CN114480521A - Preparation method of triazacyclocin C - Google Patents
Preparation method of triazacyclocin C Download PDFInfo
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- CN114480521A CN114480521A CN202011267950.2A CN202011267950A CN114480521A CN 114480521 A CN114480521 A CN 114480521A CN 202011267950 A CN202011267950 A CN 202011267950A CN 114480521 A CN114480521 A CN 114480521A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 19
- 238000000926 separation method Methods 0.000 claims abstract description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000000741 silica gel Substances 0.000 claims abstract description 12
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 12
- 238000000746 purification Methods 0.000 claims abstract description 11
- 241001454747 Streptomyces aureus Species 0.000 claims abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 52
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- 238000000855 fermentation Methods 0.000 claims description 26
- 230000004151 fermentation Effects 0.000 claims description 26
- 239000007788 liquid Substances 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 239000001963 growth medium Substances 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 239000000287 crude extract Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 238000010828 elution Methods 0.000 claims description 9
- 239000006228 supernatant Substances 0.000 claims description 8
- 101000610620 Homo sapiens Putative serine protease 29 Proteins 0.000 claims description 7
- 102100040345 Putative serine protease 29 Human genes 0.000 claims description 7
- 238000009630 liquid culture Methods 0.000 claims description 7
- 230000001580 bacterial effect Effects 0.000 claims description 6
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- 238000011894 semi-preparative HPLC Methods 0.000 claims description 6
- 239000002609 medium Substances 0.000 claims description 4
- 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 claims description 3
- 230000003213 activating effect Effects 0.000 claims description 3
- 229940041514 candida albicans extract Drugs 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- 238000004811 liquid chromatography Methods 0.000 claims description 3
- 239000012138 yeast extract Substances 0.000 claims description 3
- 238000010521 absorption reaction Methods 0.000 claims description 2
- 238000002386 leaching Methods 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 239000001974 tryptic soy broth Substances 0.000 claims 3
- 229910052581 Si3N4 Inorganic materials 0.000 claims 1
- 239000000499 gel Substances 0.000 claims 1
- 229910052710 silicon Inorganic materials 0.000 claims 1
- 239000010703 silicon Substances 0.000 claims 1
- HQVNEWCFYHHQES-UHFFFAOYSA-N silicon nitride Chemical compound N12[Si]34N5[Si]62N3[Si]51N64 HQVNEWCFYHHQES-UHFFFAOYSA-N 0.000 claims 1
- 108010050327 trypticase-soy broth Proteins 0.000 claims 1
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 10
- 238000005516 engineering process Methods 0.000 abstract description 5
- 230000000813 microbial effect Effects 0.000 abstract description 4
- 238000003810 ethyl acetate extraction Methods 0.000 abstract 1
- 238000003808 methanol extraction Methods 0.000 abstract 1
- 239000012264 purified product Substances 0.000 abstract 1
- 238000001514 detection method Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229940055738 triacin c Drugs 0.000 description 3
- NKTGCVUIESDXPU-YLEPRARLSA-N triacsin C Chemical compound CCC\C=C\C\C=C\C=C\C=N\NN=O NKTGCVUIESDXPU-YLEPRARLSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 229940124549 vasodilator Drugs 0.000 description 2
- 239000003071 vasodilator agent Substances 0.000 description 2
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102000005870 Coenzyme A Ligases Human genes 0.000 description 1
- 108010011449 Long-chain-fatty-acid-CoA ligase Proteins 0.000 description 1
- 241000702670 Rotavirus Species 0.000 description 1
- 206010067470 Rotavirus infection Diseases 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000002953 anti-rotaviral effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- -1 hydroxytriazole alkene compound Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
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- 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
- C12P13/00—Preparation of nitrogen-containing organic compounds
- C12P13/001—Amines; Imines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
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- Engineering & Computer Science (AREA)
- Wood Science & Technology (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biotechnology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
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Abstract
A preparation method of triazacyclocin C, belonging to the field of microbial technology and separation technology. In order to solve the problems in the prior art of producing the triazcins C by using a microbial method and improve the yield and the purity of the triazcins C, the invention obtains the purified product of the triazcins C by fermenting Streptomyces aureus (Streptomyces aureus Duggar) and performing methanol extraction, ethyl acetate extraction, silica gel column separation, HPLC purification and other means. Compared with the prior art, the method has the advantages that the yield can be improved by 117 percent, the yield is improved by about 3.5 times, the purity of the obtained triazacyclocin C is more than 95 percent, the method is high in safety, low in pollution and simple in steps, and the method can be used for producing the triazacyclocin C.
Description
Technical Field
The invention belongs to the fields of microbial fermentation technology and separation technology, and particularly relates to a preparation method of triazacyclocin C.
Background
Triazycin C (triacin C), a hydroxytriazole alkene compound produced by streptomyces, is an inhibitor of long-chain fatty acid acyl coenzyme A synthetase, and has the activities of regulating lipid metabolism, reducing blood pressure, a vasodilator, inhibiting the mobilization of intracellular calcium to inhibit the functions of pancreatic beta cells and the like. In addition, research shows that the triazacyclovir C and the analogue thereof also have activity of inhibiting rotavirus replication, and are expected to be developed into anti-rotavirus infection medicaments.
Since the compounds of the triazacyclocin family are only obtained by fermentation using microorganisms at the present stage, the only article ON the purification by fermentation, WS-1228A AND B, reported that 150 mg of crude extract were obtained in 18 l of fermentation broth by fermentation for 6 days, AND then purified (comprising an extraction step with the highly toxic agent benzene) to give 30 mg of the product of triazacyclocin C in a yield of 20%. The purities of the triazocins C sold on the market today are about 90 percent, and the price is about 10000 yuan/mg. In summary, the fermentation time of the prior art for producing triazacyclocin C by using a microbial method is long, the fermentation yield is low, the separation and purification process is complex and involves toxic pollution reagents, the yield is low, and the purity of the obtained product is not high, which hinders the research and application of triazacyclocin. Therefore, in order to further meet the industrial production requirements, the improvement of the fermentation process of the triazacyclocin C is urgently needed, the fermentation yield is improved, toxic pollution reagents involved in the separation and purification process of the triazacyclocin C are optimized, and the separation efficiency and the product purity are improved.
Disclosure of Invention
In order to solve the problems of the existing fermentation preparation and separation purification process of the triazcins C and improve the yield and the purity of the triazcins C, the invention provides a preparation method of the triazcins C, which comprises the following steps:
step one, activating a strain: inoculating streptomyces aureus into a TSB culture medium, and performing shake culture to obtain a bacterial liquid;
step two, fermentation culture: inoculating the bacterial liquid obtained in the step one into an ISP2 liquid culture medium, and performing fermentation culture to obtain a fermentation liquid;
step three, separation and purification: and D, filtering the fermentation liquor obtained in the step two to obtain mycelia and supernatant, sequentially extracting the mycelia with methanol, removing the methanol, extracting with ethyl acetate, extracting the supernatant with ethyl acetate, combining the extracted liquid, concentrating under reduced pressure to obtain a crude extract, preliminarily separating the crude extract through a normal-phase silica gel column, and further separating and purifying by using a semi-preparative HPLC method.
Further defined, the Latin literature name of the Streptomyces aureus in the first step is Streptomyces aureus Duggar with the deposit number of ATCC 31442.
In the embodiment of the invention, the TSB culture medium in the first step is composed of 30g/L tryptose soy broth and the balance of water; the shake culture condition is that the culture is carried out for 10-12 h at 30 ℃.
In the embodiment of the invention, the ISP2 liquid culture medium in the second step consists of 4g/L of yeast extract powder, 10g/L of malt extract powder, 4g/L of glucose and the balance of water; the pH value of the liquid culture medium is 7.2-7.4.
In the embodiment of the present invention, the rotation speed of the shaking table for the fermentation in the second step is 180rpm/min, the cultivation temperature is 30 ℃, and the cultivation period is 4 days.
In the present example, the mycelia of step three were extracted three times with methanol, concentrated under reduced pressure to remove methanol, and then extracted three times with ethyl acetate.
In the present example, the step three supernatant was extracted three times with ethyl acetate.
In the embodiment of the invention, the step three of the preliminary separation of the normal phase silica gel column is to perform gradient elution by using dichloromethane and methanol as mobile phases according to the ratio of 200:1 → 100:1 → 50:1 → 20:1 → 10:1 → 1:1 → 0:1, and taking the volume ratio of 50:1 CH2Cl2-MeOH elution site.
In the example of the present invention, the UV absorption of the semi-preparative HPLC described in step three is 330nm, and the volume ratio is 80:20 acetonitrile and water as mobile phases for liquid chromatography.
Advantageous effects
The preparation method of the triazacyclocin C provided by the invention is simple and stable to operate and has good repeatability. The yield of the finally obtained strain cultured in a shake flask is 0.243g/L, which is improved by 117 percent compared with the yield of a guiding method in the literature 'STUDIES ON NEW VASODILATORS, WS-1228A AND B', AND the whole fermentation process is shortened by 1.5 days compared with the original literature; the invention optimizes the separation and purification process of the triazcins C after large-scale culture, uses solvents such as methanol, ethyl acetate and the like which are commonly used in laboratories for extraction, obtains 1.6g of crude substance from 60 liters of fermentation liquid, and finally obtains 1.1g of a pure triazcins C product through silica gel column separation and HPLC purification, wherein the purity is higher than 95 percent, and the yield is improved by about 3.5 times compared with the yield reported in the original documents. The whole fermentation and purification process is high in safety and low in pollution, the purity of the compound obtained by separation is high, the yield is high, and the whole process is simpler and higher than that of the original document.
Drawings
FIG. 1: the structural formula of triazycin C;
FIG. 2 is a schematic diagram: TLC detection results, wherein 1 is crude extract; 2 is a component 1; 3 is component 2; 4 is component 3; 5 is component 4; 6 is component 5;
FIG. 3 is a HPLC chart of the isolation pure product of triazacyclocin C;
FIG. 4 is an HPLC plot of a trinitrogen C sample and a crude trinitrogen C extract prepared by the method of the present invention;
FIG. 5: triazacyclin C standard curve.
Detailed Description
The present invention will be described in further detail with reference to the following embodiments and the accompanying drawings, and the present invention is not limited to the following embodiments. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected. The procedures, conditions, reagents, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited. Preparing a culture medium according to the following culture medium formula for later use:
TSB medium: 30g/L of tryptose soy broth and the balance of water.
ISP2 liquid medium: 4g/L of yeast extract powder, 10g/L of malt extract powder, 4g/L of glucose and the balance of water; the pH value of the liquid culture medium is 7.2-7.4.
The S.aureus strain was purchased from the American Type Culture Collection (ATCC) and the strain was deposited under the accession number ATCC 31442.
Example 1 preparation of triazacycline C
Step one, activation of the strains
Sterilizing test tubes containing 3mL of TSB culture medium in each tube at 121 ℃ for 20min for later use, inoculating the streptomyces aureus preserved in the glycerol tubes into the test tubes, wherein the inoculation amount is 20uL per tube, performing shake culture overnight to obtain liquid bacterial liquid, and the rotation speed of the shake culture is 180rpm/min and the culture temperature is 30 ℃.
Step two, fermentation culture:
liquid ISP2 culture medium is prepared and sterilized at 115 ℃ for 20min for later use. Transferring the liquid bacterial liquid obtained by activating the strain in the step one into a 250mL conical flask filled with 50mL of ISP2 liquid culture medium according to the volume ratio of 2%, and performing shake culture to obtain fermentation liquid. Fermenting for 60L, rotating speed of rotary table is 180rpm/min, culture temperature is 30 deg.C, and culture period is 4 days.
Step three, separation and purification:
filtering the fermentation liquor obtained in the step to obtain mycelium and supernatant, leaching the mycelium with methanol for 3 times, removing methanol by means of reduced pressure concentration, and extracting with ethyl acetate for 3 times; extracting the supernatant with ethyl acetate for 3 times, mixing the above two ethyl acetate extractive solutions, and concentrating under reduced pressure to remove ethyl acetate to obtain crude extract 1.6 g.
The crude extract is separated and purified by normal phase silica gel column and semi-preparative HPLC and other technologies which are conventional in laboratories, and finally, 1.1g of pure compound triacin C is obtained, and the yield is 68%. The specific separation process is as follows:
normal phase silica gel column separation:
dissolving the extract (1.6g) with methanol, adding 50g of 100-mesh silica gel, stirring, separating the layer and the silica gel, adding 200g of the silica gel into a normal phase column after vacuum concentration, and separating the normal phase silica gel by taking dichloromethane/methanol as an eluent with the volume of 300mL, wherein the volume ratio of dichloromethane to methanol in the eluent is 200:1, 100:1, 50:1, 20:1, 10:1, 1:1 and 0:1 in sequence. Separating with normal phase silica gel to obtain 5 components, wherein component 1 is obtained from the following components in a volume ratio of 200:1 CH2Cl2-MeOH elution site; component 2 is taken from CH with a volume ratio of 100:12Cl2-MeOH elution site; component 3 was taken from 50:1 CH2Cl2-MeOH elution site; component 4 was taken from 20:1 and 10:1 CH2Cl2-MeOH elution site; component 5 is taken from the volume ratio of1:1 and 0:1 CH2Cl2-MeOH elution site. Then, the target product is concentrated in the component 3 through TLC and HPLC detection, and the TLC detection result is shown in figure 2, and the mobile phase used for TLC detection is dichloromethane: methane 2: 1.
semi-preparative HPLC separation:
and (3) performing liquid chromatography separation on the component 3 by taking acetonitrile/water as a mobile phase, wherein the volume ratio of acetonitrile to water is 80:20, and obtaining 1.1g of triacsin C by HPLC detection, wherein the purity is more than 95 percent, as shown in figure 3.
HPLC detection of the fermentation crude product:
dissolving the crude extract with small amount of methanol, detecting triazacyclin in the crude extract by high performance liquid chromatography, using C18 chromatographic column (250mm × 4.6mm, 5 μm), ultraviolet detector at 330nm, column temperature of 30 deg.C, flow rate of 1mL/min, sample amount of 10 μ L, and HPLC detection chart of the fermented crude product as shown in FIG. 4.
Drawing a standard curve of the triazcins C:
the corresponding chromatographic peak areas of standard solutions of the triazcins C with concentration gradients of 0g/L, 0.01g/L, 0.05g/L, 0.10g/L, 0.20g/L and 0.30g/L are shown in Table 1, and a standard curve of the triazcins C is drawn according to the data in the Table 1 and is shown in FIG. 5.
TABLE 1 corresponding HPLC peak areas for different concentrations of the triacin C standard
Claims (9)
1. A preparation method of triazcins C is characterized by comprising the following steps:
step one, activating a strain: inoculating streptomyces aureus into a TSB culture medium, and performing shake culture to obtain a bacterial liquid;
step two, fermentation culture: inoculating the bacterial liquid obtained in the step one into an ISP2 liquid culture medium, and performing fermentation culture to obtain a fermentation liquid;
step three, separation and purification: and D, filtering the fermentation liquor obtained in the step two to obtain mycelium and supernatant, sequentially leaching the mycelium with methanol, removing the methanol, extracting with ethyl acetate, extracting the supernatant with ethyl acetate, combining the extracted liquid, concentrating under reduced pressure to obtain a crude extract, preliminarily separating the crude extract through a normal-phase silica gel column, and further separating and purifying by using a semi-preparative HPLC method to obtain the triazacyclocin C.
2. The process according to claim 1, wherein the Streptomyces aureus has a Latin literature name of Streptomyces aureus Duggar and a collection number of ATCC 31442.
3. The method of claim 1, wherein the TSB medium of step one consists of trypticase soy broth 30g/L, and the balance is water; the shake culture condition is that the culture is carried out for 10-12 h at 30 ℃.
4. The method according to claim 1, wherein the ISP2 liquid medium of the second step consists of yeast extract powder 4g/L, malt extract powder 10g/L, glucose 4g/L, and the balance of water; the pH value of the liquid culture medium is 7.2-7.4.
5. The method according to claim 1, wherein the rotation speed of the shaker in the second step is 180rpm/min, the cultivation temperature is 30 ℃, and the cultivation period is 4 days.
6. The method according to claim 1, wherein the mycelium of the third step is extracted three times with methanol, and after removing methanol by concentration under reduced pressure, extracted three times with ethyl acetate.
7. The method of claim 1, wherein the supernatant of step three is extracted three times with ethyl acetate.
8. The method for preparing silicon nitride according to claim 1, wherein the normal phase silicon is prepared in step threeThe primary separation of the gel column is to perform gradient elution by taking dichloromethane and methanol as mobile phases according to the ratio of 200:1 → 100:1 → 50:1 → 20:1 → 10:1 → 1:1 → 0:1, and the volume ratio is 50:1 CH2Cl2-MeOH elution site.
9. The method of claim 1, wherein the semi-preparative HPLC of step three has an ultraviolet absorption at 330nm, a volume ratio of 80:20 acetonitrile and water as mobile phases for liquid chromatography.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0015540A2 (en) * | 1979-03-07 | 1980-09-17 | Fujisawa Pharmaceutical Co., Ltd. | New triazene compound, process for the preparation thereof, and pharmaceutical composition comprising the same |
| US4297096A (en) * | 1979-03-07 | 1981-10-27 | Fujisawa Pharmaceutical Co. Ltd. | Alkyl, alkenyl, and aryl substituted triazene compounds, their salts and production thereof |
| KR830002568B1 (en) * | 1980-03-07 | 1983-11-14 | 후지사와 세이야꾸 고교 가부시끼 가이샤 | Method for preparing triazene compound |
| CN1675192A (en) * | 2002-07-09 | 2005-09-28 | 法斯根有限责任公司 | Novel compunds, pharmaceutical compositions containing same, and methods of use for same |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0015540A2 (en) * | 1979-03-07 | 1980-09-17 | Fujisawa Pharmaceutical Co., Ltd. | New triazene compound, process for the preparation thereof, and pharmaceutical composition comprising the same |
| US4297096A (en) * | 1979-03-07 | 1981-10-27 | Fujisawa Pharmaceutical Co. Ltd. | Alkyl, alkenyl, and aryl substituted triazene compounds, their salts and production thereof |
| KR830002568B1 (en) * | 1980-03-07 | 1983-11-14 | 후지사와 세이야꾸 고교 가부시끼 가이샤 | Method for preparing triazene compound |
| CN1675192A (en) * | 2002-07-09 | 2005-09-28 | 法斯根有限责任公司 | Novel compunds, pharmaceutical compositions containing same, and methods of use for same |
Non-Patent Citations (1)
| Title |
|---|
| H TANAKA等: "Studies on new vasodilators, WS-1228 A and B. II. Structure and synthesis", J ANTIBIOT, vol. 35, no. 2, pages 157 - 163 * |
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