-2 ]
afatinib dimesylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	In ethyl acetate; at 20℃; for 0.7h;Product distribution / selectivity;	Ethyl acetate (2 ml) was added to 200 mg (0.41 mmol) afatimb free base and the light yellow solution was stirred at room temperature. A solution of 80 mg (0.8 mmol) methanesulphonic acid in 1 ml ethyl acetate was added at room temperature over the course of 2 min. Precipitation was observed and another 4 ml ethyl acetate was added. After stirring at ambient temperature for 40 min the solid was filtered off, washed with 3 ml ethyl acetate and dried at 48 C / 3 mbar for 4.5 h to give 257 mg (92%) of a light yellow solid.Melting point = 180 -188 C.IR (cm"1): 3018.1, 1692.8, 1638.5, 1498.5, 1455, 1367.2, 1271.4, 1207.8, 1194.4,1058.9, 783.9 and 554.7.Residual solvent: ethyl acetate = 46.3 ppm.

Reference： [1]Patent: WO2012/121764,2012,A1 .Location in patent: Page/Page column 55-56

10
[ 850140-72-6 ]
[ 110-15-6 ]
afatinib disuccinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75.7%	In ethyl acetate; at 20℃; for 6.5h;	Ethyl acetate (2 ml) was added to 200 mg (0.41 mmol) <strong>[850140-72-6]afatinib</strong> free base and the light yellow solution was stirred at room temperature. A solution of 100 mg (0.8 mmol) succinic acid in 2 ml ethanol was added over the course of 2 min. The mixture was stirred for 6.5 h and concentrated to ~1 ml. To this residue, 3 ml ethyl acetate was added and the resulting mixture was stirred at room temperature for 1.5 h. The solid was filtered off, washed with 2 ml ethyl acetate and dried at 50 C / 4 mbar for 5 h to give 225 mg (75.7%) of an off-white solid.DSC shows two endothermic peaks at 97.1 C and 103.7 C and a broad exothermic peak at 157.3 C.IR (cm'1): 3002.7, 1934.7, 1738.7, 1709.0, 1626, 1581.3, 1532.6, 1494.6, 1428.2,1210.3, 979.1, 797.8, 654.0 and 532.Residual solvent: Ethyl acetate = 4.22%, ethanol = 0.43%.

Reference： [1]Patent: WO2012/121764,2012,A1 .Location in patent: Page/Page column 58

11
[ 850140-72-6 ]
[ 77-92-9 ]
[ 1398313-22-8 ]

Yield	Reaction Conditions	Operation in experiment
57%	In ethanol; at 20℃; for 0.283333h;	Ethanol (2 ml) was added to 100 mg (0.205 mmol) <strong>[850140-72-6]afatinib</strong> free base and the light yellow solution was stirred at room temperature. A solution of 39.4 mg (0.205 mmol) citric acid in 0.5 ml ethanol was added over the course of 2 min. Another 0.5 ml ethanol was added. Precipitation was observed and the mixture was stirred for 15 min. The solid was filtered, washed with 0.5 ml ethanol and dried on rotary evaporator at 50 C for 2 h to give 80 mg (57%) of a light yellow solid.DSC shows no distinct peaks.IR (cm ): 2972.8, 1717.1, 1625.3, 1576.2, 1535.5, 1498.6, 1213.1, 879.3 and 778.9.

Reference： [1]Patent: WO2012/121764,2012,A1 .Location in patent: Page/Page column 58

12
[ 850140-72-6 ]
afatinib dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With hydrogenchloride; In isopropyl alcohol; at 20℃; for 1.31667h;	IPA (2ml) was added to 200 mg (0.41 mmol) <strong>[850140-72-6]afatinib</strong> free base and the light yellow solution was stirred for 5 min at room temperature. HCl in IPA (1.5 ml) was added over the course of 4 min. Precipitation was observed and the mixture was diluted with 1 ml IPA and stirred at room temperature for 1.25 h. The reaction mixture was further diluted with 3 ml IPA, the solid was filtered off and dried on a rotary evaporator at 50 C / 3 mbar for 7 h to give 184 mg (80%) of a yellow solid.IR- Ccm"1): 2961.6, 1680.8, 1633.5, 1572.7, 1523.4, 1499, 1477.8, 1266.0, 1067.2, 887.4 and 778.3.Residual solvent: IPA = 1.87%; ethyl acetate = 729 ppm

Reference： [1]Patent: WO2012/121764,2012,A1 .Location in patent: Page/Page column 55

13
[ 850140-72-6 ]
afatinib diphosphate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With phosphoric acid; In ethyl acetate; at 20℃; for 0.866667h;Product distribution / selectivity;	Ethyl acetate (2 ml) was added to 200 mg (0.41 mmol) <strong>[850140-72-6]afatinib</strong> free base and the light yellow solution was stirred at room temperature. A solution of 80 mg (0.8 mmol) phosphoric acid in 1 ml ethyl acetate was added over the course of 2 min at room temperature. Precipitation was observed and more ethyl acetate (5 ml) was added and stirring continued at room temperature for 50 min. The solid was filtered off, washed with 3 ml ethyl acetate and dried at 48 C / 3 mbar for 5 h to give 289 mg (93%) of a light yellow solid.IR (cm"1): 2879.6, 1741.1, 1684.6, 1639.4, 1574.8, 1498.0, 1455.3, 1265.1, 965.6 and 778.2.

Reference： [1]Patent: WO2012/121764,2012,A1 .Location in patent: Page/Page column 56-57

14
[ 850140-72-6 ]
afatinib disulphate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With sulfuric acid; In ethyl acetate; at 20℃;Product distribution / selectivity;	Ethyl acetate (2 ml) was added to 200 mg (0.41 mmol) <strong>[850140-72-6]afatinib</strong> free base and the mixture was stirred at room temperature to obtain a light yellow coloured solution. A solution of 0.09 ml (1.6 mmol) sulphuric acid in 1 ml ethyl acetate was added at room temperature over the course of 2 min. Precipitation was observed immediately upon addition of the acid. A sticky solid was observed. 3 ml ethyl acetate was added and stirring continued for 2.5 h. The solid was filtered off and dried on a rotary evaporator at 50 C/3 mbar for 3 h to give 263 mg (94%) of a light yellow solid. .DSC shows a sharp endothermic peak at 127.2 C.IR (cm_1): 3029.6, 1636.3, 1572.7, 1497.8, 1231.9, 1055.3, 882.4 and 581.Residual solvent: ethanol = 1.13%, ethyl acetate = 1.27%.

Reference： [1]Patent: WO2012/121764,2012,A1 .Location in patent: Page/Page column 54

15
[ 850140-72-6 ]
[ 98-11-3 ]
afatinib dibenzenesulphonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63.6%	In ethanol; at 20 - 70℃;	Ethanol (2 ml) was added to 200 mg (0.41 mmol) <strong>[850140-72-6]afatinib</strong> free base and the solution was stirred at 70C for 15 min. A solution of 130 mg (0.8 mmol) benzenesulphonic acid in 1 ml ethanol was added at 70 C over the course of 2 min and the solution was stirred for another 10 min. Heating was switched off and the solution was allowed to cool to room temperature over the course of 2.5 h. Diethyl ether (2.5 ml) was added and the solution was concentrated to dryness. 3 ml ethyl acetate were added and the solid was filtered off. Drying at 50 C at 5 mbar for 5 h yielded 0.21 g (63.6%, 0.3 mmol) of a light yellow solid.IR (cm'1): 3050.7, 1691.1, 1637.3, 1577, 1523.9, 1498.3, 1448.2, 1219.4, 1124.0, 1068.8, 1034.4, 1016.7, 997, 728.2, 694.8, 612.3 and 565.7.Residual solvent: ethyl acetate = 0.74%.

Reference： [1]Patent: WO2012/121764,2012,A1 .Location in patent: Page/Page column 53

16
[ 3616-56-6 ]
diethyl ((4-(3-chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazoline-6-ylcarbamoyl)methyl)phosphonate [ No CAS ]
[ 850140-72-6 ]

Yield	Reaction Conditions	Operation in experiment
78%		Preparation of the Afatinib base starting material:Afatinib base was prepared according to WO2005/037824 example 2.5.6 litres of 30percent hydrochloric acid (53.17 mol) are added to 4.4 liters of water. Then 4.28 kg of 95percent (dimethylamino)-acetaldehyde-diethyl- acetal (26.59 mol) are added dropwise within 20 mmutes at 30° C. The reaction solution is stirred for 8 hours at 35° C. stirred, cooled to 5. degree. C. and stored under argon. This solution is referred to as solution B.4.55 kg (68.06 mol) of potassium hydroxide are dissolved in 23.5 liters of water and cooled to -5. degree. C. This solution is referred to as solution C.5.88 kg (10.63 mol) of diethyl ((4-(3-cMoro-4-fluoro-phenylamino)-- 7-(tetrahydrofuran- 3-yloxy)-quinazoline-6-ylcarbamoyl)-methyl)-phosphonate and 0.45 kg of lithium chloride (10.63 mol) are placed in 23.5 liters of tetrahydrofuran and cooled to -7°C. The cold solution C is added within 10 minutes. Then solution B is added at -7° C. within 1 hour. After stirring for a further hour at -5. degree. C. the reaction mixture is heated to 30° C. and combined with 15 litres of water. After cooling to 3° C. the suspension is suction filtered, the precipitate is washed with water and dried. Yield:5.21 kg of crude product, 100percent, water content: 6.7percentThe crystallisation of the crude product is carried out with butylacetate/methylcyclohexane Yield: 78percent purity HPLC 99.4F1 percent, water content 5.4percent.

Reference： [1]Patent: WO2013/52157,2013,A1 .Location in patent: Page/Page column 13

17
[ 850140-72-6 ]
[ 70-18-8 ]
C₃₄H₄₂ClFN₈O₉S [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 9889 - 9900

19
[ 1421354-12-2 ]
[ 850140-72-6 ]

Reference： [1]Patent: WO2015/101554,2015,A1
[2]Patent: US2015/183764,2015,A1

20
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline [ No CAS ]
[ 1055943-40-2 ]
[ 850140-72-6 ]

Yield	Reaction Conditions	Operation in experiment
97.5%	In tetrahydrofuran; at 0 - 5℃;	The compound 311g (the V) (content 99.0%) was added to 2400mL of dry tetrahydrofuran, cooled to 0 ± 5 C, was added dropwise the above solution was added dropwise to 0 ± 5 C the reaction monitored by TLC until completion of the reaction, at this temperature the reaction mixture was added dropwise to a 1% aqueous sodium hydroxide to pH 8 to 9, and 30L of purified water, large amount of solid precipitate was filtered, the solid washed with water until neutral filtered, drained and dried to obtain a method erlotinib (VI) 367g, content 97.5%, the compound (V) calculated on the basis molar yield of 89.6%.
87%	In 1-methyl-pyrrolidin-2-one; water; at -5 - 0℃; for 0.5 - 0.75h;	Synthesis step: 12.46g of 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-7-((S)-tetrahydrofuran- 3-yloxy)-quinazoline (0.033 Mol) with a water content of at max 0.15 % in 60 ml of NMP are added dropwise within 15 to 30 minutes at 0 to -5C into the product solution prepared according to Example 5. The reaction mixture is kept stirring for about 15 minutes. Reaction control by HPLC shows a content 9. The alcaline water phase is extracted 3 times by stirring with 400 ml of butyl acetate. Afterwards the organic phase is extracted 3 times by stirring with 100 ml of water in order to remove NMP. The organic phase is evaporated at 60C max and 100-300 mbar and concentrated to a volume of about 80 ml, then 12.2 ml of methylcyclohexane and 2 ml of water are added and crystallization of the product is induced by inoculation, slowly cooling down to ambient temperature. The product is filtered with suction, washed with 60 ml of methylcyclohexane and dried at reduced pressure at 40C.Yield: 14.1 g (87%), purity: 99.64% (HPLC).
14.1 g	In 1-methyl-pyrrolidin-2-one; at -5 - 0℃;	4-[(3-chloro-4-fluorophenyl)amino]-6-[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline Synthesis step: 12.46 g of 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline (0.033 Mol) with a water content of at max 0.15% in 60 ml of NMP are added dropwise within 15 to 30 minutes at 0 to -5 C. into the product solution prepared according to Example 5. The reaction mixture is kept stirring for about 15 minutes. Reaction control by HPLC shows a content 9. The alcaline water phase is extracted 3 times by stirring with 400 ml of butyl acetate. Afierwards the organic phase is extracted 3 times by stirring with 100 ml of water in order to remove NMP. The organic phase is evaporated at 60 C. max and 100-300 mbar and concentrated to a volume of about 80 ml, then 12.2 ml of methylcyclohexane and 2 ml of water are added and crystallization of the product is induced by inoculation, slowly cooling down to ambient temperature. The product is filtered with suction, washed with 60 ml of methylcyclohexane and dried at reduced pressure at 40 C. 10047] Yield: 14.1 g (87%), purity: 99.64% (HPLC).

Reference： [1]Patent: CN105330652,2016,A .Location in patent: Paragraph 0035; 0038
[2]Patent: WO2015/101554,2015,A1 .Location in patent: Page/Page column 18; 19
[3]Patent: US2015/183764,2015,A1 .Location in patent: Paragraph 0045

21
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline [ No CAS ]
[ 1056149-69-9 ]
[ 850140-72-6 ]

Yield	Reaction Conditions	Operation in experiment
86.1%	With piperidine; In tetrahydrofuran; at 5 - 40℃; for 9h;	E) amidation reaction, the first 11.6g (0.09 muM) (E)-4 - dimethyl amino-crotonic acid dissolved in 70 ml of methyl tert-butyl ether, slowly dropping 18.4g (0.12 muM) phosphorus oxychloride, 80 C stirring reaction 1h, TLC board determining complete conversion, the reaction liquid and concentration to dry, obtain light yellow oily matter, to obtain (E)-4 - dimethyl amino croton acyl chloride and dissolved in 150 ml tetrahydrofuran, for use, then by step D) obtained 36.0g (0.096 muM) of 4 - [(3 - chloro -4 - fluoro phenyl) amino] -6 - amino -7 - [(S)- (tetrahydrofuran -3 - yl) oxy] quinazoline dissolved in 160 ml of tetrahydrofuran, adding 10.2g (0.12 muM,) piperidine, system reaction liquid cooling is cooled to 5 - 10 C, dropping the (E)-4 - dimethyl amino croton acyl chloride of the tetrahydrofuran solution, rose to 40 C stirring reaction under 9h to the reaction is complete, the reaction solution are saturated sodium bicarbonate solution and for the saturated salt water washing, dried with anhydrous sodium sulfate, and concentration under reduced pressure to dry, isopropanol - ethanol to recrystallize, 60 C vacuum drying 12h, a yellow solid, arab League law for Nepal (I), 26.8g, yield 86.1%, the steps of the reaction with the embodiment 1.

Reference： [1]Patent: CN106045983,2016,A .Location in patent: Paragraph 0048; 0067

22
[ 162012-69-3 ]
[ 850140-72-6 ]

Reference： [1]Patent: CN106045983,2016,A
[2]Patent: US2018/297989,2018,A1
[3]Patent: US2018/297989,2018,A1

23
[ 1621182-18-0 ]
[ 850140-72-6 ]

Reference： [1]Patent: CN106045983,2016,A

24
4-chloro-6-nitro-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline [ No CAS ]
[ 850140-72-6 ]

Reference： [1]Patent: CN106045983,2016,A

25
4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline [ No CAS ]
[ 850140-72-6 ]

Reference： [1]Patent: CN106045983,2016,A
[2]Patent: CN106916147,2017,A
[3]Patent: US2018/297989,2018,A1

26
[ 850140-72-6 ]
[ 110-16-7 ]
(2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide dimaleate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.1%	In ethanol; at 70℃;	The <strong>[850140-72-6]afatinib</strong> obtained in the previous step (20g, 0.041mol),280 mL of ethanol was added to the reaction flask.Warming up to 70 C,A solution of maleic acid (9.7 g, 0.084 mol) dissolved in 120 mL of ethanol was added and stirred.After crystals were precipitated, the mixture was cooled to 20 C and stirred for 2 hours.It was then stirred at 0 C for 3 hours for filtration.The filter cake was rinsed with ethanol and dried under reduced pressure at 40 C to give 27.7 g of <strong>[850140-72-6]afatinib</strong> dimaleate.The yield was 94.1%.
91.5%	In ethanol; at 0 - 70℃; for 5h;Large scale;	6.0 kg (12.35 mol) of (E)-4-dimethylamino-but-2-enoic acid-(4-(3-chloro-4-fluoro-phenylamino)-7-((S)-tetrahydrofuran-3-yloxy)-quinazolin-6-yl)-amide are placed in 84 litres of ethanol and heated to 70 C. and combined with a solution of 2.94 kg (25.31 mol) of maleic acid in 36 liters of ethanol. After crystallisation has set in, first the mixture is cooled to 20 C. and stined for 2 hours, then for 3 hours at 0 C. The precipitate is suction filtered, washed with 19 liters of ethanol and dried in vacuo at 40 C.
4 g	In ethyl acetate; at 20 - 30℃;	A mixture of ethyl acetate (60 ml) and <strong>[850140-72-6]Afatinib</strong> (3.Og) was stirred at 20-30C to get a clear solution. A solution of maleic acid [prepared by dissolving 1. 54g of maleic acid in 45 ml of ethyl acetate] was added to the above solution in 10-iS mm at 20-30C. The reaction mass was stirred for 2h at 20-30C. The solid thus formed was filtered,washed with ethyl acetate (1 5m1) and dried at 40C for 10 It 4 g of crystalline form F of <strong>[850140-72-6]Afatinib</strong> dimaleate was obtained.Water Content: 4.54 o (ww)

Reference： [1]Patent: CN104447713,2019,B .Location in patent: Paragraph 0057; 0062-0073
[2]Patent: WO2016/166720,2016,A2 .Location in patent: Page/Page column 16
[3]Patent: WO2016/199076,2016,A2 .Location in patent: Page/Page column 33; 34; 35; 36; 37; 38

27
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline [ No CAS ]
(E)-4-(dimethylamino)-2-butenoic acid hydrochloride [ No CAS ]
[ 850140-72-6 ]

Yield	Reaction Conditions	Operation in experiment
95%		(E)-4-Dimethylaminocroton hydrochloride 9.65 g was sequentially added to a 500 ml four-necked flask.93 g of N-methylpyrrolidone was stirred and cooled to -5 C, and 6.6 g of thionyl chloride was slowly added dropwise to the stirring solution to ensure that the temperature of the reaction solution was between 0 and -5 C, and within the above temperature range after the completion of the dropwise addition. Take a fall of 20min.N-4-[(3-chloro-4-fluorophenyl)]-7-[(3S)-tetrahydrofuran-3-yl]oxy}-4,6-quinazolinediamine 12.45g Dissolved in 62g of N-methylpyrrolidone as a dropping solution,Slowly add this solution to the above stirring solution and ensure that the temperature is between 0 and -5 C.After the completion of the dropwise addition, the mixture was stirred for 15 minutes in the above temperature range to obtain an acylation reaction liquid.Then, 100 g of water is slowly added dropwise to the above reaction solution and the temperature is controlled to not exceed 15 C, and then a 20% NaHH solution is slowly added dropwise thereto to about 66.3 g to rho Eta = 9 to 10, and the controlled temperature does not exceed 25 during the dropwise addition. C. After the dropwise addition, the reaction liquid was extracted three times (353 g X 3 ) with butyl acetate at 45 C, and the organic phase was collected, washed with water at 45 C for 5 times (250 g X 5 ), and then directly stirred for crystallization (stirring and crystallization) The temperature is selected from the table shown in Table 2) 3h. Filtration, crystals, butyl acetate 53g rinse the filter cake once, and finally dried under vacuum at 40 C for 2h to obtain a white solid. The yield, yield, purity and content of impurity I are shown in Table 2.
93%	With Bromoform; triethylamine; triphenylphosphine; In dichloromethane; at 25℃; for 1h;	50.1 g of dimethylamino croton hydrochloride,108.0 g of N4-(3-chloro-4-fluoro-phenyl)-7-((S)-tetrahydrofuran-3-yloxy)quinazoline-4,6-diamine,84.2 mL of triethylamine and 100.3 g of carbon tetrabromide were dissolved in dry 1944 mL of dichloromethane, and 79.4 g of triphenylphosphine was added in portions at 25 C with stirring.After 60 min, the reaction was filtered, and the filtrate was washed with water (1900 mL×2×).The residue was recrystallized from 390 mL of isopropanol to give 130.2 g of afatinib.The molar yield was 93% and the product purity was 98%.
87.4%		(1) To the 1 L bottle is added in three trans -4 - dimethylamino crotonic acid hydrochloride 50 g, N - methyl pyrrolidone 100 g, ethyl acetate 400 g, cooled to 5 C, to the system adds by drops the chlorination sulfoxide 36.1 g, after dropping, 5 C conditions under stirring, HPLC monitoring to the reaction is complete (SM1 residue 1.8%). (2) Will be N4 - (3 - chloro -4 - fluoro - phenyl) -7 - (S)- tetrahydrofuran -3 - oxyacetyl) quinazoline - 4, 6, - diamine (SM2) 45 g N - methyl pyrrolidone for 225 g dissolved, the solution is dropped is added to step (1) in the reaction system, after dropping, 0 C reaction, TLC monitoring reaction to SM2 reaction is complete. (3) Temperature control 20 C following, to the step (2) in the system drop of pure water 1.35 kg, for 20 weight % sodium hydroxide solution to adjust pH=9, ethyl acetate 675 g * 2 extraction, control gathering temperature is 45 C, combined with the organic phase, purified water 0.9 kg * 2 washing, organic phase in the 45 C concentrated under reduced pressure to V (the remaining system)/m (SM2) is about 10, lowering the temperature to -5 C, crystallization 2 hr, filtered, the filter cake in the 50 C vacuum drying, to obtain yellowish solid 51 g, yield 87.4%. The detection HPLC purity of 99.6%.

48 g		A mixture of (E)-4-(dimethylamino) but-2-enoic acid hydrochloride (44.1 g) and dimethyl acetamide (350 ml) was cooled at -15 to -20 C. To this solution 28.6 g of thionyl chloride was added dropwise and stirred at -15 to -20 C for 3-4 h (designated as solution-i). In a separate container N4-(3-chloro-4-fluorophenyl)-7- [(3 S)-tetrahydrofuran-3 -yloxy] quinazoline-4, 6-di amine (50 g) was dissolved in150 ml dimethylacetamide and added to the solution-i at -20 to -25 C. The reaction mixture was stirred for 1-2 h. To this reaction mass charged water (100 ml) followed by stirring for 10 min(designated as solution-2). A solution of sodium carbonate prepared separately by dissolving 125g potassium carbonate in 1900 ml of purified water(designated as solution-3). The solution-2 was addedinto the solution-3 and solid obtained stirred for 2-3hr. The solid was filtered and suspended in water and pH adjusted to 2-5 using hydrochloric acid solution. Ethyl acetate (500m1) added and reaction mass stirred for i-i.5h. Ethyl acetate layer separated and discarded. The aqueous layer was neutralized with potassium carbonate and pH was maintained at around 8-9. The solid obtained stirred forfurther 2h and filtered followed by drying to get 48g of the Afatinib.
		(E)-4-(dimethylaminobut-2-enoic acid) hydrochloride (44.1 g)And dimethylacetamide (350mL)The mixture is cooled at -10 to -20 C.To the solution, 28.6 g of thionyl chloride was added dropwise and stirred at -10 to -20 C for 3-4 h (designated as solution-1).In another container,(S)-N4-(3-chloro-4-fluorophenyl)-7-(tetrahydrofuran-3-yloxy)quinazoline-4,6-diamine (50g dissolved in 150mL dimethylacetamide, -20--25Add to solution-1 below,Stir the reaction for 1-2h,Add 100 mL to the reaction solution.Stir for 10 min (referred to as solution-2).A sodium carbonate solution (referred to as solution-3) was prepared by dissolving 125 g of potassium carbonate in 1900 mL of purified water.Add Solution-2 to Solution-3,Stir the solid for 2-3 h, filter,The solid was suspended in water and the pH was adjusted to 2-5 with a hydrochloric acid solution.Ethyl acetate (500 mL) was mixed with the solution and stirred for 1 h.The ethyl acetate layer was separated and discarded.The aqueous layer was neutralized with potassium carbonate and the pH was maintained at around 8-9.The resulting solid was stirred for additional 2 h and filtered.It was then dried to give 48 g of afatinib free base.

Reference： [1]Patent: CN108358900,2018,A .Location in patent: Paragraph 0020-0023; 0025-0044
[2]Patent: CN105061410,2018,B .Location in patent: Paragraph 0051; 0053; 0054; 0055; 0059; 0062; 0065; 0069
[3]Patent: CN107325082,2017,A .Location in patent: Paragraph 0057; 0068; 0059; 0060; 0061; 0062; 0063-0076
[4]Patent: WO2017/33107,2017,A1 .Location in patent: Page/Page column 26
[5]Patent: CN108864063,2018,A .Location in patent: Paragraph 0042-0043

28
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline [ No CAS ]
(2E)-4-(dimethylamino)but-2-enoic acid hydrochloride [ No CAS ]
[ 850140-72-6 ]

Yield	Reaction Conditions	Operation in experiment
48 g		A mixture of (E)-4-(dimethylamino) but-2-enoic acid hydrochloride (44. 1 g) and dimethyl acetamide (350 ml) was cooled at -15 to -20 0Q To this solution 28.6 g ofthionyl chloride was added dropwise and stirred at -15 to -20 0Q for 3-4 h (designated as solution-i). In a separate container N4-(3-chloro-4-fluorophenyl)-7-[(3S)- tetrahydrofuran-3-yloxy]quinazoline-4,6-diamine (50 g) was dissolved in 150 ml dimethylacetamide and added to the solution-i at -20 to -25 C. The reaction mixture was stirred for 1-2 h. To this reaction mass charged water (100 ml) followed bystirring for 10 min(designated as solution-2). A solution of sodium carbonate prepared separately by dissolving 125g potassium carbonate in 1900 ml of purified water (designated as solution-3). The solution-2 was added into the solution-3 and solid obtained stirred for 2-31w. The solid was filtered and suspended in water and pH adjusted to 2-5 using hydrochloric acid solution. Ethyl acetate (500m1) added andreaction mass stirred for i-i.5h. Ethyl acetate layer separated and discarded. The aqueous layer was neutralized with potassium carbonate and pH was maintained at around 8c). The solid obtained stirred for further 2h and filtered followed by drying to get 48g of the Afatinib free base.

Reference： [1]Patent: WO2016/199076,2016,A2 .Location in patent: Page/Page column 33; 36; 37

29
4-fluoro-3-chlorophenyl isocyanide [ No CAS ]
[ 850140-72-6 ]

Reference： [1]Patent: CN105968103,2016,A

30
7-hydroxy-N-(3-chloro-4-fluorophenyl)-6-nitroquinazolin-4-amine [ No CAS ]
[ 850140-72-6 ]

Reference： [1]Patent: CN105968103,2016,A

31
[ 27684-84-0 ]
[ 850140-72-6 ]

Reference： [1]Patent: CN105968103,2016,A

32
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline [ No CAS ]
[ 212776-19-7 ]
[ 850140-72-6 ]

Yield	Reaction Conditions	Operation in experiment
98%		At 5 C, a trimethylaluminium hexane solution at a concentration of 2M was prepared and the mixture was charged. To the reaction flask was added dichloromethane1800 mL, 22.4 g of compound W, 90 mL of a hexane solution of trimethylaluminum in a concentration of 2 M was added, and the mixture was stirred at room temperature for 2 hours,And then adding 4-dimethylaminocrotonate methyl ester 7.9g, heated to 60 C, reaction 5h, TLC monitoring reaction is completed, cooled to room temperature,The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgS04, filtered and concentrated under reduced pressure.Nylon 28.6 g, molar yield 98%, HPLC purity 99.8%.

Reference： [1]Patent: CN105968103,2016,A .Location in patent: Paragraph 00070; 0071; 0072; 0073; 0074; 0075; 0076-0078

33
C₇H₇N₃O₃ [ No CAS ]
[ 850140-72-6 ]

Reference： [1]Patent: CN105968103,2016,A

34
[ 367-21-5 ]
[ 850140-72-6 ]

Reference： [1]Patent: CN105968103,2016,A
[2]Patent: US2018/297989,2018,A1

35
[ 770-22-9 ]
[ 850140-72-6 ]

Reference： [1]Patent: CN105968103,2016,A

36
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline [ No CAS ]
[ 850140-72-6 ]

Reference： [1]Patent: CN106243092,2016,A
[2]Patent: CN106916147,2017,A
[3]Patent: CN104447713,2019,B

37
2-dimethylamino-1-hydroxyethanesulfonic acid sodium salt [ No CAS ]
C₂₆H₃₁ClFN₄O₆P [ No CAS ]
[ 850140-72-6 ]

Yield	Reaction Conditions	Operation in experiment
91.7%		To the reactorAdd anhydrous ethanol 1.2Kg,105 g (0.18 mol) Formula III,Lithium chloride 10 g (0.24 mol),Nitrogen protection.Cooling to -5 ~ 10 ,Dropwise 45% aqueous solution of potassium hydroxide 144g (65g of potassium hydroxide, 80g of water, pre-mixed with and cooled)Temperature control at -5 ~ 10 when dropping,Time consuming 2 hours.Then, 856 g of an aqueous solution of SM3 (2-dimethylamino-1-hydroxysulfonic acid) (76 g (0.4 mol) of water, 0.78 Kg of water)Temperature control in the 0 ~ 18 ,Time consuming 3 hours.0 ~ 18 holding for 4 hours,After completion of the reaction,Slowly add 2.4kg of water,Temperature control at -5 ~ 10 ,Time consuming 4 hours,After dripping for 2 hours,Filtered white wet goods,Back to the reactor after adding water 2.4Kg stirring beating,Control the temperature at 0 ~ 10 ,Stir for 2 hours,Filtration of white wet goods.45 ± 2 under reduced pressure drying (-0.09MPa),98 g of a white solid was obtained.Yield 91.7%Purity 99.21%,Cis-isomer is not detected,Moisture residue 0.25%.

Reference： [1]Patent: CN106243092,2016,A .Location in patent: Paragraph 0025; 0026; 0046-0048; 0058-0060; 0070-0072; 0082

38
[ 618061-76-0 ]
2-dimethylamino-1-hydroxyethanesulfonic acid sodium salt [ No CAS ]
[ 850140-72-6 ]

Yield	Reaction Conditions	Operation in experiment
60%	With lithium chloride; potassium hydroxide; In ethanol; water; at -10℃; for 2h;	1) in the three-mouth bottle, concentrated hydrochloric acid (120 g), water (50 ml). The low temperature drop add dimethyl amino diethyl acetal (100 g) is heated to 30 - 40 C reaction 3 h, cooled to the room temperature, 20 C following dropping 106 g sodium acid sulfite aqueous solution, stirring at the temperature for 1 h, then add 500 ml ethanol, stirring, filtering, the filter cake is ethanol, drying to obtain compound 9. 107 g, yield 90%, sealed and stored after drying. (2) 48 g compound 9 dissolved in 480 ml of water in the solution is a solution C, three bottle by adding 80 g compound 8,600 ml ethanol, adding 6.1 g anhydrous lithium chloride, stirring cooling to -10 C the following. (3) solution D: 80 g 45% potassium hydroxide aqueous solution, the solution is added to the reaction mixture drop D. The control of the inside temperature -10 C, then solution added to the reaction solution slowly dropping in C, maintain -10 C following reaction for two hours, after the reaction is complete the reaction mixture into a mixing of 2.0 in liters, to form a white suspension. Filtering, washing, and a ground line, drying. Yield by about 95%, purity 96.5%, white solid. (4) the above-mentioned solid is dissolved in butyl acetate, nylon heating to 70 C, dropping cyclohexane, and milling after cooling, filtered to obtain yellow solid, drying the product is obtained. The above product in 5 V in the ethanol beating 8 hours, cooling to room temperature. Then filtered, washing with ethanol, and a ground line to obtain the solid, drying to obtain 40 g compound 2, yield 60%, purity 99.5%.

Reference： [1]Patent: CN106916147,2017,A .Location in patent: Paragraph 0059-0064

39
[ 162012-67-1 ]
[ 850140-72-6 ]

Reference： [1]Patent: CN106916147,2017,A
[2]Patent: CN107488171,2017,A
[3]Patent: US2018/297989,2018,A1

40
[ 850140-72-6 ]
C₂₂H₂₀ClFN₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With sodium hydroxide; In methanol; water; at 50℃; for 24h;	(1) 2 g (4.1 mmol) of a compound of 2,2 mol / L aqueous sodium hydroxide solution (10 mL) And 20 mL of methanol, Add to 100mL three mouth reaction bottle, the temperature to 50 degrees Celsius, the reaction 24h; (2) The reaction solution was cooled to 25 C, diluted with water, adjusted to pH 7 with 10% hydrochloric acid, and extracted with 100 mL of ethyl acetate. (3) with methanol and methylene chloride as eluent, silica gel column separation and purification of the purified compound 1, the yield of 43% High purity liquid phase detection of its purity 99.5%, the map shown in Figure 1.

Reference： [1]Patent: CN106916147,2017,A .Location in patent: Paragraph 0066-0071

41
C₂₀H₁₈ClF₂N₅O [ No CAS ]
[ 86087-23-2 ]
[ 850140-72-6 ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium tert-butylate; In tert-butyl alcohol; at 50℃; for 1h;	Weigh 4.0g of intermediate II into a 250ml three-vial bottle.Add 50ml tert-butanol,Then add 1.0 g of (S)-3-hydroxytetrahydrofuran,Slowly add potassium tert-butoxide, temperature control does not exceed 50 C, plus complete,Stir the reaction for 1h and complete the reaction. Pour the reaction mixture into 200ml of drinking water, adjust the pH to 6.5 with 10% acetic acid solution, and filter.Drying afatinib I,Yield 89%, purity 99.6%, single impurity less than 0.1%.

Reference： [1]Patent: CN107488171,2017,A .Location in patent: Paragraph 0045; 0046; 0056; 0066; 0076; 0086

42
N-(3-chloro-4-fluorophenyl)-7-fluoro-6-amino-4-quinazolinamine [ No CAS ]
[ 850140-72-6 ]

Reference： [1]Patent: CN107488171,2017,A

43
[ 16499-57-3 ]
[ 850140-72-6 ]

Reference： [1]Tetrahedron Letters,2018,vol. 59,p. 4180 - 4182
[2]Tetrahedron Letters,2018,vol. 59,p. 4180 - 4182

44
7-[(3S)-tetrahydrofuran-3-yl]oxy-3H-quinazolin-4-one [ No CAS ]
[ 850140-72-6 ]