CN108329370A - A kind of preparation method of tartaric acid/Tylosin phosphate - Google Patents
A kind of preparation method of tartaric acid/Tylosin phosphate Download PDFInfo
- Publication number
- CN108329370A CN108329370A CN201810356481.8A CN201810356481A CN108329370A CN 108329370 A CN108329370 A CN 108329370A CN 201810356481 A CN201810356481 A CN 201810356481A CN 108329370 A CN108329370 A CN 108329370A
- Authority
- CN
- China
- Prior art keywords
- tylosin
- filtrate
- tartaric acid
- preparation
- tylosin phosphate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 235000002906 tartaric acid Nutrition 0.000 title claims abstract description 21
- 239000011975 tartaric acid Substances 0.000 title claims abstract description 21
- NBOODGNJLRRJNA-IAGPQMRQSA-N 2-[(4r,5s,6s,7r,9r,11e,13e,15r,16r)-6-[(2r,3r,4r,5s,6r)-5-[(2s,4r,5s,6s)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-16-ethyl-4-hydroxy-15-[[(2r,3r,4r,5r,6r)-5-hydroxy-3,4-dimethoxy-6-methyloxan-2-yl]oxymethyl Chemical compound OP(O)(O)=O.O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 NBOODGNJLRRJNA-IAGPQMRQSA-N 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 229940031989 tylosin phosphate Drugs 0.000 title claims abstract description 20
- 239000000706 filtrate Substances 0.000 claims abstract description 52
- 239000012530 fluid Substances 0.000 claims abstract description 21
- 239000000047 product Substances 0.000 claims abstract description 14
- 238000000605 extraction Methods 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 10
- 238000000926 separation method Methods 0.000 claims abstract description 10
- WBPYTXDJUQJLPQ-VMXQISHHSA-N tylosin Chemical compound O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 WBPYTXDJUQJLPQ-VMXQISHHSA-N 0.000 claims description 40
- 229930194936 Tylosin Natural products 0.000 claims description 39
- 239000004182 Tylosin Substances 0.000 claims description 39
- 229960004059 tylosin Drugs 0.000 claims description 39
- 235000019375 tylosin Nutrition 0.000 claims description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 34
- 238000000746 purification Methods 0.000 claims description 19
- 238000001914 filtration Methods 0.000 claims description 18
- 239000007788 liquid Substances 0.000 claims description 15
- 239000000654 additive Substances 0.000 claims description 7
- 230000000996 additive effect Effects 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 5
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical class Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 5
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 238000005119 centrifugation Methods 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000005189 flocculation Methods 0.000 claims 1
- 230000016615 flocculation Effects 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 17
- 238000000855 fermentation Methods 0.000 abstract description 13
- 230000004151 fermentation Effects 0.000 abstract description 13
- 108090000623 proteins and genes Proteins 0.000 abstract description 10
- 102000004169 proteins and genes Human genes 0.000 abstract description 10
- 238000001556 precipitation Methods 0.000 abstract description 9
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 abstract description 6
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 abstract description 6
- 239000004519 grease Substances 0.000 abstract description 5
- 125000001931 aliphatic group Chemical group 0.000 abstract description 3
- 230000035568 catharsis Effects 0.000 abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 235000011121 sodium hydroxide Nutrition 0.000 description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
- 235000010469 Glycine max Nutrition 0.000 description 6
- 244000068988 Glycine max Species 0.000 description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 5
- 235000019197 fats Nutrition 0.000 description 5
- 239000007791 liquid phase Substances 0.000 description 5
- ICVKYYINQHWDLM-KBEWXLTPSA-N (2r,3r)-2,3-dihydroxybutanedioic acid;2-[(4r,5s,6s,7r,9r,11e,13e,15r,16r)-6-[(2r,3r,4r,5s,6r)-5-[(2s,4r,5s,6s)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-16-ethyl-4-hydroxy-15-[[(2r,3r,4r,5r,6r)-5-hydroxy-3,4 Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 ICVKYYINQHWDLM-KBEWXLTPSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000011169 microbiological contamination Methods 0.000 description 4
- 238000002834 transmittance Methods 0.000 description 4
- 229960001717 tylosin tartrate Drugs 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- 238000010923 batch production Methods 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000000638 solvent extraction Methods 0.000 description 3
- 238000005507 spraying Methods 0.000 description 3
- QRPHLEPFYLNRDA-NLGRAQRVSA-N 2-[(4r,5s,6s,7r,9r,11e,13e,15r,16r)-6-[(2r,3r,4s,5s,6r)-4-(dimethylamino)-3,5-dihydroxy-6-methyloxan-2-yl]oxy-16-ethyl-4-hydroxy-15-[[(2r,3r,4r,5r,6r)-5-hydroxy-3,4-dimethoxy-6-methyloxan-2-yl]oxymethyl]-5,9,13-trimethyl-2,10-dioxo-1-oxacyclohexadeca-11,1 Chemical compound O([C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@@H]1O[C@H](C)[C@@H](O)[C@H](N(C)C)[C@H]1O QRPHLEPFYLNRDA-NLGRAQRVSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 108010070332 S-adenosyl-L-methionine-macrocin O-methyltransferase Proteins 0.000 description 2
- 241000187438 Streptomyces fradiae Species 0.000 description 2
- 241000187391 Streptomyces hygroscopicus Species 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- UFUYRGNJTFAODM-HQCAVAADSA-N macrocin Chemical compound O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](O)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 UFUYRGNJTFAODM-HQCAVAADSA-N 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000001728 nano-filtration Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- QDAVFUSCCPXZTE-VMXQISHHSA-N (4r,5s,6s,7r,9r,11e,13e,15r,16r)-6-[(2r,3r,4r,5s,6r)-5-[(2s,4r,5s,6s)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-16-ethyl-4-hydroxy-15-[[(2r,3r,4r,5r,6r)-5-hydroxy-3,4-dimethoxy-6-methyloxan-2-yl]oxymethyl]-7 Chemical compound O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CCO)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 QDAVFUSCCPXZTE-VMXQISHHSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- JUUBMADBGZQVFT-KHPPLWFESA-N (z)-2-methyloctadec-9-enoic acid Chemical compound CCCCCCCC\C=C/CCCCCCC(C)C(O)=O JUUBMADBGZQVFT-KHPPLWFESA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 1
- ZVOOGERIHVAODX-UHFFFAOYSA-N O-demycinosyltylosin Natural products O=CCC1CC(C)C(=O)C=CC(C)=CC(CO)C(CC)OC(=O)CC(O)C(C)C1OC1C(O)C(N(C)C)C(OC2OC(C)C(O)C(C)(O)C2)C(C)O1 ZVOOGERIHVAODX-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- 102000055026 Protein O-Methyltransferase Human genes 0.000 description 1
- 241000187419 Streptomyces rimosus Species 0.000 description 1
- KFRIFCPXKRVUOZ-UHFFFAOYSA-N Tylosin B Natural products CCC1OC(=O)CC(O)C(C)C(OC2OC(C)C(O)C(C2O)N(C)C)C(CC(C)C(=O)C=CC(=CC1COC3OC(C)C(O)C(OC)C3OC)C)C=O KFRIFCPXKRVUOZ-UHFFFAOYSA-N 0.000 description 1
- UFUYRGNJTFAODM-UHFFFAOYSA-N Tylosin C Natural products O=CCC1CC(C)C(=O)C=CC(C)=CC(COC2C(C(O)C(O)C(C)O2)OC)C(CC)OC(=O)CC(O)C(C)C1OC(C(C1N(C)C)O)OC(C)C1OC1CC(C)(O)C(O)C(C)O1 UFUYRGNJTFAODM-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000005261 decarburization Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000006607 hypermethylation Effects 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 235000020778 linoleic acid Nutrition 0.000 description 1
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 125000005506 phthalide group Chemical group 0.000 description 1
- 238000007781 pre-processing Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229950010526 relomycin Drugs 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
The present invention relates to a kind of preparation methods of tartaric acid/Tylosin phosphate, the filtered zymotic fluid of the present invention passes through specific lye, the specific proteins not filtered out in zymotic fluid can be carried out precipitation separation by specific pH, by the aliphatic acid for centrifuging the specific proteins that will be not filtered out in zymotic fluid and fermentation generation, amount of grease thoroughly removes, and catharsis is played to solvent butyl acetate, extracting efficient is promoted to carry out, other any influence will not be caused to solvent while purifying solvent, ensure that extraction is smoothed out, it is easy to operate simultaneously, it is at low cost, simply, processing means at low cost can reach efficiently, thoroughly reduce ferment filtrate impurity, improve the purity and dissolubility of product.
Description
Technical field
The present invention relates to a kind of preparation methods of tartaric acid/Tylosin phosphate, belong to biological pesticide preparing technical field.
Background technology
Tylosin is isolated by American scholar Hamill etc. from Thailand's soil first, and producing strains have streptomyces fradiae
(S.fradiae, NRR2702,2703), streptomyces rimosus (S.rimosns) and streptomyces hygroscopicus (S.hygro-scopicus)；
Tylosin active ingredient includes：Tylosin A (true tylosin), Tylosin B (decarburization enzyme sugar tylosin
Desmycosin) tylosin C (macrocin mucrosin) and tylosin D (relomycin Relomysin), component A >=
80%, total component A+B+C+D >=95%, potency ＞ 800IU.The chemical structural formula of each active ingredient of tylosin see the table below 1：
Table 1
The fermentation of tylosin is using soya-bean oil as primary carbon source.Glucose has apparent inhibition to make the biosynthesis of tylosin
With, if there are excessive glucose in idiophase fermentation, promote the rising of ATP levels, to inhibit the growth of tylosin,
And the oleic acid, linoleic acid in soya-bean oil form methyl oleic acid through Hypermethylation, it is the precursor substance of tylosin, can promote its life
Object synthesizes.Therefore, mainly meet needs of the producing strains to carbon source to add soya-bean oil during the fermentation.And strictly control soya-bean oil
Dosage be the key that determine fermentation success or failure.Soya-bean oil content is low, is unfavorable for mycelia and grows, and too high levels, then cannot be completely sharp
With the fatty acid accumulation of generation causes pH value to decline, thereby inhibits the activity of Macrocin o methyl transferase, affects component and contain
Amount.Temperature, PH, mycelia production status and soya-bean oil additive amount, the work to Macrocin o methyl transferase in tylosin fermentation process
Property tool characteristics index meaning, be always determine tylosin yield key point.
The fermentation of tylosin should strictly control living contaminants, if because condition is limited or inevitable or because of operation, equipment
Etc. reasons cause microbiological contamination, after tylosin broth microbiological contamination, it is of poor quality to put tank, there is foreign odor, and filtering velocity is slow, and filtrate is muddy, potency drop
Low, Residual oil is more, brings very big difficulty to production is refined, will directly affect the yield and quality of tylosin finished product.If zymotic fluid
Microbiological contamination is serious, causes it that can not handle and be forced tank switching, causes to waste and lose.The rotten reason of zymotic fluid is due to miscellaneous bacteria
Intrusion, makes the growth and breeding of Tylosin-producer be abnormal.Varied bacteria growing accounts for advantage, its metabolite, such as various
Enzyme and toxin will inhibit the normal growth of Tylosin-producer significantly, promote tylosin mycelium self-dissolving.In culture medium
Just with the presence of a large amount of colloid protein, zymotic fluid becomes muddy, and filtering velocity slows down and difficulty gives processing.
Tylosin each component has one other than with 16 common membered ring phthalides on the mould ammonia sugar of carbon of its side chain
A imino group, therefore its aobvious alkalescent.Under alkaline condition, exists in the form of tylosin alkali, be soluble in organic solvent；And in acid
Property under the conditions of with acid be combined into the form of salt, it is soluble easily in water.According to this characteristic, the extraction process of tylosin is generally adopted at present
Use solvent extraction.Specifically, zymotic fluid obtains filtrate through being separated by solid-liquid separation, and is arrived with solvent extraction after alkalization to pH value 9~10
Then organic phase is stripped into water phase with phosphoric acid or tartaric acid, most afterwards through Ca (OH)2It neutralizes and removes excessive acid, activated carbon is de-
Color, air precipitation, then obtain Tylosin phosphate or Tylosin Tartrate after nanofiltration and spray drying.
It in said extracted technique, is extracted after filtering, in filtered filtrate extraction process, has the filtered removing in part
Protein enter in organic phase, while the partial fatty acid for generation of fermenting will also enter in ester phase, cause impurity can not be by
It efficiently separates.
Therefore, impurity in tylosin broth is effectively removed, improving the quality of tylosin becomes pendulum in numerous pharmacy
Outstanding problem urgently to be resolved hurrily in face of enterprise.
Invention content
In view of the deficiencies of the prior art, the present invention provides a kind of preparation method of tartaric acid/Tylosin phosphate, the present invention
Method thoroughly eliminate the impurity such as filtered filtrate protein, Residual oil, do sufficient preparation for extraction, improve safe happy bacterium
The purity and solubility of plain product, and the preparation method simple process and low cost, process is short, utilization easy to spread.
Technical scheme is as follows：
A kind of preparation method of tartaric acid/Tylosin phosphate, including steps are as follows：
It is stirred after pre-processing to through flocculant or filter aid are added in the tylosin broth that everfermentation obtains, through sheet frame
Isolated filtrate after filtrate is purified, is extracted, and using back extraction, is decolourized, is dried to obtain tylosin product；
Wherein, the purification is that sodium hydroxide solution is added into filtrate, is then pumped into mixer and is mixed, and control pH exists
Within the scope of 7.5-8.0, mixed liquor under the rotating speed of 4000-5000 turns/min to centrifuge, and filtrate after being purified, filtrate adds after purification
Enter butyl acetate solvent to be extracted.
It is polyaluminium chloride, the additive amount of polyaluminium chloride and the weight of zymotic fluid according to currently preferred, described flocculant
For amount than being 1.0 ± 0.3% (w/w), the filter aid is the polymeric aluminum chlorides solution that mass concentration is 20-22%, polymerize chlorine
Change 0.6% (w/v) of the additive amount of aluminum solutions and the mass volume ratio of zymotic fluid；Pretreatment time is 20-30min.
It is carried out using press filtration or squeezing mode according to currently preferred, described separation of solid and liquid, press filtration or squeeze pressure
Less than or equal to 0.4Mpa.
According to currently preferred, purification control pH is 7.5-7.9, it is preferable that purification control pH is 7.5-7.7, the most excellent
Choosing, purification control pH is 7.54.
According to currently preferred, centrifugal rotational speed is that 4500-4800 turns/min, centrifugation time 0.2s-2min.
According to currently preferred, sodium hydroxide solution mass concentration is 2-6wt%.
The method of the present invention, filtrate centrifuge after being mixed with liquid caustic soda, will be separated by solid-liquid separation the protein that can not be removed and fermentation
Aliphatic acid, the amount of grease of generation thoroughly remove, and reduce impurity when filtrate extraction, after the purification processes of the present invention,
Filtrate light transmission has been increased to 92.4% by original 64.7%, and impurity significantly reduces in filtrate, while being compared by efficient liquid phase
It can be confirmed that impurity is significantly reduced or reduced in filtrate, impurity peaks number becomes 10 from original 16 impurity peaks.When extraction
Due in filtrate albumen and fat significantly reduce, after extraction, emulsion significantly reduces.Purification processes through the invention, carry
The processing capacity to microbiological contamination tank is taken to greatly enhance, the albumen and grease in feed liquid are substantially reduced the pollution of butyl ester, subsequent handling
By increasing filter and filtering accuracy, the albumen and fat in feed liquid are further retained, after improvement, existing product dissolubility
Have and be obviously improved, product content also by the 893u/mg of former technique, has been increased to 934u/mg.
The present inventor has been surprisingly found that filtered zymotic fluid can will ferment after adjusting pH by specific lye
The specific proteins not filtered out in liquid carry out precipitation separation, by centrifuging the Special Proteins that will not be filtered out in zymotic fluid
Aliphatic acid, the amount of grease that matter and fermentation generate thoroughly remove, and play catharsis to solvent butyl acetate, promote to extract
It efficiently carries out, other any influence will not be caused to solvent while purifying solvent, ensure that extraction is smoothed out, operate simultaneously
Simply, at low cost, processing means simple, at low cost can reach efficient, thorough reduction ferment filtrate impurity, improve production
The purity and dissolubility of product.
The method have the advantages that：
1, the present invention filtered zymotic fluid will can not be filtered out by specific lye, specific pH in zymotic fluid
Specific proteins carry out precipitation separation, by the fat for centrifuging the specific proteins that will be not filtered out in zymotic fluid and fermentation generation
Fat acid, amount of grease thoroughly remove, and play catharsis to solvent butyl acetate, promote extracting efficient to carry out, are purifying
Other any influence will not be caused while solvent to solvent, ensure that extraction is smoothed out, while easy to operate, at low cost, letter
Single, at low cost processing means can reach efficient, thorough reduction ferment filtrate impurity, improve purity and the dissolving of product
Property.
The raw materials used in the present invention and equipment are the prior art.
Description of the drawings
Fig. 1 is to obtain the high-efficient liquid phase chromatogram of filtrate after tylosin broth press filtration in embodiment 1；
Fig. 2 be embodiment 1 in tylosin broth press filtration add alkali carries pure after purification after filtrate high performance liquid chromatography
Figure；
Fig. 3 is to obtain the high-efficient liquid phase chromatogram of filtrate after tylosin broth press filtration in embodiment 2；
Fig. 4 be embodiment 2 in tylosin broth press filtration add alkali carries pure after purification after filtrate high performance liquid chromatography
Figure；
Fig. 5 is to obtain the high-efficient liquid phase chromatogram of filtrate after tylosin broth press filtration in embodiment 3；
Fig. 6 be embodiment 3 in tylosin broth press filtration add alkali carries pure after purification after filtrate high performance liquid chromatography
Figure.
Specific implementation mode
Below by specific embodiment, the present invention will be further described, but not limited to this.
Tylosin broth source：The zymotic fluid that tylosin fermentation plant obtains after fermentation.
Embodiment 1
A kind of preparation method of tartaric acid/Tylosin phosphate, including steps are as follows：
Tylosin broth volume 10m3, potency 12386U/mL, total hundred million be 123.9.Polyaluminium chloride is added, it is polychloride
The additive amount of aluminium and the weight ratio of zymotic fluid are 1.0 ± 0.3% (w/w), are stirred 25 ± 5 minutes.With flame filter press to fermentation
Liquid is filtered, and control feed pressure is 0.3MPa, and filtrate, as tylosin filtrate, volume 12m are obtained after press filtration3, effect
Valence is 9621U/mL.
The sodium hydroxide solution that mass concentration is 3% is squeezed into mixer through pump simultaneously with filtrate, pH is 7.7 for control, and
Mixed feed liquid is squeezed into the rotating speed in centrifuge with 4500 turns/min and centrifuges 2s, filtrate after must purifying；Filtrate after purifying
It is sent into mixer with butyl acetate, liquid caustic soda and mixes, adjust pH value and be sent into centrifuge, ester phase after 9.8 ranges, mixing
It squeezes into water body tank and cools down, is pending；Ester in water body tank mutually after cooling down, standing, is added 2% phosphoric acid/tartaric acid stirring and (adjusts
Save pH to 3.6), stand, separation, collect lower layer's water phase；Calcium hydroxide solution is added and demodulates pH to 6.1, activated carbon is added to it
It decolourizes, and is squeezed into decoloration sheet frame and be filtered, squeeze, water phase enters precipitation tank.Material in tank is carried out with nitrogen
Carrying out precipitation treatment, until material is without butyl ester.Water phase is concentrated using NF membrane, removes moisture removal, obtains tylosin concentrate；
Processing is dried to concentrate using spraying centrifugal drying tower, obtains phosphoric acid/Tylosin Tartrate powder.
Embodiment 2
A kind of preparation method of tartaric acid/Tylosin phosphate, including steps are as follows：
Tylosin broth volume 9.5m3, potency 13194U/mL, total hundred million be 126.9.Addition mass concentration is 20-
22% polymeric aluminum chlorides solution, the additive amount of polymeric aluminum chlorides solution and the mass volume ratio of zymotic fluid are 0.6% (w/v),
Stirring 40 minutes.Zymotic fluid is filtered with flame filter press, control press filtration/squeeze pressure is 4.0MPa, is obtained after press filtration
Filtrate, as tylosin filtrate, volume 11m3, potency 10832U/mL.
Sodium hydroxide solution and filtrate that mass concentration is 4wt% are squeezed into mixer through pump simultaneously, control pH 7.9,
And 2s, filtrate after must purifying are centrifuged with the rotating speed of 4800 turns/min in squeezing into mixed feed liquid in centrifuge；After purifying
Filtrate and butyl acetate, liquid caustic soda are sent into mixer and mixs, adjust pH value in 10.5 ranges, after mixing feeding centrifuge from
The heart, ester, which is mutually squeezed into water body tank, to cool down, is pending；Mutually after cooling down, standing, 2% phosphoric acid/tartaric acid is added in ester in water body tank
Stirring (adjusting pH to 3.7) is stood, separation, collects lower layer's water phase；Calcium hydroxide solution is added and demodulates pH to 6.3, activity is added
Charcoal decolourizes to it, and is squeezed into decoloration sheet frame and be filtered, squeeze, and water phase enters precipitation tank.With nitrogen to object in tank
Material carries out carrying out precipitation treatment, until material is without butyl ester.Water phase is concentrated using NF membrane, removes moisture removal, obtains tylosin
Concentrate；Processing is dried to concentrate using spraying centrifugal drying tower, obtains phosphoric acid/Tylosin Tartrate powder.
Embodiment 3
A kind of preparation method of tartaric acid/Tylosin phosphate, described in embodiment 1, the difference is that：
Sodium hydroxide solution and filtrate that mass concentration is 3wt% are squeezed into mixer through pump simultaneously, control pH 7.54,
It is extracted after centrifugation.
It is compared by Fig. 1 and Fig. 2, it can be clearly seen that, the impurity peaks after purification in the chromatogram of filtrate, which are considerably less than, schemes
1, it is compared by Fig. 3 and Fig. 4, it can be clearly seen that, the impurity peaks after purification in the chromatogram of filtrate are considerably less than Fig. 3, pass through
Fig. 5 and Fig. 6 is compared, it can be clearly seen that, the impurity peaks after purification in the chromatogram of filtrate are considerably less than Fig. 5, therefore, by this
After the purification processes of invention, by efficient liquid phase comparison it can be confirmed that impurity is significantly reduced or reduced in filtrate, impurity peaks number
Become 10 from original 16 impurity peaks.When extraction due in filtrate albumen and fat significantly reduce, after extraction, emulsion
It significantly reduces.
Comparative example 1
A kind of preparation method of tartaric acid/Tylosin phosphate, traditionally carries out, i.e., zymotic fluid is through being separated by solid-liquid separation
To filtrate, filtrate pH is 5.63, filtrate alkalize to pH value 9~10 after with solvent extraction to organic phase, then with phosphoric acid or winestone
Acid is stripped into water phase, most afterwards through Ca (OH)2It neutralizes and removes excessive acid, activated carbon decolorizing, air precipitation, through nanofiltration and spraying
Tylosin phosphate or Tylosin Tartrate are obtained after drying.
Experimental example：
1,5 batch productions are carried out using the method for embodiment 3 and comparative example 1, after embodiment 3 purifies in taking every batch of to produce
Filtrate after the filtering of filtrate and comparative example 1, and filtrates tested light transmittance, test result see the table below 2：
2 filtrate light transmittance of table compares
| Comparative example 1% | Embodiment 3% | |
| Batch 1 | 61.3 | 90.6 |
| Batch 2 | 64.8 | 91.9 |
| Batch 3 | 67.1 | 94.2 |
| Batch 4 | 62.5 | 93.7 |
| Batch 5 | 68.0 | 91.4 |
2,5 batch productions are carried out using the method for embodiment 3 and comparative example 1, takes and obtain product 3g, is dissolved into 10ml water
In, solution light transmittance is tested, test result see the table below 3：
3 product solution light transmittance of table compares
| Comparative example 1% | Embodiment 3% | |
| Batch 1 | 81.7 | 97.8 |
| Batch 2 | 76.1 | 96.9 |
| Batch 3 | 72.9 | 97.4 |
| Batch 4 | 68.2 | 98.2 |
| Batch 5 | 84.3 | 95.5 |
5 batch productions are carried out using the method for embodiment 3 and comparative example 1, take acquisition product, it is (dry to measure product potency
Base), test result see the table below 4：
4 product potency of table compares
| Comparative example 1u/mg | Embodiment 3u/mg | |
| Batch 1 | 891 | 935 |
| Batch 2 | 886 | 934 |
| Batch 3 | 897 | 931 |
| Batch 4 | 895 | 935 |
| Batch 5 | 894 | 936 |
Claims (8)
1. a kind of preparation method of tartaric acid/Tylosin phosphate, including steps are as follows：
To after flocculant or filter aid stirring pretreatment are added in the tylosin broth that everfermentation obtains, detached through sheet frame
Filtrate is obtained, after filtrate is purified, is extracted, using back extraction, decolourizes, be dried to obtain tylosin product；Wherein,
The purification is that sodium hydroxide solution is added into filtrate, is then pumped into mixer and is mixed, and pH is 7.5-for control
In 8.0 ranges, mixed liquor under the rotating speed of 4000-5000 turns/min to centrifuge, and filtrate after being purified, second is added in filtrate after purification
Acid butyl ester solvent is extracted.
2. the preparation method of tartaric acid/Tylosin phosphate according to claim 1, which is characterized in that the flocculation
Agent is polyaluminium chloride, and the additive amount of polyaluminium chloride and the weight ratio of zymotic fluid are 1.0 ± 0.3% (w/w), and the filter aid is
Mass concentration is the polymeric aluminum chlorides solution of 20-22%, the additive amount of polymeric aluminum chlorides solution and the mass volume ratio of zymotic fluid
0.6% (w/v)；Pretreatment time is 20-30min.
3. the preparation method of tartaric acid/Tylosin phosphate according to claim 1, which is characterized in that the solid-liquid
Separation is carried out using press filtration or squeezing mode, and press filtration or squeeze pressure are less than or equal to 0.4Mpa.
4. the preparation method of tartaric acid/Tylosin phosphate according to claim 1, which is characterized in that purification control pH
For 7.5-7.9.
5. the preparation method of tartaric acid/Tylosin phosphate according to claim 1, which is characterized in that purification control pH
For 7.5-7.7.
6. the preparation method of tartaric acid/Tylosin phosphate according to claim 1, which is characterized in that purification control pH
It is 7.54.
7. the preparation method of tartaric acid/Tylosin phosphate according to claim 1, which is characterized in that centrifugal rotational speed is
4500-4800 turns/min, centrifugation time 0.2s-2min.
8. the preparation method of tartaric acid/Tylosin phosphate according to claim 1, which is characterized in that sodium hydroxide is molten
Liquid mass concentration is 2-6wt%.
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| CN110407893A (en) * | 2019-08-14 | 2019-11-05 | 齐鲁制药（内蒙古）有限公司 | A method of removal D component improves Tylosin Tartrate quality |
| CN111620919A (en) * | 2020-06-05 | 2020-09-04 | 宁夏泰益欣生物科技有限公司 | Decoloration method of tylosin tartrate |
| CN112409429A (en) * | 2020-11-24 | 2021-02-26 | 中牧实业股份有限公司黄冈动物药品厂 | Refining method of tylosin tartrate and product prepared by refining method |
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| CN112409429A (en) * | 2020-11-24 | 2021-02-26 | 中牧实业股份有限公司黄冈动物药品厂 | Refining method of tylosin tartrate and product prepared by refining method |
| CN112409429B (en) * | 2020-11-24 | 2023-04-07 | 中牧实业股份有限公司黄冈动物药品厂 | Refining method of tylosin tartrate and product prepared by refining method |
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