CN109456291B - Method for producing griseofulvin by low-temperature rapid crystallization - Google Patents
Method for producing griseofulvin by low-temperature rapid crystallization Download PDFInfo
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- CN109456291B CN109456291B CN201811492042.6A CN201811492042A CN109456291B CN 109456291 B CN109456291 B CN 109456291B CN 201811492042 A CN201811492042 A CN 201811492042A CN 109456291 B CN109456291 B CN 109456291B
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- griseofulvin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
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Abstract
The invention discloses a method for producing griseofulvin by low-temperature rapid crystallization, which comprises the following steps of carrying out filter pressing, granulation, drying, acetone extraction and activated carbon decoloration on griseofulvin fermentation liquor to obtain a griseofulvin acetone decoloration solution, adding the obtained product into deionized water in a stirring state, wherein the temperature of the deionized water is 5-15 ℃, the pH is adjusted to 7-8, and the obtained product is prepared by the following steps: crystallizing and filtering deionized water at a ratio of 1-2: 2 to obtain griseofulvin wet crystals; washing the griseofulvin wet crystal by n-butyl alcohol, washing by ethanol, drying and crushing to obtain the griseofulvin raw material medicine. The method has the advantages of high product yield, small crystal particles, easy grinding and low production cost.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a method for producing griseofulvin by low-temperature rapid crystallization.
Background
Griseofulvin (griseofulvin) is an aromatic derivative antibiotic, which is an antifungal antibiotic, and is clinically used for treating infections caused by dermatophytes and is agriculturally used for resisting plant mycosis. The griseofulvin product has wide market prospect, the production process is improved, the cost is reduced, and the improvement of the competitiveness of enterprises is an important current topic.
At present, the method for preparing griseofulvin generally comprises the following steps: a. performing plate-and-frame filter pressing, filter cake granulation and acetone extraction on the griseofulvin fermentation liquor to obtain a griseofulvin acetone extracting solution; b. decoloring the griseofulvin acetone extracting solution by using activated carbon, and concentrating and crystallizing the decolored solution to obtain a griseofulvin primary coarse crystal; c. washing the griseofulvin primary coarse crystal by butanol, and dissolving by acetone to obtain a griseofulvin acetone solution; d. decoloring the griseofulvin acetone solution by using activated carbon, and concentrating and crystallizing the decolored solution to obtain griseofulvin secondary coarse crystals; e. washing the secondary griseofulvin coarse crystal with butanol, washing with ethanol, drying, and pulverizing to obtain griseofulvin raw material medicine. The method has two crystallization processes in the process steps, so that the yield loss is high in the double crystallization process, the yield of the finished product is low, the solvent loss is high, power and energy are wasted, and the production cost is increased.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a method for producing griseofulvin by low-temperature rapid crystallization, which has the advantages of high product yield, small crystal particles, easy grinding and low production cost.
The technical scheme of the invention is as follows: a method for producing griseofulvin by low-temperature rapid crystallization comprises the following steps:
s1, performing plate-and-frame filter pressing on the griseofulvin fermentation liquor, adding calcium oxide into a filter cake, granulating, drying, and extracting with acetone to obtain a griseofulvin acetone extracting solution;
s2, decoloring the griseofulvin acetone extracting solution by using an activated carbon column to obtain a griseofulvin acetone decoloring solution;
s3, adding deionized water with the temperature of 5-15 ℃ into a stirring reaction kettle, adjusting the pH value to 7-8, then adding the griseofulvin acetone destaining solution into the stirring reaction kettle at a constant speed in the stirring process, wherein the volume ratio of the added amounts of the griseofulvin acetone destaining solution to the deionized water is as follows: 1-2: 2 of griseofulvin acetone decolored solution and deionized water; after the griseofulvin acetone destaining solution is added, continuously stirring for 8-15 minutes, and after crystals are completely separated out, filtering to obtain wet griseofulvin crystals;
s4, washing the griseofulvin wet crystal by n-butyl alcohol, washing by ethanol, drying and crushing to obtain the griseofulvin raw material medicine.
Preferably, in step S3, the temperature of the deionized water is 6 to 10 ℃, and the ratio of the griseofulvin acetone decolorization solution to the deionized water is 1.3 to 1.7: 2.
Preferably, in step S3, the pH is adjusted to 7.5 to 7.8.
Preferably, in step S3, the rotation speed of the stirrer of the stirring reaction kettle is 50-100 rpm during the addition of the griseofulvin acetone destaining solution and the subsequent crystallization.
Preferably, in step S3, filtration is performed by suction filtration.
Compared with the prior art, the invention has the advantages that:
(1) the method disclosed by the invention has the advantages that the crystallization is carried out under the conditions that the pH value is 7-8 and the temperature is low, the crystallization speed is high, the crystallization efficiency is high, the crystallization times in the griseofulvin preparation process in the prior art are reduced, the yield loss caused by the recrystallization of griseofulvin is effectively avoided, the total yield of the griseofulvin can be improved by 6-8%, and the yield is as high as about 72%.
(2) The method is carried out in a stirring reaction kettle, a stirrer is started to stir in the process of adding and crystallizing the griseofulvin acetone decoloring solution at a constant speed, the griseofulvin crystal form is needle-rod-shaped and is uniformly arranged, the granularity is reduced by hundreds of times, a flour mill is used for milling, the product is easy to break, the granularity is obviously reduced, and the griseofulvin crystal form is used as a raw material medicine of an oral medicine, is more beneficial to absorption from the digestive tract and improves the drug effect.
(3) The invention has simple process steps, greatly reduces the production cost, saves energy and improves the labor productivity.
Detailed Description
In order to make the technical solution of the present invention clearer, the following describes the embodiments of the present invention in further detail by way of specific examples.
Example 1: a method for producing griseofulvin by low-temperature rapid crystallization comprises the following steps:
s1, performing plate-and-frame filter pressing on the griseofulvin fermentation liquor, adding calcium oxide into a filter cake, granulating, drying, and extracting with acetone to obtain a griseofulvin acetone extracting solution;
s2, decoloring the griseofulvin acetone extracting solution by using an activated carbon column to obtain a griseofulvin acetone decoloring solution;
s3, adding deionized water with the temperature of 6 ℃ into a stirring reaction kettle, adjusting the pH value to 7.6 by using a sodium hydroxide solution, starting a stirrer, and then adding the griseofulvin acetone decolored solution into the stirring reaction kettle at a constant speed in the stirring process with the rotating speed of 80 r/min, wherein the volume ratio of the added griseofulvin acetone decolored solution to the added deionized water is as follows: 1.7:2 of griseofulvin acetone decolorant and deionized water; after the griseofulvin acetone destaining solution is added, continuously stirring for 10 minutes at the rotating speed of 80 revolutions per minute, and filtering to obtain wet griseofulvin crystals after the crystals are completely separated out;
s4, washing the griseofulvin wet crystal by n-butyl alcohol, washing by ethanol, drying and crushing to obtain the griseofulvin raw material medicine.
The product yield of griseofulvin in this example is 71.5%.
Example 2: a method for producing griseofulvin by low-temperature rapid crystallization comprises the following steps:
s1, performing plate-and-frame filter pressing on griseofulvin fermentation liquor, adding calcium oxide into filter cakes, granulating, drying, and extracting with acetone to obtain griseofulvin acetone extract;
s2, decoloring the griseofulvin acetone extracting solution by using an activated carbon column to obtain a griseofulvin acetone decoloring solution;
s3, adding deionized water with the temperature of 8 ℃ into a stirring reaction kettle, adjusting the pH value to 7.8 by using a sodium hydroxide solution, starting a stirrer, and then adding the griseofulvin acetone decolored solution into the stirring reaction kettle at a constant speed in the stirring process at the rotating speed of 70 r/min, wherein the volume ratio of the added griseofulvin acetone decolored solution to the added deionized water is as follows: 1.5: 2 of griseofulvin acetone decolored solution and deionized water; after the griseofulvin acetone decoloration solution is added, stirring is continuously carried out for 12 minutes at the rotating speed of 70 r/min, and after crystals are completely separated out, wet griseofulvin crystals are obtained by filtration;
s4, washing the griseofulvin wet crystal with n-butyl alcohol, washing with ethanol, drying and crushing to obtain the griseofulvin raw material medicine. The product yield of griseofulvin in this example is 73.2%.
Example 3: a method for producing griseofulvin by low-temperature rapid crystallization comprises the following steps:
s1, performing plate-and-frame filter pressing on the griseofulvin fermentation liquor, adding calcium oxide into a filter cake, granulating, drying, and extracting with acetone to obtain a griseofulvin acetone extracting solution;
s2, decoloring the griseofulvin acetone extracting solution by using an activated carbon column to obtain a griseofulvin acetone decoloring solution;
s3, adding deionized water with the temperature of 10 ℃ into a stirring reaction kettle, adjusting the pH value to 7.5 by using a sodium hydroxide solution, starting a stirrer, and then adding the griseofulvin acetone decolored solution into the stirring reaction kettle at a constant speed in the stirring process at the rotating speed of 90 revolutions per minute, wherein the volume ratio of the added quantities of the griseofulvin acetone decolored solution to the deionized water is as follows: 1.3: 2 of griseofulvin acetone decolored solution and deionized water; after the griseofulvin acetone destaining solution is added, continuously stirring for 13 minutes at the rotating speed of 90 revolutions per minute, and filtering to obtain wet griseofulvin crystals after the crystals are completely separated out;
s4, washing the griseofulvin wet crystal with n-butyl alcohol, washing with ethanol, drying and crushing to obtain the griseofulvin raw material medicine.
The griseofulvin product yield of this example was 72.0%.
Claims (1)
1. A method for producing griseofulvin by low-temperature rapid crystallization comprises the following steps:
s1, performing plate-and-frame filter pressing on the griseofulvin fermentation liquor, adding calcium oxide into a filter cake, granulating, drying, and extracting with acetone to obtain a griseofulvin acetone extracting solution;
s2, decoloring the griseofulvin acetone extracting solution by using an activated carbon column to obtain a griseofulvin acetone decoloring solution;
s3, adding deionized water with the temperature of 6-10 ℃ into a stirring reaction kettle, adjusting the pH to 7.5-7.8, and then adding the gray flavomycin acetone decolored solution into the stirring reaction kettle at a constant speed in the stirring process, wherein the volume ratio of the addition amount of the gray flavomycin acetone decolored solution to the deionized water is as follows: and (3) decoloring griseofulvin acetone solution: deionized water = 1.3-1.7: 2; after the griseofulvin acetone destaining solution is added, continuously stirring for 8-15 minutes, and after crystals are completely separated out, filtering to obtain wet griseofulvin crystals; in the processes of adding griseofulvin acetone decoloration liquid and then crystallizing, the rotating speed of a stirrer of a stirring reaction kettle is 50-100 revolutions per minute, and filtering is carried out by adopting a suction filtration method;
s4, washing the griseofulvin wet crystal with n-butyl alcohol, washing with ethanol, drying and crushing to obtain the griseofulvin raw material medicine.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN86104044A (en) * | 1986-06-28 | 1987-03-25 | 南通醋酸化工厂 | Crystallization of griseofulvin grains method and device thereof |
| CN103275047A (en) * | 2013-05-23 | 2013-09-04 | 内蒙古格林特制药有限责任公司 | Preparation method of griseofulvin |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN86104044A (en) * | 1986-06-28 | 1987-03-25 | 南通醋酸化工厂 | Crystallization of griseofulvin grains method and device thereof |
| CN103275047A (en) * | 2013-05-23 | 2013-09-04 | 内蒙古格林特制药有限责任公司 | Preparation method of griseofulvin |
Non-Patent Citations (1)
| Title |
|---|
| 灰黄霉素的微粒结晶;谢巾英等;《中国抗生素杂志》;19810228(第01期);第17页右栏倒数第2-3段，表4 * |
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