Preparation methods of tyrosine kinase inhibitor and intermediates thereof
A technology of solvents and mixed solvents, applied in the direction of organic chemistry, etc., can solve the problems of unfavorable industrial production, cumbersome preparation, and high cost
- Summary
- Abstract
- Description
- Claims
- Application Information
AI Technical Summary
Problems solved by technology
Method used
Image
Examples
Embodiment 1
[0124] Example 1 Preparation of 1-(ethoxycarbonyl)cyclopropanecarboxylic acid
[0125]
[0126] Add 200ml of methanol and 30g of diethyl 1,1-cyclopropanedicarboxylate into a 500ml three-necked flask, cool to 10°C, add sodium hydroxide solution (6.4g of NaOH, 32ml of water) dropwise under stirring, and react at room temperature for 3 hours , the reaction was completed, and the solvent was evaporated under reduced pressure to obtain a white solid. 200 ml of water and 150 ml of ethyl acetate were added to the solid, the layers were stirred and separated, and the organic phase was discarded. The aqueous layer was adjusted to pH 3-4 with 2mol / L hydrochloric acid, extracted with ethyl acetate (200ml×2), dried with anhydrous sodium sulfate, filtered, and evaporated to remove the solvent under reduced pressure to obtain 20.0g of a colorless translucent oil (78.5%).
Embodiment 2
[0127] Example 2 Preparation of ethyl 1-[(3-fluoro-4-hydroxyphenyl)carbamoyl]cyclopropanecarboxylate
[0128]
[0129] Add 20 g of 1-(ethoxycarbonyl)cyclopropanecarboxylic acid and 200 ml of tetrahydrofuran prepared in Example 1 into a 500 ml three-necked flask, cool to 0-10°C, add 18.0 ml of thionyl chloride dropwise, and stir at 0-10°C After 2h, after the reaction, the solvent was distilled off under reduced pressure to obtain a colorless translucent oil. 100 ml of tetrahydrofuran was added to the oil for later use.
[0130] Add 300ml of tetrahydrofuran, 28.8g of 4-amino-2-fluorophenol and 26.5ml of triethylamine into a 1L three-necked flask, add the reaction solution dropwise at 0-10°C, and react at room temperature for 2 hours. After filtration, the filtrate was evaporated to remove the solvent under reduced pressure. Add ethyl acetate (300ml) and 2mol / L hydrochloric acid (200ml) to the residue, stir and separate layers, wash the organic phase with 2mol / L hydrochloric...
Embodiment 3
[0134] Example 3 1-[3-fluoro-4-[[6-methoxy-7-[[3-(morpholin-4-yl)propyl]oxy]quinolin-4-yl]oxy] Preparation of ethyl phenyl]cyclopropane-1,1-dicarboxamide formate
[0135]
[0136] Add 4-chloro-6-methoxy-7-[[3-(morpholin-4-yl) propyl] oxygen group] oxy] quinoline 13.5g in the three-necked bottle of 250ml, DMAP 9.8g and embodiment 2 10.7 g of the prepared ethyl 1-[(3-fluoro-4-hydroxyphenyl)carbamoyl]cyclopropanecarboxylate and 50 ml of 2,6-lutidine were stirred and heated to 140°C. After reacting for 3 hours, add 300ml of dichloromethane to the reaction solution cooled to room temperature, dissolve and wash with 1mol / L hydrochloric acid (200ml×2), 2mol / L KOH (200ml×3), and dry the organic phase with anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and column chromatography (mobile phase V / V: dichloromethane / methanol=10 / 1) gave 8.4 g (37.0%) of a yellow solid.
[0137] m.p.91.9~92.1℃;
[0138] MS: 568.4 ([M+H] + );
[0139] 1...
PUM
Login to View More Abstract
Description
Claims
Application Information
Login to View More