CN103113440A - Preparation method of erythromycin thiocyanate - Google Patents
Preparation method of erythromycin thiocyanate Download PDFInfo
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- CN103113440A CN103113440A CN2013100366329A CN201310036632A CN103113440A CN 103113440 A CN103113440 A CN 103113440A CN 2013100366329 A CN2013100366329 A CN 2013100366329A CN 201310036632 A CN201310036632 A CN 201310036632A CN 103113440 A CN103113440 A CN 103113440A
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- matachrom
- erythromycin
- acetone
- purified water
- crude product
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- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- PGNYNCTUBKSHHL-UHFFFAOYSA-N 2,3-diaminobutanedioic acid Chemical compound OC(=O)C(N)C(N)C(O)=O PGNYNCTUBKSHHL-UHFFFAOYSA-N 0.000 title abstract 6
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Natural products O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims abstract description 92
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 56
- 239000000047 product Substances 0.000 claims abstract description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000012043 crude product Substances 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 29
- 239000008213 purified water Substances 0.000 claims abstract description 27
- 238000005406 washing Methods 0.000 claims abstract description 11
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims abstract description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 7
- 238000001035 drying Methods 0.000 claims abstract description 7
- 229960003276 erythromycin Drugs 0.000 claims description 46
- 239000000243 solution Substances 0.000 claims description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 31
- 239000007788 liquid Substances 0.000 claims description 14
- 238000002425 crystallisation Methods 0.000 claims description 11
- 230000008025 crystallization Effects 0.000 claims description 11
- 238000000855 fermentation Methods 0.000 claims description 11
- 230000004151 fermentation Effects 0.000 claims description 11
- 239000000706 filtrate Substances 0.000 claims description 7
- 238000012546 transfer Methods 0.000 claims description 7
- 239000012266 salt solution Substances 0.000 claims description 5
- 150000003567 thiocyanates Chemical class 0.000 claims description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 4
- 239000003957 anion exchange resin Substances 0.000 claims description 4
- 239000011347 resin Substances 0.000 claims description 4
- 229920005989 resin Polymers 0.000 claims description 4
- 239000012467 final product Substances 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- 239000008346 aqueous phase Substances 0.000 claims description 2
- 238000004042 decolorization Methods 0.000 claims description 2
- 238000011010 flushing procedure Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 abstract description 2
- NNRXCKZMQLFUPL-WBMZRJHASA-N (3r,4s,5s,6r,7r,9r,11r,12r,13s,14r)-6-[(2s,3r,4s,6r)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-14-ethyl-7,12,13-trihydroxy-4-[(2r,4r,5s,6s)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10-dione;(2r,3 Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O.O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 NNRXCKZMQLFUPL-WBMZRJHASA-N 0.000 abstract 2
- 239000003513 alkali Substances 0.000 abstract 2
- 229940098008 erythrocin Drugs 0.000 abstract 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- 238000001914 filtration Methods 0.000 abstract 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract 1
- 239000001257 hydrogen Substances 0.000 abstract 1
- VGTPCRGMBIAPIM-UHFFFAOYSA-M sodium thiocyanate Chemical compound [Na+].[S-]C#N VGTPCRGMBIAPIM-UHFFFAOYSA-M 0.000 description 16
- 239000006166 lysate Substances 0.000 description 9
- 239000012535 impurity Substances 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 229930006677 Erythromycin A Natural products 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000011148 porous material Substances 0.000 description 4
- 230000001954 sterilising effect Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000919 ceramic Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000001728 nano-filtration Methods 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- KYTWXIARANQMCA-PGYIPVOXSA-N (3r,4s,5s,6r,7r,9r,10z,11s,12r,13s,14r)-6-[(2s,3r,4s,6r)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-14-ethyl-7,12,13-trihydroxy-10-hydroxyimino-4-[(2r,4r,5s,6s)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,7,9,11,13-hexamethyl-oxacyclotetradec Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N\O)/[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 KYTWXIARANQMCA-PGYIPVOXSA-N 0.000 description 2
- RXZBMPWDPOLZGW-XMRMVWPWSA-N (E)-roxithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N/OCOCCOC)/[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 RXZBMPWDPOLZGW-XMRMVWPWSA-N 0.000 description 2
- MQTOSJVFKKJCRP-HHZDEWPHSA-N Azythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@H]([C@@]([C@H](O)[C@H](C)N(C)C[C@@H](C)C[C@](C)(O)[C@@H](O[C@@H]2[C@H]([C@@H](C[C@H](C)O2)N(C)C)O)[C@@H]1C)(C)O)CC)[C@@H]1C[C@](C)(OC)[C@H](O)[C@@H](C)O1 MQTOSJVFKKJCRP-HHZDEWPHSA-N 0.000 description 2
- MWFRKHPRXPSWNT-UHFFFAOYSA-N Erythromycin-C Natural products CC1C(OC2C(C(CC(C)O2)N(C)C)O)C(C)(O)CC(C)C(=O)C(C)C(O)C(O)(C)C(CC)OC(=O)C(C)C1OC1CC(C)(O)C(O)C(C)O1 MWFRKHPRXPSWNT-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 229950002013 berythromycin Drugs 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 229960002626 clarithromycin Drugs 0.000 description 2
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 2
- IDRYSCOQVVUBIJ-PPGFLMPOSA-N erythromycin B Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@H]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)C)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 IDRYSCOQVVUBIJ-PPGFLMPOSA-N 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 238000010979 pH adjustment Methods 0.000 description 2
- 229960005224 roxithromycin Drugs 0.000 description 2
- 238000011218 seed culture Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000008719 thickening Effects 0.000 description 2
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- PRUSTPADOGZAML-UHFFFAOYSA-N erythromycin E Natural products O1C2C(C)C(OC3C(C(CC(C)O3)N(C)C)O)C(C)(O)CC(C)C(=O)C(C)C(O)C(O)(C)C(CC)OC(=O)C2COC21CC(C)(OC)C(O)C(C)O2 PRUSTPADOGZAML-UHFFFAOYSA-N 0.000 description 1
- PRUSTPADOGZAML-LMXGZOGMSA-N erythromycin E Chemical compound C([C@H]1C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@@H](C)[C@@H]1O1)(C)O)CC)O[C@]21C[C@@](C)(OC)[C@@H](O)[C@H](C)O2 PRUSTPADOGZAML-LMXGZOGMSA-N 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 235000014666 liquid concentrate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000000050 nutritive effect Effects 0.000 description 1
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
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- Saccharide Compounds (AREA)
Abstract
The invention discloses a preparation method of erythromycin thiocyanate; the preparation method comprises the following steps of: (1) washing erythromycin thiocyanate crude product by 40-60 DEG C purified water, dissolving into 38-48 DEG C acetone, wherein the volume of acetone is 1-4 times of that of erythromycin thiocyanate crude product, adjusting pH (potential of hydrogen) to be 9.0-10.5, then washing by saturated NaCl, separating phases, throwing water phase away, so as to obtain acetone solution containing erythrocin alkali; and (2) adding thiocyanate into the erythrocin alkali acetone solution obtained in the step (1), acidifying, crystallizing, filtering, washing by purified water and drying, finally the erythromycin thiocyanate product is obtained. The erythromycin thiocyanate prepared by the method is excellent in quality, high in yield, low in production cost, and excellent in industrial application prospect.
Description
Technical field
The present invention relates to a kind of preparation method of Matachrom.
Background technology
Matachrom (being called for short sulphur red) is the thiocyanate-of erythromycin, initial Matachrom is a kind of veterinary drug, development and application along with semisynthetic antibiotics, Matachrom becomes a kind of important medicine intermediate, be used for the synthesis of erythromycin oxime, erythromycin oxime can get clarithromycin, Roxithromycin and Azythromycin etc. by chemosynthesis.In recent years clarithromycin, Roxithromycin and the more than half synthesis of erythromycin of Azythromycin three at home and abroad the demand on market rise rapidly, also in rising trend as the demand of the Matachrom of its synthesis material.The erythromycin main active ingredient is Erythromycin A, and impurity composition mainly contains berythromycin, Erythromycin C, Erythromycin E, ErF etc., and the content of each impurity composition that different strain and different fermentations condition obtain is also different.Present most enterprise classifies to product according to erythromycin and foreign matter content, in regulation " acceptable end product ", and berythromycin≤1.5%, Erythromycin C≤2%, other impurity≤3%.Erythromycin A content is higher, foreign matter content is fewer, and its product price is higher.Therefore, the related products of the low impurity of preparation, high purity Erythromycin A has a good application prospect.
application number: 201110396176.X, denomination of invention: the Patent Application Publication of " a kind of preparation method of Matachrom " a kind of preparation method of Matachrom, comprise the steps: that (1) fermented liquid is concentrated: erythromycin fermentation liquid concentration is that to transfer pH be 7.5～9.0 for 5～20% sodium hydroxide solution, adopt the ceramic membrane filter in 50nm～100nm aperture, filtered liquid concentrates with the nanofiltration membrane of 200 molecular weight, obtains the erythromycin concentrated solution, (2) crystallization: the erythromycin concentrated solution is placed in crystallizer, every BOU erythromycin adds 5～20% sodium thiocyanate solutions of 0.15～0.2kg, it is 5.5～7.0 that glacial acetic acid solution with 20～80% is regulated pH, the crystallization Matachrom, solidliquid mixture gets the Matachrom crude product through centrifugation, the Matachrom crude product adds acetone according to 1: 1～1: 8 ratio, be that to regulate pH be 9.5～10.5 for 5%～20% sodium hydroxide solution with concentration, Matachrom is changed into erythromycin, standing, get acetone soln, every BOU erythromycin adds 5～20% sodium thiocyanate solutions of 0.15～0.2kg, transfer pH to 5.5～7.5 with 20～80% glacial acetic acid solutions, 1～3 times by the lysate volume adds 45～60 ℃ of purified water, 20～35 ℃ of crystallization control temperature, adopt variable-frequency motor slowly to stir 10 minutes, standing cooling entered whizzer in 0.5～2 hour and separates to get the Matachrom wet product again, use respectively acetone in Matachrom wet product whizzer, 45～60 ℃ of purified water drip washing, centrifugation is until the mother liquor discharge, dry, namely get the Matachrom finished product, erythromycin fermentation liquid prepares in accordance with the following steps: (1) erythromycin seed liquor is cultivated: 1. female slant pore preparation: will freezingly be kept at streptomyces erythareus (producing bacterium) spore inoculating in the sand pipe on the slant medium through sterilizing, under 32～34 ℃ of conditions of temperature, cultivated 7～9 days, 2. sub-slant pore preparation: with female slant pore, be inoculated on the slant medium of sterilization, under 32～34 ℃ of conditions of temperature, cultivated 7～9 days, 3. seed culture: with sub-slant pore, be inoculated in the seed culture medium through sterilization, through three grades of seed enlarged culturing, obtain the erythromycin seed liquor, (2) fermentation: the erythromycin seed liquor is inoculated in the substratum of sterilization by 10～20% volume ratios, passes into sterile air and open to stir, add nutritive substance, cultivate through 7～10 days, get erythromycin fermentation liquid.The Matachrom foreign matter content of the method preparation is higher, and yield is lower, requires further improvement.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of new Matachrom and the Matachrom that the method makes.
The preparation method of Matachrom of the present invention, it comprises the steps:
(1) the Matachrom crude product is rinsed with 40 ~ 60 ℃ of purified water after, be dissolved in the acetone of 38 ~ 48 ℃, the acetone volume is 1 ~ 4 times of Matachrom crude product, transfer pH to 9.0 ~ 10.5, then use saturated NaCl solution washing, phase-splitting, aqueous phase discarded must contain the acetone soln of erythromycin;
(2) get the erythromycin acetone soln of step (1), add thiocyanate-, acidifying, crystallization is filtered, and purified water is rinsed, and drying namely gets the Matachrom finished product.
Preferably, in step (1), the temperature of described purified water is 55 ℃, and the number of times of flushing is twice; Described acetone volume is 3 ~ 3.5 times of Matachrom crude product.
Preferably, in step (1), described acetone temperature is 38 ~ 45 ℃.Further preferably, in step (1), described pH value is adjusted to 9.0 ~ 9.8.
Preferably, be that 25 ~ 34%(w/w) NaOH solution is regulated the pH value with concentration.
Wherein, the technique of described step (2) is as follows: in containing the acetone soln of erythromycin, add thiocyanate salt solution, every BOU erythromycin adds 1.72 ~ 2.47mol thiocyanate-, and transferring pH is 6.0 ~ 7.8, the purified water that adds 1 ~ 2 times of volume, 20 ~ 30 ℃ of lower crystallizations, standing 1 ~ 2.4h is centrifugal, purified water is rinsed, dry getting final product.Wherein, described thiocyanate salt solution is that concentration is 40%(w/w) sodium thiocyanate solution; Acetum with 25 ~ 50%(w/w) is transferred pH.
Described Matachrom crude product can make by the following method:
1) get erythromycin fermentation liquid, filter, get filtrate through resin decolorization, concentrated, get the erythromycin concentrated solution, described resin is that macroporous acrylic is strongly basic anion exchange resin;
2) in the erythromycin concentrated solution that step 1) obtains, add thiocyanate-, acidifying is filtered, and makes the Matachrom crude product.
In described step 1), during decolouring, flow velocity 10 ~ 60BV/h, the pH of upper prop liquid are 6.5 ~ 7.5.
Wherein, described step 2) technique is as follows: in the erythromycin concentrated solution, adding concentration is 40% thiocyanate salt solution, every BOU erythromycin adds 1.72 ~ 2.47mol thiocyanate-, then uses 25 ~ 50%(w/w) acetum to transfer pH to be 6.0 ~ 7.8, to add the purified water of 1 ~ 2 times of volume, controlling temperature is 20 ~ 30 ℃, standing 1 ~ 2.4h, centrifugal, get final product.
Thiocyanate-of the present invention refers to the salt that thiocyanate ion SCN-becomes, as, potassium sulfocyanate, Sodium Thiocyanate 99 etc.
The present invention also provides the Matachrom of preceding method preparation.
The present invention is by improving in the Matachrom preparation method, the Matachrom crude product prepares the preparation technology for the treatment of process and the Matachrom crude product of erythromycin, improved the red mould finished product of thiocyanic acid purity, tire and yield, significantly reduce the content of impurity, and save the step of the wet elaboration of acetone drip washing Matachrom, and simplify processing step, reduce the acetone usage quantity, reduced widely production cost, increased economic efficiency.
The embodiment of form, be described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following embodiment.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Embodiment
Matachrom crude product and erythromycin fermentation liquid in the present invention, can obtain by buying the commercially available prod, also can adopt this area ordinary method preparation, as application number: 201110396176.X, denomination of invention: the method for the patent application document record of " a kind of preparation method of Matachrom ".
In the present invention, the concentration of sodium hydroxide solution is mass percentage concentration (w/w).
The preparation method of embodiment 1 Matachrom of the present invention
Get the Matachrom crude product, rinse with 40 ℃ of purified water.Matachrom crude product 38 ℃ of acetone solutions of 1:1, and regulate pH value 9.0 with the NaOH solution of 15% concentration, after the Matachrom crude product dissolves fully, with the saturated nacl aqueous solution washing, after phase-splitting, change lysate over to crystallizer.Sodium thiocyanate solution (the add-on: 0.14Kg Sodium Thiocyanate 99 dry product/1,000,000,000 erythromycin) that adds 40% concentration, regulate pH:6.0 with 25% acetum, add purified water, 20 ℃ of crystallization control temperature by the 1:1 of lysate volume, after standing 1 hour, put into the whizzer rejection filter.The wet product that obtains rinses twice with 50 ℃ of purified water again, obtains the Matachrom finished product after drying.
The preparation method of embodiment 2 Matachroms of the present invention
Get the Matachrom crude product, rinse twice with 60 ℃ of purified water.Dissolve in 48 ℃ of acetone of Matachrom crude product with 1:4, and regulate pH value 10.5 with the NaOH solution of 35% concentration, after the Matachrom crude product dissolves fully, with the saturated nacl aqueous solution washing, after phase-splitting, change lysate over to crystallizer.Sodium thiocyanate solution (the add-on: 0.2Kg Sodium Thiocyanate 99 dry product/1,000,000,000 erythromycin) that adds 40% concentration, regulate pH:7.8 with 50% acetum, add purified water, 30 ℃ of crystallization control temperature by the 1:2 of lysate volume, after standing 2.5 hours, put into the whizzer rejection filter.The wet product that obtains rinses twice with 60 ℃ of purified water again, obtains the Matachrom finished product after drying.
The preparation method of embodiment 3 Matachroms of the present invention
A, get erythromycin fermentation liquid 3.5m
3After 8% lye pH adjustment value 7.2, adopt the ceramic membrane filter in 0.1nm aperture, and push up with a certain amount of water and wash, with the controlled filter liquid 2500u/mI that tires.Filtrate is strongly basic anion exchange resin decolouring through macroporous acrylic, during decolouring, decolorizing column charging flow velocity 10BV/h, advance decolorizing column filtrate pH and be 6.5, destainer pH is 6.0.Filtrate after decolouring is concentrated through nanofiltration membrane again, when concentrated, controls 22 ℃ of feed pressure 0.4MPa, thickening temperatures.
B, concentrated solution is changed in the crude product crystallizer, sodium thiocyanate solution (the add-on: 0.18Kg Sodium Thiocyanate 99 dry product/1,000,000,000 erythromycin) that adds 40% concentration, regulate pH:6.0 with 5% acetum again, through the whizzer rejection filter, then rinse twice with 55 ℃ of purified water.Matachrom crude product 38 ℃ of acetone solutions of 1:3, and regulate pH value 9.0 with the NaOH solution of 25% concentration, after the Matachrom crude product dissolves fully, with the saturated nacl aqueous solution washing, after phase-splitting, change lysate over to crystallizer.Sodium thiocyanate solution (the add-on: 0.14Kg Sodium Thiocyanate 99 dry product/1,000,000,000 erythromycin) that adds 40% concentration, regulate pH:6.0 with 25% acetum, add purified water, 20 ℃ of crystallization control temperature by the 1:1 of lysate volume, after standing 1 hour, put into the whizzer rejection filter.The wet product that obtains rinses twice with 50 ℃ of purified water again, obtains the Matachrom finished product after drying.
The preparation method of embodiment 4 Matachroms of the present invention
A, get erythromycin fermentation liquid 3.5m
3,After 15% lye pH adjustment value 7.8, adopt the ceramic membrane filter in 0.1nm aperture, and push up with a certain amount of water and wash, with the controlled filter liquid 3500u/mI that tires.Macroporous acrylic is strongly basic anion exchange resin decolouring, during decolouring, decolorizing column charging flow velocity 60BV/h, advance decolorizing column filtrate pH and be 7.5, destainer pH is 7.5.Filtrate after decolouring is concentrated through nanofiltration membrane again, when concentrated,
Control 28 ℃ of feed pressure 0.4MPa, thickening temperatures.
B, concentrated solution is changed in the crude product crystallizer, sodium thiocyanate solution (the add-on: 0.25Kg Sodium Thiocyanate 99 dry product/1,000,000,000 erythromycin) that adds 40% concentration, regulate pH:7.0 with 5% acetum again, through the whizzer rejection filter, then rinse twice with 55 ℃ of purified water.Dissolve in 45 ℃ of acetone of Matachrom crude product with 1:3.5, and regulate pH value 9.8 with the NaOH solution of 34% concentration, after the Matachrom crude product dissolves fully, with the saturated nacl aqueous solution washing, after phase-splitting, change lysate over to crystallizer.Sodium thiocyanate solution (the add-on: 0.2Kg Sodium Thiocyanate 99 dry product/1,000,000,000 erythromycin) that adds 40% concentration, regulate pH:7.8 with 50% acetum, add purified water, 30 ℃ of crystallization control temperature by the 1:2 of lysate volume, after standing 2.5 hours, put into the whizzer rejection filter.The wet product that obtains rinses twice with 60 ℃ of purified water again, obtains the Matachrom finished product after drying.
Below with the formal specification of test example beneficial effect of the present invention.
Test example 1 the inventive method and existing methodical comparison
(1) comparison of product yield, purity
Getting with batch erythromycin fermentation liquid is raw material, according to method and the application number of embodiment 4
201110396176.X denomination of invention: the method for the Patent Application Publication of " a kind of preparation method of Matachrom " (method of prior art) prepares the Matachrom finished product, and both product is compared, and the results are shown in Table 1:
The contrast of table 1 quality product
As can be seen from Table 1, compare with the method for prior art, in the Matachrom finished product that the inventive method prepares, impurity B content reduces by 34.9%, impurity C content reduces by 54.4%, residue content reduces by 50%, and foreign matter content and residue content reduce very significantly, Erythromycin A content, tires and product yield also is improved.
To sum up, the inventive method can significantly improve quality product and yield, simplifies technique, reduces the acetone usage quantity, reduces production costs, and has good prospects for commercial application.
Claims (10)
1. the preparation method of a Matachrom, it is characterized in that: it comprises the steps:
(1) the Matachrom crude product is rinsed with 40 ~ 60 ℃ of purified water after, be dissolved in the acetone of 38 ~ 48 ℃, the acetone volume is 1 ~ 4 times of Matachrom crude product, transfer pH to 9.0 ~ 10.5, then use saturated NaCl solution washing, phase-splitting, aqueous phase discarded must contain the acetone soln of erythromycin;
(2) get the erythromycin acetone soln of step (1), add thiocyanate-, acidifying, crystallization is filtered, and purified water is rinsed, and drying namely gets the Matachrom finished product.
2. method according to claim 1, it is characterized in that: in step (1), the temperature of described purified water is 55 ℃, and the number of times of flushing is twice; Described acetone volume is 3 ~ 3.5 times of Matachrom crude product.
3. method according to claim 1, it is characterized in that: in step (1), described acetone temperature is 38 ~ 45 ℃.
4. method according to claim 1, it is characterized in that: in step (1), described pH value is adjusted to 9.0 ~ 9.8.
5. method according to claim 4 is characterized in that: be that 25 ~ 34%(w/w) NaOH solution is regulated the pH value with concentration.
6. method according to claim 1, it is characterized in that: the technique of described step (2) is as follows: in containing the acetone soln of erythromycin, add thiocyanate salt solution, every BOU erythromycin adds 1.72 ~ 2.47mol thiocyanate-, transfers pH to 6.0 ~ 7.8, the purified water that adds 1 ~ 2 times of volume, 20 ~ 30 ℃ of lower crystallizations, standing 1 ~ 2.4h is centrifugal, purified water is rinsed, dry getting final product.
7. method according to claim 6, it is characterized in that: the concentration of described thiocyanate salt solution is 40%(w/w); Transfer pH to adopt 25 ~ 50%(w/w) acetum.
8. method according to claim 1, it is characterized in that: described Matachrom crude product makes by the following method:
1) get erythromycin fermentation liquid, filter, get filtrate through resin decolorization, concentrated, get the erythromycin concentrated solution, described resin is that macroporous acrylic is strongly basic anion exchange resin;
2) in the erythromycin concentrated solution that step 1) obtains, add thiocyanate-, acidifying is filtered, and makes the Matachrom crude product.
9. method according to claim 8, it is characterized in that: in described step 1), during decolouring, flow velocity 10 ~ 60BV/h, the pH of upper prop liquid are 6.5 ~ 7.5.
10. the Matachrom of the described method of claim 1 ~ 9 any one preparation.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104593455A (en) * | 2013-10-30 | 2015-05-06 | 宁夏启元药业有限公司 | Method used for increasing erythromycin fermentation titer unit |
| CN105348340A (en) * | 2015-11-27 | 2016-02-24 | 宁夏启元药业有限公司 | Preparation method of erythromycin thiocyanate |
| CN110003295A (en) * | 2019-04-29 | 2019-07-12 | 宜昌东阳光药业股份有限公司 | A kind of preparation method of erythromycin thiocyanate |
| CN111848701A (en) * | 2019-04-29 | 2020-10-30 | 伊犁川宁生物技术有限公司 | Continuous crystallization method of crude erythromycin thiocyanate |
| CN112978993A (en) * | 2021-02-25 | 2021-06-18 | 宜昌东阳光生化制药有限公司 | Method for recovering thiocyanate ions from rectification waste liquid of erythromycin thiocyanate crystallization mother liquor and application |
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| CN102408462A (en) * | 2011-12-02 | 2012-04-11 | 伊犁川宁生物技术有限公司 | Preparation method of erythromycin thiocyanate |
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| CN102408462A (en) * | 2011-12-02 | 2012-04-11 | 伊犁川宁生物技术有限公司 | Preparation method of erythromycin thiocyanate |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104593455A (en) * | 2013-10-30 | 2015-05-06 | 宁夏启元药业有限公司 | Method used for increasing erythromycin fermentation titer unit |
| CN105348340A (en) * | 2015-11-27 | 2016-02-24 | 宁夏启元药业有限公司 | Preparation method of erythromycin thiocyanate |
| CN110003295A (en) * | 2019-04-29 | 2019-07-12 | 宜昌东阳光药业股份有限公司 | A kind of preparation method of erythromycin thiocyanate |
| CN110003295B (en) * | 2019-04-29 | 2020-05-12 | 宜昌东阳光药业股份有限公司 | Preparation method of erythromycin thiocyanate |
| CN111848701A (en) * | 2019-04-29 | 2020-10-30 | 伊犁川宁生物技术有限公司 | Continuous crystallization method of crude erythromycin thiocyanate |
| CN112978993A (en) * | 2021-02-25 | 2021-06-18 | 宜昌东阳光生化制药有限公司 | Method for recovering thiocyanate ions from rectification waste liquid of erythromycin thiocyanate crystallization mother liquor and application |
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