Name: 698387-09-6|(E)-N-(4-((3-Chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide|98%
Brand: Ambeed
SKU: A150970
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1
[ 524955-09-7 ]
[ 848133-88-0 ]
[ 698387-09-6 ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 1107 - 1131

2
[ 1056149-69-9 ]
[ 698387-09-6 ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 1107 - 1131

3
[ 214476-09-2 ]
[ 698387-09-6 ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 1107 - 1131

4
[ 848133-87-9 ]
[ 698387-09-6 ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 1107 - 1131

5
(E)-4-(dimethylamino)-2-butenoic acid hydrochloride [ No CAS ]
[ 698387-09-6 ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 1107 - 1131

6
4-[4-(2-pyridylmethoxy)-3-chloro]amino-6-amino-3-cyano-7-ethoxyquinoline [ No CAS ]
[ 1056149-69-9 ]
[ 698387-09-6 ]

Yield	Reaction Conditions	Operation in experiment
80 - 85%		A solution of (E)-4- (dimethylamino)-2-butenoic acid hydrochloride in 1.2 L of tetrahydrofuran (THF) and a catalytic amount of dimethylformide (DMF) (1.2 ml) was cooled to 0-5 C. Oxalyl chloride (0.95 eq) was added dropwise and the mixture was warmed to 25-30 C and stirred for 2 hours. The orange suspension was checked for complete consumption of oxalyl chloride by HPLC then cooled to 0-5 C. A solution of 111 g of 4- [4- (2-pyridylmethoxy)-3-chloro] amino-6-amino-3-cyano-7- ethoxyquinoline in 1.47 L of 1-methyl-2-pyrrolidinone was added dropwise and the mixture was stirred until < 1.0% of the starting aniline remained (3-16 hours). The reaction was quenched with water and the mixture was warmed to 40 C. Aqueous sodium hydroxide was added to bring the pH to 10-11. The resulting precipitates were filtered hot and washed with water. The wet solids were heated to reflux (70-75 C) in acetonitrile : THF (1.5 : 1) and the solution cooled over 3 hours to room temperature. The product was filtered and washed with acetonitrile : THF. The product was dried (50 C, 10 mm Hg, 24 hours) to give 80-85% yield. Melting point of maleate salt 178-183 C.

Reference： [1]Patent: WO2005/34955,2005,A1 .Location in patent: Page/Page column 13

7
[ 848139-78-6 ]
[ 698387-09-6 ]

Yield	Reaction Conditions	Operation in experiment
80 - 85%		A solution of (E)-4-(dimethylamino)-2-butenoic acid hydrochloride in 1.2 L of tetrahydrofuran (THF) and a catalytic amount of dimethylformide (DMF) (1.2 ml) was cooled to 0-5 C. Oxalyl chloride (0.95 eq) was added dropwise and the mixture was warmed to 25-30 C. and stirred for 2 hours. The orange suspension was checked for complete consumption of oxalyl chloride by HPLC then cooled to 0-5 C. A solution of 111 g of 4-[4-(2-pyridylmethoxy)-3-chloro]amino-6-amino-3-cyano-7-ethoxyquinoline in 1.47 L of 1-methyl-2-pyrrolidinone was added dropwise and the mixture was stirred until &LessFullEqual;1.0% of the starting aniline remained (3-16 hours). The reaction was quenched with water and the mixture was warmed to 40 C. Aqueous sodium hydroxide was added to bring the pH to 10-11. The resulting precipitates were filtered hot and washed with water. The wet solids were heated to reflux (70-75 C.) in acetonitrile:THF (1.5:1) and the solution cooled over 3 hours to room temperature. The product was filtered and washed with acetonitrile:THF. The product was dried (50 C., 10 mm Hg, 24 hours) to give 80-85% yield. Melting point of maleate salt 178-183 C.

Reference： [1]Patent: US2005/59678,2005,A1 .Location in patent: Page 4

8
[ 110-16-7 ]
[ 698387-09-6 ]
(2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide maleate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	In ethanol; water; at 20℃; for 1h;Inert atmosphere;	Under the protection of nitrogen, compound VII (E)-N-(4-(3-chloro-4-(2-pyridinemethoxy)phenylamino)-3-cyano-7-ethoxy quinoline-6-yl)-4-dimethylamino-2-butenamide (5.57g, 10mmol) suspended in ethanol (40 ml) in, in 30-40 C lower heat insulating stirring dissolved, slowly add maleic acid (1.16g, 10mmol) dissolved in water (5 ml) of the solution, separating white solid. Stirring for 1 hour, stirring at room temperature in 1 hour after-filtration, washing, drying, to obtain title compound 7.84g, HPLC purity 99.88%, the yield is 98%.
87.7%	With pyrographite; In water; acetone; at 20 - 40℃; for 0.666667h;	At room temperature, 800.0 mL of acetone and 200.0 mL of water were weighed, added to 5 L of reaction vessel 1, heated to 40 C, stirred and mixed to obtain an acetone/water binary solvent, and used; 21.5 g of maleic acid was weighed. The mixture was added to a 5 L reactor 2 containing 910 mL of the above acetone/water binary solvent, and the solution was stirred to obtain a maleic acid solution, which was used until use; 99.8 g of <strong>[698387-09-6]neratinib</strong> free base was weighed and added to the reaction vessel 2, Stirring was dissolved, and 2.1 g of activated carbon was weighed and added to the reaction vessel 2. After stirring for 40 minutes, the mixture was filtered, and the filtrate was transferred to the reaction vessel 3, and the temperature was lowered to 25 C to obtain a natenatidine salt solution. At room temperature, 1.0 g of natriene maleate salt form C (D90 particle size 61 mum) was weighed out as a seed crystal, added to a 50 mL reaction vessel 4 containing 25.0 mL of acetone, stirred and mixed to obtain crystals. The suspension was used; the above seed suspension was added to the reaction vessel 3 at room temperature, and then 2.73 L of acetone was weighed and slowly added dropwise to the reaction vessel 3, and the mixture was dropped in 4 hours; , matured at room temperature for 18 hours. After the aging was completed, the mixture was filtered under suction, and the cake was dried at 40 C for 8 hours to obtain a solid product. The yield was 87.7%, and the HPLC purity was 99.82%.
84 - 90%	In water; isopropyl alcohol;Product distribution / selectivity;	Formation of Salt The free base is hygroscopic and undergoes hydrolysis readily. Forming a salt of the compound, such as a flumarate or mesylate salt, stabilizes the molecule and renders the compound more soluble. The most preferred salt is a maleate salt, which has been found to be highly crystalline and to exist substantially as a single polymorph as shown by DSC thermogram in FIG. 1. Recrystallizing the product in the presence of an acid has been found to yield a stable salt form of the product. Experimental results achieved utilizing different solvents for the recrystallization are set forth in Table 7. As seen in Table 7, an improvement is observed when n-propanol/water is used as the solvent system. A maleate salt is the most preferred, as it exists in a single polymorphic form. TABLE 7 Recrystallization Scale (g) Solvent (vols)H2O (vols) Yield (%) 2.45 EtOAc (50) 0 62 1.97 n-BuOH (50) 0 66 1.00 EtOH 1L (10) 1 27 0.50 EtOAc (140) 0 88 0.50 EtOH 1L (20) 0 100 0.25 EtOAc:MeOH 0 - (100:100) 3.24 EtOH 1L (32) 0 84 1.00 EtOH 1L (15) 1 83 1.00 MeOH:EtOAc 0 86 (2:3) 1.00 EtOH 1L (15) 1 69 2.00 MeOH:EtOAc 0 91 (13.9:9.3) 4.00 MeOH:EtOAc 0 83 (13.9:9.3) 1.00 IPA (15) 4 86 1.00 IPA (13.5) 1.5 90 1.00 IPA (13.5) 1.5 84 1.00 IPA (18) 2 86 1.00 n-PrOH (18) 2 63 1.00 n-PrOH (9) 1 83 1.00 n-PrOH (13.5) 1.5 78 9.00 n-PrOH (10.8) 1.2 72 4.75 n-PrOH (12.6) 1.4 83 5.00 n-PrOH (10.8) 1.2 91 5.00 n-PrOH (10.8) 1.2 85 5.00 n-PrOH (10.8) 1.2 78 40 n-PrOH (10.8) 1.2 80 375 n-PrOH (10.8) 1.2 90 100 n-PrOH (10.8) 1.2 88 Preparation of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate, WAY-179272-B (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-dimethylamino)-2-butenamide crude free base (0.1 kg, 0.159 mole) and maleic acid (0.019 kg, 0.164 mole) were dissolved at 40-50 C. in a 10% water/n-propanol mixture (1.20 L). The hot solution was clarified and cooled over 2 h to room temperature and held for 12-15 hr. The product was filtered and washed with 10% water/n-propanol (2×0.15 L). The product was dried (50 C., 10 mm Hg, 24 h) to give 94.4 g (88% yield). DSC: 204 C. (single crystal form). 1H NMR: delta (DMSO-d6) 9.73 (s, 1H, NH), 9.62 (s, 1H, NH), 8.93 (s, 1H, Ar), 8.60 (dd, 1H, Ar), 8.50 (s, 1H, Ar), 7.88 (dd, 1H, Ar), 7.58 (d, 1H, Ar), 7.40 (m, 3H, Ar), 7.24 (m, 2H, Ar), 6.75 (d, 2H, -CHCH-), 6.03 (s, 2H, HOOC-CHCH-COOH), 5.29 (s, 2H, OCH2Pyr), 4.33 (q, 2H, OCH2CH3), 3.89 (s, 2H, NCH2), 2.76 (s, 6H, N(CH3)2), 1.47 (t, 3H, OCH2CH3). 13C NMR: delta (DMSO-d6) 168.0, 163.2, 156.9, 154.2, 153.2, 151.9, 151.3, 149.8, 148.5, 137.8, 136.5, 134.7, 133.4, 132.2, 128.0, 126.6, 124.9, 123.8, 122.3, 122.2, 117.9, 116.4, 115.1, 113.9, 109.5, 88.1, 72.0, 65.3, 57.8, 43.1, 14.9.

84 - 100%	In ethanol;Product distribution / selectivity;	Formation of Salt The free base is hygroscopic and undergoes hydrolysis readily. Forming a salt of the compound, such as a flumarate or mesylate salt, stabilizes the molecule and renders the compound more soluble. The most preferred salt is a maleate salt, which has been found to be highly crystalline and to exist substantially as a single polymorph as shown by DSC thermogram in FIG. 1. Recrystallizing the product in the presence of an acid has been found to yield a stable salt form of the product. Experimental results achieved utilizing different solvents for the recrystallization are set forth in Table 7. As seen in Table 7, an improvement is observed when n-propanol/water is used as the solvent system. A maleate salt is the most preferred, as it exists in a single polymorphic form. TABLE 7 Recrystallization Scale (g) Solvent (vols)H2O (vols) Yield (%) 2.45 EtOAc (50) 0 62 1.97 n-BuOH (50) 0 66 1.00 EtOH 1L (10) 1 27 0.50 EtOAc (140) 0 88 0.50 EtOH 1L (20) 0 100 0.25 EtOAc:MeOH 0 - (100:100) 3.24 EtOH 1L (32) 0 84 1.00 EtOH 1L (15) 1 83 1.00 MeOH:EtOAc 0 86 (2:3) 1.00 EtOH 1L (15) 1 69 2.00 MeOH:EtOAc 0 91 (13.9:9.3) 4.00 MeOH:EtOAc 0 83 (13.9:9.3) 1.00 IPA (15) 4 86 1.00 IPA (13.5) 1.5 90 1.00 IPA (13.5) 1.5 84 1.00 IPA (18) 2 86 1.00 n-PrOH (18) 2 63 1.00 n-PrOH (9) 1 83 1.00 n-PrOH (13.5) 1.5 78 9.00 n-PrOH (10.8) 1.2 72 4.75 n-PrOH (12.6) 1.4 83 5.00 n-PrOH (10.8) 1.2 91 5.00 n-PrOH (10.8) 1.2 85 5.00 n-PrOH (10.8) 1.2 78 40 n-PrOH (10.8) 1.2 80 375 n-PrOH (10.8) 1.2 90 100 n-PrOH (10.8) 1.2 88 Preparation of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate, WAY-179272-B (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-dimethylamino)-2-butenamide crude free base (0.1 kg, 0.159 mole) and maleic acid (0.019 kg, 0.164 mole) were dissolved at 40-50 C. in a 10% water/n-propanol mixture (1.20 L). The hot solution was clarified and cooled over 2 h to room temperature and held for 12-15 hr. The product was filtered and washed with 10% water/n-propanol (2×0.15 L). The product was dried (50 C., 10 mm Hg, 24 h) to give 94.4 g (88% yield). DSC: 204 C. (single crystal form). 1H NMR: delta (DMSO-d6) 9.73 (s, 1H, NH), 9.62 (s, 1H, NH), 8.93 (s, 1H, Ar), 8.60 (dd, 1H, Ar), 8.50 (s, 1H, Ar), 7.88 (dd, 1H, Ar), 7.58 (d, 1H, Ar), 7.40 (m, 3H, Ar), 7.24 (m, 2H, Ar), 6.75 (d, 2H, -CHCH-), 6.03 (s, 2H, HOOC-CHCH-COOH), 5.29 (s, 2H, OCH2Pyr), 4.33 (q, 2H, OCH2CH3), 3.89 (s, 2H, NCH2), 2.76 (s, 6H, N(CH3)2), 1.47 (t, 3H, OCH2CH3). 13C NMR: delta (DMSO-d6) 168.0, 163.2, 156.9, 154.2, 153.2, 151.9, 151.3, 149.8, 148.5, 137.8, 136.5, 134.7, 133.4, 132.2, 128.0, 126.6, 124.9, 123.8, 122.3, 122.2, 117.9, 116.4, 115.1, 113.9, 109.5, 88.1, 72.0, 65.3, 57.8, 43.1, 14.9.
84.6%	In methanol; water; at 20 - 25℃; for 3h;	<strong>[698387-09-6]Neratinib</strong> base form B6 (11.5 g) and maleic acid (2.39 g) were charged and methanol/water mixture (4:1; 47.5 mL) was added. Mixture was stirred at 20 - 25 C for 3 h. Water (34.5 mL) was added dropwise and suspension was stirred for additional 1 h. Suspension was filtered and crystals were washed with methanol/water mixture (1:2; 2 x 15 mL). Crystals were dried under vacuum at 35 C for 6 h at 10 mbar to obtain <strong>[698387-09-6]Neratinib</strong> maleate monohydrate (Y:84.6 %; HPLC purity: 99.76 Area %).
83 - 91%	In methanol; ethyl acetate;Product distribution / selectivity;	Formation of Salt The free base is hygroscopic and undergoes hydrolysis readily. Forming a salt of the compound, such as a flumarate or mesylate salt, stabilizes the molecule and renders the compound more soluble. The most preferred salt is a maleate salt, which has been found to be highly crystalline and to exist substantially as a single polymorph as shown by DSC thermogram in FIG. 1. Recrystallizing the product in the presence of an acid has been found to yield a stable salt form of the product. Experimental results achieved utilizing different solvents for the recrystallization are set forth in Table 7. As seen in Table 7, an improvement is observed when n-propanol/water is used as the solvent system. A maleate salt is the most preferred, as it exists in a single polymorphic form. TABLE 7 Recrystallization Scale (g) Solvent (vols)H2O (vols) Yield (%) 2.45 EtOAc (50) 0 62 1.97 n-BuOH (50) 0 66 1.00 EtOH 1L (10) 1 27 0.50 EtOAc (140) 0 88 0.50 EtOH 1L (20) 0 100 0.25 EtOAc:MeOH 0 - (100:100) 3.24 EtOH 1L (32) 0 84 1.00 EtOH 1L (15) 1 83 1.00 MeOH:EtOAc 0 86 (2:3) 1.00 EtOH 1L (15) 1 69 2.00 MeOH:EtOAc 0 91 (13.9:9.3) 4.00 MeOH:EtOAc 0 83 (13.9:9.3) 1.00 IPA (15) 4 86 1.00 IPA (13.5) 1.5 90 1.00 IPA (13.5) 1.5 84 1.00 IPA (18) 2 86 1.00 n-PrOH (18) 2 63 1.00 n-PrOH (9) 1 83 1.00 n-PrOH (13.5) 1.5 78 9.00 n-PrOH (10.8) 1.2 72 4.75 n-PrOH (12.6) 1.4 83 5.00 n-PrOH (10.8) 1.2 91 5.00 n-PrOH (10.8) 1.2 85 5.00 n-PrOH (10.8) 1.2 78 40 n-PrOH (10.8) 1.2 80 375 n-PrOH (10.8) 1.2 90 100 n-PrOH (10.8) 1.2 88 Preparation of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate, WAY-179272-B (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-dimethylamino)-2-butenamide crude free base (0.1 kg, 0.159 mole) and maleic acid (0.019 kg, 0.164 mole) were dissolved at 40-50 C. in a 10% water/n-propanol mixture (1.20 L). The hot solution was clarified and cooled over 2 h to room temperature and held for 12-15 hr. The product was filtered and washed with 10% water/n-propanol (2×0.15 L). The product was dried (50 C., 10 mm Hg, 24 h) to give 94.4 g (88% yield). DSC: 204 C. (single crystal form). 1H NMR: delta (DMSO-d6) 9.73 (s, 1H, NH), 9.62 (s, 1H, NH), 8.93 (s, 1H, Ar), 8.60 (dd, 1H, Ar), 8.50 (s, 1H, Ar), 7.88 (dd, 1H, Ar), 7.58 (d, 1H, Ar), 7.40 (m, 3H, Ar), 7.24 (m, 2H, Ar), 6.75 (d, 2H, -CHCH-), 6.03 (s, 2H, HOOC-CHCH-COOH), 5.29 (s, 2H, OCH2Pyr), 4.33 (q, 2H, OCH2CH3), 3.89 (s, 2H, NCH2), 2.76 (s, 6H, N(CH3)2), 1.47 (t, 3H, OCH2CH3). 13C NMR: delta (DMSO-d6) 168.0, 163.2, 156.9, 154.2, 153.2, 151.9, 151.3, 149.8, 148.5, 137.8, 136.5, 134.7, 133.4, 132.2, 128.0, 126.6, 124.9, 123.8, 122.3, 122.2, 117.9, 116.4, 115.1, 113.9, 109.5, 88.1, 72.0, 65.3, 57.8, 43.1, 14.9.
66%	In butan-1-ol;Product distribution / selectivity;	Formation of Salt The free base is hygroscopic and undergoes hydrolysis readily. Forming a salt of the compound, such as a flumarate or mesylate salt, stabilizes the molecule and renders the compound more soluble. The most preferred salt is a maleate salt, which has been found to be highly crystalline and to exist substantially as a single polymorph as shown by DSC thermogram in FIG. 1. Recrystallizing the product in the presence of an acid has been found to yield a stable salt form of the product. Experimental results achieved utilizing different solvents for the recrystallization are set forth in Table 7. As seen in Table 7, an improvement is observed when n-propanol/water is used as the solvent system. A maleate salt is the most preferred, as it exists in a single polymorphic form. TABLE 7 Recrystallization Scale (g) Solvent (vols)H2O (vols) Yield (%) 2.45 EtOAc (50) 0 62 1.97 n-BuOH (50) 0 66 1.00 EtOH 1L (10) 1 27 0.50 EtOAc (140) 0 88 0.50 EtOH 1L (20) 0 100 0.25 EtOAc:MeOH 0 - (100:100) 3.24 EtOH 1L (32) 0 84 1.00 EtOH 1L (15) 1 83 1.00 MeOH:EtOAc 0 86 (2:3) 1.00 EtOH 1L (15) 1 69 2.00 MeOH:EtOAc 0 91 (13.9:9.3) 4.00 MeOH:EtOAc 0 83 (13.9:9.3) 1.00 IPA (15) 4 86 1.00 IPA (13.5) 1.5 90 1.00 IPA (13.5) 1.5 84 1.00 IPA (18) 2 86 1.00 n-PrOH (18) 2 63 1.00 n-PrOH (9) 1 83 1.00 n-PrOH (13.5) 1.5 78 9.00 n-PrOH (10.8) 1.2 72 4.75 n-PrOH (12.6) 1.4 83 5.00 n-PrOH (10.8) 1.2 91 5.00 n-PrOH (10.8) 1.2 85 5.00 n-PrOH (10.8) 1.2 78 40 n-PrOH (10.8) 1.2 80 375 n-PrOH (10.8) 1.2 90 100 n-PrOH (10.8) 1.2 88 Preparation of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate, WAY-179272-B (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-dimethylamino)-2-butenamide crude free base (0.1 kg, 0.159 mole) and maleic acid (0.019 kg, 0.164 mole) were dissolved at 40-50 C. in a 10% water/n-propanol mixture (1.20 L). The hot solution was clarified and cooled over 2 h to room temperature and held for 12-15 hr. The product was filtered and washed with 10% water/n-propanol (2×0.15 L). The product was dried (50 C., 10 mm Hg, 24 h) to give 94.4 g (88% yield). DSC: 204 C. (single crystal form). 1H NMR: delta (DMSO-d6) 9.73 (s, 1H, NH), 9.62 (s, 1H, NH), 8.93 (s, 1H, Ar), 8.60 (dd, 1H, Ar), 8.50 (s, 1H, Ar), 7.88 (dd, 1H, Ar), 7.58 (d, 1H, Ar), 7.40 (m, 3H, Ar), 7.24 (m, 2H, Ar), 6.75 (d, 2H, -CHCH-), 6.03 (s, 2H, HOOC-CHCH-COOH), 5.29 (s, 2H, OCH2Pyr), 4.33 (q, 2H, OCH2CH3), 3.89 (s, 2H, NCH2), 2.76 (s, 6H, N(CH3)2), 1.47 (t, 3H, OCH2CH3). 13C NMR: delta (DMSO-d6) 168.0, 163.2, 156.9, 154.2, 153.2, 151.9, 151.3, 149.8, 148.5, 137.8, 136.5, 134.7, 133.4, 132.2, 128.0, 126.6, 124.9, 123.8, 122.3, 122.2, 117.9, 116.4, 115.1, 113.9, 109.5, 88.1, 72.0, 65.3, 57.8, 43.1, 14.9.
63 - 91%	In propan-1-ol; water; at 20 - 50℃; for 14 - 17h;Product distribution / selectivity;	Formation of Salt The free base is hygroscopic and undergoes hydrolysis readily. Forming a salt of the compound, such as a flumarate or mesylate salt, stabilizes the molecule and renders the compound more soluble. The most preferred salt is a maleate salt, which has been found to be highly crystalline and to exist substantially as a single polymorph as shown by DSC thermogram in FIG. 1. Recrystallizing the product in the presence of an acid has been found to yield a stable salt form of the product. Experimental results achieved utilizing different solvents for the recrystallization are set forth in Table 7. As seen in Table 7, an improvement is observed when n-propanol/water is used as the solvent system. A maleate salt is the most preferred, as it exists in a single polymorphic form. TABLE 7 Recrystallization Scale (g) Solvent (vols)H2O (vols) Yield (%) 2.45 EtOAc (50) 0 62 1.97 n-BuOH (50) 0 66 1.00 EtOH 1L (10) 1 27 0.50 EtOAc (140) 0 88 0.50 EtOH 1L (20) 0 100 0.25 EtOAc:MeOH 0 - (100:100) 3.24 EtOH 1L (32) 0 84 1.00 EtOH 1L (15) 1 83 1.00 MeOH:EtOAc 0 86 (2:3) 1.00 EtOH 1L (15) 1 69 2.00 MeOH:EtOAc 0 91 (13.9:9.3) 4.00 MeOH:EtOAc 0 83 (13.9:9.3) 1.00 IPA (15) 4 86 1.00 IPA (13.5) 1.5 90 1.00 IPA (13.5) 1.5 84 1.00 IPA (18) 2 86 1.00 n-PrOH (18) 2 63 1.00 n-PrOH (9) 1 83 1.00 n-PrOH (13.5) 1.5 78 9.00 n-PrOH (10.8) 1.2 72 4.75 n-PrOH (12.6) 1.4 83 5.00 n-PrOH (10.8) 1.2 91 5.00 n-PrOH (10.8) 1.2 85 5.00 n-PrOH (10.8) 1.2 78 40 n-PrOH (10.8) 1.2 80 375 n-PrOH (10.8) 1.2 90 100 n-PrOH (10.8) 1.2 88 Preparation of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate, WAY-179272-B (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-dimethylamino)-2-butenamide crude free base (0.1 kg, 0.159 mole) and maleic acid (0.019 kg, 0.164 mole) were dissolved at 40-50 C. in a 10% water/n-propanol mixture (1.20 L). The hot solution was clarified and cooled over 2 h to room temperature and held for 12-15 hr. The product was filtered and washed with 10% water/n-propanol (2×0.15 L). The product was dried (50 C., 10 mm Hg, 24 h) to give 94.4 g (88% yield). DSC: 204 C. (single crystal form). 1H NMR: delta (DMSO-d6) 9.73 (s, 1H, NH), 9.62 (s, 1H, NH), 8.93 (s, 1H, Ar), 8.60 (dd, 1H, Ar), 8.50 (s, 1H, Ar), 7.88 (dd, 1H, Ar), 7.58 (d, 1H, Ar), 7.40 (m, 3H, Ar), 7.24 (m, 2H, Ar), 6.75 (d, 2H, -CHCH-), 6.03 (s, 2H, HOOC-CHCH-COOH), 5.29 (s, 2H, OCH2Pyr), 4.33 (q, 2H, OCH2CH3), 3.89 (s, 2H, NCH2), 2.76 (s, 6H, N(CH3)2), 1.47 (t, 3H, OCH2CH3). 13C NMR: delta (DMSO-d6) 168.0, 163.2, 156.9, 154.2, 153.2, 151.9, 151.3, 149.8, 148.5, 137.8, 136.5, 134.7, 133.4, 132.2, 128.0, 126.6, 124.9, 123.8, 122.3, 122.2, 117.9, 116.4, 115.1, 113.9, 109.5, 88.1, 72.0, 65.3, 57.8, 43.1, 14.9.
62 - 88%	In ethyl acetate;Product distribution / selectivity;	Formation of Salt The free base is hygroscopic and undergoes hydrolysis readily. Forming a salt of the compound, such as a flumarate or mesylate salt, stabilizes the molecule and renders the compound more soluble. The most preferred salt is a maleate salt, which has been found to be highly crystalline and to exist substantially as a single polymorph as shown by DSC thermogram in FIG. 1. Recrystallizing the product in the presence of an acid has been found to yield a stable salt form of the product. Experimental results achieved utilizing different solvents for the recrystallization are set forth in Table 7. As seen in Table 7, an improvement is observed when n-propanol/water is used as the solvent system. A maleate salt is the most preferred, as it exists in a single polymorphic form. TABLE 7 Recrystallization Scale (g) Solvent (vols)H2O (vols) Yield (%) 2.45 EtOAc (50) 0 62 1.97 n-BuOH (50) 0 66 1.00 EtOH 1L (10) 1 27 0.50 EtOAc (140) 0 88 0.50 EtOH 1L (20) 0 100 0.25 EtOAc:MeOH 0 - (100:100) 3.24 EtOH 1L (32) 0 84 1.00 EtOH 1L (15) 1 83 1.00 MeOH:EtOAc 0 86 (2:3) 1.00 EtOH 1L (15) 1 69 2.00 MeOH:EtOAc 0 91 (13.9:9.3) 4.00 MeOH:EtOAc 0 83 (13.9:9.3) 1.00 IPA (15) 4 86 1.00 IPA (13.5) 1.5 90 1.00 IPA (13.5) 1.5 84 1.00 IPA (18) 2 86 1.00 n-PrOH (18) 2 63 1.00 n-PrOH (9) 1 83 1.00 n-PrOH (13.5) 1.5 78 9.00 n-PrOH (10.8) 1.2 72 4.75 n-PrOH (12.6) 1.4 83 5.00 n-PrOH (10.8) 1.2 91 5.00 n-PrOH (10.8) 1.2 85 5.00 n-PrOH (10.8) 1.2 78 40 n-PrOH (10.8) 1.2 80 375 n-PrOH (10.8) 1.2 90 100 n-PrOH (10.8) 1.2 88 Preparation of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate, WAY-179272-B (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-dimethylamino)-2-butenamide crude free base (0.1 kg, 0.159 mole) and maleic acid (0.019 kg, 0.164 mole) were dissolved at 40-50 C. in a 10% water/n-propanol mixture (1.20 L). The hot solution was clarified and cooled over 2 h to room temperature and held for 12-15 hr. The product was filtered and washed with 10% water/n-propanol (2×0.15 L). The product was dried (50 C., 10 mm Hg, 24 h) to give 94.4 g (88% yield). DSC: 204 C. (single crystal form). 1H NMR: delta (DMSO-d6) 9.73 (s, 1H, NH), 9.62 (s, 1H, NH), 8.93 (s, 1H, Ar), 8.60 (dd, 1H, Ar), 8.50 (s, 1H, Ar), 7.88 (dd, 1H, Ar), 7.58 (d, 1H, Ar), 7.40 (m, 3H, Ar), 7.24 (m, 2H, Ar), 6.75 (d, 2H, -CHCH-), 6.03 (s, 2H, HOOC-CHCH-COOH), 5.29 (s, 2H, OCH2Pyr), 4.33 (q, 2H, OCH2CH3), 3.89 (s, 2H, NCH2), 2.76 (s, 6H, N(CH3)2), 1.47 (t, 3H, OCH2CH3). 13C NMR: delta (DMSO-d6) 168.0, 163.2, 156.9, 154.2, 153.2, 151.9, 151.3, 149.8, 148.5, 137.8, 136.5, 134.7, 133.4, 132.2, 128.0, 126.6, 124.9, 123.8, 122.3, 122.2, 117.9, 116.4, 115.1, 113.9, 109.5, 88.1, 72.0, 65.3, 57.8, 43.1, 14.9.
27 - 83%	In ethanol; water;Product distribution / selectivity;	Formation of Salt The free base is hygroscopic and undergoes hydrolysis readily. Forming a salt of the compound, such as a flumarate or mesylate salt, stabilizes the molecule and renders the compound more soluble. The most preferred salt is a maleate salt, which has been found to be highly crystalline and to exist substantially as a single polymorph as shown by DSC thermogram in FIG. 1. Recrystallizing the product in the presence of an acid has been found to yield a stable salt form of the product. Experimental results achieved utilizing different solvents for the recrystallization are set forth in Table 7. As seen in Table 7, an improvement is observed when n-propanol/water is used as the solvent system. A maleate salt is the most preferred, as it exists in a single polymorphic form. TABLE 7 Recrystallization Scale (g) Solvent (vols)H2O (vols) Yield (%) 2.45 EtOAc (50) 0 62 1.97 n-BuOH (50) 0 66 1.00 EtOH 1L (10) 1 27 0.50 EtOAc (140) 0 88 0.50 EtOH 1L (20) 0 100 0.25 EtOAc:MeOH 0 - (100:100) 3.24 EtOH 1L (32) 0 84 1.00 EtOH 1L (15) 1 83 1.00 MeOH:EtOAc 0 86 (2:3) 1.00 EtOH 1L (15) 1 69 2.00 MeOH:EtOAc 0 91 (13.9:9.3) 4.00 MeOH:EtOAc 0 83 (13.9:9.3) 1.00 IPA (15) 4 86 1.00 IPA (13.5) 1.5 90 1.00 IPA (13.5) 1.5 84 1.00 IPA (18) 2 86 1.00 n-PrOH (18) 2 63 1.00 n-PrOH (9) 1 83 1.00 n-PrOH (13.5) 1.5 78 9.00 n-PrOH (10.8) 1.2 72 4.75 n-PrOH (12.6) 1.4 83 5.00 n-PrOH (10.8) 1.2 91 5.00 n-PrOH (10.8) 1.2 85 5.00 n-PrOH (10.8) 1.2 78 40 n-PrOH (10.8) 1.2 80 375 n-PrOH (10.8) 1.2 90 100 n-PrOH (10.8) 1.2 88 Preparation of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate, WAY-179272-B (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-dimethylamino)-2-butenamide crude free base (0.1 kg, 0.159 mole) and maleic acid (0.019 kg, 0.164 mole) were dissolved at 40-50 C. in a 10% water/n-propanol mixture (1.20 L). The hot solution was clarified and cooled over 2 h to room temperature and held for 12-15 hr. The product was filtered and washed with 10% water/n-propanol (2×0.15 L). The product was dried (50 C., 10 mm Hg, 24 h) to give 94.4 g (88% yield). DSC: 204 C. (single crystal form). 1H NMR: delta (DMSO-d6) 9.73 (s, 1H, NH), 9.62 (s, 1H, NH), 8.93 (s, 1H, Ar), 8.60 (dd, 1H, Ar), 8.50 (s, 1H, Ar), 7.88 (dd, 1H, Ar), 7.58 (d, 1H, Ar), 7.40 (m, 3H, Ar), 7.24 (m, 2H, Ar), 6.75 (d, 2H, -CHCH-), 6.03 (s, 2H, HOOC-CHCH-COOH), 5.29 (s, 2H, OCH2Pyr), 4.33 (q, 2H, OCH2CH3), 3.89 (s, 2H, NCH2), 2.76 (s, 6H, N(CH3)2), 1.47 (t, 3H, OCH2CH3). 13C NMR: delta (DMSO-d6) 168.0, 163.2, 156.9, 154.2, 153.2, 151.9, 151.3, 149.8, 148.5, 137.8, 136.5, 134.7, 133.4, 132.2, 128.0, 126.6, 124.9, 123.8, 122.3, 122.2, 117.9, 116.4, 115.1, 113.9, 109.5, 88.1, 72.0, 65.3, 57.8, 43.1, 14.9.
	In propan-1-ol; water; at 50 - 60℃; for 0.25h;	Example 8 Preparation of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-di-methylamino)-2-butenamide crude free base (17 g, 0.027 mole, 88% strength) and maleic acid (3.60 g, 0.031 mole) were dissolved at 50-60 C. in a 5% water/n-propanol mixture (0.12 L) and stirred for 15 min. To the hot solution was added charcoal (1.7 g) and the mixture stirred for 20 min. The hot solution was clarified and cooled to room temperature and held for 12-15 hr. The product was filtered and washed with 5% water/n-propanol (3*0.017 L). The product was dried (60 C., 10 mm Hg, 24 h) to give the titled compound (9.83 g, 54%, uncorrected for strength). The product (7.0 g) was recrystallized from 7.5% water/propanol to give 5.7 g. DSC: 196 C. (single crystal form). 1H NMR: delta (DMSO-d6) 9.74 (s, 1H, NH), 9.63 (s, 1H, NH), 8.94 (s, 1H, Ar), 8.60 (dd, 1H, Ar), 8.50 (s, 1H, Ar), 7.88 (dd, 1H, Ar), 7.59 (d, 1H, Ar), 7.42-7.35 (m, 3H, Ar), 7.28-7.19 (m, 2H, Ar), 6.76 (d, 2H, -CH=CH-), 6.05 (s, 2H, HOOC-CH=CH-COOH), 5.29 (s, 2H, OCH2Pyr), 4.33 (q, 2H, OCH2CH3), 3.91 (d, 2H, N-(CH2), 2.77 (s, 6H, N(CH3)2), 1.45 (t, 3H, OCH2CH3). 13C NMR: delta (DMSO-d6) 167.3, 162.4, 156.1, 153.4, 152.5, 151.2, 150.5, 149.1, 147.7, 137.0, 135.8, 134.0, 132.6, 131.6, 127.3, 125.9, 124.2, 123.0, 121.5, 121.4, 117.1, 115.6, 114.3, 113.2, 108.7, 87.3, 71.3, 64.6, 57.0, 42.3, 14.2.
	In nitromethane; at 20℃; for 12h;	50.0 mg of compound of Formula (I) was dissolved into 2.0 mL of nitromethane, and 12.1 mg of maleic acid was added into the solution, then it was stirred at room temperature for 12 hours and centrifuged to give a solid. 1HNMR data of the maleate product prepared by the above method are in the following, and the data indicates the molar rate of the compound of Formula (I) and maleic acid is 1:1, so the maleate salt above is a mono-maleate. 1HNMR (400 MHz, DMSO-d6) delta 9.79 (s, 1H), 9.66 (s, 1H), 8.93 (s, 1H), 8.60 (d, J=4.2 Hz, 1H), 8.50 (s, 1H), 7.88 (td, J1=7.7 Hz, J2=1.7 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.45-7.34 (m, 3H), 7.20-7.27 (m, 2H), 6.82-6.69 (m, 2H), 6.05 (s, 2H), 5.29 (s, 2H), 4.33 (q, J=7.1 Hz, 2H), 3.93 (d, J=3.5 Hz, 2H), 2.79 (s, 6H), 1.46 (t, J=7.0 Hz, 3H).

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9
[ 848139-78-6 ]
[ 1055943-40-2 ]
[ 698387-09-6 ]

Yield	Reaction Conditions	Operation in experiment
93%	With triethylamine; In tetrahydrofuran; at 0 - 10℃; for 1h;Inert atmosphere;	Under the protection of nitrogen, compound V 4-(4-((pyridin-2-yl)methoxy)-3-chloroaniline)-7-ethoxy-6-amino-3-cyano quinoline (4.46g, 10mmol) and triethylamine (3.03g, 30mmol) suspended in tetrahydrofuran (10 ml) in, in 0-10 C lower heat insulating, slowly adding (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride (1.85g, 10mmol), stirring for 1 hour. Decompression concentrating reaction liquid, by adding water, dilute hydrochloric acid for adjusting PH to 8-9 rear, separating white solid, stirring for half an hour after-filtration, washing, drying, to obtain title compound 5.18g, yield 93%.
86.72%	In 1-methyl-pyrrolidin-2-one; at -25 - -20℃; for 5h;	(2) To the solution of trans-4-dimethylaminocrotonyl chloride hydrochloride obtained in step (1), 18 g of 6-amino-4-[[3-chloro-4-[(pyridine-2- Group) methoxy] phenyl] amino] -3-cyano-7-ethoxyquinoline (also known as aminoquinoline) in 70 ml of N-methylpyrrolidone solution. After 1 hour of dropwise addition, the reaction temperature is controlled at -25 -20 , holding reaction for 4h, HPLC detection (at this time, the content of aminoquinoline in the reaction solution is 0.08%, its retention time is 27.08min, the content of lenatinib is 98.56%, and its retention time is 30.04 min), stop the reaction, add 10 ml of methanol dropwise, suction filter, and rinse twice with 10 ml of dichloromethane. The obtained lenatinib hydrochloride is ready for use, with a purity of 99.38%, and the retention time of lenatinib is 30.04 min.(3) Add the lenatinib hydrochloride, 200ml acetonitrile and 100ml water obtained in step (2) to a 500ml three-necked flask and stir at room temperature. Add a 5% sodium hydroxide solution dropwise to the constant pressure dropping funnel and adjust the pH to 8-9. After 1 hour of dropwise addition, the reaction temperature is controlled at 35-40 C, the reaction is kept for 1 hour, the reaction is stopped, suction filtered, rinsed twice with 10 ml of water, 19.5 g of lenatinib is dried under vacuum, the yield is 86.72% The purity was 99.31%, and the retention time of lenatinib was 30.04min.
68 - 90%	In tetrahydrofuran; 1-methyl-pyrrolidin-2-one; at 0 - 5℃; for 5h;Product distribution / selectivity;	An acid chloride of formula R'2-(CO)-Cl, a mixed anhydride or an activated carboxylate R'2-(CO)-LG derived from the corresponding carboxylic acid, may be used to couple a side chain at the 6 position to form a 6-amido-4-amino-3 cyanoquinoline. R'2 may be alkyl of 1-6 carbon atoms, which may be mono- or di-substituted with amino groups or cycloamino groups, or R'2 may be alkenyl of 2-6 carbon atoms which may be mono- or di-substituted with amino groups or cycloamino groups. Using the 2-step sequence shown below, an activated carboxylate is prepared in situ and coupled with the aniline. Although the acid chloride can be prepared in acetonitile, a better yield was obtained when the acid chloride was prepared in THF. In both cases, the aniline should be dissolved in NMP before amidation. It is believed that formation of product is better due to better solubility of the aniline in a THF/NMP mixture rather than in an ACN/NMP combination. The amount of 4-N,N-dimethylaminocrotonic acid needed was 2 equivalents with respect to aniline. A slight undercharge of 1.95 eq of oxalyl chloride was added along with a catalytic amount (3 mol %) of DMF. The acid chloride was formed via the Vilsmeier intermediate. The completion test for the acid chloride reaction consists of quenching an aliquot of the reaction into ethanol and detecting by HPLC the crotonic acid ethyl ester. This method serves as a check to ensure complete consumption of oxalyl chloride. Excess oxalyl chloride will form diethyl oxalate when quenched in ethanol. The acid chloride is stable after holding for up to 5 hours at 0-10 C., when decomposition begins. After 20 hours, complete decomposition takes place. If the acid chloride is allowed to warm, decomposition occurs and its effectiveness is diminished. The quality of the starting crotonic acid also plays a role in this coupling reaction, as commercially available crotonic acid may contain acetic acid. Acetic acid is detrimental to this reaction. 6-N-acetyl quinoline can be formed which is difficult to remove from the final product. The acetic acid can be removed by re-slurrying the crotonic acid in 4 volumes of isopropanol at room tempature, filtering and drying preferably to a level of less than 0.01%. It was found that the addition of the aniline solution in NMP to the acid chloride gave a better yield as compared to adding the acid chloride to the aniline. The addition is done keeping the temperature at 0-5 C. The coupling reaction is slow and requires holding overnight at this temperature. It is not desirable to raise the reaction temperature as the stability of the acid chloride diminishes. The reaction is quenched using aqueous sodium hydroxide at 40 C. and then filtered at that temperature. Quenching the reaction at 40 C. gives bigger crystals that are easily filterable. It was observed that filtration at 40 C. was faster than at room temperature. The product is recrystallized from a 1.5:1 mixture of acetonitrile:THF (15 volumes) at 70-75 C. This in-process purification beneficially removes unreacted aniline. The recovery yields are typically greater than 85%. To demonstrate a specific synthesis of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide, a solution of 4-N,N-dimethylaminocrotonic acid hydrochloride (186 g, 1.12 mol) in THF (1.88 L) and a catalytic amount of DMF (2 mL) was cooled to 0-5 C. Oxalyl chloride (97 mL, 1.09 mol, 0.95 eq) was added dropwise over 45 minutes. The mixture was then warmed to 25-30 C. and stirred for 2 hours. The yellow solution was checked for complete consumption of oxalyl chloride by HPLC, then cooled to 0-5 C. When the reaction is deemed complete, a solution of 4-[4-(2-pyridylmethoxy)-3-chloro]amino-6-amino-3-cyano-7-ethoxyquinoline (250 g, 0.56 mol) in N-methyl-2-pyrolidinone (1.88 L) was added dropwise over 2 hours keeping the temperature at 0-5 C. The mixture was stirred for at least 3 hours until less than about 2% of the starting aniline remains by HPLC, which takes about 3 hours. Upon completion, the reaction was quenched with water (3.0 L), held for 30 minutes and then warmed to 40 C. Aqueous sodium hydroxide (170 g in 1.25 L water) was added over 1.25 hours to bring the pH to 10-11. The mixture was stirred for an hour, then cooled to room temperature and held for 3 hours. The resulting precipitates were filtered and washed with water (100 mL) and heptane (100 mL). The wet solids were heated to reflux (70-75 C.) in acetonitrile:THF and the solution cooled over 3 hours to room temperature. The product was filtered and washed with cold acetonitrile:THF. The product was dried (40-50 C., 10 mm Hg, 24 hours) to give 83% uncorrected yield.; Results obtained with different reaction procedures at different degrees of scale-up for synthesis of the 2-pyridylmethoxy analog are shown in Table 5. TABLE 5 Side Chain Coupling Scale Yield (g) Solvent (%) Purity LC (%) Comments 1 ACN 64 84 add acid chloride to an...

64%	In 1-methyl-pyrrolidin-2-one; acetonitrile;Product distribution / selectivity;	An acid chloride of formula R'2-(CO)-Cl, a mixed anhydride or an activated carboxylate R'2-(CO)-LG derived from the corresponding carboxylic acid, may be used to couple a side chain at the 6 position to form a 6-amido-4-amino-3 cyanoquinoline. R'2 may be alkyl of 1-6 carbon atoms, which may be mono- or di-substituted with amino groups or cycloamino groups, or R'2 may be alkenyl of 2-6 carbon atoms which may be mono- or di-substituted with amino groups or cycloamino groups. Using the 2-step sequence shown below, an activated carboxylate is prepared in situ and coupled with the aniline. Although the acid chloride can be prepared in acetonitile, a better yield was obtained when the acid chloride was prepared in THF. In both cases, the aniline should be dissolved in NMP before amidation. It is believed that formation of product is better due to better solubility of the aniline in a THF/NMP mixture rather than in an ACN/NMP combination. The amount of 4-N,N-dimethylaminocrotonic acid needed was 2 equivalents with respect to aniline. A slight undercharge of 1.95 eq of oxalyl chloride was added along with a catalytic amount (3 mol %) of DMF. The acid chloride was formed via the Vilsmeier intermediate. The completion test for the acid chloride reaction consists of quenching an aliquot of the reaction into ethanol and detecting by HPLC the crotonic acid ethyl ester. This method serves as a check to ensure complete consumption of oxalyl chloride. Excess oxalyl chloride will form diethyl oxalate when quenched in ethanol. The acid chloride is stable after holding for up to 5 hours at 0-10 C., when decomposition begins. After 20 hours, complete decomposition takes place. If the acid chloride is allowed to warm, decomposition occurs and its effectiveness is diminished. The quality of the starting crotonic acid also plays a role in this coupling reaction, as commercially available crotonic acid may contain acetic acid. Acetic acid is detrimental to this reaction. 6-N-acetyl quinoline can be formed which is difficult to remove from the final product. The acetic acid can be removed by re-slurrying the crotonic acid in 4 volumes of isopropanol at room tempature, filtering and drying preferably to a level of less than 0.01%. It was found that the addition of the aniline solution in NMP to the acid chloride gave a better yield as compared to adding the acid chloride to the aniline. The addition is done keeping the temperature at 0-5 C. The coupling reaction is slow and requires holding overnight at this temperature. It is not desirable to raise the reaction temperature as the stability of the acid chloride diminishes. The reaction is quenched using aqueous sodium hydroxide at 40 C. and then filtered at that temperature. Quenching the reaction at 40 C. gives bigger crystals that are easily filterable. It was observed that filtration at 40 C. was faster than at room temperature. The product is recrystallized from a 1.5:1 mixture of acetonitrile:THF (15 volumes) at 70-75 C. This in-process purification beneficially removes unreacted aniline. The recovery yields are typically greater than 85%. To demonstrate a specific synthesis of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide, a solution of 4-N,N-dimethylaminocrotonic acid hydrochloride (186 g, 1.12 mol) in THF (1.88 L) and a catalytic amount of DMF (2 mL) was cooled to 0-5 C. Oxalyl chloride (97 mL, 1.09 mol, 0.95 eq) was added dropwise over 45 minutes. The mixture was then warmed to 25-30 C. and stirred for 2 hours. The yellow solution was checked for complete consumption of oxalyl chloride by HPLC, then cooled to 0-5 C. When the reaction is deemed complete, a solution of 4-[4-(2-pyridylmethoxy)-3-chloro]amino-6-amino-3-cyano-7-ethoxyquinoline (250 g, 0.56 mol) in N-methyl-2-pyrolidinone (1.88 L) was added dropwise over 2 hours keeping the temperature at 0-5 C. The mixture was stirred for at least 3 hours until less than about 2% of the starting aniline remains by HPLC, which takes about 3 hours. Upon completion, the reaction was quenched with water (3.0 L), held for 30 minutes and then warmed to 40 C. Aqueous sodium hydroxide (170 g in 1.25 L water) was added over 1.25 hours to bring the pH to 10-11. The mixture was stirred for an hour, then cooled to room temperature and held for 3 hours. The resulting precipitates were filtered and washed with water (100 mL) and heptane (100 mL). The wet solids were heated to reflux (70-75 C.) in acetonitrile:THF and the solution cooled over 3 hours to room temperature. The product was filtered and washed with cold acetonitrile:THF. The product was dried (40-50 C., 10 mm Hg, 24 hours) to give 83% uncorrected yield.; Results obtained with different reaction procedures at different degrees of scale-up for synthesis of the 2-pyridylmethoxy analog are shown in Table 5. TABLE 5 Side Chain Coupling Scale Yield (g) Solvent (%) Purity LC (%) Comments 1 ACN 64 84 add acid chloride to an...
		Example 2: Process 24-Dimethylaminocrotonoyl chloride hydrochloride and its coupling with 6-amino-4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-7-ethoxyquinoline-3-carbonitrile (procedure with phosphorus oxychloride and DMAc). A suspension of 4-dimethylaminocrotonic acid (6.70 kg, 40.4 mol) in DMAc (64.3 kg) was cooled to -14 to -19 0C. Neat POCI3 (6.15 kg, 40.1 mol) was added to the slurry at a rate to maintain the temperature in the reactor in the above range (moderate exotherm). The reaction mixture was held at -15 0C for 2-3 hrs. Conversion of the acid to acid chloride was monitored by HPLC: an aliquot of the reaction mixture was quenched into anhydrous ethanol and the solution was analyzed by HPLC using SIELC Primesep 200 column capable of retaining polar compounds. The conversion was calculated as a ratio of peak areas corresponding to the starting acid and its ethyl ester formed by reaction of the acid chloride with ethanol. After conversion reached the maximum (usually 85 to 95% after 2 to 3 hours), a solution of the aminoquinoline (12.6 kg, 28.3 mol) in DMAc (99.4 kg) was added to the reactor maintaining the temperature in the -14 to -19 0C range. Resulting mixture was held for 5 hr at approximately - 15 0C. At this point HPLC analysis showed residual aniline level at or below 0.5%. The thick suspension of the hydrochloride salt of the coupled product was quenched with water (87.1 kg) maintaining the batch temperature between -7 to -16 0C. The resulting clear solution in was warmed to 37-42 0C and its pH was adjusted to 10-1 1 with a 25% aqueous solution of KOH (approx. 53 kg of the solution was added). The suspension was further diluted with water (95 kg) and the solids were filtered on a polypropylene cloth filter. The cake was washed with water until neutral pH of the washes and dried first in the nitrogen flow on the filter and then on trays in vacuum at 45 to 50 0C to afford crude (E)-Lambda/-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)- 3-cyano-7-ethoxyquinolin6-yl)-4-(dimethylamino)but-2-enamide (15.75 kg, 94%) as a bright- yellow crystalline solid.
104 g	In 1-methyl-pyrrolidin-2-one; at 0 - 20℃;	4-N,N-dimethylaminocrotonic acid hydrochloride (72 g, 0.44 mol), tetrahydrofuran (800 ml) and dimethylformamide (0.8 ml) were added to a 2L three-necked flask and cooled to 0 to 5 C. To the reaction solution was added oxalyl chloride (36 ml, 0.42 mol). and then heated to 25 ~ 30 C stirring 2 ~ 3h. The reaction solution was cooled to 0 to 5 C again, and Compound 3 (100 g, 0.22 mol) of N-methylpyrrolidone (NMP) solution (800 ml) was added dropwise. After the drop, stir at room temperature overnight. The reaction solution was transferred to a 10 L autoclave, cooled to 0 to 5 C, quenched with water (500 ml), and kept at 0-5 C for 30 min. Then heat up to 40 C, A 1 mol / L sodium hydroxide solution (6 L) was added dropwise. After the drop, keep stirring at 40 C for 1 h. The filter cake was washed with purified water (about 6 L) to pH 7. The wet cake was transferred to a 2 L flask, and tetrahydrofuran: acetonitrile (2: 3, 1.2 L) was added, refluxed at 70-75 C for 1 h and filtered while hot. The hot filtrate was allowed to cool to room temperature and stirred overnight. Filtration of the suspension, cold tetrahydrofuran: acetonitrile (2: 3) solution (400ml) washing, 50 ~ 60 C vacuum drying under vacuum for 10 hours, to obtain tenacitron crude product 104g, HPLC purity 98.2%, single complex content see Table 2, Figure 1

Reference： [1]Patent: CN105330646,2016,A .Location in patent: Paragraph 0052; 0053
[2]Patent: CN110357854,2019,A .Location in patent: Page/Page column 10-11
[3]Patent: US2006/270668,2006,A1 .Location in patent: Page/Page column 21
[4]Patent: US2006/270668,2006,A1 .Location in patent: Page/Page column 21
[5]Patent: WO2010/48477,2010,A2 .Location in patent: Page/Page column 9-10
[6]Patent: CN105949176,2016,A .Location in patent: Paragraph 0032; 0034-0035

10
[ 110-16-7 ]
[ 698387-09-6 ]
[ 1144516-12-0 ]

Yield	Reaction Conditions	Operation in experiment
	With water; In propan-1-ol; at 25 - 60℃;Product distribution / selectivity;	Crude (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4- (dimethylamino)-2-butenamide free base (0.100 kg, 0.159 mole) is rinsed with a 10% solution of USP purified water in n-propanol (0.082 kg, 0.10 L) followed by the addition of watenn-propanol solution (0.74 kg, 0.90 L). Maleic acid is added (0.0191 kg, 0.164 mole) and the mixture is rinsed with 10% watenn-propanol (0.082 kg, 0.10 L). The mixture is quickly heated to 50-600C and held for a minimum of 15 min. until a solution is obtained. The hot solution is clarified through a pre-heated 50-600C, 0.2 Mm filter cartridge and the filtrates are collected in a preheated 45-550C, 2 L multi-neck flask. The filter cartridge is rinsed through with 10% watenn- propanol pre-heated to 45-55 0C (0.082 kg, 0.10 L). The solution is cooled over at least one hour to 400C and held at that temperature for 12 hours then cooled to room temperature (250C) over a minimum of four hours and held at that temperature for at least two hours. The mixture id filtered on a 12.5 cm diameter Buchner funnel for 5 min., then rinsed and washed with pre- filtered 10% watenn-propanol solution (2 x 0.12 kg, 2 x 0.15 L). The cake is dammed and suction maintained until dripping essentially stops, about 1 h.

Reference： [1]Patent: WO2009/52264,2009,A2 .Location in patent: Page/Page column 28

11
[ 848139-78-6 ]
(E)-4-(dimethylamino)-2-butenoic acid hydrochloride [ No CAS ]
[ 698387-09-6 ]

Yield	Reaction Conditions	Operation in experiment
52%		Preparation of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide free base. A solution of 4-N,N-dimethylaminocrotonic acid hydrochloride (22.3 g, 0.135 mol, 2.0 eq.) in tetrahydrofuran (0.225 L) and a catalytic amount of dimethylformamide (0.5 mL) was cooled to 0-5 C. Oxalyl chloride (11.4 mL, 0.131 mol, 1.95 eq) was added dropwise over 15 min. The mixture was then warmed to 25-30 C. and stirred for 2 h then cooled to 0-5 C. N-Methyl-2-pyrrolidinone (15 ml) was added. A filtered solution of warm (30 C.) 6-amino-4-[3-chloro-4-(2-pyridylmethoxy)]anilino-3-cyano-7-ethoxy-quinoline (30 g, 0.067 mole, 1.0 eq.) in N-methyl-2-pyrrolidinone (0.27 L) was added dropwise over 30 min keeping the temperature 0-10 C. The mixture was stirred for a minimum of 20 h. Upon completion, the reaction was quenched with water (0.36 L), held for 30 min and then warmed to 40-45 C. Aqueous sodium hydroxide (19 g in 0.15 L water) was added over 30 min to bring the pH to 9-10 followed by adding water (0.39 L). The mixture was stirred for 1 hr, then cooled to room temperature. The resulting precipitates were filtered and washed with water (3×60 mL) until the pH of the washes were 7-8. The wet solids were heated to reflux (70-75 C.) in 1.5:1 acetonitrile:tetrahydrofuran (0.33 L) and the solution cooled over 2 h to room temperature. The product was filtered and washed with cold 1.5:1 acetonitrile:tetrahydrofuran (3×0.01 L). The product was dried (60 C., 10 mm Hg, 24 h) to give the titled compound (19.4 g, 52% uncorrected for strength). 1H NMR: delta (DMSO-d6) 9.59 (s, 1H, NH), 9.47 (s, 1H, NH), 8.96 (s, 1H, Ar), 8.60 (dd, 1H, Ar), 8.47 (s, 1H, Ar), 7.87 (dd, 1H, Ar), 7.58 (d, 1H, Ar), 7.39-7.34 (m, 3H, Ar), 7.27-7.20 (m, 2H, Ar), 6.81-6.73 (m, 1H, CH2-CHCH-), 6.59 (d, 1H, CH2-CHCH-), 5.28 (s, 2H, OCH2Pyr), 4.31 (q, 2H, OCH2CH3), 3.09 (d, 2H, N-(CH2), 2.18 (s, 6H, N(CH3)2), 1.47 (t, 3H, OCH2CH3).

Reference： [1]Patent: US2006/270669,2006,A1 .Location in patent: Page/Page column 19

12
[ 698387-09-6 ]
[ 1376615-55-2 ]

Yield	Reaction Conditions	Operation in experiment
10%		Example 19 - Formula 57 - Compound 19a19a: (E)-4-((4-((3-Chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin- 6-yl)amino)-N,N-dimethyl-4-oxobut-2-en-1 -amine oxide To a solution of compound A (200 mg, 0.36 mmol, 1 .0 eq) in CH2CI2 (20 mL) was added m- CPBA (74 mg, 0.43 mmol, 1 .2 eq) and the resulting mixture was stirred at room temperature for 4 h. A saturated aqueous solution of NaHC03 (20 mL) was then added and the organic layer was separated, dried over Na2S04 and concentrated under reduced pressure. The residue was purified by preparative TLC (CH2CI2/MeOI-l, 10/1 , v/v) to give (E)-4-((4-((3-chloro- 4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)amino)-N,N-dimethyl-4- oxobut-2-en-1 -amine oxide (20 mg, 10%) as a yellow solid.LC-MS (Agilent): Rt 3.03 min; m/z calculated for C3oH29CIN604 [M+H]+ 573.19, found 573.2.1H NMR: (400 MHz, CD3OD) delta (ppm): 8.98 (s, 1 H), 8.57 (m, 1 H), 8.39 (s, 1 H), 7.92 (td, J = 7.2, 1 .6 Hz, 1 H), 7.72 (d, J = 8.0 Hz, 1 H), 7.39 (m, 1 H), 7.36 (d, J = 2.4 Hz, 1 H), 7.28 (s, 1 H), 7.24- 7.13 (m, 3H), 6.74 (d, J = 15.6 Hz, 1 H), 5.29 (s, 2H), 4.32 (q, J = 6.8 Hz, 2H), 4.20 (d, J = 7.2 Hz, 2H), 3.28 (s, 6H), 1.57 (t, J = 6.8 Hz, 3H).
10%	With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 4h;	To a solution of compound A (200 mg, 0.36 mmol, 1.0 eq) in CH2Cl2 (20 mL) was added m-CPBA (74 mg, 0.43 mmol, 1.2 eq) and the resulting mixture was stirred at room temperature for 4 h. A saturated aqueous solution of NaHCO3 (20 mL) was then added and the organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2/MeOH, 10/1, v/v) to give (E)-4-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)amino)-N,N-dimethyl-4-oxobut-2-en-1-amine oxide (20 mg, 10%) as a yellow solid. LC-MS (Agilent): Rt 3.03 min; m/z calculated for C30H29ClN6O4 [M+H]+ 573.19. found 573.2. 1H NMR: (400 MHz, CD3OD) delta (ppm): 8.98 (s, 1H), 8.57 (m, 1H), 8.39 (s, 1H), 7.92 (td, J=7.2, 1.6 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.39 (m, 1H), 7.36 (d, J=2.4 Hz, 1H), 7.28 (s, 1H), 7.24-7.13 (m, 3H), 6.74 (d, J=15.6 Hz, 1H), 5.29 (s, 2H), 4.32 (q, J=6.8 Hz, 2H), 4.20 (d, J=7.2 Hz, 2H), 3.28 (s, 6H), 1.57 (t, J=6.8 Hz, 3H).

Reference： [1]Patent: WO2012/63085,2012,A2 .Location in patent: Page/Page column 101-102
[2]Patent: US2013/225594,2013,A1 .Location in patent: Paragraph 0358; 0359

13
N-(4-[3-chloro-4-(pyridin-2-ylmethoxy)phenylamino]-3-cyano-7-ethoxyquinoline-6-yl)acetamide [ No CAS ]
[ 698387-09-6 ]