A kind of anti-inflammatory, analgesic medicine and preparation thereof

Abstract

The present invention belongs to the technical field of medicine. The present invention relates to a synthesis process of 2-[(2,6-dichlorophenyl)amino]phenylacetic acid 1-(acetoxyl)ethyl ester and the preparation of a fat emulsion injection thereof. Diclofenac sodium is reacted with 1-bromoethylacetic ester to obtain 2-[(2,6-dichlorophenyl)amino]phenylacetic acid 1-(acetoxyl)ethyl ester (referred to as diclofenac ester for short), in the presence of a basic catalyst, the chemical structure of which is as follows. The compound of the present invention is a non-steroidal anti-inflammatory drug, which is prepared into a fat emulsion injection which can be used for intravenous injection. Compared with diclofenac sodium intravenous injectable preparations sold abroad, the diclofenac sodium fat emulsion injection is not only highly safe when used, but also has better anti-inflammatory and analgesic effects in vivo.

Description

technical field

[0001] The invention belongs to the technical field of medicine, and the invention relates to a kind of 2-[(2,6-dichlorophenyl)amino]phenylacetic acid 1-(acetoxy)ethyl ester and its synthesis method, and its fat emulsion injection preparation. Background technique

[0002] Diclofenac sodium (Diclofenac sodium, DS), the chemical name is 2-[(2,6-dichlorophenyl) amino] sodium phenylacetate, which belongs to the phenylacetic acid non-steroidal anti-inflammatory drugs. Its mechanism of action is to block the conversion of arachidonic acid into prostaglandins (PGs) by inhibiting the activity of cyclooxygenase, thereby producing analgesic and anti-inflammatory effects. At the same time, compared with other non-selective non-steroidal anti-inflammatory drugs, due to DS to inhibit 50% cyclooxygenase-2 activity required blood concentration (IC 50 ) is lower, and shows similar inhibitory activity to cyclooxygenase-1 in vitro, so its efficacy is better and side effects...

Examples

Embodiment 1

[0054] Embodiment 1: Preparation example of compound of the present invention

[0055] Add 1mol of 2-[(2,6-dichlorophenyl)amino]phenylacetic acid sodium into the reaction vessel, add 1L of N,N-dimethylacetamide to dissolve, add 1.1mol of sodium carbonate as a catalyst, and After stirring at low temperature for 2 hours, 1.2 mol of 1-bromoethyl acetate was added dropwise, and the temperature was raised to 40° C. after 10 minutes of reaction at room temperature, and cooled to room temperature after 4 hours of reaction; a mixed solvent of 3L ethyl acetate and water (acetic acid Ethyl ester: water 1:1), separate the organic phase, wash with 3L of water, wash with 3L aqueous sodium thiosulfate (pH=10), and finally wash with 3L saturated brine; the organic phase is obtained by rotary evaporation of the organic solvent The crude product was vacuum-dried for 10 hours to remove the residual organic solvent to obtain 272.46 g of viscous oily substance, which was the target product diclof...

Embodiment 2

[0059] Embodiment 2: Preparation example of compound of the present invention

[0060]Add 1mol of sodium 2-[(2,6-dichlorophenyl)amino]phenylacetate to the reaction vessel, add 0.5L of N,N-dimethylformamide and 0.3L of acetone to dissolve, add 1.2mol of carbonic acid Potassium was used as a catalyst. After stirring at room temperature for 4 hours, 1.5 mol of 1-bromoethyl acetate was added dropwise. After 30 minutes of reaction at room temperature, the temperature was raised to 80 ° C. After 8 hours of reaction, it was cooled to room temperature; 5L of ethyl acetate and Mixed solvent of water (ethyl acetate: water 1.5:1), separate the organic phase, wash with 5L of water, wash with 5L of sodium thiosulfate aqueous solution (pH=11), and finally wash with 5L of saturated brine; the organic phase is rotated After evaporating the organic solvent, a viscous oily crude product was obtained. After the crude product was vacuum-dried for 24 hours to remove the organic solvent residue, 26...

Embodiment 3

[0061] Embodiment 3: Preparation example of compound of the present invention

[0062] Add 1mol of sodium 2-[(2,6-dichlorophenyl)amino]phenylacetate to the reaction vessel, add 0.5L of N,N-dimethylacetamide and 0.3L of acetone to dissolve, add 1mol of sodium carbonate As a catalyst, after stirring at room temperature for 1 hour, add 1.1 mol of 1-bromoethyl acetate dropwise, react at room temperature for 20 minutes, then heat up to 50°C, and cool to room temperature after reacting for 5 hours; add 4L of ethyl acetate and water mixed solvent (ethyl acetate:water 1.2:1), separate the organic phase, wash with 4L of water, wash with 4L aqueous sodium thiosulfate (pH=10.2), and finally wash with 4L saturated brine; the organic phase is rotary evaporated After the organic solvent was removed, a viscous oily crude product was obtained. After the crude product was vacuum-dried for 8 hours to remove the residual organic solvent, 268.02 g of a viscous oily substance was obtained. 1 HNMR...

technical field

[0001] The invention belongs to the technical field of medicine, and the invention relates to a kind of 2-[(2,6-dichlorophenyl)amino]phenylacetic acid 1-(acetoxy)ethyl ester and its synthesis method, and its fat emulsion injection preparation. Background technique

[0002] Diclofenac sodium (Diclofenac sodium, DS), the chemical name is 2-[(2,6-dichlorophenyl) amino] sodium phenylacetate, which belongs to the phenylacetic acid non-steroidal anti-inflammatory drugs. Its mechanism of action is to block the conversion of arachidonic acid into prostaglandins (PGs) by inhibiting the activity of cyclooxygenase, thereby producing analgesic and anti-inflammatory effects. At the same time, compared with other non-selective non-steroidal anti-inflammatory drugs, due to DS to inhibit 50% cyclooxygenase-2 activity required blood concentration (IC 50 ) is lower, and shows similar inhibitory activity to cyclooxygenase-1 in vitro, so its efficacy is better and side effects...

Examples

Embodiment 1

[0054] Embodiment 1: Preparation example of compound of the present invention

[0055] Add 1mol of 2-[(2,6-dichlorophenyl)amino]phenylacetic acid sodium into the reaction vessel, add 1L of N,N-dimethylacetamide to dissolve, add 1.1mol of sodium carbonate as a catalyst, and After stirring at low temperature for 2 hours, 1.2 mol of 1-bromoethyl acetate was added dropwise, and the temperature was raised to 40° C. after 10 minutes of reaction at room temperature, and cooled to room temperature after 4 hours of reaction; a mixed solvent of 3L ethyl acetate and water (acetic acid Ethyl ester: water 1:1), separate the organic phase, wash with 3L of water, wash with 3L aqueous sodium thiosulfate (pH=10), and finally wash with 3L saturated brine; the organic phase is obtained by rotary evaporation of the organic solvent The crude product was vacuum-dried for 10 hours to remove the residual organic solvent to obtain 272.46 g of viscous oily substance, which was the target product diclof...

Embodiment 2

[0059] Embodiment 2: Preparation example of compound of the present invention

[0060]Add 1mol of sodium 2-[(2,6-dichlorophenyl)amino]phenylacetate to the reaction vessel, add 0.5L of N,N-dimethylformamide and 0.3L of acetone to dissolve, add 1.2mol of carbonic acid Potassium was used as a catalyst. After stirring at room temperature for 4 hours, 1.5 mol of 1-bromoethyl acetate was added dropwise. After 30 minutes of reaction at room temperature, the temperature was raised to 80 ° C. After 8 hours of reaction, it was cooled to room temperature; 5L of ethyl acetate and Mixed solvent of water (ethyl acetate: water 1.5:1), separate the organic phase, wash with 5L of water, wash with 5L of sodium thiosulfate aqueous solution (pH=11), and finally wash with 5L of saturated brine; the organic phase is rotated After evaporating the organic solvent, a viscous oily crude product was obtained. After the crude product was vacuum-dried for 24 hours to remove the organic solvent residue, 26...

Embodiment 3

[0061] Embodiment 3: Preparation example of compound of the present invention

[0062] Add 1mol of sodium 2-[(2,6-dichlorophenyl)amino]phenylacetate to the reaction vessel, add 0.5L of N,N-dimethylacetamide and 0.3L of acetone to dissolve, add 1mol of sodium carbonate As a catalyst, after stirring at room temperature for 1 hour, add 1.1 mol of 1-bromoethyl acetate dropwise, react at room temperature for 20 minutes, then heat up to 50°C, and cool to room temperature after reacting for 5 hours; add 4L of ethyl acetate and water mixed solvent (ethyl acetate:water 1.2:1), separate the organic phase, wash with 4L of water, wash with 4L aqueous sodium thiosulfate (pH=10.2), and finally wash with 4L saturated brine; the organic phase is rotary evaporated After the organic solvent was removed, a viscous oily crude product was obtained. After the crude product was vacuum-dried for 8 hours to remove the residual organic solvent, 268.02 g of a viscous oily substance was obtained. 1 HNMR...

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