Neratinib

ChEBI: A quinoline compound having a cyano group at the 3-position, a 3-chloro-4-(2-pyridylmethoxy)anilino group at the 4-position, a 4-dimethylamino-trans-but-2-enamido group at the 6-position, and an ethoxy group at the 7-position.

Neratinib is a quinoline compound having a cyano group at the 3-position, a 3-chloro-4-(2-pyridylmethoxy)anilino group at the 4-position, a 4-dimethylamino-trans-but-2-enoylamido group at the 6-position, and an ethoxy group at the 7-position. It has a role as a tyrosine kinase inhibitor and an antineoplastic agent. It is a member of quinolines and a nitrile.|Neratinib was approved in July 2017 for use as an extended adjuvant therapy in Human Epidermal Growth Factor Receptor 2 (HER2) positive breast cancer. Approval was granted to Puma Biotechnology Inc. for the tradename Nerlynx. Neratinib is currently under investigation for use in many other forms of cancer.|Neratinib is a Kinase Inhibitor. The mechanism of action of neratinib is as a Kinase Inhibitor, and P-Glycoprotein Inhibitor.|Neratinib is an orally available tyrosine kinase receptor inhibitor that is used in the extended adjuvant therapy of early stage breast cancer. Neratinib is associated with a low rate of transient elevations in serum aminotransferase levels during therapy, but has not been convincingly linked to cases of clinically apparent liver injury with jaundice.|Neratinib is an orally available, 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile irreversible inhibitor of the HER-2 receptor tyrosine kinase with potential antineoplastic activity. Neratinib binds to the HER-2 receptor irreversibly, thereby reducing autophosphorylation in cells, apparently by targeting a cysteine residue in the ATP-binding pocket of the receptor. Treatment of cells with this agent results in inhibition of downstream signal transduction events and cell cycle regulatory pathways; arrest at the G1-S (Gap 1/DNA synthesis)-phase transition of the cell division cycle; and ultimately decreased cellular proliferation. Neratinib also inhibits the epidermal growth factor receptor (EGFR) kinase and the proliferation of EGFR-dependent cells.

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).3-Methyl-1-butanol (isopentanol) ( 40 ml) was added to (E)-N-{ 4-[3-chloro-4-(pyridin-2-yl methoxy)anilino ]-3-cyano-7-ethoxyquinolin-6-yl }-4-( dimethylamino )but-2-enamide (I gm) at25-30C and stirred for 5 minutes at the same temperature. Heated the reaction mixture to 40-450C and added maleic acid (500 mg) and stirred for I 0 min at same temperature. Cooled thereaction mixture to 0-5C and stirred for 40 min at same temperature. Filtered the precipitatedsolid and then dried to get title compound. (Yield: 81 0 mg).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.(E)-4-(dimethylamino)but-2-enoic acid hydrochloride (8.92 g; 53.82 mmoL) was charged to glass reactor (250 mL) inertized with nitrogen. Dichloromethane (85 mL) and dimethylformamide (DMF; 318 tL; 4.12 mmoL) were added. Suspension was cooled to 0- 5 C and oxalyl chloride (4.0 mL; 45.76 mL) was added dropwise during 5 - 10 mm. Dropping funnel was washed with dichloromethane (5 mL). Reaction mixture was stirred for 8- 9 h in nitrogen atmosphere and monitored by HPLC. After finish of reaction, solution of 6- amino-4-((3 -chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3 -carbonitrile (12.0 g; 26.91 mmoL) in N-methyl-2-pyrrolidone (NMP, 120 mL) was added dropwise during 15 - 30 mm while maintaining the temperature below 10 C. Reaction mixture was heated to 20 - 25 C and stirred for 2 - 16 h (reaction was monitored by HPLC until NRT-3 was below0.2 Area %). After completion of reaction, water (120 mL) was added and layers separated.Into water layer NMP (48 mL) and THF (96 mL) were added and pH was adjusted to 10.0 -10.5 by addition of 2 M NaOH while maintaining the temperature at 20 -25 C. Mixture wasstirred at 20 - 25 C for 2 h, cooled to 0 - 5 C duringi h, stirred for 2 h and filtered. Crystalswere washed with THF/water mixture (1:2; 2 x 15 mL) and dried under vacuum at 50 C for16 h at 10 mbar to obtain 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). 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. (1) In a three-necked flask, tetrahydrofuran (2.5 L)A solution of 6 - [(E) -4- (dimethylamino) -2-butenamido] -7-ethoxy-4-chloro-3-quinolinecarbonitrile (I) (358.82 g, 1.00eq)With 2-chloro-4-aminophenol (II) (143.57 g, 1 mol, 1 eq), Nitrogen replacement three times, The reaction system was heated to 65 C, Dimethylpyridine hydrochloride (III) dissolved in 1 L of tetrahydrofuran was added dropwise, (237.70 g, 1.46 mol, 1.05 eq), A total of 4 hours, After the dropwise addition, the incubation reaction was carried out for 2 hours, 4-Chloro-4-chloro-3-quinolinecarbonitrile (I) ' [(E) -4- (dimethylamino) -2-butenamido]0.3%;2) The reaction system was cooled to room temperature, Potassium carbonate (553.48 g, 4 mol, 4 eq)And potassium iodide (16.69 g, 0.1 mol, 0.1 eq), The reaction system was heated to 60 C, Insulation reaction 16 hours, HPLC monitoring of intermediate states(E) -N- {4- [3-chloro-4-hydroxyanilino] 3-cyano-7-ethoxy-6-quinoline} -4-dimethylamino-2-butenamide ) ' 0.3%.(3) The reaction system was cooled to room temperature, Stirring slowly adding water 5L, There is light yellow solid precipitation, Stirring for 2 hours, Water 1L wash cake, The filter cake was dried at 50 C for 16 hours under reduced pressure, The resulting solid was added to a 10 L three-necked flask, Adding 3 L of acetonitrile and 1.5 L of tetrahydrofuran, Slowly cooled to room temperature, With yellow solid precipitation, filtration, The filter cake was dried at 50 C, (Lenapine) (438.56 g, 0.79 mol, yield 82.73%).The dimethylaminoacetaldehyde-bisulfite adduct was prepared by the method disclosed in W02007085638, and 8.3 g (0.04 mol) of dimethylaminoacetaldehyde-sodium bisulfite adduct was dissolved in 50 mL of water (spare solution B) Standby. To 150mL of absolute ethanol were added successively N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolinyl]-2-diethylphosphate-acetamide 12.5g (0.02mol), lithium chloride, 0.85g (0.02mol), cooled to 0C, sodium ethoxide was added 5.1g (0.06mol), stirred for 0.5h, drops plus alternate solution B, the reaction was continued to 3h. Poured into 500mL water, 3 × 300mL aqueous layer was extracted with ethyl acetate, the organic layers combined, washed with water and saturated brine, dried over anhydrous sodium sulfate.Concentrated under reduced pressure to dryness, acetonitrile / THF and recrystallized to give a pale yellow solid 10.5g, a yield of 94.1%.To 150mL Anhydrous ethanol in turn added to a solution of N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolinyl]-2-diethylphosphate-acetamide in (12.5 g, 0.02 mol)Lithium chloride 4.2 g (0.1 mol)Down to -5 C, Adding sodium ethoxide 4. 1g (0.06 mil)Stirring 0.5h, Dropping 0.06 mol of dimethylaminoacetaldehyde diethyl acetal prepared by liquid A, Drip continued to respond 40min.500 mL of ethyl acetate was added, Filtered and the filtrate was added to 500 mL of water.The organic layer was separated and washed with 2 X 200 mL of ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over anhydrous sodium sulfate. Concentrated to dryness under reduced pressure and recrystallized from acetonitrile / THF to give 10.7 g of a pale yellow powder, Yield 95.9%.

An oral, irreversible dual EGFR/HER2 inhibitor for breast and non-small cell lung cancer. Antitumor agent

Molecular Weight:557.0
XLogP3:4.9
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:8
Rotatable Bond Count:11
Exact Mass:556.1989665
Monoisotopic Mass:556.1989665
Topological Polar Surface Area:112
Heavy Atom Count:40
Complexity:881
Defined Bond Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes