Preparation method of medical intermediate ketone ester

Abstract

The invention discloses a preparation method of a medical intermediate ketone ester, which comprises the following steps: S1, taking citric acid and alcohol according to a certain proportion, putting into a reactor, stirring for a period of time, heating, and keeping the temperature; s2, when the temperature reaches a set temperature, adding an acid catalyst, and continuously stirring for a period of time to obtain a crude product; s3, an alkaline substance is added into the reactor, the pH value is adjusted, after the alkaline substance reacts with the acid catalyst, the solution in the reactor is filtered, and a citrate aqueous solution is obtained; s4, detecting acidic substances in the reactor, and detecting the concentration of citrate; s5, the reactor is heated, water is evaporated, citrate is obtained, by using an acid catalyst, the reaction efficiency is improved, the interior of the reactor is acidic through the acid catalyst, the stability of citrate is guaranteed, and by adjusting the pH value, the stability in the reactor is guaranteed.

Description

Technical Field

[0001] The invention relates to the technical field of preparation of pharmaceutical intermediate ketone ester, and in particular to a preparation method of pharmaceutical intermediate ketone ester. Background Art

[0002] Since C. Wehmer began early research work in the 1890s, people have poured great enthusiasm and a large amount of investment into various methods for producing citric acid by fermentation. As far as this is concerned, almost all of the citric acid produced in the world each year, not less than 700 million pounds, comes from fermentation methods, for example, through a carbon source such as molasses, using the microorganism Aspergillus Niger for fermentation. Usually, the fermentation broth from this fermentation contains about not less than 10% (weight) citric acid, and about not less than 1000ppm of salt, about 1% (weight) of carbohydrates, and 2% (weight) of protein, amino acids and other substances.

[0003] Purification of citric acid from this medium has been a subject of great interest in academia and industry. Generally speaking, three techniques have been used so far, namely precipitation, solvent extraction and adsorption on solid phase polymers followed by desorption. For the first technique, precipitation, we can safely say that it is a more preferred technique for industrial scale adoption, although great efforts have been made for the other two techniques. In the precipitation method, calcium hydroxide (lime) is usually added to the fermented medium to form slightly soluble tricalcium citrate tetrahydrate. When properly operated, this precipitation leaves most of the impurities in solution. Further impurities can be removed by washing the filtered precipitate. To further purify the product, the wet precipitate can be reacted with sulfuric acid to obtain a solution of calcium sulfate (gypsum) and free acid. The free acid solution is then treated with activated carbon and ion exchange resins and evaporated to form a crystalline citric acid product. As we have realized, the efficiency of this precipitation method depends to a large extent on the proper and careful performance of the various steps involved.

[0004] The existing method for preparing the pharmaceutical intermediate ketoester is to obtain the product through the reaction of citric acid and alcohol. However, in this method, the acidity is too high during use, which inhibits the production of citric acid esters and leads to low yield. Summary of the invention

[0005] The purpose of the present invention is to solve at least one of the technical problems existing in the prior art, and to provide a method for preparing a pharmaceutical intermediate ketoester, wherein an acid catalyst is used to increase the reaction efficiency, and the acid catalyst makes the inside of the reactor acidic, thereby ensuring the stability of the citrate ester, and the stability in the reactor is ensured by adjusting the pH value.

[0006] The present invention also provides a method for preparing the above-mentioned pharmaceutical intermediate ketoester, comprising the following steps:

[0007] S1, taking citric acid and alcohol in a certain proportion and putting them into a reactor, stirring for a period of time, heating and keeping the temperature;

[0008] S2. When the temperature reaches the set temperature, add an acid catalyst and continue stirring for a period of time to obtain a crude product;

[0009] S3, adding an alkaline substance to the reactor, adjusting the pH value, and filtering the solution in the reactor after the alkaline substance reacts with the acid catalyst to obtain a citrate aqueous solution;

[0010] S4, detecting the acidic substances in the reactor to detect the concentration of citrate;

[0011] S5. The reactor is heated to evaporate the water to obtain citrate.

[0012] According to a method for preparing a pharmaceutical intermediate ketoester provided by the present invention, the certain ratio in S1 is specifically citric acid:alcohol=1:3.

[0013] According to the method for preparing a pharmaceutical intermediate ketoester provided by the present invention, the stirring period in S1 is specifically 30-60 minutes.

[0014] According to the method for preparing a pharmaceutical intermediate ketoester provided by the present invention, the acid catalyst in S2 is specifically one of sulfuric acid or hydrochloric acid.

[0015] According to the method for preparing a pharmaceutical intermediate ketoester provided by the present invention, the concentration of the sulfuric acid is 0.1-5.0%, and the concentration of the hydrochloric acid is 0.1-3%.

[0016] According to the method for preparing a pharmaceutical intermediate ketoester provided by the present invention, the step of adding an acid catalyst in S2 specifically comprises adding 1-2 g of an acid catalyst.

[0017] According to the method for preparing a pharmaceutical intermediate ketoester provided by the present invention, the continuous stirring for a period of time in S2 is specifically continuous stirring for 20-40 minutes.

[0018] According to the method for preparing a pharmaceutical intermediate ketoester provided by the present invention, the alkaline substance in S3 is specifically calcium hydroxide.

[0019] According to the method for preparing a pharmaceutical intermediate ketoester provided by the present invention, adjusting the pH in S3 specifically involves adjusting the pH to 5.5-7.

[0020] According to the method for preparing a pharmaceutical intermediate ketoester provided by the present invention, the detection of the acidic substance in the reactor in S4 is specifically detecting the remaining amount of citrate ester and acid catalyst.

[0021] Compared with the prior art, the preparation method of the pharmaceutical intermediate ketoester, particularly the preparation method of the citrate ester, increases the reaction efficiency by using an acid catalyst, and the acid catalyst makes the inside of the reactor acidic, thereby ensuring the stability of the citrate ester, and the stability in the reactor is ensured by adjusting the pH value. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] The present invention is further described below in conjunction with the accompanying drawings and embodiments;

[0023] Figure 1 The present invention is a flow chart of the preparation method of the pharmaceutical intermediate ketoester. DETAILED DESCRIPTION

[0024] This section will describe in detail the specific embodiments of the present invention. The preferred embodiments of the present invention are shown in the accompanying drawings. The purpose of the accompanying drawings is to supplement the description of the text part of the specification with graphics, so that people can intuitively and vividly understand each technical feature and the overall technical solution of the present invention, but it cannot be understood as a limitation on the scope of protection of the present invention.

[0025] Reference Figure 1 The present invention provides a method for preparing a pharmaceutical intermediate ketoester, which comprises the following steps:

[0026] S1. Put citric acid and alcohol into a reactor according to a certain ratio, stir for a period of time, then heat up and keep the temperature. The certain ratio is citric acid: alcohol = 1:3, and stir for a period of time, specifically 30-60 minutes.

[0027] S2. When the temperature reaches the set temperature, an acid catalyst is added and stirred for a period of time to obtain a crude product. The acid catalyst is specifically one of sulfuric acid or hydrochloric acid. The concentration of sulfuric acid is 0.1-5.0%, and the concentration of hydrochloric acid is 0.1-3%. The addition of the acid catalyst is specifically 1-2 g of the acid catalyst, and the stirring is continued for a period of time, specifically 20-40 min.

[0028] S3, adding an alkaline substance to the reactor, adjusting the pH value, filtering the solution in the reactor after the alkaline substance reacts with the acid catalyst to obtain a citrate aqueous solution, wherein the alkaline substance is specifically calcium hydroxide, and adjusting the pH value is specifically adjusting the pH value to 5.5-7;

[0029] S4, detecting the acidic substances in the reactor, detecting the concentration of the citrate ester, and detecting the acidic substances in the reactor specifically detecting the remaining amount of the citrate ester and the acid catalyst;

[0030] S5. The reactor is heated to evaporate the water to obtain citrate.

[0031] The embodiments of the present invention are described in detail above with reference to the accompanying drawings. However, the present invention is not limited to the above embodiments. Various changes can be made within the knowledge scope of ordinary technicians in the technical field without departing from the purpose of the present invention.

Claims

1. A method for preparing a pharmaceutical intermediate ketoester, characterized in that: The following steps are involved: S1, taking citric acid and alcohol in a certain proportion and putting them into a reactor, stirring for a period of time, heating and keeping the temperature; S2. When the temperature reaches the set temperature, add an acid catalyst and continue stirring for a period of time to obtain a crude product; S3, adding an alkaline substance to the reactor, adjusting the pH value, and filtering the solution in the reactor after the alkaline substance reacts with the acid catalyst to obtain a citrate aqueous solution; S4, detecting the acidic substances in the reactor to detect the concentration of citrate; S5. The reactor is heated to evaporate the water to obtain citrate.

2. The method for preparing a pharmaceutical intermediate ketoester according to claim 1, characterized in that: The certain ratio in S1 is specifically citric acid:alcohol=1:

3.

3. The method for preparing a pharmaceutical intermediate ketoester according to claim 1, characterized in that: The stirring period in S1 is specifically 30-60 minutes.

4. The method for preparing a pharmaceutical intermediate ketoester according to claim 1, characterized in that: The acid catalyst in S2 is specifically one of sulfuric acid or hydrochloric acid.

5. The method for preparing a pharmaceutical intermediate ketoester according to claim 4, characterized in that: The concentration of the sulfuric acid is 0.1-5.0%, and the concentration of the hydrochloric acid is 0.1-3%.

6. The method for preparing a pharmaceutical intermediate ketoester according to claim 1, characterized in that: The step of adding the acid catalyst in S2 specifically comprises adding 1-2 g of the acid catalyst.

7. The method for preparing a pharmaceutical intermediate ketoester according to claim 1, characterized in that: The continuous stirring for a period of time in S2 is specifically continuous stirring for 20-40 minutes.

8. The method for preparing a pharmaceutical intermediate ketoester according to claim 1, characterized in that: The alkaline substance in S3 is specifically calcium hydroxide.

9. The method for preparing a pharmaceutical intermediate ketoester according to claim 1, characterized in that: The pH adjustment in S3 specifically includes adjusting the pH to 5.5-7.

10. The method for preparing a pharmaceutical intermediate ketoester according to claim 1, characterized in that: The detection of the acidic substance in the reactor in S4 specifically includes detecting the remaining amount of the citrate ester and the acid catalyst.

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