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Green synthesis method of sulindac

A technology of green synthesis and sulindac, which is applied in the field of green synthesis of sulindac, can solve problems such as difficult operation, increased production of three wastes, and non-compliance with the concept of synthetic production, so as to simplify the process operation, improve the utilization rate of raw materials and process Environmental Effects

Pending Publication Date: 2020-06-05
ANHUI HERYI CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Therefore, two Knoevenagel reactions occurred continuously in this synthetic route, and the two Knoevenagel reactions were isolated, and the cyano group was hydrolyzed and decarboxylated first, which made the production process cumbersome, complicated and difficult to operate, and also increased the production of three wastes , does not conform to today's green and simple synthetic production concept

Method used

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Embodiment 1

[0027] Synthesis of 5-fluoro-2-methyl-1-(4-methylthiobenzylidene)-3-indeneacetic acid (Intermediate 5):

[0028] Under nitrogen protection, drop into 164g 6-fluoro-2-methylindanone (1mol), 1640g 5% methanol solution of sodium methylate, 103g cyanoacetic acid (1.2mol) and 60g ammonium acetate (0.78mol) in reaction flask, stir Lower the temperature and reflux for 26 hours; after the central control raw material 6-fluoro-2-methylindanone basically disappeared, put in 160g p-methylthiobenzaldehyde (1.05mol) and continue to reflux for 5 hours; Sodium hydroxide aqueous solution was hydrolyzed under reflux for 30 hours; after cooling, the pH was adjusted to <3 with hydrochloric acid, a yellow solid was obtained by suction filtration and water washing, and 299 g of the product was obtained by drying. The yield was 88%, and the HPLC purity was 98.2%.

[0029] Synthesis of sulindac (compound 1):

[0030] Put 299g of intermediate 5 and 850mL of acetic acid obtained in the previous step ...

Embodiment 2

[0032] The difference between embodiment 2 and embodiment 1 is that chromium boride is added as a catalyst during the oxidation reaction of intermediate 5, and the rest are completely the same as embodiment 1.

[0033] Synthesis of sulindac (compound 1):

[0034] Put 299g of intermediate 5 and 850mL of acetic acid obtained in the previous step into the reaction bottle, stir and cool down to 20°C, then start to add 110mL of 30% hydrogen peroxide solution and 8g of chromium boride dropwise, continue the reaction for 2 hours, and recover the acetic acid and chromium boride 500mL of water was added to the residue, the solid was filtered out with suction, and refined with ethyl acetate to obtain 291g of product with a yield of 93% and a purity of 99.7% by HPLC.

Embodiment 3

[0036] The difference between embodiment 3 and embodiment 1 is that chromium boride is added as a catalyst during the oxidation reaction of intermediate 5, and the rest are completely the same as embodiment 1.

[0037] Synthesis of sulindac (compound 1):

[0038] 299g of intermediate 5 and 850mL of acetic acid obtained in the previous step were dropped into the reaction flask, and after stirring and cooling to 20°C, 110mL of 30% hydrogen peroxide solution and diatomaceous earth-loaded nano-cobalt tetroxide (8g, calculated as cobalt tetroxide) were added dropwise, and continued After 2 hours of reaction, acetic acid and chromium boride were recovered; 500 mL of water was added to the residue, the solid was filtered out with suction, and refined with ethyl acetate to obtain 305 g of the product with a yield of 97% and a purity of 99.6% by HPLC.

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Abstract

The invention discloses a green synthesis method of sulindac and relates to the technical field of organic synthesis. The method comprises the following steps that: 6-fluoro-2-methyl indanone as a rawmaterial and cyanoacetic acid undergo a Knoevenagel reaction to obtain an intermediate 3, the intermediate 3 and p-methylthiobenzaldehyde undergo a Knoevenagel reaction to obtain an intermediate 4, the intermediate 4 undergoes a hydrolysis decarboxylation reaction to obtain an intermediate 5, and the intermediate 5 undergoes an oxidation reaction to obtain sulindac 1. Compared with an existing synthesis process, the process operation is greatly simplified, the raw material utilization rate and the process environmental protection property are improved, the total yield of sulindac reaches 80%or above, and the purity of sulindac reaches 99% or above.

Description

Technical field: [0001] The invention relates to the technical field of organic synthesis, in particular to a green synthesis method of sulindac. Background technique: [0002] Sulindac is an excellent NSAID for the treatment of colonic polyps, its chemical name is 5-fluoro-2-methyl-1-[(4-methylsulfinylphenyl)methylene] -1H-indene-3-acetic acid. The existing synthetic method is to use 6-fluoro-2-methylindanone as the starting raw material, condense and hydrolyze with cyanoacetic acid to obtain 5-fluoro-2-methyl-3-indene acetic acid, and then react with p-methylthiobenzaldehyde Condensate in the presence of sodium methoxide to obtain 5-fluoro-2-methyl-1-(4-methylthiobenzylidene)-3-indene acetic acid, and finally oxidize with sodium periodate as an oxidant to obtain the target product sulindac acid. [0003] [0004] The carbonyl group in the starting material 6-fluoro-2-methylindanone first undergoes a methylation reaction with the active methylene group in cyanoacetic ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C253/30C07C255/41C07C319/20C07C323/62C07C315/02C07C317/44
CPCC07C253/30C07C319/20C07C315/02C07C2602/08C07C255/41C07C323/62C07C317/44
Inventor 董来山
Owner ANHUI HERYI CHEM
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