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A technology of fenofibric acid and bromoisobutyric acid is applied in the field of preparation of fenofibric acid, which can solve the problems of long reaction time, thick system, burning of stirring paddle motor, etc., and achieve good sample stability and system viscosity. The effect of low consistency and short reaction time
Active Publication Date: 2017-10-10
YANGTZE RIVER PHARM GRP CO LTD
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[0005] In summary, although the above two routes can obtain relatively satisfactory yields, there are also many defects.
There are following disadvantages in the preparation of fenofibric acid by condensation reaction: 1. Use expensive phase transfer catalyst TEBA or tetra-n-butylammonium bromide; 2. The reaction time is as long as 25h; the reaction is carried out under phase transfer catalytic conditions, which is heterogeneous reaction, not conducive to mass production
However, the substitution reaction to prepare fenofibric acid has the following disadvantages: 1. The reaction time is as long as 16 to 24 hours; big difficulty
[0007] Fenofibric acid has a good market prospect, and the current process reports are not suitable for industrialized production. Therefore, it is very urgent and necessary to find a process suitable for industrialized production of fenofibric acid
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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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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...
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