CN103275047B - Preparation method of griseofulvin - Google Patents
Preparation method of griseofulvin Download PDFInfo
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- CN103275047B CN103275047B CN201310193738.XA CN201310193738A CN103275047B CN 103275047 B CN103275047 B CN 103275047B CN 201310193738 A CN201310193738 A CN 201310193738A CN 103275047 B CN103275047 B CN 103275047B
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Abstract
The invention discloses a preparation method of griseofulvin. The preparation method comprises the following steps of: A, heating griseofulvin fermentation liquor, adding calcium oxide to adjust the PH, carrying out solid-liquid separation by using a sheet frame, adding calcium oxide to a filter cake to granulate, and extracting by using acetone to obtain a griseofulvin acetone extracting solution; B, decoloring the griseofulvin acetone extracting solution by using an active carbon column to obtain a griseofulvin decoloring solution, feeding the decoloring solution into a concentration tank, and crystallizing by concentrating to obtain wet griseofulvin crystals; and C, washing the wet griseofulvin crystals once by using a dichloromethane and ethanol mixed solution while stirring, then washing the wet griseofulvin crystals once by using medicinal ethanol with the concentration of 95 percent while stirring, drying the crystals by using a vacuum drier, and carrying out superfine grinding on the dried crystals to obtain the griseofulvin product. Compared with a traditional preparation method, the preparation method disclosed by the invention has the advantages that the crystallization times in the process of preparing the griseofulvin in the prior art is reduced, the yield loss caused by recrystalization of griseofulvin is effectively avoided, the total yield of the griseofulvin is improved by 7-10 percent, and the production cost is greatly reduced.
Description
Technical field
The present invention relates to bulk drug preparation method, be specifically related to a kind of preparation method of grisovin.
Background technology
Grisovin is antibiotics bulk drug, English name Griseofulvin, Chinese another name Spirofulvin, crystallite grisovin, English another name Fulcin, Fulcine, Fulvicin, Fungivin, Grifulvin, Grisactin, Grisefulin, Griseofulvinum, [CAS] 126-07-8, this product is the fines of white or off-white color; This product mainly has good anti-microbial effect to superficial mycosiss such as trichophyta, sporidiole bacteria, Epidermophytons.
Grisovin is applicable to the sick treatment of various tinea, comprises favus of the scalp, barber's itch, ringworm of the body, jock itch, tinea pedis and onychomycosis.
At present, prepare the method for grisovin, generally comprise following steps: a: obtain grisovin acetone extract with the heating of grisovin fermented liquid, sheet frame solid-liquid separation, filter cake granulation, acetone extraction; B, grisovin acetone extract activated carbon decolorizing, destainer condensing crystal obtains grisovin crude product; C, grisovin crude product obtain grisovin acetone solution liquid with acetone solution, and grisovin acetone solution liquid is through activated carbon decolorizing, and the crystallization of destainer reconcentration obtains grisovin recrystallization body; The washing of d, grisovin recrystallization body butanols, then by washing with alcohol, be dried, micronizing obtains grisovin bulk drug.In the method processing step, have two times of crystallization, this just causes its yield losses in dual crystallisation process many, and product yield is low, and solvent loss is large, causes the waste of power, the energy simultaneously, has strengthened production cost.Prepare as stated above grisovin, its total recovery is generally 63%.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, and a kind of preparation method of grisovin is provided, its production cost is low, product yield is high.
Technical scheme of the present invention is as follows:
A preparation method for grisovin, is made up of following steps:
A, grisovin fermented liquid is heated to 80～100 DEG C, adds calcium oxide and adjust PH5.5～7, sheet frame solid-liquid separation, filter cake to add that calcium oxide is granulated, acetone extraction obtains grisovin acetone extract;
B, grisovin acetone extract, through activated carbon column decoloring, obtain grisovin acetone destainer, and destainer enters concentration tank, and the mode that vacuumizes reduction acetone boiling point with logical steam cycle heating and tank body in chuck is carried out concentrating under reduced pressure, and thickening temperature is controlled at 27 ± 3
oC, vacuum degree control is at-0.09～-0.07MPa, condensing crystal, when acetone does not evaporate completely, remaining a small amount of acetone is put to concentrated suction filtration tank suction filtration, under vacuum condition together with xln, by concentrated mother liquor elimination, until drain mother liquor, obtain the wet crystal of grisovin while hot;
C, the wet crystal of grisovin, under agitation wash once with methylene dichloride, alcohol mixeding liquid, churning time is 2～3 hours, suction filtration 0.5～1 hour, then the medicinal alcohol that is under agitation 95% by concentration washs once, churning time is 0.5～1 hour, suction filtration 0.5～1 hour, obtains grisovin wet-milling after draining, dry through Vacuumdrier, micronizing, obtains grisovin product; Wherein, in methylene dichloride, alcohol mixeding liquid, methylene dichloride accounts for 60～75%(volume ratio), the grisovin crystal (weight) that wets: methylene dichloride, alcohol mixeding liquid (volume)=1:0.8～0.9kg/L, the grisovin crystal (weight) that wets: medicinal alcohol (volume)=1: 0.8kg/L.
The invention has the advantages that: reduced prior art at the crystallization number of times of preparing in grisovin process, the yield losses of effectively having avoided grisovin recrystallization to cause, can make grisovin total recovery improve 7～10%, reach 70～73%, significantly reduce production cost, save the energy simultaneously, improved labour productivity.
Below embodiment, the invention will be further described.
embodiment 1a preparation method for grisovin, is made up of following steps:
A, grisovin fermented liquid is heated to 80 DEG C, adds calcium oxide and adjust PH to 5.5, sheet frame solid-liquid separation, filter cake to add that calcium oxide is granulated, acetone extraction obtains grisovin acetone extract;
B, grisovin acetone extract, through activated carbon column decoloring, obtain grisovin acetone destainer, and destainer enters concentration tank, and the mode that vacuumizes reduction acetone boiling point with logical steam cycle heating and tank body in chuck is carried out concentrating under reduced pressure, and thickening temperature is controlled at 27
oC, vacuum degree control is at-0.09MPa, after concentrated, acetone evaporates rapidly, cooling recovery, recycles, and crystallization is separated out naturally, when acetone does not evaporate completely, remaining a small amount of acetone is put to concentrated suction filtration tank suction filtration together with xln, under vacuum condition, while hot by concentrated mother liquor elimination, until drain mother liquor, obtain the wet crystal of grisovin;
C, the wet crystal of grisovin, under agitation wash once with methylene dichloride, alcohol mixeding liquid, churning time is 2 hours, suction filtration 0.5 hour, then the medicinal alcohol that is under agitation 95% by concentration washs once, churning time is 0.5 hour, suction filtration 0.5 hour, obtains grisovin wet-milling after draining, grisovin wet-milling is dry through Vacuumdrier, micronizing, obtains grisovin product; Wherein, in methylene dichloride, alcohol mixeding liquid, methylene dichloride accounts for 60%(volume ratio), the grisovin crystal (weight) that wets: methylene dichloride, alcohol mixeding liquid (volume)=1:0.8 kg/L, the grisovin crystal (weight) that wets: medicinal alcohol (volume)=1: 0.8 kg/L.
The present embodiment grisovin product yield is 70%.
embodiment 2a preparation method for grisovin, is made up of following steps:
A, grisovin fermented liquid is heated to 100 DEG C, adds calcium oxide and adjust PH to 6, sheet frame solid-liquid separation, filter cake to add that calcium oxide is granulated, acetone extraction obtains grisovin acetone extract;
B, grisovin acetone extract, through activated carbon column decoloring, obtain grisovin acetone destainer, and destainer enters concentration tank, and the mode that vacuumizes reduction acetone boiling point with logical steam cycle heating and tank body in chuck is carried out concentrating under reduced pressure, and thickening temperature is controlled at 24
oc, vacuum degree control is at-0.07MPa, after concentrated, acetone evaporates rapidly, cooling recovery, recycles, and crystallization is separated out naturally, when acetone does not evaporate completely, remaining a small amount of acetone is put to concentrated suction filtration tank suction filtration together with xln, under vacuum condition, while hot by concentrated mother liquor elimination, until drain mother liquor, obtain the wet crystal of grisovin;
C, the wet crystal of grisovin, under agitation wash once with methylene dichloride, alcohol mixeding liquid, churning time is 3 hours, suction filtration 1 hour, then the medicinal alcohol that is under agitation 95% by concentration washs once, churning time is 1 hour, suction filtration 1 hour, obtains grisovin wet-milling after draining, dry through Vacuumdrier, micronizing, obtains grisovin product; Wherein, in methylene dichloride, alcohol mixeding liquid, methylene dichloride accounts for 75%(volume ratio), the grisovin crystal (weight) that wets: methylene dichloride, alcohol mixeding liquid (volume)=1:0.9 kg/L, the grisovin crystal (weight) that wets: medicinal alcohol (volume)=1: 0.8 kg/L.
The present embodiment grisovin product yield is 72.1%.
embodiment 3a preparation method for grisovin, is made up of following steps:
A, grisovin fermented liquid is heated to 90 DEG C, adds calcium oxide and adjust PH to 6.5, sheet frame solid-liquid separation, filter cake to add that calcium oxide is granulated, acetone extraction obtains grisovin acetone extract;
B, grisovin acetone extract, through activated carbon column decoloring, obtain grisovin acetone destainer, and destainer enters concentration tank, and the mode that vacuumizes reduction acetone boiling point with logical steam cycle heating and tank body in chuck is carried out concentrating under reduced pressure, and thickening temperature is controlled at 30
oC, vacuum degree control is at-0.08MPa, after concentrated, acetone evaporates rapidly, cooling recovery, recycles, and crystallization is separated out naturally, when acetone does not evaporate completely, remaining a small amount of acetone is put to concentrated suction filtration tank suction filtration together with xln, under vacuum condition, while hot by concentrated mother liquor elimination, until drain mother liquor, obtain the wet crystal of grisovin;
C, the wet crystal of grisovin, under agitation wash once with methylene dichloride, alcohol mixeding liquid, churning time is 2.5 hours, suction filtration 0.8 hour, then the medicinal alcohol that is under agitation 95% by concentration washs once, churning time is 0.8 hour, suction filtration 0.8 hour, obtains grisovin wet-milling after draining, dry through Vacuumdrier, micronizing, obtains grisovin product; Wherein, in methylene dichloride, alcohol mixeding liquid, methylene dichloride accounts for 65%(volume ratio), the grisovin crystal (weight) that wets: methylene dichloride, alcohol mixeding liquid (volume)=1:0.85 kg/L, the grisovin crystal (weight) that wets: medicinal alcohol (volume)=1: 0.8 kg/L.
The present embodiment grisovin product yield is 72.5%.
embodiment 4a preparation method for grisovin, is made up of following steps:
A, grisovin fermented liquid is heated to 95 DEG C, adds calcium oxide and adjust PH to 7, sheet frame solid-liquid separation, filter cake to add that calcium oxide is granulated, acetone extraction obtains grisovin acetone extract;
B, grisovin acetone extract, through activated carbon column decoloring, obtain grisovin acetone destainer, and destainer enters concentration tank, and the mode that vacuumizes reduction acetone boiling point with logical steam cycle heating and tank body in chuck is carried out concentrating under reduced pressure, and thickening temperature is controlled at 28
oC, vacuum degree control is at-0.08MPa, after concentrated, acetone evaporates rapidly, cooling recovery, recycles, and crystallization is separated out naturally, when acetone does not evaporate completely, remaining a small amount of acetone is put to concentrated suction filtration tank suction filtration together with xln, under vacuum condition, while hot by concentrated mother liquor elimination, until drain mother liquor, obtain the wet crystal of grisovin;
C, the wet crystal of grisovin, under agitation wash once with methylene dichloride, alcohol mixeding liquid, churning time is 2.4 hours, suction filtration 0.9 hour, then the medicinal alcohol that is under agitation 95% by concentration washs once, churning time is 0.9 hour, suction filtration 0.7 hour, obtains grisovin wet-milling after draining, dry through Vacuumdrier, micronizing, obtains grisovin product; Wherein, in methylene dichloride, alcohol mixeding liquid, methylene dichloride accounts for 68%(volume ratio), the grisovin crystal (weight) that wets: methylene dichloride, alcohol mixeding liquid (volume)=1:0.85 kg/L, the grisovin crystal (weight) that wets: medicinal alcohol (volume)=1: 0.8 kg/L.
The present embodiment grisovin product yield is 73%.
embodiment 5a preparation method for grisovin, is made up of following steps:
A, grisovin fermented liquid is heated to 85 DEG C, adds calcium oxide and adjust PH to 6, sheet frame solid-liquid separation, filter cake to add that calcium oxide is granulated, acetone extraction obtains grisovin acetone extract;
B, grisovin acetone extract, through activated carbon column decoloring, obtain grisovin acetone destainer, and destainer enters concentration tank, and the mode that vacuumizes reduction acetone boiling point with logical steam cycle heating and tank body in chuck is carried out concentrating under reduced pressure, and thickening temperature is controlled at 26
oC, vacuum degree control is at-0.09MPa, after concentrated, acetone evaporates rapidly, cooling recovery, recycles, and crystallization is separated out naturally, when acetone does not evaporate completely, remaining a small amount of acetone is put to concentrated suction filtration tank suction filtration together with xln, under vacuum condition, while hot by concentrated mother liquor elimination, until drain mother liquor, obtain the wet crystal of grisovin;
C, the wet crystal of grisovin, under agitation wash once with methylene dichloride, alcohol mixeding liquid, churning time is 2.6 hours, suction filtration 0.8 hour, then the medicinal alcohol that is under agitation 95% by concentration washs once, churning time is 0.6 hour, suction filtration 0.8 hour, obtains grisovin wet-milling after draining, dry through Vacuumdrier, micronizing, obtains grisovin product; Wherein, in methylene dichloride, alcohol mixeding liquid, methylene dichloride accounts for 72%(volume ratio), the grisovin crystal (weight) that wets: methylene dichloride, alcohol mixeding liquid (volume)=1:0.85 kg/L, the grisovin crystal (weight) that wets: medicinal alcohol (volume)=1: 0.8 kg/L.
The present embodiment grisovin product yield is 71%.
Claims (1)
1. a preparation method for grisovin, is characterized in that, is made up of following steps:
A, grisovin fermented liquid is heated to 80～100 DEG C, adds calcium oxide and adjust pH5.5～7, sheet frame solid-liquid separation, filter cake to add that calcium oxide is granulated, acetone extraction obtains grisovin acetone extract;
B, grisovin acetone extract are through activated carbon column decoloring, obtain grisovin acetone destainer, destainer enters concentration tank, the mode that vacuumizes reduction acetone boiling point with logical steam cycle heating and tank body in chuck is carried out concentrating under reduced pressure, thickening temperature is controlled at 27 ± 3 DEG C, vacuum degree control is at-0.09～-0.07MPa, condensing crystal, when acetone does not evaporate completely, remaining a small amount of acetone is put to concentrated suction filtration tank suction filtration together with xln, under vacuum condition, while hot by concentrated mother liquor elimination, until drain mother liquor, obtain the wet crystal of grisovin;
C, the wet crystal of grisovin, under agitation wash once with methylene dichloride, alcohol mixeding liquid, churning time is 2～3 hours, suction filtration 0.5～1 hour, then the medicinal alcohol that is under agitation 95% by concentration washs once, churning time is 0.5～1 hour, suction filtration 0.5～1 hour, obtains grisovin wet-milling after draining, dry through Vacuumdrier, micronizing, obtains grisovin product; Wherein, in methylene dichloride, alcohol mixeding liquid, methylene dichloride accounts for 60～75%(volume ratio), the grisovin crystal (weight) that wets: methylene dichloride, alcohol mixeding liquid (volume)=1:0.8～0.9kg/L, the grisovin crystal (weight) that wets: medicinal alcohol (volume)=1: 0.8kg/L.
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| CN109055350A (en) * | 2018-10-16 | 2018-12-21 | 内蒙古格林特制药有限责任公司 | A method of passing through dithyl sulfate and ultraviolet mutagenesis griseofulvin strain |
| CN109456291B (en) * | 2018-11-30 | 2022-09-20 | 赤峰制药股份有限公司 | Method for producing griseofulvin by low-temperature rapid crystallization |
| CN110317841B (en) * | 2019-07-10 | 2022-11-22 | 内蒙古格林特制药有限责任公司 | Fermentation production culture medium for griseofulvin |
| CN110747511A (en) * | 2019-10-23 | 2020-02-04 | 中山大学 | Compound single crystal and method for producing same |
| CN112094874A (en) * | 2020-09-16 | 2020-12-18 | 内蒙古格林特制药有限责任公司 | Culture medium for producing griseofulvin through fermentation |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1046987A (en) * | 1965-07-13 | 1966-10-26 | Le Nii Antibiotikov | Method of isolating the antibiotic crude griseofulvin from a methylene chloride extract |
| CN86104044A (en) * | 1986-06-28 | 1987-03-25 | 南通醋酸化工厂 | Crystallization of griseofulvin grains method and device thereof |
| CN101812489A (en) * | 2010-04-29 | 2010-08-25 | 赤峰制药股份有限公司 | Culture medium for producing griseofulvin by fermentation |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1046987A (en) * | 1965-07-13 | 1966-10-26 | Le Nii Antibiotikov | Method of isolating the antibiotic crude griseofulvin from a methylene chloride extract |
| CN86104044A (en) * | 1986-06-28 | 1987-03-25 | 南通醋酸化工厂 | Crystallization of griseofulvin grains method and device thereof |
| CN101812489A (en) * | 2010-04-29 | 2010-08-25 | 赤峰制药股份有限公司 | Culture medium for producing griseofulvin by fermentation |
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Inventor after: Hu Zhiyuan Inventor after: Zhao Yinan Inventor after: Tu Shungen Inventor after: Hu Jiayue Inventor after: Tu Shu Inventor after: Song Miao Inventor after: Xu Si Inventor after: Zhang Shijun Inventor after: Li Guoping Inventor before: Hu Zhiyuan Inventor before: Zhao Yinan Inventor before: Tu Genshun Inventor before: Hu Jiayue Inventor before: Tu Shu Inventor before: Song Miao Inventor before: Xu Si Inventor before: Zhang Shijun |
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Denomination of invention: A preparation method of griseofulvin Effective date of registration: 20210120 Granted publication date: 20140903 Pledgee: Agricultural Bank of China Limited Chifeng Changqing sub branch Pledgor: INNER MONGOLIA GLINT PHARMACEUTICAL Co.,Ltd. Registration number: Y2021150000003 |
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