Preparation method of flurbiprofen

Abstract

The invention discloses a preparation method of flurbiprofen. The method comprises the following steps: adding 2-(3-fluoro-4-bromophenyl)propionic acid and phenylboronic acid into a water-system solvent under alkaline conditions, and carrying out a palladium-carbon catalyzed coupling reaction to obtain flurbiprofen. The method has the advantages that operation is simpler, the prepared flurbiprofenis higher in purity, industrialized production is facilitated.

Description

technical field

[0001] The invention belongs to the field of preparation of pharmaceutical compounds, and relates to a synthesis method of a non-steroidal anti-inflammatory analgesic, in particular to a preparation method of flurbiprofen. Background technique

[0002] Flurbiprofen, also known as phenylflubuprofen, has a chemical name of 2-(2-fluorobiphenyl-4-phenyl)propionic acid, and its structure is as follows:

[0003]

[0004] Flurbiprofen is a non-steroidal anti-inflammatory pain reliever. It was developed by the British Boots Company in 1976 and has been included in the 1988 edition of the British Pharmacopoeia. Flurbiprofen Babu Ointment, currently sold in more than 70 countries, is clinically applicable to rheumatoid arthritis, osteoarthritis and flexural spondylitis, etc. Compared with similar drugs, it has a small dosage and good curative effect High, fast onset, small side effects and other advantages. So far, domestic raw materials mainly rely on imports. ...

Examples

Embodiment 1

[0045] The synthesis of embodiment 1 compound flurbiprofen

[0046] Preparation of ethyl 2-(3-fluoro-4-nitrophenyl)methylmalonate (FBS-1)

[0047] Take 80ml of N,N-dimethylformamide and add it to a 250ml three-necked flask, add 2.77g of sodium hydroxide, stir to make it insoluble, add 11.39g of diethyl methylmalonate and stir to react, then add 10.00g of 2, 4-Difluoronitrobenzene, stirred and reacted for 5h, poured the system into 240ml water to quench, added ethyl acetate for extraction (3*100ml), and spin-dried the organic phase to obtain 2-(3-fluoro-4nitrophenyl) Ethyl methylmalonate 19.69g, yield 99.75%.

[0048] Preparation of 3-fluoro-4-nitro-α-methylphenylacetic acid (FBS-5)

[0049] Take 19.69g of ethyl 2-(3-fluoro-4nitrophenyl)methylmalonate, add it to a 500ml three-necked flask, add 50ml of glacial acetic acid and stir to dissolve, add 13ml of concentrated sulfuric acid, 36ml of water, heat Reflux for 24 hours, add dichloromethane for extraction (3*60ml), concentr...

Embodiment 2

[0058] Example 2 Repeated use of secondary Pd / C to synthesize compound flurbiprofen

[0059] Add 15g of FBS-7 to a 1000ml three-necked flask, then add 600ml of purified water, 8.90g of phenylboronic acid, 13.50g of sodium carbonate, 1.50g of Pd / C, stir and raise the temperature to reflux, and keep the reflux state for 6h. After the reaction is over, stop heating and stirring the system to cool down, until T≤40°C, filter the system, recover palladium carbon, under the condition of ice-water bath, stir and cool the filtrate to 5-10°C, adjust the pH to 2-3 with concentrated hydrochloric acid, precipitate a white solid, filter , The filter cake was dried in a blast oven to obtain 14.30 g of white powder, with a yield of 96.42%. Add the white powder to a 250ml three-necked bottle, add 57ml of absolute ethanol, stir to dissolve, add 0.14g of activated carbon, stir to decolorize, filter, transfer the filtrate to a 250ml three-necked bottle, add 57ml of purified water to the filtrate ...

Embodiment 3

[0061] Example 3 Repeated use of Pd / C three times to synthesize the compound flurbiprofen

[0062] Add 10g of FBS-7 to a 1000ml three-necked flask, then add 400ml of purified water, 5.92g of phenylboronic acid, 9.01g of sodium carbonate, 0.10g of Pd / C, stir and raise the temperature to reflux, and keep the reflux state for 6h. After the reaction is over, stop heating and stirring the system to cool down, until T≤40°C, filter the system, recover palladium carbon, under the condition of ice-water bath, stir and cool the filtrate to 5-10°C, adjust the pH to 2-3 with concentrated hydrochloric acid, precipitate a white solid, filter , The filter cake was dried in a forced air drying oven to obtain 9.33 g of white powder, with a yield of 94.36%. Add the white powder into a 250ml three-necked bottle, add 37ml of absolute ethanol, stir to dissolve, add 0.10g of activated carbon, stir to decolorize, filter, transfer the filtrate to a 250ml three-necked bottle, add 37ml of purified wate...

technical field

[0001] The invention belongs to the field of preparation of pharmaceutical compounds, and relates to a synthesis method of a non-steroidal anti-inflammatory analgesic, in particular to a preparation method of flurbiprofen. Background technique

[0002] Flurbiprofen, also known as phenylflubuprofen, has a chemical name of 2-(2-fluorobiphenyl-4-phenyl)propionic acid, and its structure is as follows:

[0003]

[0004] Flurbiprofen is a non-steroidal anti-inflammatory pain reliever. It was developed by the British Boots Company in 1976 and has been included in the 1988 edition of the British Pharmacopoeia. Flurbiprofen Babu Ointment, currently sold in more than 70 countries, is clinically applicable to rheumatoid arthritis, osteoarthritis and flexural spondylitis, etc. Compared with similar drugs, it has a small dosage and good curative effect High, fast onset, small side effects and other advantages. So far, domestic raw materials mainly rely on imports. ...

Examples

Embodiment 1

[0045] The synthesis of embodiment 1 compound flurbiprofen

[0046] Preparation of ethyl 2-(3-fluoro-4-nitrophenyl)methylmalonate (FBS-1)

[0047] Take 80ml of N,N-dimethylformamide and add it to a 250ml three-necked flask, add 2.77g of sodium hydroxide, stir to make it insoluble, add 11.39g of diethyl methylmalonate and stir to react, then add 10.00g of 2, 4-Difluoronitrobenzene, stirred and reacted for 5h, poured the system into 240ml water to quench, added ethyl acetate for extraction (3*100ml), and spin-dried the organic phase to obtain 2-(3-fluoro-4nitrophenyl) Ethyl methylmalonate 19.69g, yield 99.75%.

[0048] Preparation of 3-fluoro-4-nitro-α-methylphenylacetic acid (FBS-5)

[0049] Take 19.69g of ethyl 2-(3-fluoro-4nitrophenyl)methylmalonate, add it to a 500ml three-necked flask, add 50ml of glacial acetic acid and stir to dissolve, add 13ml of concentrated sulfuric acid, 36ml of water, heat Reflux for 24 hours, add dichloromethane for extraction (3*60ml), concentr...

Embodiment 2

[0058] Example 2 Repeated use of secondary Pd / C to synthesize compound flurbiprofen

[0059] Add 15g of FBS-7 to a 1000ml three-necked flask, then add 600ml of purified water, 8.90g of phenylboronic acid, 13.50g of sodium carbonate, 1.50g of Pd / C, stir and raise the temperature to reflux, and keep the reflux state for 6h. After the reaction is over, stop heating and stirring the system to cool down, until T≤40°C, filter the system, recover palladium carbon, under the condition of ice-water bath, stir and cool the filtrate to 5-10°C, adjust the pH to 2-3 with concentrated hydrochloric acid, precipitate a white solid, filter , The filter cake was dried in a blast oven to obtain 14.30 g of white powder, with a yield of 96.42%. Add the white powder to a 250ml three-necked bottle, add 57ml of absolute ethanol, stir to dissolve, add 0.14g of activated carbon, stir to decolorize, filter, transfer the filtrate to a 250ml three-necked bottle, add 57ml of purified water to the filtrate ...

Embodiment 3

[0061] Example 3 Repeated use of Pd / C three times to synthesize the compound flurbiprofen

[0062] Add 10g of FBS-7 to a 1000ml three-necked flask, then add 400ml of purified water, 5.92g of phenylboronic acid, 9.01g of sodium carbonate, 0.10g of Pd / C, stir and raise the temperature to reflux, and keep the reflux state for 6h. After the reaction is over, stop heating and stirring the system to cool down, until T≤40°C, filter the system, recover palladium carbon, under the condition of ice-water bath, stir and cool the filtrate to 5-10°C, adjust the pH to 2-3 with concentrated hydrochloric acid, precipitate a white solid, filter , The filter cake was dried in a forced air drying oven to obtain 9.33 g of white powder, with a yield of 94.36%. Add the white powder into a 250ml three-necked bottle, add 37ml of absolute ethanol, stir to dissolve, add 0.10g of activated carbon, stir to decolorize, filter, transfer the filtrate to a 250ml three-necked bottle, add 37ml of purified wate...

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