Golvatinib is an orally bioavailable dual kinase inhibitor of c-Met (hepatocyte growth factor receptor) and VEGFR-2 (vascular endothelial growth factor receptor-2) tyrosinekinases with potential antineoplastic activity. c-Met/VEGFR kinase inhibitor E7050 binds to and inhibits the activities of both c-Met and VEGFR-2, which may inhibit tumor cell growth and survival of tumor cells that overexpress these receptor tyrosine kinases. c-Met and VEGFR-2 are upregulated in a variety of tumor cell types and play important roles in tumor cell growth, migration and angiogenesis.

Golvatinib has been investigated for the treatment of Platinum-Resistant Squamous Cell Carcinoma of the Head and Neck.

PATENT

WO 2007023768

WO 2008023698

WO 2008102870

PATENT

WO 2012133416

Method for producing a phenoxy pyridine derivative (3)

The present invention, hepatocyte growth factor receptor (Hepatocyte growth factor receptor; hereinafter, abbreviated as “HGFR”) inhibitory action, antitumor action, anti-tumor agents with such angiogenesis inhibitory activity and cancer metastasis inhibitory action, a cancer metastasis suppressing the method for producing a useful phenoxy pyridine derivatives as agents.

Patent Document 1 has a HGFR inhibitory activity, anti-tumor agents, useful phenoxy pyridine derivative as an angiogenesis inhibitor or cancer metastasis inhibitor has been disclosed.

(In the formula, ^{R 1,} .R ² and ^{R 3} means such as 3-10 membered non-aromatic heterocyclic ^{group, .R 4, R 5, R} 6 and ^{R 7} which represents a hydrogen atom, same or different, a hydrogen atom, a halogen atom, .R ⁸ to mean a C _1-6 alkyl group, .R ⁹ to mean a hydrogen atom or the like is and 3-10 membered non-aromatic heterocyclic group meaning .n is .X to mean 1 to 2 integer, it refers to a group or a nitrogen atom represented by the formula -CH =.)

As a method for producing the phenoxy pyridine derivative, to the Example 48 of Patent Document 1, N, N-dimethylformamide, triethylamine and benzotriazol-1-yloxytris (dimethylamino) or lower in the presence of a phosphonium hexafluorophosphate discloses that perform the reaction.

Patent Document 2, as a manufacturing method suitable for industrial mass synthesis of the phenoxy pyridine derivative in the presence a condensing agent, production method of reacting an aniline derivative with a carboxylic acid derivative.

(In the formula, ^{R 1,} is ^{.R 2, R 3,} R ⁴ and ^{R 5,} which means such good azetidin-1-yl group which may have a substituent, the same or different and each represents a hydrogen atom or fluorine It refers to an atom .R ⁶ means a hydrogen atom or a fluorine atom.)

Patent Document 3, another manufacturing method of the phenoxy pyridine derivative, there is disclosed the manufacturing method shown in the following scheme.

(In the formula, ^{R 1} means a 4- (4-methylpiperazin-1-yl) piperidin-1-yl group or a 3-hydroxy-1-yl group ^{.R 2, R 3,} R ⁴ and R ⁵ are the same or different, represents a hydrogen atom or a fluorine atom. ^However, among R ^2, R 3, ^{R 4} and ^{R 5,} 2 or 3 is a hydrogen atom .R ⁶ is a hydrogen atom or .R ⁷ to mean a fluorine atom, .Ar which means a protecting group for the amino group means a phenyl group.)

International Publication No. WO 2007/023768 International Publication No. WO 2008/026577 International Publication No. WO 2009/104520

PATENT

WO 2009104520

Example A-5: Preparation of N- (2-fluoro-4 – {[2 – ({[4- (4-methylpiperazin- 1 –yl) piperidin- 1 – yl] carbonyl} amino) pyridin- oxy} phenyl) -N ‘- (4-fluorophenyl) cyclopropane-1,1 dicarboxamide
[Formula
17] 4- (4-methylpiperazin-1-yl) piperidine-1-carboxylic acid [4- ( To a solution of N, N-dimethylformamide (1 ml) of 4-amino-3-fluorophenoxy) pyridin-2-yl] amide (100 mg) and 1- (4-fluorophenylcarbamoyl) cyclopropanecarboxylic acid (78 mg) Triethylamine (71 mg) and O- (7-Azabenzotriazol-1-yl) -N, N, N ‘, N’- tetramethyluronium hexafluorophosphate (HATU) (222 mg) were added and stirred at room temperature for 21 hours. A 1 N sodium hydroxide aqueous solution (2 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 ml). After separation, the organic layer was washed with 5% brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a residue. The residue was dissolved in ethyl acetate (3 ml) and extracted with 2 N hydrochloric acid (3 ml × 1, 2 ml × 1). The aqueous layer was rendered alkaline with 5 N aqueous sodium hydroxide solution (5.5 ml). After extraction with ethyl acetate and drying over anhydrous magnesium sulfate, the solvent was distilled off to give the title compound (87 mg).
¹ H-NMR Spectrum (DMSO-d ₆) .Delta. (Ppm): 1.22-1.33 (2H, m), 1.54-1.63 (4H, m), 1.68-1.78 (2H, m), 2.12 (3H , S), 2.12-2.40 (5H, m), 2.40-2.60 (4H, m), 2.68-2.78 (2H, m), 4.06-4.14 (2H, t, J = 8 Hz), 7.22 (2H, m), 6.60 (1H, dd, J = 2.4 Hz, 5.6 Hz), 7.00 (1 H, dd, J = 2.4 Hz, 11.2 Hz), 7.40 (1 H, s), 7.61 (2 H, dd, J = 5.2 Hz, 8 Hz), 7.93 J = 8.8 Hz), 8.13 (1 H, d, J = 5.6 Hz), 9.21 (1 H, s), 9.90 (1 H, brs), 10.55 (1 H, brs).

PAPER

Journal of Medicinal Chemistry (2017), 60(7), 2973-2982