CN108929335B - Preparation method of tacrolimus coarse crystal - Google Patents
Preparation method of tacrolimus coarse crystal Download PDFInfo
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- CN108929335B CN108929335B CN201811007773.7A CN201811007773A CN108929335B CN 108929335 B CN108929335 B CN 108929335B CN 201811007773 A CN201811007773 A CN 201811007773A CN 108929335 B CN108929335 B CN 108929335B
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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
Abstract
The invention provides a preparation method of tacrolimus coarse crystals, which comprises the steps of acidifying a tacrolimus fermentation liquid, and adsorbing resin; filtering to remove supernatant, washing with water to remove mycelium to obtain resin rich in tacrolimus; then stirring and soaking the mixture by using acetone to obtain a tacrolimus soaking solution, and concentrating the tacrolimus soaking solution under reduced pressure to obtain a concentrate; adding an organic solvent, stirring, removing solids, and standing the obtained solution to remove a water layer to obtain an organic solution; adding saturated sodium bicarbonate solution for washing, removing a water layer to obtain an organic phase, washing the organic phase to be neutral by purified water, then carrying out layering to obtain an organic solution layer, and finally carrying out reduced pressure concentration on the organic solution to obtain a dark brown oily substance; adding a polar solvent, stirring for dissolving, adding a non-polar solvent, crystallizing, and filtering to obtain tacrolimus crystals; and (5) drying under reduced pressure to obtain a crude tacrolimus product. The method has the advantages of low production cost, simple process, convenient operation, suitability for industrial production and the like.
Description
[ technical field ] A method for producing a semiconductor device
The invention belongs to the field of biological pharmaceutical engineering, relates to a preparation method of a microbial drug, and particularly relates to a preparation method of tacrolimus coarse crystals.
[ background of the invention ]
Tacrolimus (FK-506) is a macrolide powerful immunosuppressant extracted from fermentation liquor of S.tsukubaensis, the immunocompetence of the macrolide powerful immunosuppressant is 10-100 times of that of cyclosporine A, and the effect of preventing rejection reaction of various organ transplants is better than that of cyclosporine. Tacrolimus can reduce acute and chronic rejection of liver and kidney transplant recipients, the bacterial and viral infection rate of a patient after use is lower than that of a patient treated by cyclosporine, particularly, the tacrolimus has stronger hepatotropic property and stronger effect on liver transplantation than that of the cyclosporine, and the FK-506, MMF (mycophenolate mofetil) and Pred (prednisone) triple drug use has obvious synergistic effect and better effect. The tacrolimus can be used for preventing the immune response of organ transplantation and treating the immune response and autoimmune diseases such as systemic lupus erythematosus, and has wide application prospect.
At present, tacrolimus is generally produced by microbial fermentation, besides tacrolimus, a fermentation liquor also contains a culture medium which is not completely utilized, an acidic compound (such as fatty acid), a basic substance (such as alkaloid, polypeptide, a fat-soluble compound such as neutral fat) and an inorganic salt, the content of tacrolimus in the above products is low, a dark brown concentrate extracted from the fermentation liquor is generally viscous, the content of tacrolimus contained in the concentrate is lower than 40%, the purity of the concentrate is lower than 60% by High Performance Liquid Chromatography (HPLC), and the content of main heterocystomycin and dihydrotacrolimus is higher than 15%. Tacrolimus is easily degraded in a liquid state and is not beneficial to storage and transportation in a viscous concentrate, so that the dark brown concentrate obtained by fermentation is usually immediately purified into tacrolimus crystals with higher purity so as to be convenient for storage and transportation. However, in order to purify the dark brown concentrate into tacrolimus crystals with high purity, the tacrolimus crystals can be obtained through a series of complicated procedures such as column chromatography and the like.
In view of this, an improved method for preparing tacrolimus coarse crystals, which has the advantages of low production cost, simple process and convenient operation and is suitable for industrial production, is urgently needed for industrial production of tacrolimus bulk drugs. The invention provides a preparation method of tacrolimus coarse crystals, and products in the form of tacrolimus coarse crystals are not found in the current market.
[ summary of the invention ]
The invention aims to solve the technical problem of providing a preparation method of tacrolimus coarse crystals, which has the advantages of low production cost, simple process and convenient operation and is suitable for industrial production.
The invention is realized by the following steps:
a preparation method of tacrolimus coarse crystals is characterized in that tacrolimus fermentation liquor generated by fermentation of streptomyces tsukubaensis is operated by the following steps:
(1) enrichment and washing: acidifying tacrolimus fermentation liquor, and adsorbing by resin; filtering to remove supernatant, washing mycelium and resin with water, and removing mycelium to obtain resin rich in tacrolimus;
(2) soaking and concentrating: stirring and soaking the resin rich in tacrolimus obtained by the treatment in the step (1) with acetone to obtain a tacrolimus soaking solution, and concentrating under reduced pressure to obtain a concentrate;
(3) and (3) extraction: adding an organic solvent to the concentrate obtained by the treatment in the step (2), stirring, then filtering or centrifuging to remove solids, standing the obtained solution to separate the solution into two layers of water and an organic solution, and removing a water layer to obtain an organic solution;
(4) washing and concentrating: adding a saturated sodium bicarbonate solution into the organic solution obtained through the treatment in the step (3), wherein the volume ratio of the saturated sodium bicarbonate solution to the organic solution is 0.1-1: 1, washing the organic solution, removing a water layer to obtain an organic phase, continuously washing the organic phase with purified water until the water layer is neutral, then layering to obtain an organic solution layer, and finally concentrating the organic solution under reduced pressure to obtain a black brown oily substance;
(5) and (3) crystallization: adding a polar solvent into the oily substance obtained by the treatment in the step (4), stirring and dissolving to obtain a tacrolimus solution, wherein the volume ratio of the polar solvent to the oily substance is 0.1-0.5: 1, then adding a non-polar solvent, wherein the volume ratio of the non-polar solvent to the oily substance is 5-15: 1, standing at room temperature for 20-30 h, and filtering to remove liquid after crystallization to obtain tacrolimus crystals;
(6) and (3) drying: and (3) placing the obtained tacrolimus crystal at 40-50 ℃ for reduced pressure drying, comparing the obtained product with a tacrolimus standard product, and determining the product as a crude tacrolimus product.
Further, the resin in the step (1) is a nonpolar macroporous resin with a styrene-divinylbenzene copolymer as a framework, the resin particle size is 60-120 meshes, and the resin dosage is 1.0-3.5 g/100mL (W/V) of the fermentation liquor.
Further, the nonpolar macroporous resin is one of HP20, HB16, D101 or HZ 816.
Further, the organic solvent in the step (3) is butanol, and the volume ratio of the organic solvent to the soaking solution in the step (2) is 0.05-0.5: 1.
further, in the step (5), the polar solvent is butanol, and the nonpolar solvent is at least one of petroleum ether, hexane and cyclohexane.
Further, the preparation method also comprises the following steps:
(7) and (3) detection: detecting the purity of the tacrolimus product obtained in the step (6) by adopting high performance liquid chromatography;
the detection conditions of the high performance liquid chromatography are as follows: a chromatographic column: ZORBAX SB-CN column, chromatographic column specification: 5 μm, 4.6mm × 250mm, mobile phase: the volume ratio is acetonitrile: water: phosphoric acid 57:43:0.1 mixed solution of acetonitrile and water, detection wavelength: 210nm, column temperature: 60 ℃, flow rate: 1 mL/min.
The invention has the following advantages:
the tacrolimus fermentation liquor can obtain tacrolimus coarse crystals only by the steps of enrichment washing, soaking concentration, adsorption extraction, washing concentration, washing crystallization, crystal washing drying and the like without a series of complicated procedures such as column chromatography and the like, avoids using a large amount of organic solvents, and has the advantages of simple preparation process, convenient operation, low cost and suitability for industrial production. The invention greatly improves the purity and content of tacrolimus, and the product has the advantages of convenient storage and transportation.
[ description of the drawings ]
The invention will be further described with reference to the following examples with reference to the accompanying drawings.
FIG. 1 is an HPLC chromatogram of the fermentation of Streptomyces to produce tacrolimus of example 1 in the present invention.
FIG. 2 is an HPLC chromatogram of resin HP20 tacrolimus soak in example 1 of the present invention.
FIG. 3 is an HPLC chromatogram of tacrolimus crystals obtained by drying in example 1 of the present invention.
[ detailed description ] embodiments
The invention relates to a preparation method of tacrolimus coarse crystals, which is characterized in that tacrolimus fermentation liquor generated by fermentation of streptomyces tsukubaensis is operated by the following steps:
(1) enrichment and washing: adjusting the pH value of a tacrolimus fermentation liquid to 3.0-4.0 for acidification and resin adsorption; filtering to remove supernatant, washing mycelium and resin with water, and removing mycelium to obtain resin rich in tacrolimus; the resin is nonpolar macroporous resin taking a styrene-divinylbenzene copolymer as a framework, the particle size of the resin is 60-120 meshes, and the dosage of the resin is 1.0-3.5 g/100mL (W/V) of fermentation liquor.
(2) Soaking and concentrating: stirring and soaking the resin rich in tacrolimus obtained by the treatment in the step (1) with acetone to obtain a tacrolimus soaking solution, and concentrating under reduced pressure to obtain a concentrate;
(3) and (3) extraction: adding an organic solvent to the concentrate obtained by the treatment in the step (2), stirring, then filtering or centrifuging to remove solids, standing the obtained solution to separate the solution into two layers of water and an organic solution, and removing a water layer to obtain an organic solution; the organic solvent is butanol, and the volume ratio of the organic solvent to the soaking solution in the step (2) is 0.05-0.5: 1;
(4) washing and concentrating: adding a saturated sodium bicarbonate solution into the organic solution obtained through the treatment in the step (3), wherein the volume ratio of the saturated sodium bicarbonate solution to the organic solution is 0.1-1: 1, washing the organic solution, removing a water layer to obtain an organic phase, continuously washing the organic phase with purified water until the water layer is neutral, then layering to obtain an organic solution layer, and finally concentrating the organic solution under reduced pressure to obtain a black brown oily substance;
(5) and (3) crystallization: adding a polar solvent into the oily matter obtained by the treatment in the step (4), stirring and dissolving to obtain a tacrolimus solution, wherein the volume ratio of the polar solvent to the oily matter is 0.1-0.5: 1, then adding a non-polar solvent, wherein the volume ratio of the non-polar solvent to the oily matter is 5-15: 1, standing at room temperature for 24 hours, and filtering to remove liquid after crystallization to obtain tacrolimus crystals; the polar solvent is butanol, and the nonpolar solvent is at least one of petroleum ether, hexane and cyclohexane.
(6) And (3) drying: and (3) placing the obtained tacrolimus crystals at 45 ℃ for decompression drying, comparing the obtained product with a tacrolimus standard product, and determining the product as a crude tacrolimus product.
(7) And (3) detection: detecting the purity of the tacrolimus product obtained in the step (6) by adopting high performance liquid chromatography;
the detection conditions of the high performance liquid chromatography are as follows: a chromatographic column: ZORBAX SB-CN column, chromatographic column specification: 5 μm, 4.6mm × 250mm, mobile phase: the volume ratio is acetonitrile: water: phosphoric acid 57:43:0.1 mixed solution of acetonitrile and water, detection wavelength: 210nm, column temperature: 60 ℃, flow rate: 1 mL/min.
The nonpolar macroporous resin is one of HP20, HB16, D101 or HZ 816.
The present invention will be further described with reference to the following examples.
Example one
(1) Enrichment and washing: adjusting the pH of 650L of tacrolimus fermentation liquor to 3.5 by using 6N hydrochloric acid for acidification, wherein the titer of the fermentation liquor is 1522 mug/mL, and performing resin adsorption, wherein the resin is macroporous resin HP20, the particle size of the resin is 60-120 meshes, and the dosage of the resin is 2.8g/100mL (W/V) of the fermentation liquor; filtering to remove supernatant, washing mycelium and resin with water, and removing mycelium to obtain resin rich in tacrolimus;
(2) soaking and concentrating: stirring and soaking the resin rich in tacrolimus in 50L of acetone for 2 times, combining to obtain 100L of tacrolimus soaking solution, and concentrating under reduced pressure to obtain a concentrate;
(3) and (3) extraction: adding 10L of butanol into the concentrate obtained by the treatment in the step (2), stirring, filtering to remove solids, standing the obtained solution to separate the solution into two layers of water and an organic solution, and removing a water layer to obtain an organic solution;
(4) washing and concentrating: adding 2L of saturated sodium bicarbonate solution into the organic solution obtained by the treatment in the step (3), washing the organic solution, removing a water layer to obtain an organic phase, adding 2L of purified water, washing until the water layer is neutral, then layering to obtain an organic solution layer, and finally concentrating the organic solution under reduced pressure to obtain a black brown oily substance;
(5) and (3) crystallization: adding butanol into the oily substance obtained by the treatment in the step (4), stirring and dissolving to obtain a tacrolimus solution, wherein the volume ratio of the butanol to the oily substance is 0.1:1, then adding petroleum ether, wherein the volume ratio of the petroleum ether to the oily substance is 10:1, standing at room temperature for 24 hours, crystallizing, and filtering to remove liquid to obtain tacrolimus crystals;
(6) and (3) drying: the obtained tacrolimus crystals were dried at 45 ℃ under reduced pressure to obtain 1233.4g of crude tacrolimus.
Compared with a tacrolimus standard product, the purity of the tacrolimus coarse crystals is 91.5 percent, the contents of the main heterocystomycin and the dihydrotacrolimus are 7.9 percent, the tacrolimus content in the tacrolimus coarse crystals is 68.5 percent, and the actual yield is 85.4 percent through high performance liquid chromatography detection.
Referring to fig. 1-3, wherein fig. 1 is an HPLC chromatogram of tacrolimus produced by streptomyces fermentation in example 1 of the present invention, it can be seen from fig. 1 that the purity of tacrolimus in fermentation broth is 40.8%, and the contents of primary heterocystomycin and dihydrotacrolimus are 8.0%;
fig. 2 is an HPLC chromatogram of resin HP20 tacrolimus soaking solution in example 1 of the present invention, and it can be seen from fig. 2 that the purity of tacrolimus in the resin soaking solution is 78.0%, and the contents of primary heterocystomycin and dihydrotacrolimus are 12.8%;
FIG. 3 is an HPLC chromatogram of the tacrolimus crystals obtained by drying in example 1 of the present invention, and it can be seen from FIG. 3 that the purity of tacrolimus in the crystals is 91.5% and the contents of primary heterocystomycin and dihydrotacrolimus are 7.5%.
Example two
(1) Enrichment and washing: adjusting the pH of 600L of tacrolimus fermentation liquor to 3.5 by using 6N hydrochloric acid for acidification, wherein the titer of the fermentation liquor is 1539 mu g/mL, and performing resin adsorption, wherein the resin is macroporous resin HP20, the particle size of the resin is 60-120 meshes, and the dosage of the resin is 3.0g/100mL (W/V) of the fermentation liquor; filtering to remove supernatant, washing mycelium and resin with water, and removing mycelium to obtain resin rich in tacrolimus;
(2) soaking and concentrating: stirring and soaking the resin rich in tacrolimus in 50L of acetone for 2 times, combining to obtain 100L of tacrolimus soaking solution, and concentrating under reduced pressure to obtain a concentrate;
(3) and (3) extraction: adding 15L of butanol into the concentrate obtained by the treatment in the step (2), stirring, centrifuging to remove solids, standing the obtained solution to separate the solution into two layers of water and an organic solution, and removing a water layer to obtain an organic solution;
(4) washing and concentrating: adding 2L of saturated sodium bicarbonate solution into the organic solution obtained by the treatment in the step (3), washing the organic solution, removing a water layer to obtain an organic phase, adding 2L of purified water, washing until the water layer is neutral, then layering to obtain an organic solution layer, and finally concentrating the organic solution under reduced pressure to obtain a black brown oily substance;
(5) and (3) crystallization: adding butanol into the oily substance obtained by the treatment in the step (4), stirring and dissolving to obtain a tacrolimus solution, wherein the volume ratio of the butanol to the oily substance is 0.3:1, then adding hexane, wherein the volume ratio of the hexane to the oily substance is 8:1, standing at room temperature for 24 hours, crystallizing, and filtering to remove liquid to obtain tacrolimus crystals;
(6) and (3) drying: the obtained tacrolimus crystals were dried at 45 ℃ under reduced pressure to obtain 1133.6g of crude tacrolimus.
Compared with a tacrolimus standard product, the purity of the tacrolimus coarse crystals is 91.3 percent, the contents of the main heterocystomycin and the dihydrotacrolimus are 4.5 percent, the tacrolimus content in the tacrolimus coarse crystals is 70.3 percent, and the actual yield is 86.3 percent through high performance liquid chromatography detection.
EXAMPLE III
(1) Enrichment and washing: adjusting the pH value of 680L of tacrolimus fermentation liquor to 3.5 by using 6N hydrochloric acid for acidification, wherein the titer of the fermentation liquor is 1390 mu g/mL, and performing resin adsorption, wherein the resin is macroporous resin HP20, the particle size of the resin is 60-120 meshes, and the using amount of the resin is 1.0-3.5% of the fermentation liquor; filtering to remove supernatant, washing mycelium and resin with water, and removing mycelium to obtain resin rich in tacrolimus;
(2) soaking and concentrating: soaking tacrolimus-rich resin in 50L acetone under stirring for 2 times, mixing to obtain tacrolimus soaking solution 100L, concentrating under reduced pressure to obtain concentrate
(3) And (3) extraction: adding 12L of butanol into the concentrate obtained by the treatment in the step (2), stirring, filtering to remove solids, standing the obtained solution to separate the solution into two layers of water and an organic solution, and removing a water layer to obtain an organic solution;
(4) washing and concentrating: adding 2L of saturated sodium bicarbonate solution into the organic solution obtained by the treatment in the step (3), washing the organic solution, removing a water layer to obtain an organic phase, adding 50L of purified water to wash until the water layer is neutral, then layering to obtain an organic solution layer, and finally concentrating the organic solution under reduced pressure to obtain a black brown oily substance;
(5) and (3) crystallization: adding butanol into the oily substance obtained by the treatment in the step (4), stirring and dissolving to obtain a tacrolimus solution, wherein the volume ratio of the butanol to the oily substance is 0.2:1, then adding petroleum ether, wherein the volume ratio of the petroleum ether to the oily substance is 10:1, standing at room temperature for 24 hours, crystallizing, and filtering to remove liquid to obtain tacrolimus crystals;
(6) and (3) drying: the obtained tacrolimus crystals were dried at 45 ℃ under reduced pressure to obtain 1186.4g of crude tacrolimus.
Compared with a tacrolimus standard product, the purity of the tacrolimus coarse crystals is 91.8 percent, the contents of the main heterocystomycin and the dihydrotacrolimus are 4.1 percent, the tacrolimus content in the tacrolimus coarse crystals is 67.8 percent, and the actual yield is 85.1 percent through high performance liquid chromatography detection.
The invention has the advantages that: the tacrolimus coarse crystals can be obtained by acidifying the tacrolimus fermentation liquor, washing with resin enriched water, soaking and concentrating, adsorbing and extracting, washing and concentrating, washing and crystallizing, washing, crystallizing, drying crystals and the like. The method has the advantages of no need of a series of complicated procedures such as column chromatography and the like, avoiding the use of a large amount of organic solvents, protecting the environment, reducing the cost, obtaining the tacrolimus coarse crystals only by simple and conventional experimental operations, along with simple preparation process, convenient operation and suitability for industrial production. The invention greatly improves the purity and content of tacrolimus, and the product has the advantages of convenient storage and transportation.
Although specific embodiments of the invention have been described above, it will be understood by those skilled in the art that the specific embodiments described are illustrative only and are not limiting upon the scope of the invention, and that equivalent modifications and variations can be made by those skilled in the art without departing from the spirit of the invention, which is to be limited only by the appended claims.
Claims (2)
1. A preparation method of tacrolimus coarse crystals is characterized by comprising the following steps: the method comprises the following steps of:
(1) enrichment and washing: adjusting the pH value of a tacrolimus fermentation liquid to 3.0-4.0 for acidification and resin adsorption; filtering to remove supernatant, washing mycelium and resin with water, and removing mycelium to obtain resin rich in tacrolimus;
the resin is nonpolar macroporous resin taking a styrene-divinylbenzene copolymer as a framework, the particle size of the resin is 60-120 meshes, and the dosage of the resin is 1.0-3.5 g/100mL (W/V) of fermentation liquor; the nonpolar macroporous resin is one of HP20, HB16 and D101;
(2) soaking and concentrating: stirring and soaking the resin rich in tacrolimus obtained by the treatment in the step (1) with acetone to obtain a tacrolimus soaking solution, and concentrating under reduced pressure to obtain a concentrate;
(3) and (3) extraction: adding an organic solvent to the concentrate obtained by the treatment in the step (2), stirring, then filtering or centrifuging to remove solids, standing the obtained solution to separate the solution into two layers of water and an organic solution, and removing a water layer to obtain an organic solution;
(4) washing and concentrating: adding a saturated sodium bicarbonate solution into the organic solution obtained through the treatment in the step (3), wherein the volume ratio of the saturated sodium bicarbonate solution to the organic solution is 0.1-1: 1, washing the organic solution, removing a water layer to obtain an organic phase, continuously washing the organic phase with purified water until the water layer is neutral, then layering to obtain an organic solution layer, and finally concentrating the organic solution under reduced pressure to obtain a black brown oily substance;
(5) and (3) crystallization: adding a polar solvent into the oily substance obtained by the treatment in the step (4), stirring and dissolving to obtain a tacrolimus solution, wherein the volume ratio of the polar solvent to the oily substance is 0.1-0.5: 1, then adding a non-polar solvent, wherein the volume ratio of the non-polar solvent to the oily substance is 5-15: 1, standing at room temperature for 20-30 h, and filtering to remove liquid after crystallization to obtain tacrolimus crystals;
(6) and (3) drying: placing the obtained tacrolimus crystals at 40-50 ℃ for decompression drying, comparing the obtained product with a tacrolimus standard product, and determining the product as a crude tacrolimus product;
the organic solvent in the step (3) is butanol, and the volume ratio of the organic solvent to the soaking solution in the step (2) is 0.05-0.5: 1;
in the step (5), the polar solvent is butanol, and the nonpolar solvent is petroleum ether.
2. The method for preparing tacrolimus macrocrystalline according to claim 1, characterized in that: the preparation method also comprises the following steps:
(7) and (3) detection: detecting the purity of the tacrolimus product obtained in the step (6) by adopting high performance liquid chromatography;
the detection conditions of the high performance liquid chromatography are as follows: a chromatographic column: ZORBAX SB-CN column, chromatographic column specification: 5 μm, 4.6mm × 250mm, mobile phase: the volume ratio is acetonitrile: water: phosphoric acid =57:43:0.1 mixed solution of acetonitrile and water, detection wavelength: 210nm, column temperature: 60 ℃, flow rate: 1 mL/min.
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| AU2003286417A1 (en) * | 2003-12-05 | 2005-06-24 | Biocon Limited | Process for the purification of macrolides |
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| CN102372726B (en) * | 2011-11-08 | 2014-02-19 | 福建省微生物研究所 | Preparation method for sirolimus coarse crystal |
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