Nintedanib esylate

Nintedanib esylate (BIBF 1120 esylate) is a potent triple angiokinase inhibitor for VEGFR1/2/3, FGFR1/2/3 and PDGFRα/β with IC50s of 34 nM/13 nM/13 nM, 69 nM/37 nM/108 nM and 59 nM/65 nM, respectively.

Nintedanib esylate is an organosulfonate salt obtained by combining nintedanib with one molar equivalent of ethanesulfonic acid. A kinase inhibitor used for the treatment of idiopathic pulmonary fibrosis and cancer. It has a role as an angiogenesis inhibitor, an antineoplastic agent, a fibroblast growth factor receptor antagonist, a tyrosine kinase inhibitor and a vascular endothelial growth factor receptor antagonist. It contains a nintedanib(1+).|Nintedanib Esylate is the esylate salt form of nintedanib, an orally bioavailable, indolinone-derived inhibitor of multiple receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs), with potential antiangiogenic, antifibrotic and antineoplastic activities. Upon administration, nintedanib selectively binds to and inhibits vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), and colony stimulating factor 1 receptor (CSF1R) tyrosine kinases, which may result in the induction of endothelial cell apoptosis, the reduction in tumor vasculature, the inhibition of tumor cell proliferation and migration, and antifibrotic activity in pulmonary fibrosis. In addition, nintedanib also binds to and inhibits members of the Src family of tyrosine kinases, including Src, Lck and Lyn, and fms-like tyrosine kinase 3 (FLT-3). VEGFR, FGFR, PDGFR and CSF1R RTKs play key roles in tumor angiogenesis, tumor cell proliferation and metastasis, as well as pulmonary fibrosis.

Three 25ml flask were added successively 2.0g Trinidad Technip, 7.5g ethanesulfonic acid, 10ml methanol was heated to reflux, stirred at reflux for 4h, heating was stopped, the solvent was evaporated to dryness, the resulting solid was slurried add 15ml of acetone, suction filtered to give a pale yellow solid 2.4g, yield: 100percent.Purity by HPLC: 99.75percentExample 8: Synthesis of the 3-Z-[1 -(4-(N-((4-methyl-piperazin-1 -yl)- methylcarbonyl)-N-methyl-amino)-anilino)-1 -phenyl-methylene]-6- To a Suspension of (Z)-methyl-3-(((4-(N-methyl-2-(4-methylpiperazin-1-yl) acetami- de)-phenyl) amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate 6 (36 g, 0.066 mol) in methanol (237 mL) and water (2.88 mL) ethanesulfonic acid (7.92 g 0.0719 mol) in water (2.88 mL) was added at 60-65°C. The resulting suspension was cooled to 50C, and was diluted with isopropanol (237 mL). The reaction mixture was cooled to 0C and stirred for 1h. The precipitate obtained was filtered and washed with mixture of methanol and isopropanol (50percent) (50 ml), product was dried to obtain crude Nintedanib monoethane sulfonate (36.6 g) which was crystallized from methanol (5 Vol) to obtain pure Nintedanib monoethane sulfonate salt as yellow crystals (33 g) (HPLC purity >99percent). DSC: 298C; IR (KBr, cm500 grams of the crystalline compound of Example 5 is suspended in 10 liters of ethanol, heated to 50 ° C and 180 grams of 70percent aqueous ethanesulfonic acid are added. The resulting solution was cooled to 40 ° C, An additional 4.5 liters of t-butyl ether was added. Crystallize after a few minutes. To achieve complete precipitation, the mixture was stirred for a further 16 hours at room temperature. After cooling to 10 ° C, suction filtration, washing with 2 t-butyl ether and drying under vacuum at 40 ° C, Ethanesulfonate compounds are obtained.Yield: 538 g (89.7percent yield).605 [G] (1.12 mol) of [3-Z- [1- (4- (N- ( (4-METHYL-PIPERAZIN-1-YL)-METHYLCARBONYL)-N-METHYL-] [AMINO)-ANILINO)-1-PHENYL-METHYLENE]-6-METHOXYCARBONYL-2-INDOLINONE] are suspended in 9 litres of methanol and heated to [50°C.] 183.7 [G] (1.121 mol) of 70percent aqueous [ETHANESULPHONIC] acid are added. The solution obtained is cooled to [40°C] and 4. 5 litres of [TERT.-BUTYLMETHYLETHER] are added. After a few minutes crystallisation sets in. To achieve total precipitation the mixture is stirred for another 16 hours at ambient temperature. After cooling to [10°C] it is suction filtered, washed with 2 litres of tert.- butylmethylether and dried [AT 40°C IN VACUO.] Yield : 638 g (87.6percent of theory) Tm. [P.] = 305 [5°C] (DSC 1 OK/min) Purity according to HPLC: 99.4percent Water content: 1.0 to 2.0percent (KF)Suspension of (Z)-methyl-3-(((4-(N-methyl-2-(4-methylpiperazin-l-yl)acetamide)phenyl) amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate (36 gm, 0.066 mol) in methanol (237 ml) and water (2.88 ml)was heated to 60-65°C and aq. ethane sulfonic acid was added to the reaction mixture. The resulting solution was cooled to 50°C, seeds diluted with isopropanol (237 ml) was added. The reaction mixture was cooled at 0°C for lhr. Filtered the precipitate, washed with mixture of methanol and isopropanol (50 ml), dried to obtain crude Nintedanib monoethane sulfonate (36.6 gm) and crystallized from methanol (5 Vol) to obtained pure Nintedanib monoethane sulfonate salt as yellow crystals (33 gm) (80percent) (HPLC purity >99percent). DSC: 298°C; IR (KBr, cm-1): 3321, 3273, 1710, 1652, 1615, 1515, 1435, 1378, 1289, 1209, 1161, 1087; 1H-NMR (400 MHz, DMSO): δ 1.08 (t, 3H, J = 7.31 Hz), 2.41-2.47 (q, 2H), 2.50-3.16 (broad m, 13H), 3.37 (s, 3H), 3.76 (s, 3H), 5.82 (d, 1H, J = 7.88Hz), 6.87 (d, 2H, J = 7.36 Hz), 7.14-7.20 (m, 3H), 7.49 (s, 1H), 7.49 (d, 2H, J = 6.68 Hz), 7.56-7.63 (m, 3H), 9.45 (s, 1H), 10.99 (s, 1H), 12.25 (s, 1H), 13C-NMR (100 MHz, DMSO): δ 37.15, 42.79, 45.65, 49.40, 52.26, 53.10, 58.04, 98.25, 110.01, 117.78, 121.97, 124.32, 124.59, 128.27, 128.90, 129.36, 130.00, 131.00, 132.52, 136.79, 137.93, 140.00, 158.66, 166.85, 168.47 and 170.65; MS: m/z 540[M]

Molecular Weight:649.8
Hydrogen Bond Donor Count:3
Hydrogen Bond Acceptor Count:10
Rotatable Bond Count:9
Exact Mass:649.25701977
Monoisotopic Mass:649.25701977
Topological Polar Surface Area:164
Heavy Atom Count:46
Complexity:997
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes