CN109053805B - Preparation method of thiazine feed additive - Google Patents
Preparation method of thiazine feed additive Download PDFInfo
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- CN109053805B CN109053805B CN201811182535.XA CN201811182535A CN109053805B CN 109053805 B CN109053805 B CN 109053805B CN 201811182535 A CN201811182535 A CN 201811182535A CN 109053805 B CN109053805 B CN 109053805B
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- nitrile
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- 239000003674 animal food additive Substances 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical compound N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 title claims abstract description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 34
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 17
- 108010046334 Urease Proteins 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 6
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 4
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 3
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 99
- 238000003756 stirring Methods 0.000 claims description 77
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 70
- 238000001816 cooling Methods 0.000 claims description 57
- 238000010438 heat treatment Methods 0.000 claims description 53
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 52
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 45
- 239000002994 raw material Substances 0.000 claims description 41
- 239000000243 solution Substances 0.000 claims description 41
- 238000001035 drying Methods 0.000 claims description 38
- 238000001914 filtration Methods 0.000 claims description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 33
- 239000012295 chemical reaction liquid Substances 0.000 claims description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 29
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 25
- 239000012074 organic phase Substances 0.000 claims description 25
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 23
- 239000011259 mixed solution Substances 0.000 claims description 23
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 22
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000000706 filtrate Substances 0.000 claims description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- 239000003054 catalyst Substances 0.000 claims description 16
- 239000012065 filter cake Substances 0.000 claims description 16
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 15
- FNRMMDCDHWCQTH-UHFFFAOYSA-N 2-chloropyridine;3-chloropyridine;4-chloropyridine Chemical compound ClC1=CC=NC=C1.ClC1=CC=CN=C1.ClC1=CC=CC=N1 FNRMMDCDHWCQTH-UHFFFAOYSA-N 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 229910052797 bismuth Inorganic materials 0.000 claims description 13
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 claims description 13
- 229910052706 scandium Inorganic materials 0.000 claims description 13
- SIXSYDAISGFNSX-UHFFFAOYSA-N scandium atom Chemical compound [Sc] SIXSYDAISGFNSX-UHFFFAOYSA-N 0.000 claims description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 11
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 9
- 239000008367 deionised water Substances 0.000 claims description 9
- 229910021641 deionized water Inorganic materials 0.000 claims description 9
- FILKGCRCWDMBKA-UHFFFAOYSA-N 2,6-dichloropyridine Chemical compound ClC1=CC=CC(Cl)=N1 FILKGCRCWDMBKA-UHFFFAOYSA-N 0.000 claims description 8
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 7
- 230000000694 effects Effects 0.000 claims description 7
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 6
- 229910052786 argon Inorganic materials 0.000 claims description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 6
- 235000019253 formic acid Nutrition 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- -1 polytetrafluoroethylene Polymers 0.000 claims description 6
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- FBXVOTBTGXARNA-UHFFFAOYSA-N bismuth;trinitrate;pentahydrate Chemical compound O.O.O.O.O.[Bi+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O FBXVOTBTGXARNA-UHFFFAOYSA-N 0.000 claims description 5
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
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- YSUBIGXLOCNYKB-UHFFFAOYSA-N scandium(3+) trinitrate hexahydrate Chemical compound O.O.O.O.O.O.[N+](=O)([O-])[O-].[Sc+3].[N+](=O)([O-])[O-].[N+](=O)([O-])[O-] YSUBIGXLOCNYKB-UHFFFAOYSA-N 0.000 claims description 3
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- 239000004317 sodium nitrate Substances 0.000 claims description 3
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- XGPOMXSYOKFBHS-UHFFFAOYSA-M sodium;trifluoromethanesulfonate Chemical compound [Na+].[O-]S(=O)(=O)C(F)(F)F XGPOMXSYOKFBHS-UHFFFAOYSA-M 0.000 claims description 3
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- 239000011592 zinc chloride Substances 0.000 claims description 3
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- 238000002791 soaking Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 150000004897 thiazines Chemical class 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000011667 zinc carbonate Substances 0.000 description 1
- 235000004416 zinc carbonate Nutrition 0.000 description 1
- 229910000010 zinc carbonate Inorganic materials 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65615—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing a spiro condensed ring system of the formula where at least one of the atoms X or Y is a hetero atom, e.g. S
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
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Abstract
The invention discloses a preparation method of thiazine feed additives, belonging to the technical field of synthesis of feed additives. The technical scheme provided by the invention has the key points that:
compared with the prior art, the invention has the following beneficial effects: the invention has simple synthesis method, novel molecular structure and
Description
Technical Field
The invention belongs to the technical field of feed additive synthesis, and particularly relates to a preparation method of thiazine feed additives.
Background
Urease is also called urea hydrolase, is a nickel-containing oligomeric enzyme, has absolute specificity, can specifically catalyze urea to hydrolyze into ammonia and carbon dioxide, and the hydrolysate ammonia can provide a nitrogen source for the metabolism of a plurality of microorganisms and plants and plays a key role in regulating the pH value of the surrounding environment; at the same time, this also causes many negative effects in nature. For example, urease can excessively catalyze and degrade volatile ammonia and carbon dioxide produced by urea, so that the loss of the fertilizer effect of the nitrogen fertilizer is caused, the concentration of ammonia ions in soil is increased, the pH value is increased, and the normal growth of plants is influenced; urease can also be used as a pathogen toxin to cause diseases such as gastritis, gastric ulcer and gastric cancer. For example, helicobacter pylori uses a large amount of urease produced by helicobacter pylori itself to catalyze the hydrolysis of urea, resulting in an increase in the surrounding pH, which counteracts the killing action of gastric acid. Therefore, it is necessary to find a suitable urease inhibitor to scientifically regulate and control the activity of urease and eliminate the negative effects generated by the urease inhibitor, and the currently reported urease inhibitors mainly comprise two types, namely transition metal ion type urease inhibitors and organic compound type urease inhibitors, wherein the transition metal ion type urease inhibitors and the organic compound type urease inhibitors are limited in application due to the fact that heavy metal ions have high toxicity; the latter has limitations in application due to short effective inhibition time, low efficiency and toxic and side effects. If the organic small molecules and the heavy metal ions form the complex, the organic ligand and the metal ions are both fixed in the complex framework, so that the toxicity is greatly reduced, the acting time is prolonged, and the potential is good.
Urease, which decomposes urea to NH, is widely present in the stomach of ruminants3At a rate of not catalytically decomposing 1014Double, the use of NH by rumen microorganisms3The rate of the nitrogen is 4 times that of the nitrogen, the utilization rate of the nitrogen is greatly reduced, and is usually only 30% -40%, so that not only is the serious waste of agricultural and animal husbandry resources caused and the production cost increased, but also the growth of animals and plants and the ecological environment and the like are seriously damaged, and serious water source pollution, water eutrophication and the like can be caused. Therefore, how to solve the problems of economy, environment and health caused by urease is a challenging subject to be solved urgently in the sustainable development of economy, agriculture and animal husbandry in the world today.
Thiazine derivatives are important nitrogen-and sulfur-containing heterocyclic compounds with no bactericidal and antifungal effects, for example, 1,3, 5-thiadiazine-2-thione compounds have long been recognized as being effective in killing microorganisms in soil, 3, 5-dimethyl-tetrahydro-1, 3, 5-thiadiazine-2-thione can kill mold and nematodes in soil, and 3, 5-diphenyl-tetrahydro-1, 3, 5-thiadiazine-2-thione can be used as a medicine for inhibiting fungi infecting human skin. Zinc is one of indispensable trace elements of all animals, for example, zinc is an essential trace element for poultry growth, the poultry zinc deficiency can cause the reduction of chicken growth performance and leg bone deformation, the zinc also has great influence on chicken reproductive performance, and in addition, the zinc also has certain immunologic function. In the absence of zinc, growing chickens grow slowly, feathers grow badly, and dermatitis is induced. The egg yield of adult chickens is reduced, the eggshells become thin, the hatching rate of eggs is reduced, and the embryos have deformity. Zinc oxide and zinc carbonate can be added into the feed for poultry to eat in the process of raising chickens. Pig zinc requirement: the zinc content in the daily ration is closely related to the zinc requirement of the pigs, and if the zinc content in the daily ration cannot meet the requirements of animals, the piglets can be reduced in size, and the development is influenced. The production of boar sperms can be influenced, and the whole reproductive cycle of the sows is closely related to zinc, for example, the sows suffer from delayed oestrus, easy abortion and the like due to zinc deficiency. The zinc requirement of cattle and sheep: in severe zinc deficiency, breeding disorder of cattle and sheep can occur, and gonad of bull and male lamb can be underdeveloped. It is known that the zinc content in the feed can not meet the needs of animals except fish meal, so the addition of zinc is noticed in the daily ration of livestock and poultry, otherwise the above adverse conditions can occur, and the loss of benefits is brought to production and breeding people.
Therefore, we have modified the thiazine compound to coordinate and complex with zinc ions, and synthesized a novel structure thiazine compound, which can be used as non-protein nitrogen, has a certain inhibitory effect on urease, has bactericidal and anti-ulcer effects, and can be used as an excellent animal feed additive.
Disclosure of Invention
The invention solves the technical problem of providing a preparation method of thiazine feed additive with simple synthesis method, low raw material price, novel structure and better biological activity.
The invention adopts the following technical scheme for solving the technical problems, and the molecular structure of the thiazide urea feed additive is as follows:
the invention adopts the following technical scheme for solving the technical problems, and the preparation method of the thiazine feed additive is characterized by comprising the following specific steps of:
(1) respectively adding activated carbon and sodium nitrate into a reaction bottle, slowly adding concentrated sulfuric acid at the temperature of 0 ℃, mechanically stirring uniformly, adding perchloric acid, heating to 50 ℃, stirring for a period of time, adding deionized water, heating to 80 ℃, stirring for a period of time, taking out the reaction bottle, adding deionized water and hydrogen peroxide at room temperature, standing, precipitating, cooling to room temperature, washing, centrifuging for a plurality of times, and performing ultrasonic treatment and freeze drying to obtain oxidized activated carbon; adding all the obtained oxidized activated carbon into N, N-dimethylformamide, performing ultrasonic dispersion, weighing bismuth nitrate pentahydrate and scandium nitrate hexahydrate to dissolve in the N, N-dimethylformamide, weighing sodium trifluoromethanesulfonate to dissolve in ethylene glycol, and stirring for a period of time; mixing and stirring the solution uniformly, pouring the solution into a polytetrafluoroethylene high-pressure hydrothermal kettle, carrying out hydrothermal reaction at 140 ℃ for a period of time, naturally cooling to room temperature, alternately washing with ethanol and deionized water, centrifuging, and drying the precipitate in a forced air drying oven at 80 ℃ to obtain an activated carbon-loaded bismuth/scandium catalyst; the mass ratio of the active carbon to the bismuth nitrate pentahydrate to the scandium nitrate trihydrate is 10:4.8: 2.3.
(2) Adding 2, 6-dichloropyridine into a mixed solution of trifluoroacetic anhydride, formic acid and dimethyl sulfoxide in a high-pressure reaction kettle at an internal temperature of 5-10 ℃ under the protection of argon, keeping the temperature unchanged, and adding an activated carbon loaded bismuth/scandium catalyst; slowly heating to 90 ℃, stirring for a period of time, and introducing ammonia gas into the reaction kettle to enable the pressure in the kettle to reach 0.1 MPa; keeping the pressure unchanged, continuously raising the temperature to 140 ℃, reacting until the raw materials completely react, cooling to room temperature, filtering the reaction solution, adding water into the filtrate, extracting with dichloromethane for multiple times, combining organic phases, drying with anhydrous magnesium sulfate, and concentrating to obtain 2, 6-dichloro-4-formamide pyridine; the mass ratio of the 2, 6-dichloropyridine to the activated carbon-loaded bismuth/scandium catalyst is 10: 1; the activated carbon supported bismuth/scandium catalyst can be reused three times.
(3) Adding 2, 6-dichloro-4-formamide pyridine into 1, 4-dioxane, adding trifluoroacetic anhydride and triethylamine, heating to a certain temperature under the protection of nitrogen until the raw materials completely react, cooling the reaction liquid to room temperature, adding water, extracting the reaction liquid for multiple times by using ethyl acetate, combining organic phases, drying by using anhydrous magnesium sulfate, and concentrating to obtain 2, 6-dichloro-4-nitrile-pyridine; the feeding amount molar ratio of the 2, 6-dichloro-4-formamide pyridine to the trifluoroacetic anhydride and the triethylamine is 1:2: 2; the reaction temperature was 90 ℃.
(4) Adding 2, 6-dichloro-4-nitrile-pyridine into thionyl chloride at the internal temperature of 5-10 ℃, slowly heating to 90 ℃, uniformly stirring, cooling to room temperature, slowly adding chlorosulfonic acid while stirring, continuously heating to a certain temperature after dropwise adding, reacting until the raw materials completely react, cooling to room temperature, filtering the reaction liquid, adding water into the filtrate, extracting with dichloromethane for multiple times, combining organic phases, drying with anhydrous magnesium sulfate, and concentrating to obtain 2, 6-dichloro-4-nitrile-5-sulfonic acid chloro-pyridine; the feeding amount molar ratio of the 2, 6-dichloro-4-nitrile-pyridine to the chlorosulfonic acid is 1: 1-2; the reaction temperature is 50-70 ℃.
(5) Adding 2, 6-dichloro-4-nitrile-5-sulfonic acid chloro-pyridine and zinc powder into dimethyl sulfoxide, stirring uniformly, then slowly dropwise adding 2M sulfuric acid at 0 ℃, stirring while dropwise adding until the raw materials disappear, cooling the reaction liquid to room temperature, pouring into water, allowing a large amount of solids to appear, filtering, placing a filter cake into a mixed solution of acetone and ethanol, heating to reflux, stirring for a period of time, slowly cooling, carrying out suction filtration on the reaction liquid again, and drying the filter cake to obtain 2, 6-dichloro-4-nitrile-5-mercapto-pyridine; the feeding amount molar ratio of the 2, 6-dichloro-4-nitrile-5-sulfonic acid chlorine-pyridine to the zinc powder is 1: 1-2.
(6) Adding 2, 6-dichloro-4-nitrile-5-mercapto-pyridine and benzylamine into N, N-dimethylformamide, heating to 100 ℃ until the raw materials disappear, cooling the reaction liquid to room temperature, pouring into water, extracting the reaction liquid with ethyl acetate for three times, combining organic phases, drying with anhydrous magnesium sulfate, and concentrating to obtain the 2, 6-dibenzyl-4-nitrile-5-mercapto-pyridine.
(7) Adding 2, 6-dibenzyl-4-nitrile-5-mercapto-pyridine and palladium carbon (the content of 5%) into methanol, introducing hydrogen into an autoclave, reacting at a certain temperature until the raw materials react completely, filtering the reaction solution, and concentrating the filtrate to obtain pure 2, 6-amino-4-nitrile-5-mercapto-pyridine; the reaction temperature was 40 ℃.
(8) Adding phosphorus oxychloride into dichloromethane, adding a dichloromethane mixed solution in which 2, 6-amino-4-nitrile-5-mercapto-pyridine is dissolved into a constant-pressure dropping funnel, dropwise adding the mixed solution at room temperature under the protection of nitrogen, continuously stirring until the raw materials completely react, introducing ammonia gas into a reaction bottle, observing by a thermometer inserted into the reaction solution, rapidly increasing the reaction temperature, then rapidly decreasing the reaction temperature, finishing the reaction when the reaction temperature decreases to room temperature, filtering the reaction solution, drying an organic phase by anhydrous magnesium sulfate, and concentrating to obtain the 2, 6-dimethylureido-4-nitrile-5-mercapto-pyridine.
(9) Adding 2, 6-dimethylureido-4-nitrile-5-mercapto-pyridine and a catalyst Raney nickel into ethanol, introducing ammonia gas into a high-pressure kettle to enable the pressure to reach 0.1MPa, keeping the pressure, stirring for a period of time, introducing hydrogen to enable the pressure to reach 0.3MPa, enabling the reaction temperature to be 40 ℃, reacting for a period of time, reducing the pressure to 0.1MPa, introducing ammonia gas to enable the pressure to reach 0.2MPa, keeping the pressure and stirring for a period of time, introducing hydrogen again to enable the pressure to reach 0.3MPa, continuing to react until the raw materials react completely, filtering reaction liquid, and concentrating filtrate to obtain the 2, 6-dimethylureido-4-methylamine-5-mercapto-pyridine.
(10) Adding 2, 6-dimethylureido-4-methylamine-5-sulfydryl-pyridine into a reaction bottle, heating the mixture into dichloromethane, stirring the mixture at the temperature of-10 ℃ under the protection of nitrogen, slowly dropwise adding thiophosgene, monitoring the complete reaction of raw materials by TLC (thin layer chromatography), adding water, extracting the mixture by ethyl acetate, drying the mixture by anhydrous sodium sulfate, filtering the dried mixture, evaporating the solvent to dryness, and separating the solvent by silica gel column chromatography to obtain the compound
(11) Handle of bicycle
Adding zinc powder into a mixed solution of acetone and water, stirring uniformly, slowly adding saturated dilute hydrochloric acid solution dropwise at the temperature of 0 ℃, stirring while adding dropwise, slowly heating to reflux after adding dropwise, reacting for 1h, then monitoring by TLC to show that the raw materials disappear, cooling the reaction solution to room temperature, pouring the reaction solution into water, allowing a large amount of solids to appear, filtering, adding a filter cake into the mixed solution of acetone and ethanol, heating to reflux, stirring for a period of time, slowly cooling, performing suction filtration on the reaction solution again, and drying the filter cake to obtain the final product
(12) Dissolving zinc chloride in acetonitrile,
dissolving in methanol, mixing the above solutions, heating to 70 deg.C, stirring for a period of time, cooling to room temperature, adding anhydrous diethyl ether, standing, slowly volatilizing to obtain crystal, and collecting reaction solution to obtain complex
The invention adopts the following technical scheme for solving the technical problems, and the preparation method of the thiazine feed additive is characterized by comprising the following specific steps of:
Detailed Description
The present invention is described in further detail below with reference to examples, but it should not be construed that the scope of the above subject matter of the present invention is limited to the following examples, and that all the technologies realized based on the above subject matter of the present invention belong to the scope of the present invention.
Example 1
Respectively adding 10g of activated carbon and 10g of sodium nitrate into a reaction bottle, slowly adding 150mL of concentrated sulfuric acid at 0 ℃, mechanically stirring for 10min, adding 50g of perchloric acid, heating to 50 ℃, stirring for 1h, adding 500mL of deionized water, heating to 80 ℃, stirring for 50min, taking out the reaction bottle, adding 200mL of deionized water and 100mL of hydrogen peroxide at room temperature, standing, precipitating, cooling to room temperature, washing and centrifuging for several times, continuously performing ultrasonic treatment for 8h, and freeze-drying for 10h to obtain oxidized activated carbon; the obtained oxidized activated carbon was completely added to 60mL of N, N-dimethylformamide, ultrasonic dispersion was carried out, 4.8g of bismuth nitrate pentahydrate and 2.3g of scandium nitrate hexahydrate were weighed and dissolved in 40mL of N, N-dimethylformamide, 10g of sodium trifluoromethanesulfonate was weighed and dissolved in 40mL of ethylene glycol, and then stirring was carried out for 1.5 hours. The above solutions were mixed and stirred for 1h and then stopped. Pouring the mixed solution into a polytetrafluoroethylene high-pressure hydrothermal kettle, carrying out hydrothermal reaction at 140 ℃ for 24h, naturally cooling to room temperature after the reaction is stopped, alternately washing with ethanol and deionized water, centrifuging, and drying the precipitate in an air-blast drying oven at 80 ℃ for 12h to obtain 13g of the activated carbon-loaded bismuth/scandium catalyst.
Example 2
In a high-pressure reaction kettle, under the protection of argon, starting cooling, adding 15g of 2, 6-dichloropyridine into a mixed solution of 42g of trifluoroacetic anhydride, 9.2g of formic acid and 150mL of dimethyl sulfoxide, keeping the temperature unchanged, and adding 1.5g of an activated carbon loaded bismuth/scandium catalyst; slowly heating to 90 ℃, stirring for 50min, and introducing ammonia gas into the reaction kettle to enable the pressure in the kettle to reach 0.1 MPa; keeping the pressure unchanged, continuously raising the temperature to 140 ℃, reacting for 2 hours, then monitoring the reaction completion of the raw materials by TLC (thin layer chromatography), cooling to room temperature, filtering the reaction solution, adding 100mL of water into the filtrate, extracting for multiple times by using 100mL of dichloromethane, combining organic phases, drying by using anhydrous magnesium sulfate, and concentrating to obtain 16g of 2, 6-dichloro-4-formamide pyridine; call for C6H4N2Cl2O:C,37.73；H,2.11；N,14.67.Found:C,37.58；H,2.13；N,14.74。
Example 3
In a high-pressure reaction kettle, under the protection of argon, starting cooling, adding 15g of 2, 6-dichloropyridine into a mixed solution of 42g of trifluoroacetic anhydride, 9.2g of formic acid and 150mL of dimethyl sulfoxide, keeping the temperature unchanged, and adding 1.5g of an activated carbon loaded bismuth/scandium catalyst (repeated once); slowly heating to 90 ℃, stirring for 50min, and introducing ammonia gas into the reaction kettle to enable the pressure in the kettle to reach 0.1 MPa; keeping the pressure unchanged, continuously raising the temperature to 140 ℃, reacting for 2 hours, then monitoring the reaction completion of the raw materials by TLC (thin layer chromatography), cooling to room temperature, filtering the reaction solution, adding 100mL of water into the filtrate, extracting for multiple times by using 100mL of dichloromethane, combining organic phases, drying by using anhydrous magnesium sulfate, and concentrating to obtain 14g of 2, 6-dichloro-4-formamide pyridine; call for C6H4N2Cl2O:C,37.73；H,2.11；N,14.67.Found:C,37.58；H,2.13；N,14.74。
Example 4
In a high-pressure reaction kettle, under the protection of argon, starting cooling, adding 15g of 2, 6-dichloropyridine into a mixed solution of 42g of trifluoroacetic anhydride, 9.2g of formic acid and 150mL of dimethyl sulfoxide, keeping the temperature unchanged, and adding 1.5g of an activated carbon loaded bismuth/scandium catalyst (repeating twice); slowly heating to 90 ℃, stirring for 50min, and introducing ammonia gas into the reaction kettle to enable the pressure in the kettle to reach 0.1 MPa; keeping the pressure unchanged, continuously raising the temperature to 140 ℃, reacting for 2 hours, then monitoring the reaction completion of the raw materials by TLC (thin layer chromatography), cooling to room temperature, filtering the reaction solution, adding 100mL of water into the filtrate, extracting for multiple times by using 100mL of dichloromethane, combining organic phases, drying by using anhydrous magnesium sulfate, and concentrating to obtain 13g of 2, 6-dichloro-4-formamide pyridine; call for C6H4N2Cl2O:C,37.73；H,2.11；N,14.67.Found:C,37.58；H,2.13；N,14.74。
Example 5
In a high-pressure reaction kettle, under the protection of argon, starting cooling, adding 15g of 2, 6-dichloropyridine into a mixed solution of 42g of trifluoroacetic anhydride, 9.2g of formic acid and 150mL of dimethyl sulfoxide, keeping the temperature unchanged, and adding 1.5g of an activated carbon loaded bismuth/scandium catalyst (repeating for three times); slowly heating to 90 ℃, stirring for 50min, and introducing ammonia gas into the reaction kettle to enable the pressure in the kettle to reach 0.1 MPa; keeping the pressure unchanged, continuously raising the temperature to 140 ℃, reacting for 2 hours, then monitoring the reaction completion of the raw materials by TLC (thin layer chromatography), cooling to room temperature, filtering the reaction solution, adding 100mL of water into the filtrate, extracting for multiple times by using 100mL of dichloromethane, combining organic phases, drying by using anhydrous magnesium sulfate, and concentrating to obtain 9g of 2, 6-dichloro-4-formamide pyridine; call for C6H4N2Cl2O:C,37.73；H,2.11；N,14.67.Found:C,37.58；H,2.13；N,14.74。
Example 6
Adding 19g of 2, 6-dichloro-4-formamide pyridine into 200mL of 1, 4-dioxane in a reaction bottle, adding 42g of trifluoroacetic anhydride and 20g of triethylamine, heating to 90 ℃ under the protection of nitrogen, monitoring the complete reaction of raw materials by TLC, cooling the reaction liquid to room temperature, adding 100mL of water, extracting the reaction liquid for multiple times by using 100mL of ethyl acetate, combining organic phases, drying by anhydrous magnesium sulfate, concentrating to obtain 15g of 2, 6-dichloro-4-nitrile-pyridine,1H NMR(400MHz,DMSO-d6):7.46(s,1H),7.19(s,1H)；13C NMR(100MHz,DMSO-d6):154.32,131.15,127.39,116.42。
example 7
Adding 17g of 2, 6-dichloro-4-nitrile-pyridine into 200mL of thionyl chloride in a reaction bottle at the internal temperature of 5-10 ℃, slowly heating to 90 ℃, stirring for 10min, cooling to room temperature, slowly adding 12g of chlorosulfonic acid while stirring, continuously heating to 50 ℃ after dropwise adding, reacting for 2h, monitoring by TLC that the raw materials are completely reacted, cooling to room temperature, filtering the reaction solution, adding 300mL of water into the filtrate, extracting with 100mL of dichloromethane for multiple times, combining organic phases, drying with anhydrous magnesium sulfate, and concentrating to obtain 16g of 2, 6-dichloro-4-nitrile-5-sulfonic acid chloro-pyridine; call for C6HN2Cl3O2S:C,26.54；H,0.37；N,10.32.Found:C,26.29；H,0.39；N,10.43。
Example 8
Adding 17g of 2, 6-dichloro-4-nitrile-pyridine into 200mL of thionyl chloride in a reaction bottle at the internal temperature of 5-10 ℃, slowly heating to 90 ℃, stirring for 10min, cooling to room temperature, slowly adding 12g of chlorosulfonic acid while stirring, continuously heating to 55 ℃ after dropwise adding, reacting for 2h, monitoring by TLC that the raw materials are completely reacted, cooling to room temperature, filtering the reaction solution, adding 300mL of water into the filtrate, extracting with 100mL of dichloromethane for multiple times, combining organic phases, drying with anhydrous magnesium sulfate, and concentrating to obtain 23g of 2, 6-dichloro-4-nitrile-5-sulfonic acid chloro-pyridine; call for C6HN2Cl3O2S:C,26.54；H,0.37；N,10.32.Found:C,26.29；H,0.39；N,10.43。
Example 9
Adding 17g of 2, 6-dichloro-4-nitrile-pyridine into 200mL of thionyl chloride in a reaction bottle at the internal temperature of 5-10 ℃, slowly heating to 90 ℃, stirring for 10min, cooling to room temperature, slowly adding 12g of chlorosulfonic acid while stirring, continuously heating to 60 ℃ after dropwise adding, reacting for 2h, monitoring by TLC that the raw materials are completely reacted, cooling to room temperature, filtering the reaction solution, adding 300mL of water into the filtrate, extracting with 100mL of dichloromethane for multiple times, combining organic phases, drying with anhydrous magnesium sulfate, and concentrating to obtain 21g of 2, 6-dichloro-4-nitrile-5-sulfonic acid chloro-pyridine; call for C6HN2Cl3O2S:C,26.54；H,0.37；N,10.32.Found:C,26.29；H,0.39；N,10.43。
Example 10
Adding 17g of 2, 6-dichloro-4-nitrile-pyridine into 200mL of thionyl chloride in a reaction bottle at the internal temperature of 5-10 ℃, slowly heating to 90 ℃, stirring for 10min, cooling to room temperature, slowly adding 12g of chlorosulfonic acid while stirring, continuously heating to 70 ℃ after dropwise adding, reacting for 2h, monitoring the complete reaction of the raw materials by TLC (thin layer chromatography), cooling to room temperature, filtering the reaction solution, and adding the mixture into the reaction bottleAdding 300mL of water into the filtrate, extracting for multiple times by using 100mL of dichloromethane, combining organic phases, drying by using anhydrous magnesium sulfate, and concentrating to obtain 18g of 2, 6-dichloro-4-cyano-5-sulfonic acid chloro-pyridine; call for C6HN2Cl3O2S:C,26.54；H,0.37；N,10.32.Found:C,26.29；H,0.39；N,10.43。
Example 11
Adding 17g of 2, 6-dichloro-4-nitrile-pyridine into 200mL of thionyl chloride in a reaction bottle at the internal temperature of 5-10 ℃, slowly heating to 90 ℃, stirring for 10min, cooling to room temperature, slowly adding 18g of chlorosulfonic acid while stirring, continuously heating to 55 ℃ after dropwise adding, reacting for 2h, monitoring by TLC that the raw materials are completely reacted, cooling to room temperature, filtering the reaction solution, adding 300mL of water into the filtrate, extracting with 100mL of dichloromethane for multiple times, combining organic phases, drying with anhydrous magnesium sulfate, and concentrating to obtain 24g of 2, 6-dichloro-4-nitrile-5-sulfonic acid chloro-pyridine; call for C6HN2Cl3O2S:C,26.54；H,0.37；N,10.32.Found:C,26.29；H,0.39；N,10.43。
Example 12
Adding 17g of 2, 6-dichloro-4-nitrile-pyridine into 200mL of thionyl chloride in a reaction bottle at the internal temperature of 5-10 ℃, slowly heating to 90 ℃, stirring for 10min, cooling to room temperature, slowly adding 24g of chlorosulfonic acid while stirring, continuously heating to 55 ℃ after dropwise adding, reacting for 2h, monitoring by TLC that the raw materials are completely reacted, cooling to room temperature, filtering the reaction solution, adding 300mL of water into the filtrate, extracting with 100mL of dichloromethane for multiple times, combining organic phases, drying with anhydrous magnesium sulfate, and concentrating to obtain 13g of 2, 6-dichloro-4-nitrile-5-sulfonic acid chloro-pyridine; call for C6HN2Cl3O2S:C,26.54；H,0.37；N,10.32.Found:C,26.29；H,0.39；N,10.43。
Example 13
Adding 27g of 2, 6-dichloro-4-nitrile-5-sulfonic acid chloro-pyridine and 13g of zinc powder into 250mL of dimethyl sulfoxide in a reaction bottle, uniformly stirring, slowly dropwise adding 50mL of 2M sulfuric acid at 0 ℃, stirring while dropwise adding, reacting for 1h, then TLC monitoring shows that the raw materials disappear, cooling the reaction liquid to room temperature, pouring the reaction liquid into 500mL of water, allowing a large amount of solids to appear, filtering, adding a filter cake into a mixed solution of 20mL of ethanol and 50mL of ethanol, heating to reflux, stirring for 20min, slowly cooling, performing suction filtration on the reaction liquid again, and drying the filter cake to obtain 14g of 2, 6-dichloro-4-nitrile-5-mercapto-pyridine;1H NMR(400M,DMSO-d6):8.19(s,1H),3.35(s,1H)；MS(ESI)m/z:204.9[M+H]+。
example 14
Adding 27g of 2, 6-dichloro-4-nitrile-5-sulfonic acid chloro-pyridine and 10g of zinc powder into 250mL of dimethyl sulfoxide in a reaction bottle, uniformly stirring, slowly dropwise adding 50mL of 2M sulfuric acid at 0 ℃, stirring while dropwise adding, reacting for 1h, then TLC monitoring shows that the raw materials disappear, cooling the reaction liquid to room temperature, pouring the reaction liquid into 500mL of water, allowing a large amount of solids to appear, filtering, adding a filter cake into a mixed solution of 20mL of ethanol and 50mL of ethanol, heating to reflux, stirring for 20min, slowly cooling, performing suction filtration on the reaction liquid again, and drying the filter cake to obtain 18g of 2, 6-dichloro-4-nitrile-5-mercapto-pyridine;1H NMR(400M,DMSO-d6):8.19(s,1H),3.35(s,1H)；MS(ESI)m/z:204.9[M+H]+。
example 15
In the reaction flask, handleAdding 27g of 2, 6-dichloro-4-nitrile-5-sulfonic acid chloro-pyridine and 6.5g of zinc powder into 250mL of dimethyl sulfoxide, stirring uniformly, slowly adding 50mL of 2M sulfuric acid dropwise at 0 ℃, stirring while dropwise adding, reacting for 1h, then TLC monitoring shows that the raw materials disappear, cooling the reaction liquid to room temperature, pouring the reaction liquid into 500mL of water, allowing a large amount of solids to appear, filtering, adding a filter cake into a mixed solution of 20mL of acetone and 50mL of ethanol, heating to reflux, stirring for 20min, slowly cooling, performing suction filtration on the reaction liquid again, and drying the filter cake to obtain 8g of 2, 6-dichloro-4-nitrile-5-mercapto-pyridine;1H NMR(400M,DMSO-d6):8.19(s,1H),3.35(s,1H)；MS(ESI)m/z:204.9[M+H]+。
example 16
In a reaction bottle, adding 20g of 2, 6-dichloro-4-nitrile-5-mercapto-pyridine and 25g of benzylamine into 130mL of N, N-dimethylformamide, heating to 100 ℃, reacting for 1h, then monitoring by TLC to show that the raw materials disappear, cooling the reaction liquid to room temperature, and pouring into 100mL of water; extracting the reaction liquid for three times by using 100mL of ethyl acetate, combining organic phases, drying the organic phases by using anhydrous magnesium sulfate, and concentrating the organic phases to obtain 29g of 2, 6-dibenzyl-4-nitrile-5-mercapto-pyridine;1H NMR(400M,CDCl3):7.76-7.74(m,2H),7.41(d,J＝12.0Hz,2H),7.35(d,J＝12.0Hz,2H),7.21-7.18(m,4H),6.55(s,1H),4.69-4.67(m,4H),3.49(s,1H)；MS(ESI)m/z:347.2[M+H]+。
example 17
Adding 34g of 2, 6-dibenzyl-4-nitrile-5-mercapto-pyridine and 1.7g of palladium carbon (content is 5%) into 200mL of methanol in a 500mL reaction bottle, introducing hydrogen into an autoclave, controlling the pressure to be 0.2MPa and the reaction temperature to be 40 ℃, reacting for 12h, monitoring the raw materials by TLC to react completely, filtering the reaction solution, and concentrating the filtrate to obtain 14g of pure 2, 6-amino-4-nitrile-5-mercapto-pyridine;1H NMR(400M,DMSO-d6):7.93-7.91(m,4H),6.82(s,1H),3.36(s,1H)；MS(ESI)m/z:167.4[M+H]+。
example 18
Adding 30g of phosphorus oxychloride into 300mL of dichloromethane in a reaction bottle, adding 100mL of dichloromethane in which 17g of 2, 6-amino-4-nitrile-5-mercapto-pyridine is dissolved into a constant-pressure dropping funnel, dropwise adding the mixed solution at room temperature under the protection of nitrogen, continuing stirring for 1h after dropwise adding, monitoring the complete reaction of raw materials by TLC, introducing ammonia gas into the reaction bottle, observing by a thermometer inserted with the reaction solution, rapidly increasing the reaction temperature, then rapidly decreasing, finishing the reaction when the reaction temperature is decreased to room temperature, filtering the reaction solution, drying an organic phase by anhydrous magnesium sulfate, and concentrating to obtain 28g of 2, 6-dimethylureido-4-nitrile-5-mercapto-pyridine;1H NMR(400M,DMSO-d6):6.75(s,1H),3.50(s,1H),4.14-4.13(m,2H),2.25-2.23(m,8H)；MS(ESI)m/z:323.4[M+H]+.Anal.Calcd for C6H12N8O2P2S:C,22.36；H,3.75；N,34.78.Found:C,22.61；H,3.82；N,34.46。
example 19
Adding 32g of 2, 6-dimethylureido-4-nitrile-5-mercapto-pyridine and 3.2g of Raney nickel serving as a catalyst into 200mL of ethanol in a 500mL reaction bottle, introducing ammonia gas into an autoclave until the pressure reaches 0.1MPa, keeping the pressure, stirring for 1h, introducing hydrogen gas until the pressure reaches 0.3MPa, reacting at the temperature of 40 ℃ for 30min, reducing the pressure to 0.1MPa, introducing ammonia gas until the pressure reaches 0.2MPa, keeping the pressure, stirring for 10min, introducing hydrogen gas again until the pressure reaches 0.3MPa, continuing to react for 2h, monitoring the complete reaction of the raw materials by TLC, filtering the reaction liquid, concentrating the filtrate to obtain pure 2, 6-dimethylureido-4-methylamine-5-mercapto-pyridine24g；1H NMR(400M,DMSO-d6):8.93(s,2H),5.88(s,1H),4.47(d,J＝8.0Hz,2H),3.56(s,1H),4.11(s,2H),2.19-2.17(m,8H)；MS(ESI)m/z:327.6[M+H]+.Anal.Calcd for C6H16N8O2P2S:C,22.09；H,4.94；N,34.35.Found:C,22.27；H,4.86；N,34.52。
Example 20
Adding 32g of 2, 6-dimethylureido-4-methylamine-5-mercapto-pyridine into a reaction bottle, heating the mixture to 200mL of dichloromethane, stirring the mixture at the temperature of-10 ℃ under the protection of nitrogen, slowly dropwise adding 15g of thiophosgene, monitoring the complete reaction of raw materials by TLC (thin layer chromatography), adding 200mL of water, 300mL of ethyl acetate for extraction, drying the mixture by anhydrous sodium sulfate, filtering the mixture, evaporating the solvent to dryness, and carrying out silica gel column chromatography (V)Methanol：VMethylene dichloride1:20) to obtain
32g；1H NMR(400M,DMSO-d6):6.77(s,1H),4.29(s,2H),3.99(s,2H),2.29-2.26(m,8H),2.16(s,1H)；13C NMR(100M,DMSO-d6):174.3,158.9,151.6,139.1,122.8,104.5,43.7；MS(ESI)m/z:369.2[M+H]+.Anal.Calcd for C7H14N8O2P2S2:C,22.83；H,3.83；N,30.42.Found:C,22.61；H,3.86；N,30.71。
Example 21
In the reaction flask, handle
Adding 37g of zinc powder and 13g of zinc powder into a mixed solution of acetone and water, stirring uniformly, and slowly dropwise adding saturated dilute salt at the temperature of 0 DEG CDropwise adding an acid solution while stirring, slowly heating to reflux after dropwise adding, reacting for 1h, then TLC monitoring shows that the raw materials disappear, cooling the reaction liquid to room temperature, pouring into 100mL of water, allowing a large amount of solids to appear, filtering, placing a filter cake into a mixed solution of acetone and ethanol, heating to reflux, stirring for 20min, slowly cooling, performing suction filtration again on the reaction liquid, and drying the filter cake to obtain the final product
29g；1H NMR(400M,DMSO-d6):6.69(s,1H),4.93-4.91(m,1H),4.25-4.24(m,2H),3.91-3.89(m，2H),2.26-2.24(m,8H),1.95(s,1H),1.57(s,1H)；13C NMR(100M,DMSO-d6):163.5,151.4,147.3,128.6,117.4,77.8,44.2；MS(ESI)m/z:371.1[M+H]+.Anal.Calcd for C7H16N8O2P2S2:C,22.70；H,4.35；N,30.26.Found:C,22.52；H,4.45；N,30.42。
Example 22
Dissolving 14g of zinc chloride in 500mL of acetonitrile,
dissolving 55g of the mixture in 500mL of methanol, mixing the solutions, heating to 70 ℃, stirring for 30min, cooling to room temperature, adding 800mL of anhydrous ether, standing, slowly volatilizing, generating crystals in a bottle after two days, and obtaining a reaction solution with a yield to obtain the complex
51g。
Elemental analysis
The results of the elemental analysis of carbon, hydrogen and nitrogen are shown in table 1, and the content of zinc in the product is determined by EDTA coordination titration. The results are averaged five times and are shown in table 1.
TABLE 1 results of elemental analysis of the product
And (4) conclusion: the elemental analysis results of the samples were in agreement with the theoretical values.
Example 23
In vitro urease inhibition assay
After feeding the cattle for 1h, collecting 400mL of rumen fluid by a special rumen fluid collector through an artificial rumen fistula, and filtering the rumen fluid by 4 layers of gauze for later use. After adding the corresponding reagents in the amount shown in Table 1 into each culture tube, 4 drops of paraffin were added dropwise and the mixture was gently shaken on a constant temperature water bath shaker at 39.0. + -. 0.5 ℃. At 1,2,4,6 and 8h of culture, part of the culture tubes were taken out from each group, and 4 drops of saturated mercuric chloride solution were immediately added and shaken to terminate the reaction. The ammonia nitrogen content of each tube is measured by a Kjeldahl half-trace-saturated magnesium oxide distillation method.
Percent inhibition (%) (control ammonia content-test ammonia content) ÷ control ammonia content × 100%
| Time (h) | Inhibition rate of control group | Test 1 group inhibition | Test 2 group inhibition | Test 3 groups inhibition |
| 1 | 0％ | 4.3％ | 7.9％ | 16.6％ |
| 2 | 0％ | 9.1％ | 14.6％ | 26.4％ |
| 4 | 0％ | 19.4％ | 21.9％ | 33.6％ |
| 6 | 0％ | 25.6％ | 28.7％ | 41.7％ |
| 8 | 0％ | 33.8％ | 38.5％ | 55.2％ |
Example 24
Biological activity assay
Coli (gram-negative brevibacterium) and staphylococcus aureus (gram-positive bacterium) were selected as the test subjects for antibacterial activity. Firstly, preparing a liquid culture medium (1 g of peptone, 0.5g of yeast extract, 1g of sodium chloride and 100mL of distilled water are placed in a 250mL conical flask and are placed on an electric furnace to be heated while stirring, when the peptone, the yeast extract, the sodium chloride and the distilled water are mixed and clarified uniformly, the heating is stopped, and the bottleneck is sequentially sealed by gauze and kraft paper for standby) and a solid culture medium (1 g of peptone, 0.5g of yeast extract, 1g of sodium chloride, 2g of agar and 100mL of distilled water are placed in a 250mL conical flask and are placed on an electric furnace to be heated while stirring, when the peptone, the yeast extract, the agar and the distilled water are mixed and clarified uniformly, the heating is stopped, and the bottleneck is sequentially sealed by gauze and; then the culture medium is sterilized by an autoclave. Secondly, preparing bacterial liquid, namely activating escherichia coli and staphylococcus aureus strains, transferring 100 mu L of activated bacterial liquid by using a liquid transfer gun, and putting the activated bacterial liquid into sterilized 100mL of distilled water for uniformly mixing. And finally, sterilizing the flat plate by an ultraviolet lamp, quickly pouring the culture medium into the flat plate while the culture medium is hot, uniformly paving the flat plate with the thickness of about 0.15cm, standing the flat plate, slowly solidifying the flat plate, and putting the solidified flat plate into an incubator at 37 ℃ for culturing for one day for carrying out non-impurity bacteria detection.
The target compound and the control compound solutions are prepared respectively with DMF and placed in volumetric flasks for later use. Punching a hole on the filter paper by using a puncher, wherein the aperture is 5mm, and then sterilizing the filter paper sheet and soaking the filter paper sheet in a sample solution with the concentration of 1mg/mL for later use.
On a clean bench, an alcohol lamp was lit, and 10. mu.L of diluted culture solution was applied to the surface of the solid medium with a pipette and spread uniformly. The soaked round filter paper sheet was spread on the surface of the medium with sterile forceps. 4 plates were placed on each plate and 3 replicates were run, one of which was blank controlled. The plate with the tablets was incubated at 37 ℃ for 24h and observed for signs. The transparent circular rings-bacteriostatic rings with different sizes are respectively arranged on the agar culture medium, and the bacteriostatic activity of each sample can be seen by measuring the diameters of the bacteriostatic rings.
Example 25
The novel feed additive is subjected to oral acute toxicity tests according to the technical requirements of general toxicity tests of novel veterinary drugs and GB 15193.3-2003: on the basis of a pre-test, 20 mice and 20 rats are respectively orally administrated twice at intervals of 4h, the administration dose is 16.0g/kg, the administration volume is 0.2mL/10g of body weight, and as a result, the animals normally eat, drink water, excrement and act within 14d without any toxic reaction, and the novel compound preparation is novelFeed additive for oral administration of LD to mice and rats50Are all more than 16.0 g/kg.
The foregoing embodiments illustrate the principles, principal features and advantages of the invention, and it will be understood by those skilled in the art that the invention is not limited to the foregoing embodiments, which are merely illustrative of the principles of the invention, and that various changes and modifications may be made therein without departing from the scope of the principles of the invention.
Claims (9)
1. A preparation method of thiazine feed additive is characterized in that the molecular structure of the thiazine feed additive is as follows:
the preparation method of the thiazine feed additive comprises the following specific preparation steps:
(1) respectively adding activated carbon and sodium nitrate into a reaction bottle, slowly adding concentrated sulfuric acid at 0 ℃, mechanically stirring uniformly, adding perchloric acid, heating to 50 ℃, stirring for a period of time, adding deionized water, heating to 80 ℃, stirring for a period of time, taking out the reaction bottle, adding deionized water and hydrogen peroxide at room temperature, standing, precipitating, cooling to room temperature, washing, centrifuging for a plurality of times, and performing ultrasonic treatment and freeze drying to obtain oxidized activated carbon; adding all the obtained oxidized activated carbon into N, N-dimethylformamide, performing ultrasonic dispersion, weighing bismuth nitrate pentahydrate and scandium nitrate hexahydrate, dissolving into N, N-dimethylformamide, weighing sodium trifluoromethanesulfonate, dissolving into ethylene glycol, and stirring for a period of time; mixing and stirring the solution uniformly, pouring the solution into a polytetrafluoroethylene high-pressure hydrothermal kettle, carrying out hydrothermal reaction at 140 ℃ for a period of time, naturally cooling to room temperature, alternately washing with ethanol and deionized water, centrifuging, and drying the precipitate in a forced air drying oven at 80 ℃ to obtain an activated carbon-loaded bismuth/scandium catalyst;
(2) adding 2, 6-dichloropyridine into a mixed solution of trifluoroacetic anhydride, formic acid and dimethyl sulfoxide in a high-pressure reaction kettle at the internal temperature of 5-10 ℃ under the protection of argon, keeping the temperature unchanged, and adding an activated carbon loaded bismuth/scandium catalyst; slowly heating to 90 ℃, stirring for a period of time, and introducing ammonia gas into the reaction kettle to enable the pressure in the kettle to reach 0.1 MPa; keeping the pressure unchanged, continuously raising the temperature to 140 ℃, reacting until the raw materials completely react, cooling to room temperature, filtering the reaction solution, adding water into the filtrate, extracting with dichloromethane for multiple times, combining organic phases, drying with anhydrous magnesium sulfate, and concentrating to obtain 2, 6-dichloro-4-formamide pyridine;
(3) adding 2, 6-dichloro-4-pyrimethanil into 1, 4-dioxane, adding trifluoroacetic anhydride and triethylamine, heating to a certain temperature under the protection of nitrogen until the raw materials completely react, cooling the reaction liquid to room temperature, adding water, extracting the reaction liquid for multiple times by using ethyl acetate, combining organic phases, drying by using anhydrous magnesium sulfate, and concentrating to obtain 2, 6-dichloro-4-cyano-pyridine;
(4) adding 2, 6-dichloro-4-nitrile-pyridine into thionyl chloride at the internal temperature of 5-10 ℃, slowly heating to 90 ℃, uniformly stirring, cooling to room temperature, slowly adding chlorosulfonic acid while stirring, continuously heating to a certain temperature after dropwise adding, reacting until the raw materials completely react, cooling to room temperature, filtering the reaction liquid, adding water into the filtrate, extracting with dichloromethane for multiple times, combining organic phases, drying with anhydrous magnesium sulfate, and concentrating to obtain 2, 6-dichloro-4-nitrile-5-sulfonic acid chloro-pyridine;
(5) adding 2, 6-dichloro-4-nitrile-5-sulfonic acid chloro-pyridine and zinc powder into dimethyl sulfoxide, stirring uniformly, then placing at 0 ℃, slowly dropwise adding 2M sulfuric acid while stirring until the raw materials disappear, cooling the reaction liquid to room temperature, pouring into water, allowing a large amount of solids to appear, filtering, placing a filter cake into a mixed solution of acetone and ethanol, heating to reflux, stirring for a period of time, slowly cooling, carrying out suction filtration on the reaction liquid again, and drying the filter cake to obtain 2, 6-dichloro-4-nitrile-5-mercapto-pyridine;
(6) adding 2, 6-dichloro-4-nitrile-5-mercapto-pyridine and benzylamine into N, N-dimethylformamide, heating to 100 ℃ until the raw materials disappear, cooling the reaction liquid to room temperature, pouring into water, extracting the reaction liquid with ethyl acetate for three times, combining organic phases, drying with anhydrous magnesium sulfate, and concentrating to obtain 2, 6-dibenzyl-4-nitrile-5-mercapto-pyridine;
(7) adding 2, 6-dibenzyl-4-nitrile-5-mercapto-pyridine and palladium carbon with the content of 5 wt.% into methanol, introducing hydrogen into an autoclave, reacting at a certain temperature until the raw materials completely react, filtering the reaction liquid, and concentrating the filtrate to obtain pure 2, 6-amino-4-nitrile-5-mercapto-pyridine;
(8) adding phosphorus oxychloride into dichloromethane, adding a dichloromethane mixed solution in which 2, 6-amino-4-nitrile-5-mercapto-pyridine is dissolved into a constant-pressure dropping funnel, dropwise adding the mixed solution at room temperature under the protection of nitrogen, continuously stirring until the raw materials completely react, introducing ammonia gas into a reaction bottle, observing by a thermometer inserted into the reaction solution, rapidly increasing the reaction temperature, then rapidly decreasing the reaction temperature, finishing the reaction when the reaction temperature decreases to room temperature, filtering the reaction solution, drying an organic phase by anhydrous magnesium sulfate, and concentrating to obtain 2, 6-dimethylureido-4-nitrile-5-mercapto-pyridine;
(9) adding 2, 6-dimethylureido-4-nitrile-5-mercapto-pyridine and a catalyst Raney nickel into ethanol, introducing ammonia gas into a high-pressure kettle to enable the pressure to reach 0.1MPa, keeping the pressure, stirring for a period of time, introducing hydrogen gas to enable the pressure to reach 0.3MPa, enabling the reaction temperature to be 40 ℃, reacting for a period of time, reducing the pressure to 0.1MPa, introducing ammonia gas to enable the pressure to reach 0.2MPa, keeping the pressure and stirring for a period of time, introducing hydrogen gas again to enable the pressure to reach 0.3MPa, continuing to react until the raw materials react completely, filtering reaction liquid, and concentrating filtrate to obtain 2, 6-dimethylureido-4-methylamine-5-mercapto-pyridine;
(10) adding 2, 6-dimethylureido-4-methylamine-5-sulfydryl-pyridine into a reaction bottle, heating the mixture into dichloromethane, placing the mixture at the temperature of minus 10 ℃ under the protection of nitrogen, starting stirring, slowly dropwise adding thiophosgene, adding water until the raw materials completely react after dropwise adding, extracting the mixture by using ethyl acetate, drying the mixture by using anhydrous sodium sulfate, filtering the dried mixture, evaporating the solvent to dryness, and separating the dried mixture by using a silica gel column chromatography to obtain the compound
(11) Handle of bicycle
Adding zinc powder into a mixed solution of acetone and water, stirring uniformly, placing at 0 ℃, slowly dropwise adding a saturated dilute hydrochloric acid solution while stirring, slowly heating to reflux after dropwise adding, reacting until the raw materials disappear, cooling the reaction solution to room temperature, pouring into water, allowing a large amount of solids to appear, filtering, placing a filter cake into a mixed solution of acetone and ethanol, heating to reflux, stirring for a period of time, slowly cooling, performing suction filtration on the reaction solution again, and drying the filter cake to obtain the final product
(12) Dissolving zinc chloride in acetonitrile,
dissolving in methanol, mixing the above solutions, heating to 70 deg.C, stirring for a period of time, cooling to room temperature, adding anhydrous diethyl ether, standing, slowly volatilizing to obtain crystal, and filtering to obtain complex
2. The preparation method of thiazine feed additive according to claim 1, wherein the mass ratio of the active carbon to the added amounts of bismuth nitrate pentahydrate and scandium nitrate trihydrate in step (1) is 10:4.8: 2.3.
3. The preparation method of thiazine feed additive according to claim 1, wherein the mass ratio of the 2, 6-dichloropyridine to the activated carbon-supported bismuth/scandium catalyst in step (2) is 10: 1; the activated carbon supported bismuth/scandium catalyst can be reused three times.
4. The preparation method of thiazine feed additive according to claim 1, wherein the molar ratio of the charged 2, 6-dichloro-4-formamide pyridine to trifluoroacetic anhydride and triethylamine in step (3) is 1:2: 2; the reaction temperature was 90 ℃.
5. The preparation method of thiazine feed additive according to claim 1, wherein the molar ratio of the 2, 6-dichloro-4-nitrile-pyridine to chlorosulfonic acid fed in step (4) is 1: 1-2; the reaction temperature is 50-70 ℃.
6. The preparation method of the thiazine feed additive according to claim 1, wherein the molar ratio of the 2, 6-dichloro-4-nitrile-5-sulfonic acid chloro-pyridine to the zinc powder in the step (5) is 1: 1-2.
7. The method for preparing a thiazide feed additive according to claim 1, wherein the reaction temperature in step (7) is 40 ℃.
8. The method for preparing thiazine feed additive according to claim 1, wherein the specific synthetic route in the preparation process is:
9. the use of a thiazine feed additive of claim 1, which has some urease-inhibiting and bactericidal and antiulcer effects, as a non-protein nitrogen for feed in the preparation of an animal feed additive.
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| CN102178068A (en) * | 2010-07-06 | 2011-09-14 | 新疆农业大学 | Application method of feed additive for lowering incidence rate of urinary calculi in sheep |
| CN106721203A (en) * | 2016-11-21 | 2017-05-31 | 天津市盛鑫肉牛养殖有限公司 | A kind of ox concentrated feed |
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| CN102178068A (en) * | 2010-07-06 | 2011-09-14 | 新疆农业大学 | Application method of feed additive for lowering incidence rate of urinary calculi in sheep |
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