Inhibitors of the fibroblast growth factor receptor
A technology of nucleophiles and compounds, applied in the field of fibroblast growth factor receptor inhibitors, can solve problems such as no evidence
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example 1
[0143] Example 1: Synthesis of N-(2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methyl-7- Oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylphenyl)propene Amide Compound 43
[0144]
[0145]
[0146] Step 1: Synthesis of ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate
[0147]
[0148] Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (5.0 g, 21.5 mmol) and 29% methylamine (5.75 g, 53.72 mmol) in tetrahydrofuran (THF) (100 mL) were stirred at room temperature. , methanol (MeOH) solution) mixture for 2 h. Then, the reaction mixture was concentrated, followed by the addition of sodium bicarbonate (NaHCO 3) (20 mL in water), and the resulting solution was extracted with ethyl acetate (EtOAc) (3 x 50 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated to afford ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate (4.68 g) as a light yellow solid , 96%). MS(ES+)C ...
Embodiment 2
[0176] Embodiment 2: Synthesis of N-(2-((6-(2,6-dichloro-3,5-dimethoxyphenyl) quinazoline -2-yl)amino)-3-methoxyphenyl)acrylamide compound 30
[0177]
[0178] Step 1: Synthesis of (2-amino-5-bromophenyl)methanol
[0179]
[0180] To a solution of 2-amino-5-bromobenzoic acid (10.0 g, 46.3 mmol) in THF (150 mL) was added BH3-THF (1M, 231 mL) at room temperature, and the reaction mixture was stirred overnight. An aliquot of the reaction mixture was analyzed by LCMS and indicated that the reaction had proceeded to completion. The reaction was quenched with water (150 mL), extracted with EtOAc (3 x 500 mL). The organic layers were separated, combined, washed with water (200 mL) and brine (200 mL), dried over sodium sulfate, filtered and concentrated to give the title compound (10 g, crude material), which was used directly in the next step without further purification . MS(ES+)C 7 h 8 Required value of BrNO: 201, experimental value: 202,204[M+H] + .
[0181] Step ...
example 3
[0205] Example 3: Synthesis of Compound 25
[0206]
[0207] Synthesis of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-(2-methyl-6-nitrophenyl)quinazolin-2-amine
[0208]
[0209] 2-Chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazoline (35) (5g, 13.5mmol), 2-methyl-6-nitroaniline ( 3.09g, 20.3mmol), Cs 2 CO 3 (13.2g, 40.6mmol), Pd 2 (dba) 3 (1.24g, 1.35mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) (1.29g, 2.71mmol) were dissolved in DMA (100ml) and washed with N 2 Purify for 5 minutes. The reaction mixture was heated to 110 °C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with DCM (500ml), washed 3 times with 10% HCl (3 x 300ml), and washed 3 times with brine. The organic mixture was dried over sodium sulfate and loaded directly onto silica gel and purified using a 0-100% EtOAc / hexanes gradient. 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-N-(2-methyl-6-nitrophenyl)quinazolin-2-amine was recovered as a yellow sol...
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