Synthesis method and application of intermediate of sulindac analogue

A synthesis method and analog technology, which are applied in the field of synthesis and application of intermediates of sulindac analogs, can solve problems such as damage to the environment, corrode equipment and air pollution, and achieve reduced equipment corrosion, reduced air pollution, and high yield. Effect

Inactive Publication Date: 2011-04-27
XIAMEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method uses thionyl chloride and aluminum trichloride to complete the Friedel-Crafts reaction, which produces volatile acid gases during the reaction, which inevitably corrodes equipment and causes air pollution and damages the environment.

Method used

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  • Synthesis method and application of intermediate of sulindac analogue
  • Synthesis method and application of intermediate of sulindac analogue
  • Synthesis method and application of intermediate of sulindac analogue

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1: Preparation of 4-fluoro-2-methylcinnamic acid (2)

[0038] In a 500 mL three-necked flask equipped with a condenser, add 52.0 mL (480 mmol) of 4-fluorobenzaldehyde (1), 72.8 g (528 mmol) of anhydrous potassium carbonate powder and 124.0 mL of propionic anhydride. After stirring evenly, slowly heat to 160°C and keep for 12h. After cooling, add 50mL of water, and then add about 10g of sodium carbonate to make the solution alkaline. After slight heating, filter, and carefully acidify the filtrate to pH=2-3 with concentrated hydrochloric acid under the condition of ice-water bath. After the crystals were completely precipitated, suction filtration was performed, and the light yellow crude product was purified to obtain 82.1 g of 4-fluoro-2-methylcinnamic acid (2).

Embodiment 2

[0039] Example 2: Preparation of 3-(4-fluorophenyl)-2-methylpropionic acid (3)

[0040] Dissolve 15.0 g of 4-fluoro-2-methylcinnamic acid (2) in methanol, heat slightly until fully dissolved and add it to a 100 mL autoclave, add 1.2 g of palladium carbon with 10% palladium content, then seal and ventilate hydrogen in 0.8Mpa, stirred at room temperature for 10h. After the reaction, the catalyst was filtered off (recovered and used more than twice), the filter cake was washed with a small amount of methanol, and the filtrate was combined to remove the solvent under reduced pressure to obtain 3-(4-fluorophenyl)-2-methylpropane Acid (3) 14.7g, two-step reaction yield 93%.

Embodiment 3

[0041] Example 3: Preparation of 3-(4-fluorophenyl)-2-methylpropionic acid (3)

[0042] The preparation process of 4-fluoro-2-methylcinnamic acid (2) is the same as in Example 1, except that the base is replaced by sodium propionate, and the reaction time is 16 hours. Then the catalytic hydrogenation reaction is the same as in Example 2 to obtain 3-(4-fluorophenyl)-2-methylpropionic acid (3), and the two-step reaction yield is 87.0%.

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Abstract

The invention discloses a synthesis method and application of intermediates of a sulindac analogue, relating to intermediates of a sulindac analogue. The intermediates are 5-fluoro-2-metyl-3-indene ethyl acetate (5a) and 5-fluoro-2-metyl-3-indene acetic acid (5b). The synthesis method comprises the following steps of: subjecting 4-fluorobenzaldehyde as an initial raw material, propionic anhydride as a solvent and propionic anhydride to a perkin reaction to obtain 4-fluoro-2-metyl-methylcinnamic acid; catalyzing the 4-fluoro-2-metyl-methylcinnamic acid with palladium carbon with the palladium content of 5-20 percent and reducing in the hydrogen gas atmosphere to obtain 3-(4-fluorine phenyl)-2-methyl propionate; subjecting the 3-(4-fluorine phenyl)-2-methyl propionate to the intramolecilar friedel-crafts acyl browning reaction under the action of polyphosphoric acid under the heating condition to form 6-fluoro-2-methyl indene ketone; and subjecting the 6-fluoro-2-methyl indene ketone and halogenated acetate to reformatsky reaction under the action of the activated zinc powder to obtain a crude product and eliminating the crude product in an acid solution to obtain 5-fluoro-2-metyl-3-indene acetate. The intermediates can be used for preparing novel sulindac analogues with anticancer activity.

Description

technical field [0001] The present invention relates to an intermediate of sulindac analogues, in particular to a kind of sulindac intermediate 5-fluoro-2-methyl-3-indene ethyl acetate (5a) and 5-fluoro-2-methyl The synthetic method of base-3-indene acetic acid (5b), and its use in the synthesis of sulindac analogue 5-fluoro-2-methyl-1-(4-methylbenzylidene)-3 with anticancer activity -indene acetic acid (named K-80001), 5-fluoro-2-methyl-1-(4-ethylbenzylidene)-3-indene acetic acid (named K-80002) and 5-fluoro-2 - Application in methyl-1-(4-isopropylbenzylidene)-3-indene acetic acid (named K-80003). [0002] Background technique [0003] The synthesis of sulindac (Sulindac) intermediates 5-fluoro-2-methyl-3-indene ethyl acetate (5a) and 5-fluoro-2-methyl-3-indene acetic acid (5b), domestic and foreign reports Most of them use 4-fluorobenzaldehyde as raw material (world patents WO9747295, WO9747303, WO9603987, U.S. patents US5902827, US5776962, European patent EP508586). ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/65C07C67/343C07C57/62C07C51/353C07C51/09
Inventor 黄培强陈贵阳危珍罗世鹏
Owner XIAMEN UNIV
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