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Industrialized preparation method of guacetisal and medical application of dry suspension

A technology of guacityl and catalyst, which is applied in the field of preparation of guacityl, can solve the problems of lowering system temperature by external circulation of cold water, high reaction temperature, long reaction time, etc., and achieves lower system temperature, mild reaction conditions, and production short time effect

Inactive Publication Date: 2014-09-03
DALIAN MINGSEN PHARMA
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  • Abstract
  • Description
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AI Technical Summary

Problems solved by technology

[0011] In the currently existing synthetic methods, the reaction temperature of salicylic acid and guaiacol is relatively high, the reaction time is long, and the energy consumption is large, resulting in high production cost.
Phosphorus oxychloride is used as the esterification agent in the esterification reaction. It is difficult to use phosphorus oxychloride for post-treatment. The existing technology is to pour the reaction solution into a large amount of water, which is complicated to operate and requires external circulation of cold water to lower the system temperature, otherwise heat will be released Large lead to high temperature, easy to cause danger

Method used

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  • Industrialized preparation method of guacetisal and medical application of dry suspension
  • Industrialized preparation method of guacetisal and medical application of dry suspension
  • Industrialized preparation method of guacetisal and medical application of dry suspension

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] The first step: synthesis of guaiacol salicylate

[0038] Salicylic acid (200g, 1.45mol, 1.0eq) and guaiacol (180g, 1.45mol, 1.0eq) and DMAP (3.54g, 0.029mol, 2mol%) were added in the reactor, heated to 60±2 ℃ (at present existing reaction temperature is about 105 ℃, the present invention reduces the reaction temperature to 60 ℃ by adding catalyst, greatly reduces energy consumption, reduces cost), and phosphorus oxychloride (104.5g, 0.68mol, 0.47eq) was slowly dropped into the reaction solution (temperature control 65±2°C). After dripping, keep stirring and react for 3h. Add ethanol (300mL) dropwise, cool to 10-20°C, precipitate a solid, filter, wash the filter cake with ethanol (200mL), and vacuum-dry the filter cake at 45°C for 4h to obtain guaiacol salicylate, a white solid ( 311.2g, purity 98.5%, yield 88%).

[0039] The second step: the synthesis of Guaxitilian

[0040] Guaiacyl salicylate (311.2 g, 1.27 mol, 1.0 eq), acetic anhydride (156.1 g, 1.53 mol, 1.2 e...

Embodiment 2

[0042] The first step: synthesis of guaiacol salicylate

[0043]Salicylic acid (1kg, 7.24mol, 1.0eq) and guaiacol (944g, 7.6mol, 1.05eq) and pyridine (17.4g, 0.22mol, 3mol%) were added in the reactor, heated to 60±2 °C, slowly drop phosphorus oxychloride (555 g, 3.62 mol, 0.5 eq) into the reaction solution (temperature control 65±2 °C). After dripping, keep stirring and react for 3h. Drop in isopropanol (1.2L), cool to 10-20°C, precipitate solid, filter, wash the filter cake with isopropanol (1L), and vacuum-dry the filter cake at 45°C for 4 hours to obtain guaiacol salicylate Ester, white solid (1.5kg, purity 98.8%, yield 85%).

[0044] The second step: the synthesis of Guaxitilian

[0045] Guaiacyl salicylate (1.5kg, 6.14mol, 1.0eq), acetic anhydride (627.0g, 6.14mol, 1.0eq) and DMF (561.2g, 7.68mol, 1.25eq) were added to the reactor, Heat to 60-65°C, keep stirring and react for 2 hours. Control the temperature at 50-60°C, add methanol (3L) into the reaction liquid, sti...

Embodiment 3

[0047] The first step: synthesis of guaiacol salicylate

[0048] Salicylic acid (5kg, 36.2mol, 1.0eq) and guaiacol (5.39kg, 43.44mol, 1.2eq) and DMF (132.3g, 1.81mol, 5mol%) were added in the reactor, heated to 60± At 2°C, phosphorus oxychloride (4.44kg, 28.96mol, 0.8eq) was slowly dropped into the reaction solution (temperature controlled at 65±2°C). After dripping, keep stirring and react for 3h. Add n-propanol (6L) dropwise, cool to 10-20°C, precipitate solids, filter, wash the filter cake with n-propanol (4L), and vacuum-dry the filter cake at 45°C for 4 hours to obtain guaiacol salicylate , white solid (7.96kg, purity 98.3%, yield 90%).

[0049] The second step: the synthesis of Guaxitilian

[0050] Guaiacyl salicylate (7.96kg, 32.6mol, 1.0eq), acetic anhydride (4.99kg, 48.9mol, 1.5eq) and DMAP (6.77kg, 55.4mol, 1.7eq) were added to the reactor, Heat to 60-70°C, keep stirring and react for 2 hours. Control the temperature at 50-60° C., add ethanol (15 L) into the rea...

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Abstract

The invention discloses an industrialized preparation method of guacetisal, which comprises the following steps: based on salicylic acid and guaiacol as raw materials, carrying out esterification on the raw materials so as to obtain salicylic acid-guaiacol ester; and then, carrying out acetylization on hydroxy so as to obtain guacetisal, wherein in the esterification reaction, one of pyridine, 4-dimethylamino-pyridine and dimethylformamide is selected as a catalyst; and in the step of carrying out acetylization on hydroxy, one of pyridine, 4-dimethylamino-pyridine and dimethylformamide is added and used as an auxiliary alkali reagent. According to the invention, the technological production cost is low, the synthetic route is short, the reaction rate is improved, and the reaction temperature is reduced, so that the reaction temperature is milder and the preparation method is suitable for industrialized production; the post-treatment processes of esterification and acetylization reactions are simple, complicated quenching, extraction and solvent replacement operations are avoided, the time of batch production is greatly reduced, and the application amount of organic solvents is maximally reduced; and therefore, the industrialized preparation method of guacetisal is particularly suitable for industrialized production.

Description

technical field [0001] The present invention relates to the preparation method of Guacitil, more specifically, the industrialized preparation method of Guacitil, which is especially suitable for preparing dry suspension. Background technique [0002] Guacitil, a salicylic acid derivative, the structure is as follows. Guacetyl, which was launched in Italy in 1981, is an antipyretic and analgesic drug that can delay bronchospasm caused by kinin, inhibit the synthesis of prostaglandin PG, stabilize the solvent membrane, and have anti-inflammatory, antipyretic and analgesic effects. effect. In addition, it can dissolve mucus, so it has the effect of reducing phlegm and expectorant, and it is especially suitable for infants and young children. Guaxitilian is clinically used to treat acute and chronic respiratory inflammation and mucous membrane inflammation accompanied by fever and pain. [0003] [0004] At present, there are mainly two methods for the preparation of Guaci...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C69/86C07C67/08A61K9/14A61K31/621A61P29/00A61P11/10
Inventor 曾伟孙庆发李炳明李彦冰
Owner DALIAN MINGSEN PHARMA
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