Method for synthetizing diflunisal and derivative thereof through one-step method
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A technology for diflunisal and derivatives is applied in the field of iron-catalyzed synthesis of one-step synthesis of diflunisal and derivatives thereof, which can solve problems such as insufficient preparation methods of diflunisal, and achieve low cost and low toxicity. Effect
Active Publication Date: 2019-10-25
BEIJING NORMAL UNIVERSITY
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Problems solved by technology
[0011] In summary, there are obvious deficiencies in the existing preparation methods of diflunisal
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Embodiment 1
[0037] The preparation of embodiment 1, diflunisal
[0038]
[0039] In an argon atmosphere, add Ti(OEt) into a 25mL three-neck flask 4 (456mg, 2mmol) and 2mL THF, add 17mL 2,4-difluorophenylmagnesium bromide tetrahydrofuran solution dropwise at room temperature (from 2,4-difluorobromobenzene according to the literature method [Osborne, C.A.; Endean, T.B.D.; Jarvo .E.R.Org.Lett., 2015,17,5340.]; 1M in THF, 17mmol), stirring was continued for 30min after dropping, and the resulting mixture was set aside.
[0040] Take another three-necked flask, add 5-iodosalicylic acid (1.32g, 5mmol) and 5mL THF under argon atmosphere, stir for a while, then add FeCl 3 (81.2mg, 0.5mmol), TMEDA (232mg, 2.0mmol) and 8mL toluene (THF / toluene 3:1), after stirring for about 10 minutes, slowly add the titanium reagent prepared above, and stir and reflux for 6-8 Hours, the reaction ended (TLC tracking), and dilute hydrochloric acid was added to the system until the reaction was clear. Extracted...
Embodiment 2
[0042] The preparation of embodiment 2, diflunisal
[0043]
[0044] 5-bromosalicylic acid (1.09g, 5mmol) was used to replace 5-iodosalicylic acid, and the rest of the operation was the same as above to obtain 1.04g of the product, yield: 83%.
Embodiment 3
[0045] Embodiment 3, the preparation of diflunisal
[0046]
[0047] 5-chlorosalicylic acid (863mg, 5mmol) was used instead of 5-iodosalicylic acid, and the remaining operation Example 1 was used to obtain 788mg of the product, yield: 63%.
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Abstract
The invention discloses a method for synthetizing diflunisal and a derivative thereof through a one-step method. The method comprises the steps: under joint catalysis of an iron salt, a ligand and titanate, 2,4-difluorophenylmagnesium halide and 5-halogenated salicylic acid or a 5-halogenated salicylic acid derivative are mixed, heated and coupled in a solvent, and the diflunisal and the derivative thereof are obtained. The method has the advantages that (1) high-priced palladium or high-toxicity nickel does not need to be adopted as catalytic metal, only low-toxicity, high-yield and inexpensive iron salts and titanate need to be used, thus the cost is low, and environmental friendliness is achieved; (2) a zinc salt does not need to be used, or step preparation of a boron reagent is not needed, a Grignard reagent is directly used, the preparation steps are few, and raw material and energy consumption is low; and (3) operation is easy and convenient, conditions are mild, amplification is easy, and the method is suitable for industrial production.
Description
technical field [0001] The invention relates to the field of preparation and catalytic synthesis of medicines and derivatives, in particular to an iron-catalyzed synthesis method for one-step synthesis of diflunisal and its derivatives. Background technique [0002] Diflunisal (diflunisal), also known as fluorophenyl salicylic acid, chemically named 5-(2,4-difluorophenyl) salicylic acid (see the structure shown in the following structural formula), is an important non-steroidal Anti-inflammatory and analgesic clinical drug, used for the treatment of rheumatoid arthritis, rheumatoid arthritis, osteoarthritis and analgesia [Sun Deben, Chinese Journal of New Drugs, 2000, 9: 494]. The drug was developed and marketed by Merck in the United States, and has been marketed in more than 70 countries around the world, and has been recorded in many countries and Chinese pharmacopoeias. It is worth noting that with the continuous in-depth research on diflunisal, many diflunisal derivati...
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