Home Cart 0 Sign in  

[ CAS No. 915942-22-2 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
Chemical Structure| 915942-22-2
Chemical Structure| 915942-22-2
Structure of 915942-22-2 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 915942-22-2 ]

Related Doc. of [ 915942-22-2 ]

Alternatived Products of [ 915942-22-2 ]

Product Details of [ 915942-22-2 ]

CAS No. :915942-22-2 MDL No. :MFCD30607264
Formula : C34H33ClN6O7 Boiling Point : -
Linear Structure Formula :- InChI Key :VXZCUHNJXSIJIM-MEBGWEOYSA-N
M.W : 673.11 Pubchem ID :67307512
Synonyms :
HKI-272 maleate

Calculated chemistry of [ 915942-22-2 ]

Physicochemical Properties

Num. heavy atoms : 48
Num. arom. heavy atoms : 22
Fraction Csp3 : 0.18
Num. rotatable bonds : 14
Num. H-bond acceptors : 11.0
Num. H-bond donors : 4.0
Molar Refractivity : 181.46
TPSA : 187.0 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : No
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -8.88 cm/s

Lipophilicity

Log Po/w (iLOGP) : 4.18
Log Po/w (XLOGP3) : 2.15
Log Po/w (WLOGP) : 5.3
Log Po/w (MLOGP) : 0.77
Log Po/w (SILICOS-IT) : 5.14
Consensus Log Po/w : 3.51

Druglikeness

Lipinski : 2.0
Ghose : None
Veber : 2.0
Egan : 1.0
Muegge : 3.0
Bioavailability Score : 0.11

Water Solubility

Log S (ESOL) : -4.78
Solubility : 0.0111 mg/ml ; 0.0000165 mol/l
Class : Moderately soluble
Log S (Ali) : -5.71
Solubility : 0.00131 mg/ml ; 0.00000195 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -10.15
Solubility : 0.0000000473 mg/ml ; 0.0000000001 mol/l
Class : Insoluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 4.59

Safety of [ 915942-22-2 ]

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

Application In Synthesis of [ 915942-22-2 ]

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

  • Downstream synthetic route of [ 915942-22-2 ]

[ 915942-22-2 ] Synthesis Path-Downstream   1~4

  • 1
  • [ 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 ]
YieldReaction ConditionsOperation 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).

  • 2
  • neratinib maleate [ No CAS ]
  • [ 698387-09-6 ]
YieldReaction ConditionsOperation in experiment
88.7% With sodium hydroxide; In methanol; 1 g of the maleate salt of the compound of the formula (I) was weighed and suspended in 10 mL of methanol, and 2.5 ml of 5% NaOH was added dropwise.Concentrate to about 5 times, add 10 mL of isopropanol, concentrate to about 8 times, filter by suction, and filter cake under vacuum at 25 C to obtain 710 mg of solid, the yield is 88.7%, and the water content is 3.95%.The solid obtained is the crystalline form II of the compound of formula (I).
With triethylamine; In ethanol; acetonitrile; at 73℃; Neratinib maleate monohydrate (20.0 g) was suspended in 1000 mL of 96% ethanol.Suspension was heated up to 73 C and into the obtained solution 110 mL of 10% v/v solutionof triethylamine in acetonitrile (ACN) was added dropwise. Afterwards, 1000 mL of water was added to the solution dropwise. Solution was cooled to RT and stirred for additional 4hours. Obtained suspension was filtered and wet product was dried at 60C and 50 mbar for 4hours. Neratinib base Form B3 was confirmed by PXRD as presented in figure 3.
  • 3
  • [ 110-16-7 ]
  • [ 698387-09-6 ]
  • neratinib maleate [ No CAS ]
YieldReaction ConditionsOperation in experiment
11.6 g In methanol; dichloromethane; at 20℃; To the reaction flask, 70 mL of a mixed solvent of ranatinib 10.0 g, 2.5 g of maleic acid, and a mixed solvent of methylene chloride and methanol (volume ratio 2:1) was added, and the mixture was stirred and dissolved at room temperature.Filter to remove insoluble impurities.240 mL of isopropanol was added dropwise to the filtrate and dripped over 4 hours.Continue stirring for 2 hours.After suction filtration, the cake was dried under vacuum at 40C to a constant weight to give 11.6 g of rod-shaped crystals (Figure 3). The average particle size was 30-50 mum.Residual solvent test results: 0.03% dichloromethane, methanol was not detected, 0.28% isopropanol, in line with pharmacopoeia requirements.
  • 4
  • [ 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 tri-maleate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In dichloromethane; at 20℃; for 12h; 101.2 mg of compound of Formula (I) was dissolved into 4.0 mL of dichloromethane, and 73.3 mg of maleic acid was added to 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 process are in the following, and the data indicates that the molar ratio of the compound of the Formula (I) and maleic acid is 1:3, so the maleate above is a tri-maleate. 1HNMR (400 MHz, DMSO-d6) delta 9.81 (s, 1H), 9.76 (s, 1H), 8.95 (s, 1H), 8.60 (d, J=4.1 Hz, 1H), 8.54 (s, 1H), 7.88 (td, J1=7.7 Hz, J2=1.7 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.37-7.42 (m, 3H), 7.21-7.26 (m, 2H), 6.82-6.70 (m, 2H), 6.20 (s, 6H), 5.29 (s, 2H), 4.33 (q, J=6.9 Hz, 2H), 3.96 (d, J=5.4 Hz, 2H), 2.81 (s, 6H), 1.47 (t, J=6.9 Hz, 3H).
Same Skeleton Products
Historical Records