Fenofibric acid preparation method

Abstract

The invention discloses a fenofibric acid preparation method. The fenofibric acid preparation method comprises the following steps: (1) stirring and mixing 4-chloro-4'-hydroxybenzophenone and strong alkali in butanone, wherein the stirring is performed under a heating condition for at least 20 minutes; (2) adding a protic solvent into the mixture obtained in the step (1), performing stirring, keeping the temperature, dropwisely adding a butanone solution of 2-bromoisobutyric acid, and then performing a reaction for 2-6 hours; (3) performing posttreatment, and performing separation to obtain a fenofibric acid crude product; and (4) performing refinement to obtain a fenofibric acid refined product. The method is convenient to operate, and does not produce redundant waste as compared with the existing reported process; meanwhile, the method greatly shortens the reaction time and changes the reaction system and the viscosity condition thereof; and the purity of the fenofibric acid prepared by the method disclosed by the invention is higher as compared with a product prepared by the existing reported method, and the purity can be up to 99.5% or above.

Description

technical field

[0001] The invention belongs to the field of medicine preparation, in particular, the invention relates to a preparation method of fenofibric acid. Background technique

[0002] Fenofibrate is one of the phenoxylate lipid-lowering drugs currently used clinically. Compared with fenofibrate, fenofibric acid is an active substance metabolized in the body, and it has a very high concentration in the small intestine. Solubility, thus increasing bioavailability, and its bioavailability is not affected by food.

[0003] There are few reports on the preparation process of fenofibric acid in the published materials, basically all of which use 4-hydroxy-4'-chlorobenzophenone as the starting material to condense or replace to produce fenofibric acid. Qiao Deyang, Li Gan (Synthetic Chemistry, 2009) described a kind of 50% potassium hydroxide solution as solvent in TEBA catalyzed synthesis of fenofibric acid, 4-hydroxyl-4'-chlorobenzophenone, chloroform, acetone Fenofib...

Examples

Embodiment 1a

[0046] Embodiment 1a (synthesis of fenofibric acid)

[0047]Weigh 1kg of 4-chloro-4'-hydroxybenzophenone, add it to a 50L dry reaction kettle, add 12kg methyl ethyl ketone and 0.77kg sodium hydroxide, heat up to 45-60℃ under stirring, stir for 30 minutes, add 0.2 kg of purified water, stirred for 1 hour, kept at 45-60°C, and added dropwise 2-bromoisobutyric acid butanone solution (1kg 2-bromoisobutyric acid dissolved in 3kg butanone) to the kettle, and the reaction was completed 3 to 5 hours.

Embodiment 1b

[0048] Embodiment 1b (synthesis of fenofibric acid)

[0049] Weigh 1kg of 4-chloro-4'-hydroxybenzophenone, add it to a 50L dry reaction kettle, add 12kg methyl ethyl ketone and 0.77kg sodium hydroxide, heat up to 45-60℃ under stirring, stir for 30 minutes, add 0.2 kg of methanol, stirred for 1 hour, kept at 45-60°C, added dropwise 2-bromoisobutyric acid butanone solution (1kg 2-bromoisobutyric acid dissolved in 3kg butanone) to the kettle, after addition, reaction 5 ~6 hours.

Embodiment 1c

[0050] Embodiment 1c (synthesis of fenofibric acid)

[0051] Weigh 1kg of 4-chloro-4'-hydroxybenzophenone, add it to a 50L dry reaction kettle, add 12kg methyl ethyl ketone and 0.77kg sodium hydroxide, heat up to 45-60℃ under stirring, stir for 30 minutes, add 0.2 kg of ethanol, stirred for 1 hour, kept at 45-60°C, added dropwise 2-bromoisobutyric acid butanone solution (1kg 2-bromoisobutyric acid dissolved in 3kg butanone) to the kettle, after addition, reaction 5 ~6 hours.

technical field

[0001] The invention belongs to the field of medicine preparation, in particular, the invention relates to a preparation method of fenofibric acid. Background technique

[0002] Fenofibrate is one of the phenoxylate lipid-lowering drugs currently used clinically. Compared with fenofibrate, fenofibric acid is an active substance metabolized in the body, and it has a very high concentration in the small intestine. Solubility, thus increasing bioavailability, and its bioavailability is not affected by food.

[0003] There are few reports on the preparation process of fenofibric acid in the published materials, basically all of which use 4-hydroxy-4'-chlorobenzophenone as the starting material to condense or replace to produce fenofibric acid. Qiao Deyang, Li Gan (Synthetic Chemistry, 2009) described a kind of 50% potassium hydroxide solution as solvent in TEBA catalyzed synthesis of fenofibric acid, 4-hydroxyl-4'-chlorobenzophenone, chloroform, acetone Fenofib...

Examples

Embodiment 1a

[0046] Embodiment 1a (synthesis of fenofibric acid)

[0047]Weigh 1kg of 4-chloro-4'-hydroxybenzophenone, add it to a 50L dry reaction kettle, add 12kg methyl ethyl ketone and 0.77kg sodium hydroxide, heat up to 45-60℃ under stirring, stir for 30 minutes, add 0.2 kg of purified water, stirred for 1 hour, kept at 45-60°C, and added dropwise 2-bromoisobutyric acid butanone solution (1kg 2-bromoisobutyric acid dissolved in 3kg butanone) to the kettle, and the reaction was completed 3 to 5 hours.

Embodiment 1b

[0048] Embodiment 1b (synthesis of fenofibric acid)

[0049] Weigh 1kg of 4-chloro-4'-hydroxybenzophenone, add it to a 50L dry reaction kettle, add 12kg methyl ethyl ketone and 0.77kg sodium hydroxide, heat up to 45-60℃ under stirring, stir for 30 minutes, add 0.2 kg of methanol, stirred for 1 hour, kept at 45-60°C, added dropwise 2-bromoisobutyric acid butanone solution (1kg 2-bromoisobutyric acid dissolved in 3kg butanone) to the kettle, after addition, reaction 5 ~6 hours.

Embodiment 1c

[0050] Embodiment 1c (synthesis of fenofibric acid)

[0051] Weigh 1kg of 4-chloro-4'-hydroxybenzophenone, add it to a 50L dry reaction kettle, add 12kg methyl ethyl ketone and 0.77kg sodium hydroxide, heat up to 45-60℃ under stirring, stir for 30 minutes, add 0.2 kg of ethanol, stirred for 1 hour, kept at 45-60°C, added dropwise 2-bromoisobutyric acid butanone solution (1kg 2-bromoisobutyric acid dissolved in 3kg butanone) to the kettle, after addition, reaction 5 ~6 hours.

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