CN101143815A - The preparation method of felbinac - Google Patents

Abstract

The invention relates to a preparation method of a non-steroidal anti-inflammatory drug felbinac, which comprises the following steps in sequence: 1) synthesizing felbinac with biphenyl as a raw material, through three-step reactions of chloromethylation, Grignard reaction and hydrolysis The crude product of felbinac is synthesized; wherein the molar ratio of biphenyl, formaldehyde, phosphoric acid, and acetic acid is 1:1:3:3, concentrated hydrochloric acid is excessive, and hydrogen chloride gas is passed into the reaction solution while chloromethylation reaction, The flow rate of the hydrogen chloride gas is 1-50 l/h; 2) refining the crude felbinac obtained in the above step 1) with 30-70% (weight) acetic acid solution for recrystallization to obtain pure felbinac. The beneficial effect of the present invention is that: no toxic compounds are used in the reaction process of the present invention, and the environmental pollution is small; the raw materials are easy to obtain and the price is cheap; the equipment used is also common chemical equipment, and the operation is simple , The total yield of crude product is 38%～46%.

Description

The preparation method of felbinac

technical field

The invention relates to the field of chemical synthesis medicine, in particular to a preparation method of felbinac, a non-steroidal anti-inflammatory drug.

Background technique

Felbinac is a non-steroidal anti-inflammatory drug. Its anti-inflammatory activity is similar to fenbufen. It has anti-inflammatory, analgesic and good transdermal properties. Its 3% gel ointment is widely used in osteoarthritis, frozen shoulder, Tenosynovitis, muscle pain, soft tissue injury, etc., have high effectiveness and safety. In September 1986, the Japanese Lederle Company's ointment under the trade name "Napageln" was launched in Japan for the first time. Later, the drug was launched in the UK under the trade name "Traxamgel". Currently, the drug has been listed in more than a dozen countries. According to domestic and foreign literature reports, there are more than ten synthetic routes of felbinac, including seven starting materials. For example:

(1) Taking p-bromophenylacetic acid or ethyl p-bromophenylacetic acid as a raw material can synthesize felbinac in one or two steps, and taking p-bromophenylacetic acid as a raw material synthetic route is as follows:

Although the process route is short and easy to operate, the raw material is expensive, difficult to obtain, and the cost is high; (2) using 4-biphenyl formaldehyde as a raw material, one of the synthetic routes is as follows:

The route is complex in operation, low in yield, difficult to obtain raw materials, and high in cost;

(3) Taking phenylacetonitrile and biphenylacetonitrile as raw materials, it is very polluting to the environment, and it is also very harmful to the operator's body. Below is the synthetic route of taking phenylacetonitrile as raw material:

(4) With phenylacetic acid as raw material, complicated operation and low yield, the synthetic route is as follows:

(5) Because biphenyl is cheap and easy to obtain, biphenyl is usually used as raw material to synthesize felbinac. At present, there are five synthetic routes, but most of them are complicated to operate, pollute, and the reagents used in the reaction process are difficult to prepare. One of them synthesizes The route is as follows:

In summary, the above process routes are not suitable for enterprise production.

Contents of the invention

The technical problem to be solved by the present invention is to provide a new preparation method of felbinac with simple operation, little pollution, low cost, easy access to raw materials and suitable for enterprise production in view of the deficiencies in the prior art.

The technical scheme that the present invention adopts for solving the above-mentioned problem is: the preparation method of felbinac comprises the following steps in sequence:

1) synthesis of felbinac

Using biphenyl as raw material, the crude product of felbinac is synthesized through three steps of chloromethylation, Grignard reaction and hydrolysis; the molar ratio of biphenyl, formaldehyde, phosphoric acid and acetic acid is 1:1:3:3, concentrated hydrochloric acid Excessive, and feed hydrogen chloride gas into the reaction solution while chloromethylation reaction, the flow rate of the hydrogen chloride gas is 1～50L/h;

2) refined

The crude product of felbinac obtained in the above step 1) is recrystallized with 30-70% (weight) acetic acid solution to obtain pure felbinac.

According to the above scheme, the biphenyl chloride methane obtained by the chloromethylation in the step 1) is recrystallized with cyclohexane.

According to the above scheme, the Grignard reaction in the step 1) triggers the generation of the Grignard reagent with bromoethane.

According to the above scheme, the solvent used for the Grignard reaction in the step 1) is diethyl ether or tetrahydrofuran.

The present invention prepares the method for felbinac, and synthetic route is as follows:

Feeding hydrogen chloride gas helps to improve the yield of biphenyl chloride; recrystallization of biphenyl chloride with cyclohexane can reduce the generation of by-products in the Grignard reaction; triggering the Grignard reaction with bromoethane reduces the reaction temperature , shortened the reaction time, its infrared spectrum and nuclear magnetic resonance spectrum are shown in accompanying drawings 1-3.

The beneficial effects of the present invention are:

In the reaction process of the present invention, no toxic compounds are used or produced, and the environmental pollution is small; the raw materials are easy to obtain and the price is cheap; the equipment used is also common chemical equipment, and the operation is simple, and the total yield of the crude product is 38 %~46%.

Description of drawings

Fig. 1 is the infrared spectrogram of product felbinac obtained from the present invention;

Fig. 2 is gained product of the present invention 1H nuclear magnetic resonance spectrogram;

Fig. 3 is the ¹³ C nuclear magnetic resonance spectrum of the product obtained in the present invention.

Detailed ways

The present invention is further illustrated below by examples, but the present invention is not limited thereto.

Example 1:

(1) Preparation of biphenyl chloride

On the 250ml three-necked flask, a thermometer, a mechanical stirrer, an air guide tube, and a reflux condenser were installed through a connecting pipe, and 15.4g (0.1mol) of biphenyl, 8.3g (0.1mol) of formaldehyde, 34.5g (0.3mol) of phosphoric acid, Acetic acid 18.75g (0.3mol), concentrated hydrochloric acid 25ml. Heat to 80-90°C on an electronic temperature-adjusting heating mantle, stir vigorously for 18-24 hours, and feed HCl gas into the reaction solution every 30 minutes. The flow rate of hydrogen chloride gas is 45L/h. The reaction was stopped, cooled to below 15°C, and solids were precipitated. Filter under reduced pressure, wash the filter cake twice, each time with about 40ml of water, and then wash once with 20ml of 5% K ₂ CO ₃ solution. Drain the filter cake, transfer it to a 250ml separatory funnel, add 40ml ether and 10ml 5% K ₂ CO ₃ solution, oscillate, let stand, separate the lye layer, add 20g of anhydrous potassium carbonate to the ether layer and place it for 24 hours dry. Ether was distilled off, and the obtained crude product was recrystallized once from cyclohexane. The product is vacuum dried. 18.27 g of the product was obtained, the purity was 83.62%, and the yield of this step was 75.4%.

(2) preparation of felbinac

In a 250ml three-necked flask equipped with a condenser (with a calcium chloride drying tube attached to the top), a thermometer and an atmospheric dropping funnel, add 2.4g (0.1mol) of magnesium chips and 0.2g (0.002mol) of iodine crystals. Measure 90ml of ether, pour in an appropriate amount of ether just to cover the magnesium chips, and dissolve the remaining ether to dissolve the biphenyl chloride methane obtained in the previous step and put it in an atmospheric dropping funnel for use. Add 3ml of bromoethane to initiate the reaction. After the iodine crystal color disappears, slowly add the ether solution of chloromethylbiphenyl dropwise. During the dropwise addition, use a cold water bath to maintain the reaction with a small amount of reflux. After the dropwise addition was completed, the dropping funnel was rinsed with 10 ml of ether, stirred at room temperature for 15 minutes, and then refluxed at 35° C. for 2 hours. After the reaction is complete, cool down to below 8°C with an ice-water bath, and pass CO ₂ gas for 2 to 3 hours. After completion, an appropriate amount of ice cubes was added to the reaction solution, and 10% dilute hydrochloric acid was added dropwise until acidic. Ether was distilled off, filtered under reduced pressure, the filter cake was washed, and drained. Transfer the filter cake into a beaker, add 80ml of 8% NaOH solution, heat to 80°C to dissolve, cool to room temperature to obtain a white turbid solution, filter under reduced pressure, and collect the filtrate; repeat the above operation twice for the filter cake. The collected filtrates were combined, acidified by adding 20% hydrochloric acid, and a white colloid was precipitated. It was filtered under reduced pressure and dried to obtain 8.80 g of a white scaly solid with a melting point of 158-161° C. and a total yield of crude felbinac of 41.9%.

(3) Refined felbinac

The crude product of felbinac was recrystallized with 50% acetic acid to obtain 5.52 g of pure felbinac, with a content of 99.74%, a melting point of 163-165°C, and a yield of 62.7%.

Example 2:

(1) Preparation of diphenylchloromethane is the same as in Example 1.

(2) In a 250ml three-neck flask equipped with a condenser (with a calcium chloride drying tube attached to the top), a thermometer and an atmospheric dropping funnel, add 2.4g (0.1mol) of magnesium chips and 0.2g (0.002mol) of iodine crystals. . Measure 90ml of tetrahydrofuran, pour an appropriate amount of tetrahydrofuran just to cover the magnesium chips, and dissolve the remaining tetrahydrofuran with the biphenyl chloride methane obtained in the previous step, and put it in the normal pressure dropping funnel for use. Others are the same as above. 9.7 grams of felbinac crude product were obtained, and the total yield of the crude product was 45.6%.

(3) The refinement of felbinac was the same as that in Example 1. Recrystallization was carried out with 70% acetic acid to obtain 5.78 g of pure felbinac, with a content of 99.79%, a melting point of 163-165° C., and a yield of 59.5 percent in this step.

Claims (4)

1. the preparation method of felbinac is characterized in that including the next coming in order step:

1) synthetic felbinac

With biphenyl is raw material, by chloromethylation, grignard reaction, hydrolysis three-step reaction synthetic the felbinac crude product; Wherein the mol ratio of biphenyl, formaldehyde, phosphoric acid, acetic acid is 1: 1: 3: 3, and concentrated hydrochloric acid is excessive, and feeds hydrogen chloride gas in chloromethylation in reaction soln, and the flow of described hydrogen chloride gas is 1～50L/h;

2) refining

Above-mentioned steps 1) gained felbinac crude product carries out recrystallization with 30～70% (weight) acetic acid solution, gets the pure product of felbinac.

2. by the preparation method of the described felbinac of claim 1, it is characterized in that chloromethylation gained biphenyl methyl chloride carries out recrystallization with hexanaphthene in the described step 1).

3. by the preparation method of claim 1 or 2 described felbinac, it is characterized in that grignard reaction causes the Grignard reagent generation with monobromethane in the described step 1).

4. by the preparation method of claim 1 or 2 described felbinac, it is characterized in that the grignard reaction solvent for use is ether or tetrahydrofuran (THF) in the described step 1).

Images