CN111100900A - Method for preparing demethyltetracycline by fermentation method - Google Patents
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- 238000000855 fermentation Methods 0.000 title claims abstract description 26
- 230000004151 fermentation Effects 0.000 title claims abstract description 26
- 238000000034 method Methods 0.000 title claims abstract description 21
- RMVMLZHPWMTQGK-SOUFLCLCSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1([C@H]2O)=CC=CC(O)=C1C(O)=C1[C@@H]2C[C@H]2[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]2(O)C1=O RMVMLZHPWMTQGK-SOUFLCLCSA-N 0.000 title abstract description 10
- JCSGAUKCDAVARS-UHFFFAOYSA-N demethyltetracycline Natural products CN(C1C(=C(C(C2(C(=C3C(C4=C(C=CC=C4C(C3CC12)O)O)=O)O)O)=O)C(=O)N)O)C JCSGAUKCDAVARS-UHFFFAOYSA-N 0.000 title abstract description 10
- 238000012258 culturing Methods 0.000 claims abstract description 14
- 238000001914 filtration Methods 0.000 claims abstract description 14
- 239000012043 crude product Substances 0.000 claims abstract description 11
- 238000001035 drying Methods 0.000 claims abstract description 10
- 239000007788 liquid Substances 0.000 claims abstract description 10
- 238000001816 cooling Methods 0.000 claims abstract description 9
- 238000003756 stirring Methods 0.000 claims abstract description 9
- 241000894006 Bacteria Species 0.000 claims abstract description 7
- 239000000725 suspension Substances 0.000 claims abstract description 7
- 239000012629 purifying agent Substances 0.000 claims abstract description 6
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims abstract description 5
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims abstract description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 5
- 239000000047 product Substances 0.000 claims abstract description 5
- 239000008213 purified water Substances 0.000 claims abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000008394 flocculating agent Substances 0.000 claims abstract description 3
- 239000004098 Tetracycline Substances 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- 229960002180 tetracycline Drugs 0.000 claims description 8
- 235000019364 tetracycline Nutrition 0.000 claims description 8
- 229930101283 tetracycline Natural products 0.000 claims description 8
- 150000003522 tetracyclines Chemical class 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 238000009423 ventilation Methods 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 239000012528 membrane Substances 0.000 claims description 4
- 238000001728 nano-filtration Methods 0.000 claims description 4
- 238000010899 nucleation Methods 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 239000002535 acidifier Substances 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 229940075930 picrate Drugs 0.000 claims description 2
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 claims description 2
- 238000004321 preservation Methods 0.000 claims description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 claims description 2
- 229960001860 salicylate Drugs 0.000 claims description 2
- 238000000605 extraction Methods 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- 239000002904 solvent Substances 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 description 1
- WXHLLJAMBQLULT-UHFFFAOYSA-N 2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-n-(2-methyl-6-sulfanylphenyl)-1,3-thiazole-5-carboxamide;hydrate Chemical compound O.C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1S WXHLLJAMBQLULT-UHFFFAOYSA-N 0.000 description 1
- WTJXVDPDEQKTCV-UHFFFAOYSA-N 4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydron;chloride Chemical compound Cl.C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2C1CC1C(N(C)C)C(=O)C(C(N)=O)=C(O)C1(O)C2=O WTJXVDPDEQKTCV-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CYDMQBQPVICBEU-UHFFFAOYSA-N chlorotetracycline Natural products C1=CC(Cl)=C2C(O)(C)C3CC4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-UHFFFAOYSA-N 0.000 description 1
- 229960004475 chlortetracycline Drugs 0.000 description 1
- 235000019365 chlortetracycline Nutrition 0.000 description 1
- 238000006298 dechlorination reaction Methods 0.000 description 1
- -1 demethyl aureomycin Chemical compound 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229960004023 minocycline Drugs 0.000 description 1
- 229960002421 minocycline hydrochloride Drugs 0.000 description 1
- 230000024053 secondary metabolic process Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P29/00—Preparation of compounds containing a naphthacene ring system, e.g. tetracycline
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Wood Science & Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Biotechnology (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing demethyl tetracycline by a fermentation method, which comprises the following steps: step a: culturing the culture solution by using engineering bacteria according to a standard formula; step b: inoculating the liquid into a sterilized seed tank for culturing; step c: after the seed tank culture is finished, inoculating the obtained culture seeds into a fermentation tank to obtain fermentation liquor; step d: after the fermentation liquor is put into a tank, the fermentation liquor is filtered, and filter residues are reserved for use; step e: adding purified water into the filter residue to prepare suspension, adding a purifying agent and a flocculating agent, standing, and filtering to obtain a purified solution; step f: concentrating, crystallizing and drying the purified solution to obtain a crude product; step g: adding active carbon, stirring, decolorizing, and filtering to obtain decolorized solution; step h: cooling, crystallizing and drying to obtain the finished product. The extraction process is carried out under the conditions of normal temperature and normal pressure, a general solvent is used, the safety risk is reduced, the demethyl tetracycline is directly obtained through fermentation and purification, and the yield is improved to more than 90%.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a method for preparing demethyltetracycline by a fermentation method.
Background
The demethyl tetracycline is an intermediate of the first step of minocycline hydrochloride synthesis, and the traditional synthesis method comprises the steps of fermenting and purifying demethyl aureomycin, and then synthesizing the demethyl tetracycline through dechlorination reaction with the total yield of 80%; the reaction needs to be filled with hydrogen, the reaction pressure is up to 4MPa, the temperature is close to 60 ℃, and meanwhile, a palladium-carbon catalyst with high price is used, so that the process has extremely high safety risk, can cause explosion by a little carelessness, has higher requirements on equipment and operation precision, and has high production difficulty and production cost.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a method for producing demethylated tetracycline by using engineering bacteria as an initial material, fermenting and culturing the engineering bacteria and depending on the secondary metabolism of microorganisms.
The technical scheme adopted by the invention is as follows: a method for preparing demethyl tetracycline by a fermentation method comprises the following steps: step a: culturing the culture solution by using engineering bacteria according to a standard formula;
step b: inoculating the liquid into a sterilized seed tank for culturing;
step c: after the seed tank culture is finished, inoculating the obtained culture seeds into a fermentation tank; transferring the seed by 20 percent, and culturing for 5-15 days to obtain fermentation liquor;
step d: placing in a tank, heating the fermentation liquor, cooling to room temperature, filtering, draining the filtrate, and reserving the filter residue;
step e: adding the filter residue into purified water, stirring well to obtain suspension, adjusting to alkalinity with liquid alkali, adding purifying agent and flocculating agent PAM, standing, and filtering again to obtain purified liquid;
step f: concentrating the purified solution by using a nanofiltration membrane, adding an acidifying agent into the concentrated solution to adjust the pH value for crystallization, and drying to obtain a crude product;
step g: dissolving the crude product in an acidic organic solvent, adding active carbon, stirring for decoloring, and filtering to obtain a decolored solution;
step h: adding an alkalizer into the decolored solution, cooling, crystallizing and drying to obtain a finished product.
Further, the conditions of the seeding tank culture in the step b and the fermenter culture in the step c are as follows: the culture temperature is 28 ℃, the tank pressure is 0.02-0.04 MPa, the ventilation volume is 1vvm, the dissolved oxygen is controlled in a linkage manner to be more than or equal to 30%, and the rotating speed is 300-800 rpm.
Further, in the step d, the heating temperature is 60-70 ℃, and the heat preservation time is 30-60 minutes.
Furthermore, the concentration of the suspension in the step e is the same as that of the fermentation liquor in the step c, the alkalinity is adjusted to 10-11, the purifying agent is one or two of salicylate, phosphate and picrate, and the adding amount is 500-1000 ppm.
Further, the concentration in the step f is 10000-15000 u/mL, and the crystallization pH is 4-6.
Further, the organic solvent in the step g is C1-C3 alcohol or ketone, the content of the organic solvent is 50-90%, and the acidic pH value is 1-2.
Further, the crystallization pH value in the step h is 4-6, and the crystallization temperature is 5-15 ℃.
The beneficial effects obtained by the invention are as follows: the invention determines the process for preparing the nortetracycline by the fermentation method, the whole extraction process is carried out under the conditions of normal temperature and normal pressure, hydrogen and palladium-carbon catalysts are not needed, a general solvent is used, the safety risk is reduced, the demethyltetracycline is directly obtained by fermentation and purification, the yield is improved to more than 90 percent, the equipment investment is reduced, the production cost is reduced, and the process is green and environment-friendly and has positive significance.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments.
Example 1: culturing the seed solution by using engineering bacteria according to a standard formula, inoculating the seed solution into a sterilization seeding tank for culturing, wherein the culture temperature is 28 ℃, the tank pressure is 0.03MPa, the ventilation volume is 1vvm, the dissolved oxygen is controlled in a linkage manner to be more than or equal to 30%, and the rotating speed is 800 rpm; after the seed tank is cultured, the seed tank is connected into a fermentation tank, the culture temperature is 28 ℃, the tank pressure is 0.03MPa, the ventilation volume is 1vvm, the dissolved oxygen is controlled in a linkage manner to be more than or equal to 30%, and the rotating speed is 800 rpm; transferring amount of 20%, culturing period of 9 days, placing into a tank with titer of 9300u/mL and volume of 60L.
Placing in a tank, heating the fermentation liquor to 70 ℃, preserving heat for 60 minutes, cooling to room temperature, filtering with a plate frame, draining the filtrate, and reserving the filter residue for use; adding the filter residue into purified water with the same amount as the filtrate, stirring well to obtain suspension, adjusting pH to 10.5 with liquid alkali, adding 500ppm calcium phosphate and 50ppm PAM flocculant, standing for 30min, and filtering again to obtain purified solution. Concentrating the purified solution to 12000u/mL by using a nanofiltration membrane, adding hydrochloric acid into the concentrated solution to adjust the pH value to 5.2, crystallizing and drying to obtain a crude product.
Dissolving the crude product in 80% acetone with pH of 1.5, adding active carbon 0.04 times of the crude product, stirring, decolorizing for 30min, and filtering; adding ammonia water into the decolorized solution, adjusting the pH value to 4.5, cooling to 8 ℃, crystallizing, and drying to obtain 520g of finished product with the total yield of 93%.
Example 2: culturing the seed solution by using engineering bacteria according to a standard formula, inoculating the seed solution into a sterilization seed tank for culturing, wherein the culture temperature is 28 ℃, the tank pressure is 0.04MPa, the ventilation volume is 1vvm, the dissolved oxygen is controlled in a linkage manner to be more than or equal to 30%, and the rotating speed is 600 rpm; and (3) inoculating the strain tank into a fermentation tank after the culture of the strain tank is finished, wherein the culture temperature is 28 ℃, the tank pressure is 0.04MPa, the ventilation volume is 1vvm, the dissolved oxygen is controlled in a linkage mode to be more than or equal to 30%, the rotating speed is 600rpm, the strain transfer volume is 20%, the strain tank is placed in a culture period of 9 days, the strain tank placing potency is 10200u/mL, and the volume is 57L.
Placing in a tank, heating the fermentation liquor to 65 ℃, preserving heat for 40 minutes, cooling to room temperature, filtering with a plate frame, draining the filtrate, and reserving filter residues for use; adding the filter residue into purified water with the same amount as the filtrate, stirring well to obtain suspension, adjusting pH to 10.8 with liquid alkali, adding 1000ppm sulfosalicylic acid and 50ppm PAM flocculant, standing for 30min, and filtering again to obtain purified liquid. Concentrating the purified solution to 10000u/mL by using a nanofiltration membrane, adding hydrochloric acid into the concentrated solution to adjust the pH value to 4.6, crystallizing and drying to obtain a crude product.
Dissolving the crude product in 70% ethanol with pH of 1.0, adding active carbon 0.04 times of the crude product, stirring, decolorizing for 30min, and filtering. Adding ammonia water into the decolorized solution, adjusting the pH value to 5.0, cooling to 10 ℃, crystallizing, and drying to obtain 535g of a finished product with a total yield of 92%.
The obtained demethyl tetracycline meets the quality standard of the minocycline intermediate.
Claims (7)
1. A method for preparing demethylated tetracycline by a fermentation method is characterized by comprising the following steps:
step a: culturing the culture solution by using engineering bacteria according to a standard formula;
step b: inoculating the liquid into a sterilized seed tank for culturing;
step c: after the seed tank culture is finished, inoculating the obtained culture seeds into a fermentation tank; transferring the seed by 20 percent, and culturing for 5-15 days to obtain fermentation liquor;
step d: placing in a tank, heating the fermentation liquor, cooling to room temperature, filtering, draining the filtrate, and reserving the filter residue;
step e: adding the filter residue into purified water, stirring well to obtain suspension, adjusting to alkalinity with liquid alkali, adding purifying agent and flocculating agent PAM, standing, and filtering again to obtain purified liquid;
step f: concentrating the purified solution by using a nanofiltration membrane, adding an acidifying agent into the concentrated solution to adjust the pH value for crystallization, and drying to obtain a crude product;
step g: dissolving the crude product in an acidic organic solvent, adding active carbon, stirring for decoloring, and filtering to obtain a decolored solution;
step h: adding an alkalizer into the decolored solution, cooling, crystallizing and drying to obtain a finished product.
2. The method for preparing demethylated tetracycline according to claim 1, wherein: the conditions of the seeding tank culture in the step b and the fermentation tank culture in the step c are as follows: the culture temperature is 28 ℃, the tank pressure is 0.02-0.04 MPa, the ventilation volume is 1vvm, the dissolved oxygen is controlled in a linkage manner to be more than or equal to 30%, and the rotating speed is 300-800 rpm.
3. The method for preparing demethylated tetracycline according to claim 1, wherein: in the step d, the heating temperature is 60-70 ℃, and the heat preservation time is 30-60 minutes.
4. The method for preparing demethylated tetracycline according to claim 1, wherein: and e, adjusting the concentration of the suspension in the step e to be the same as that of the fermentation liquor in the step c, adjusting the pH to 10-11 in an alkaline manner, wherein the purifying agent is one or two of salicylate, phosphate and picrate, and the addition amount of the purifying agent is 500-1000 ppm.
5. The method for preparing demethylated tetracycline according to claim 1, wherein: and in the step f, the concentration is 10000-15000 u/mL, and the crystallization pH is 4-6.
6. The method for preparing demethylated tetracycline according to claim 1, wherein: in the step g, the organic solvent is C1-C3 alcohol or ketone, the content is 50-90%, and the acidic pH is 1-2.
7. The method for preparing demethylated tetracycline according to claim 1, wherein: the crystallization pH in the step h is 4-6, and the crystallization temperature is 5-15 ℃.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201911314452.6A CN111100900A (en) | 2019-12-19 | 2019-12-19 | Method for preparing demethyltetracycline by fermentation method |
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| CN201911314452.6A CN111100900A (en) | 2019-12-19 | 2019-12-19 | Method for preparing demethyltetracycline by fermentation method |
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