CN109232643B - Preparation method of phosphamide cattle feed additive - Google Patents
Preparation method of phosphamide cattle feed additive Download PDFInfo
- Publication number
- CN109232643B CN109232643B CN201811182526.0A CN201811182526A CN109232643B CN 109232643 B CN109232643 B CN 109232643B CN 201811182526 A CN201811182526 A CN 201811182526A CN 109232643 B CN109232643 B CN 109232643B
- Authority
- CN
- China
- Prior art keywords
- reaction
- cyanoethylamine
- pressure
- nitrophenyl
- temperature
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000003674 animal food additive Substances 0.000 title claims abstract description 22
- 241000283690 Bos taurus Species 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- MCWXGJITAZMZEV-UHFFFAOYSA-N dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 title description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 40
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 20
- DMSZORWOGDLWGN-UHFFFAOYSA-N ctk1a3526 Chemical compound NP(N)(N)=O DMSZORWOGDLWGN-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims description 91
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 72
- -1 2- (3-chlorphenyl) -2-cyanoethylamine Chemical compound 0.000 claims description 60
- 239000012074 organic phase Substances 0.000 claims description 44
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- 239000000243 solution Substances 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 239000012295 chemical reaction liquid Substances 0.000 claims description 26
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 25
- 238000003756 stirring Methods 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 22
- 238000001035 drying Methods 0.000 claims description 21
- 239000011259 mixed solution Substances 0.000 claims description 21
- 239000002994 raw material Substances 0.000 claims description 21
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 238000001816 cooling Methods 0.000 claims description 13
- 239000005457 ice water Substances 0.000 claims description 13
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 11
- 239000012312 sodium hydride Substances 0.000 claims description 11
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 11
- WBUOVKBZJOIOAE-UHFFFAOYSA-N 3-chlorobenzonitrile Chemical compound ClC1=CC=CC(C#N)=C1 WBUOVKBZJOIOAE-UHFFFAOYSA-N 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 10
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 claims description 10
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 10
- 229940071536 silver acetate Drugs 0.000 claims description 10
- UYCAUPASBSROMS-AWQJXPNKSA-M sodium;2,2,2-trifluoroacetate Chemical compound [Na+].[O-][13C](=O)[13C](F)(F)F UYCAUPASBSROMS-AWQJXPNKSA-M 0.000 claims description 10
- 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 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 229910052786 argon Inorganic materials 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 239000012071 phase Substances 0.000 claims description 8
- 238000010791 quenching Methods 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 7
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- MKFNREFULCOQHJ-UHFFFAOYSA-N 1-[2-(1,1-diaminopropan-2-yl)-4-methylphenyl]-3-methylurea Chemical compound NC(C(C)C1=C(C=CC(=C1)C)NC(=O)NC)N MKFNREFULCOQHJ-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 6
- SONOBVZDCFRJLC-UHFFFAOYSA-N tert-butyl 2-hydrazinyl-3-[5-methyl-2-(methylcarbamoylamino)phenyl]butanoate Chemical compound CC1=CC(=C(C=C1)NC(=O)NC)C(C)C(C(=O)OC(C)(C)C)NN SONOBVZDCFRJLC-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 5
- 230000003247 decreasing effect Effects 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 235000010333 potassium nitrate Nutrition 0.000 claims description 5
- 239000004323 potassium nitrate Substances 0.000 claims description 5
- 238000001704 evaporation Methods 0.000 claims description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 239000007868 Raney catalyst Substances 0.000 claims description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 3
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical class C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 3
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- GTIKLPYCSAMPNG-UHFFFAOYSA-N 2-(3-chlorophenyl)acetonitrile Chemical compound ClC1=CC=CC(CC#N)=C1 GTIKLPYCSAMPNG-UHFFFAOYSA-N 0.000 claims description 2
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 claims description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 2
- 108090000623 proteins and genes Proteins 0.000 abstract description 8
- 102000004169 proteins and genes Human genes 0.000 abstract description 8
- 108010046334 Urease Proteins 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 230000009286 beneficial effect Effects 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 abstract 1
- 230000009931 harmful effect Effects 0.000 abstract 1
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- 241000282849 Ruminantia Species 0.000 description 8
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 7
- 239000004202 carbamide Substances 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- 210000004767 rumen Anatomy 0.000 description 6
- 238000012360 testing method Methods 0.000 description 5
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 239000012530 fluid Substances 0.000 description 3
- 241000282414 Homo sapiens Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N monoethyl amine Natural products CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- VZJMLYLSKHEAPQ-UHFFFAOYSA-N 8-(4-ethylpiperazin-1-yl)-7-(2-hydroxy-3-propan-2-yloxypropyl)-3-methylpurine-2,6-dione Chemical compound C1CN(CC)CCN1C(N1CC(O)COC(C)C)=NC2=C1C(=O)NC(=O)N2C VZJMLYLSKHEAPQ-UHFFFAOYSA-N 0.000 description 1
- 241000282832 Camelidae Species 0.000 description 1
- 241000282994 Cervidae Species 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 206010016717 Fistula Diseases 0.000 description 1
- VGGLHLAESQEWCR-UHFFFAOYSA-N N-(hydroxymethyl)urea Chemical compound NC(=O)NCO VGGLHLAESQEWCR-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- DZHMRSPXDUUJER-UHFFFAOYSA-N [amino(hydroxy)methylidene]azanium;dihydrogen phosphate Chemical compound NC(N)=O.OP(O)(O)=O DZHMRSPXDUUJER-UHFFFAOYSA-N 0.000 description 1
- 231100000460 acute oral toxicity Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- XKMRRTOUMJRJIA-UHFFFAOYSA-N ammonia nh3 Chemical compound N.N XKMRRTOUMJRJIA-UHFFFAOYSA-N 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- OHJMTUPIZMNBFR-UHFFFAOYSA-N biuret Chemical compound NC(=O)NC(N)=O OHJMTUPIZMNBFR-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000019621 digestibility Nutrition 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000012851 eutrophication Methods 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- 230000003890 fistula Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000006651 lactation Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical class [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- LWJROJCJINYWOX-UHFFFAOYSA-L mercury dichloride Chemical class Cl[Hg]Cl LWJROJCJINYWOX-UHFFFAOYSA-L 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 239000002601 urease inhibitor Substances 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/224—Phosphorus triamides
-
- 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
- A23K20/10—Organic substances
- A23K20/111—Aromatic compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Animal Husbandry (AREA)
- Zoology (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of a phosphoramide cattle feed additive, 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 a phosphoramide cattle feed additive.
Background
Insufficient protein resources are one of the major problems facing human society, and the development of animal husbandry is severely restricted. Rumen microorganisms of ruminants such as cows, breeding, deer, camels and the like can utilize a plurality of nonprotein nitrogen as nitrogen sources to synthesize mycoprotein to be utilized by the ruminants, so that protein feed resources are saved, the feed cost is reduced, and the problems of animal husbandry development and grain earning of human beings are greatly alleviated. Thus, the development of non-protein nitrogen has become an important area of international ruminant nutrition research.
To date, more than 20 nitrogen-containing compounds have been available for non-protein nitrogen feed premixes for ruminants, roughly classified into 3 major groups: urea and its derivatives, amino salts and amide compounds, especially urea and its derivatives. Among them, urea, ammonia, biuret, urea phosphate, methylol urea, etc. have been used for production. Based on factors such as comprehensive economy, conversion efficiency and the like, the urea is the cheapest non-protein nitrogen substitute feed widely used in ruminant production at present due to the advantages of low cost, wide source, high nitrogen content, simple feeding method and the like. Urea plays a very important role in ruminant production, has positive effects on growth, weight increment, feed intake improvement, digestibility, lactation, health care and the like of ruminants, and opens up a new way for solving the problem of lack of protein feed.
However, since urease widely existing in the stomach of ruminant is a specific enzyme for decomposing urea, it decomposes urea into NH3At 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.
We modify on the basis of benzene ring to synthesize a phosphoramide compound with a novel structure, which can be used as non-protein nitrogen, has a certain inhibition effect on urease and can be used as a cattle feed additive.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation method of the phosphorus amide cattle feed additive which has the advantages of simple synthesis method, low raw material price, novel structure and multiple biological activity functions.
The invention adopts the following technical scheme for solving the technical problems, and the structure of the phosphoramide cattle feed additive is as follows:
the invention adopts the following technical scheme for solving the technical problems, and the preparation method of the phosphoramide cattle feed additive is characterized by comprising the following specific steps:
(1) starting cooling in a high-pressure reaction kettle under the protection of argon, adding 3-chlorobenzonitrile into a mixed solution of halogenated methane and dimethyl sulfoxide at the internal temperature of 5-10 ℃, keeping the temperature unchanged, adding a certain amount of catalyst combination, adding a certain amount of sodium hydride, stirring for a period of time at the internal temperature of 10-20 ℃, and introducing ammonia gas into the reaction kettle to ensure that the pressure in the kettle reaches a certain pressure; keeping the pressure unchanged, slowly raising the temperature to 45 ℃, adding ice water to quench the reaction solution after the reaction is finished, standing, separating a lower organic phase, extracting a water phase for multiple times by using dichloromethane, combining the organic phases, drying by using anhydrous magnesium sulfate, and concentrating to obtain 2- (3-chlorphenyl) -2-cyanoethylamine; the halogenated methane is dibromomethane or diiodomethane; the catalyst combination is palladium acetate, silver acetate and sodium trifluoroacetate; the molar ratio of the 3-chlorobenzeneacetonitrile to the palladium acetate, the silver acetate and the sodium trifluoroacetate is 1:0.01:0.01: 0.02; the feeding amount molar ratio of the 3-chlorobenzonitrile to the sodium hydride is 1: 2-4; the pressure in the reaction kettle is 0.05-0.15 MPa.
(2) Adding 2- (3-chlorphenyl) -2-cyanoethylamine into sulfuric acid at a certain temperature, adding potassium nitrate, reacting at room temperature for a period of time, pouring the reaction liquid into an ice-water mixed solution, uniformly stirring, extracting the reaction liquid for multiple times by using ethyl acetate, combining organic phases, washing the reaction liquid twice by using a saturated sodium carbonate solution, drying by using anhydrous magnesium sulfate, and concentrating to obtain a mixture of 2- (3-chloro-5-nitrophenyl) -2-amidoethylamine and 2- (3-chloro-5-nitrophenyl) -2-cyanoethylamine; the reaction temperature is-5-10 ℃.
(3) Adding 2- (3-chloro-5-nitrophenyl) -2-acylaminoethylamine into 1, 4-dioxane, adding trifluoroacetic anhydride and triethylamine, heating to 90 ℃ under the protection of nitrogen, cooling the reaction liquid to room temperature after the raw materials completely react, 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- (3-chloro-5-nitrophenyl) -2-cyanoethylamine; the feeding amount molar ratio of the 2- (3-chloro-5-nitrophenyl) -2-acylamino ethylamine to the trifluoroacetic anhydride and the triethylamine is 1:1: 1.
(4) Adding 2- (3-chloro-5-nitrophenyl) -2-cyanoethylamine and benzylamine into N, N-dimethylformamide, heating to 100 ℃, reacting until the raw materials disappear, cooling the reaction liquid to room temperature, and pouring into water; extracting the reaction liquid with ethyl acetate for three times, combining organic phases, drying the organic phases with anhydrous magnesium sulfate, and concentrating to obtain the 2- (3-benzylamino-5-nitrophenyl) -2-cyanoethylamine.
(5) Dissolving 2- (3-benzylamino-5-nitrophenyl) -2-cyanoethylamine in methanol, adding a mixed solution of triethanolamine and di-tert-butyl dicarbonate under the protection of nitrogen, performing reflux reaction until the raw materials react completely, performing rotary evaporation to remove the methanol, adding dichloromethane, washing with a certain amount of water, separating an organic phase, and evaporating the organic phase to obtain the N-Boc-2- (3-benzylamino-5-nitrophenyl) -2-cyanoethylamine.
(6) Adding N-Boc-2- (3-benzylamino-5-nitrophenyl) -2-cyanoethylamine and a catalyst palladium carbon into methanol, introducing hydrogen into an autoclave, reacting until the raw materials react completely when the pressure reaches 0.2MPa and the reaction temperature is 40 ℃, filtering reaction liquid, and concentrating filtrate to obtain N-Boc-2- (3, 5-diaminophenyl) -2-cyanoethylamine; the mass ratio of the N-Boc-2- (3-benzylamino-5-nitrophenyl) -2-cyanoethylamine to the palladium carbon is 100: 2-5.
(7) Adding N-Boc-2- (3, 5-diaminophenyl) -2-cyanoethylamine into dichloromethane, slowly dropwise adding methyl isocyanate at 0 ℃, slowly heating to room temperature after dropwise adding, and concentrating a reaction solution after the reaction is finished to obtain the N-Boc-2- (3, 5-dimethylureidophenyl) -2-cyanoethylamine.
(8) Adding N-Boc-2- (3, 5-dimethylureidophenyl) -2-cyanoethylamine and a catalyst Raney nickel into ethanol, introducing ammonia gas into a high-pressure kettle to ensure that the pressure reaches 0.1MPa, keeping the pressure, stirring for a period of time, introducing hydrogen to ensure that the pressure reaches 0.3MPa, keeping the reaction temperature at 40 ℃, reducing the pressure to 0.1MPa for a period of time, introducing ammonia gas to ensure that the pressure reaches 0.2MPa, keeping the pressure and stirring for a period of time, introducing hydrogen again to ensure that the pressure reaches 0.3MPa, continuing to react until the raw materials completely react, filtering reaction liquid, and concentrating filtrate to obtain 1-Boc-amino-2- (3, 5-dimethylureidophenyl) -propylamine.
(9) Adding 1-Boc-amino-2- (3, 5-dimethylureidophenyl) -propylamine and trifluoroacetic acid into dichloromethane, stirring at room temperature for reaction until the raw materials react completely, adding a certain amount of water to wash the reaction solution, separating an organic phase, and distilling the organic phase to obtain the 1-amino-2- (3, 5-dimethylureidophenyl) -propylamine.
(10) Adding phosphorus oxychloride into dichloromethane, adding a dichloromethane mixed solution dissolved with 1-amino-2- (3, 5-dimethylureidophenyl) -propylamine into a constant-pressure dropping funnel, dropwise adding the mixed solution at room temperature under the protection of nitrogen, continuously stirring to react 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 is decreased to room temperature, filtering the reaction solution, drying an organic phase by anhydrous magnesium sulfate, and concentrating to obtain the 1, 3-diphosphotriamide-2- (3, 5-dimethylureidophenyl) -propane.
The invention adopts the following technical scheme for solving the technical problems, and the preparation method of the phosphoramide cattle feed additive is characterized by comprising the following specific steps:
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
In a high-pressure reaction kettle, under the protection of argon, starting cooling, adding 15g of 3-chlorobenzonitrile into a mixed solution of 50mL of dichloromethane and 100mL of dimethyl sulfoxide at the internal temperature of 5-10 ℃, keeping the temperature unchanged, adding 0.23g of palladium acetate, 0.17g of silver acetate and 0.27g of sodium trifluoroacetate, and adding 12g (with the content of 60%) of sodium hydride; keeping the internal temperature at 10-20 ℃, stirring for 30min, and introducing ammonia gas into the reaction kettle to enable the pressure in the kettle to reach 0.1 MPa; keeping the pressure unchanged, slowly raising the temperature to 45 ℃, adding 100mL of ice water to quench the reaction solution after reacting for 2h,standing, separating a lower organic phase, extracting a water phase for multiple times by using 100mL of dichloromethane, combining the organic phases, drying by using anhydrous magnesium sulfate, and concentrating to obtain 11g of 2- (3-chlorphenyl) -2-cyanoethylamine;1H NMR(400M,CDCl3):7.61(s,1H),7.33(d,J＝8.0Hz,1H),7.26(s,1H),7.12(d,J＝4.0Hz,1H),5.19(s,2H),5.06(s,1H),3.49(d,J＝8.0Hz,2H).MS(ESI)m/z:181.1[M+H]+。
example 2
In a high-pressure reaction kettle, under the protection of argon, starting cooling, adding 15g of 3-chlorobenzonitrile into a mixed solution of 20mL of diiodomethane and 100mL of dimethyl sulfoxide at the internal temperature of 5-10 ℃, keeping the temperature unchanged, adding 0.23g of palladium acetate, 0.17g of silver acetate and 0.27g of sodium trifluoroacetate, and adding 12g (the content is 60%) of sodium hydride; keeping the internal temperature at 10-20 ℃, stirring for 30min, and introducing ammonia gas into the reaction kettle to enable the pressure in the kettle to reach 0.1 MPa; keeping the pressure unchanged, slowly raising the temperature to 45 ℃, adding 100mL of ice water to quench the reaction solution after reacting for 2h, standing, separating a lower organic phase, extracting a water phase with 100mL of dichloromethane for multiple times, combining the organic phases, drying with anhydrous magnesium sulfate, and concentrating to obtain 17g of 2- (3-chlorophenyl) -2-cyanoethylamine;1H NMR(400M,CDCl3):7.61(s,1H),7.33(d,J＝8.0Hz,1H),7.26(s,1H),7.12(d,J＝4.0Hz,1H),5.19(s,2H),5.06(s,1H),3.49(d,J＝8.0Hz,2H).MS(ESI)m/z:181.1[M+H]+。
example 3
In a high-pressure reaction kettle, under the protection of argon, starting cooling, adding 15g of 3-chlorobenzonitrile into a mixed solution of 20mL of diiodomethane and 100mL of dimethyl sulfoxide at the internal temperature of 5-10 ℃, keeping the temperature unchanged, adding 0.23g of palladium acetate, 0.17g of silver acetate and 0.27g of sodium trifluoroacetate, and adding 8g (the content is 60%) of sodium hydride; keeping the internal temperature at 10-20 ℃, stirring for 30min, introducing ammonia gas into the reaction kettle to enable the pressure in the kettle to reach 01 MPa; keeping the pressure unchanged, slowly raising the temperature to 45 ℃, adding 100mL of ice water to quench the reaction solution after reacting for 2h, standing, separating a lower organic phase, extracting a water phase with 100mL of dichloromethane for multiple times, combining the organic phases, drying with anhydrous magnesium sulfate, and concentrating to obtain 14g of 2- (3-chlorophenyl) -2-cyanoethylamine;1H NMR(400M,CDCl3):7.61(s,1H),7.33(d,J＝8.0Hz,1H),7.26(s,1H),7.12(d,J＝4.0Hz,1H),5.19(s,2H),5.06(s,1H),3.49(d,J＝8.0Hz,2H).MS(ESI)m/z:181.1[M+H]+。
example 4
In a high-pressure reaction kettle, under the protection of argon, starting cooling, adding 15g of 3-chlorobenzonitrile into a mixed solution of 20mL of diiodomethane and 100mL of dimethyl sulfoxide at the internal temperature of 5-10 ℃, keeping the temperature unchanged, adding 0.23g of palladium acetate, 0.17g of silver acetate and 0.27g of sodium trifluoroacetate, and adding 16g (the content is 60%) of sodium hydride; keeping the internal temperature at 10-20 ℃, stirring for 30min, and introducing ammonia gas into the reaction kettle to enable the pressure in the kettle to reach 0.1 MPa; keeping the pressure unchanged, slowly raising the temperature to 45 ℃, adding 100mL of ice water to quench the reaction solution after reacting for 2h, standing, separating a lower organic phase, extracting a water phase with 100mL of dichloromethane for multiple times, combining the organic phases, drying with anhydrous magnesium sulfate, and concentrating to obtain 16g of 2- (3-chlorophenyl) -2-cyanoethylamine;1H NMR(400M,CDCl3):7.61(s,1H),7.33(d,J＝8.0Hz,1H),7.26(s,1H),7.12(d,J＝4.0Hz,1H),5.19(s,2H),5.06(s,1H),3.49(d,J＝8.0Hz,2H).MS(ESI)m/z:181.1[M+H]+。
example 5
In a high-pressure reaction kettle, under the protection of argon, starting cooling, adding 15g of 3-chlorobenzonitrile into a mixed solution of 20mL of diiodomethane and 100mL of dimethyl sulfoxide at the internal temperature of 5-10 ℃, keeping the temperature unchanged, adding 0.23g of palladium acetate, 0.17g of silver acetate and 0.27g of sodium trifluoroacetate, and adding 12g of sodium hydride (with the content of sodium hydride being 12 g)60%); keeping the internal temperature at 10-20 ℃, stirring for 30min, and introducing ammonia gas into the reaction kettle to enable the pressure in the kettle to reach 0.05 MPa; keeping the pressure unchanged, slowly raising the temperature to 45 ℃, adding 100mL of ice water to quench the reaction solution after reacting for 2h, standing, separating a lower organic phase, extracting a water phase with 100mL of dichloromethane for multiple times, combining the organic phases, drying with anhydrous magnesium sulfate, and concentrating to obtain 8g of 2- (3-chlorophenyl) -2-cyanoethylamine;1H NMR(400M,CDCl3):7.61(s,1H),7.33(d,J＝8.0Hz,1H),7.26(s,1H),7.12(d,J＝4.0Hz,1H),5.19(s,2H),5.06(s,1H),3.49(d,J＝8.0Hz,2H).MS(ESI)m/z:181.1[M+H]+。
example 6
In a high-pressure reaction kettle, under the protection of argon, starting cooling, adding 15g of 3-chlorobenzonitrile into a mixed solution of 20mL of diiodomethane and 100mL of dimethyl sulfoxide at the internal temperature of 5-10 ℃, keeping the temperature unchanged, adding 0.23g of palladium acetate, 0.17g of silver acetate and 0.27g of sodium trifluoroacetate, and adding 12g (the content is 60%) of sodium hydride; keeping the internal temperature at 10-20 ℃, stirring for 30min, and introducing ammonia gas into the reaction kettle to enable the pressure in the kettle to reach 0.15 MPa; keeping the pressure unchanged, slowly raising the temperature to 45 ℃, adding 100mL of ice water to quench the reaction solution after reacting for 2h, standing, separating a lower organic phase, extracting a water phase with 100mL of dichloromethane for multiple times, combining the organic phases, drying with anhydrous magnesium sulfate, and concentrating to obtain 15.5g of 2- (3-chlorophenyl) -2-cyanoethylamine;1H NMR(400M,CDCl3):7.61(s,1H),7.33(d,J＝8.0Hz,1H),7.26(s,1H),7.12(d,J＝4.0Hz,1H),5.19(s,2H),5.06(s,1H),3.49(d,J＝8.0Hz,2H).MS(ESI)m/z:181.1[M+H]+。
example 7
In a reaction bottle, 18g of 2- (3-chlorphenyl) -2-cyanoethylamine is added into 180mL of concentrated sulfuric acid at the temperature of 0 ℃, 15g of potassium nitrate is added, the reaction is carried out for 30min at the room temperature, and the reaction liquid is pouredAdding into 1000mL of ice-water mixed solution, stirring for 10min, extracting with 200mL of ethyl acetate for 3 times, combining organic phases, washing the reaction solution twice with saturated sodium carbonate solution, drying with anhydrous magnesium sulfate, and concentrating to obtain 19g of 2- (3-chloro-5-nitrophenyl) -2-acylaminoethylamine; MS (ESI) M/z 244.1[ M + H ]]+。
Example 8
Adding 18g of 2- (3-chlorphenyl) -2-cyanoethylamine into 180mL of concentrated sulfuric acid at-5 ℃ in a reaction bottle, adding 15g of potassium nitrate, reacting for 30min at room temperature, pouring the reaction solution into 1000mL of ice-water mixed solution, stirring for 10min, extracting and reacting for 3 times by using 200mL of ethyl acetate, combining organic phases, washing the reaction solution twice by using a saturated sodium carbonate solution, drying by using anhydrous magnesium sulfate, and concentrating to obtain 12g of 2- (3-chloro-5-nitrophenyl) -2-amidoethylamine; MS (ESI) M/z 244.1[ M + H ]]+。
Example 9
Adding 18g of 2- (3-chlorphenyl) -2-cyanoethylamine into 180mL of concentrated sulfuric acid in a reaction flask at 10 ℃, adding 15g of potassium nitrate, reacting for 30min at room temperature, pouring the reaction liquid into 1000mL of ice-water mixed liquid, stirring for 10min, extracting and reacting for 3 times by using 200mL of ethyl acetate, combining organic phases, washing the reaction liquid twice by using a saturated sodium carbonate solution, drying by using anhydrous magnesium sulfate, and concentrating to obtain 15g of 2- (3-chloro-5-nitrophenyl) -2-amidoethylamine; MS (ESI) M/z 244.1[ M + H ]]+。
Example 10
In a reaction flask, 24g of 2- (3-chloro-5-nitrophenyl) -2-amidoethylamine and 11g of benzylamine were added to 100mL of N, N-dimethylformamide, and the mixture was heated to 1At 00 ℃, TLC monitoring after 1 hour of reaction shows that the raw materials disappear, the reaction liquid is cooled to room temperature, poured into 100mL of water, extracted with 100mL of ethyl acetate for three times, combined with organic phases, dried by anhydrous magnesium sulfate and concentrated to obtain 25g of 2- (3-benzylamino-5-nitrophenyl) -2-acylamidoethylamine; MS (ESI) M/z 315.4[ M + H ]]+。
Example 11
Adding 31g of 2- (3-benzylamino-5-nitrophenyl) -2-acylamino ethylamine into 300mL of 1, 4-dioxane in a reaction bottle, adding 21g of trifluoroacetic anhydride and 10g of triethylamine, heating to 90 ℃ under the protection of nitrogen, monitoring by TLC (thin layer chromatography) to ensure that raw materials are completely reacted, cooling 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, and concentrating to obtain 24g of 2- (3-benzylamino-5-nitrophenyl) -2-cyanoethylamine;1H NMR(400M,CDCl3):7.71(s,1H),7.63(s,1H),7.39(d,J＝4.0Hz,1H),7.39-7.37(m,2H),7.25-7.23(m,2H),7.03(s,2H),6.91(d,J＝4.0Hz,1H),5.12(s,2H),4.09(d,J＝4.0Hz,1H),3.35(d,J＝8.0Hz,2H).MS(ESI)m/z:297.1[M+H]+。
example 12
Dissolving 30g of 2- (3-benzylamino-5-nitrophenyl) -2-cyanoethylamine in 200mL of methanol in a 500mL reaction bottle, slowly adding 50mL of mixed solution of triethanolamine and 32g of di-tert-butyl dicarbonate under the protection of nitrogen, carrying out reflux reaction at 70 ℃ for 12h after the addition is finished, monitoring the complete reaction of raw materials by TLC (thin layer chromatography), carrying out rotary evaporation to remove the methanol, adding 150mL of dichloromethane, adding 150mL of water to wash twice, separating out an organic phase, and evaporating the organic phase to obtain 35g of N-Boc-2- (3-benzylamino-5-nitrophenyl) -2-cyanoethylamine;1H NMR(400M,CDCl3):8.06(s,1H),7.66-7.65(m,1H),7.52(s,1H),7.36(d,J＝8.0Hz,2H),7.23(dd,J1＝4.0Hz,J2＝4.0Hz,2H),7.19(s,2H),6.91(s,1H),4.99-4.98(m,1H),4.32(d,J＝4.0Hz,1H),3.47(d,J＝8.0Hz,2H),1.33-1.32(m,9H).MS(ESI)m/z:397.2[M+H]+.Anal.Calcd for C21H24N4O4:C,63.62；H,6.10；N,14.13.Found:C,63.39；H,6.05；N,14.17。
example 13
Adding 40g of N-Boc-2- (3-benzylamino-5-nitrophenyl) -2-cyanoethylamine and 2g of palladium carbon serving as a catalyst into 300mL of methanol in a 500mL reaction bottle, introducing hydrogen into an autoclave, controlling the reaction temperature to be 40 ℃ at 0.2MPa, monitoring the reaction of raw materials by TLC after 12 hours of reaction, filtering reaction liquid, and concentrating filtrate to obtain 26g of pure N-Boc-2- (3, 5-diaminophenyl) -2-cyanoethylamine;1H NMR(400M,DMSO-d6):7.99(s,1H),7.47(s,1H),7.05(s,2H),6.33-6.31(m,4H),4.54(d,J＝8.0Hz,1H),3.55(d,J＝8.0Hz,2H),1.31(s,9H).MS(ESI)m/z:277.1[M+H]+.Anal.Calcd for C14H20N4O2:C,60.85；H,7.30；N,20.28.Found:C,60.62；H,7.41；N,20.44。
example 14
Adding 28g of N-Boc-2- (3, 5-diaminophenyl) -2-cyanoethylamine into 200mL of dichloromethane in a reaction bottle, slowly dropwise adding 12g of methyl isocyanate at 0 ℃, slowly heating to room temperature after dropwise adding, continuously reacting for 20min, and concentrating the reaction solution to obtain 37g of N-Boc-2- (3, 5-dimethylureidophenyl) -2-cyanoethylamine; MS (ESI) M/z 391.2[ M + H]+.Anal.Calcd for C18H26N6O4:C,55.37；H,6.71；N,21.52.Found:C,55.69；H,6.65；N,21.68。
Example 15
Adding 40g of N-Boc-2- (3, 5-dimethylureidophenyl) -2-cyanoethylamine and 4g 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, keeping the reaction temperature at 40 ℃, reacting 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 completion of the reaction of the raw materials by TLC, filtering the reaction liquid, and concentrating the filtrate to obtain 34g of pure 1-Boc-amino-2- (3, 5-dimethylureidophenyl) -propylamine;1H NMR(400M,DMSO-d6):8.25(s,1H),7.89(s,1H),7.53-7.52(m,2H),6.17-6.15(m,4H),5.13(s,2H),3.72(d,J＝12.0Hz,1H),3.26(d,J＝8.0Hz,2H),2.99(dd,J1＝8.0Hz,J2＝8.0Hz,2H)；2.77-2.75(m,6H),1.27(s,9H).MS(ESI)m/z:395.3[M+H]+.Anal.Calcd for C18H30N6O4:C,54.81；H,7.67；N,21.30.Found:C,54.68；H,7.59；N,21.42。
example 16
In a 500mL reaction flask, 40g of 1-Boc-amino-2- (3, 5-dimethylureidophenyl) -propylamine and 12g of trifluoroacetic acid were added to 300mL of dichloromethane, stirred at room temperature for 24h, TLC monitored that the starting materials reacted completely, 200mL of water was added to wash the reaction mixture, the organic phase was separated, and the organic phase was distilled off to obtain 24g of 1-amino-2- (3, 5-dimethylureidophenyl) -propylamine;1H NMR(400M,DMSO-d6):8.17(s,1H),7.66-7.65(m,2H),6.14-6.11(m,4H),5.28-5.5-26(m,4H),3.55(d,J＝4.0Hz,1H),2.93(dd,J1＝4.0Hz,J2＝4.0Hz,4H)；2.81-2.79(m,6H).MS(ESI)m/z:295.2[M+H]+.Anal.Calcd for C13H22N6O2:C,53.04；H,7.53；N,28.55.Found:C,53.49；H,7.47；N,28.71。
example 17
Adding 32g of phosphorus oxychloride into 100mL of dichloromethane in a reaction bottle, adding 200mL of dichloromethane mixed solution dissolved with 30g of 1-amino-2- (3, 5-dimethylureidophenyl) -propylamine 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 reaction completion 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 reduced to room temperature, filtering the reaction solution, drying an organic phase by anhydrous magnesium sulfate, and concentrating to obtain 41g of 1, 3-diphosphorytriamide-2- (3, 5-dimethylureidophenyl) -propane;1H NMR(400M,DMSO-d6):8.25(s,1H),7.71(s,2H),6.27-6.22(m,2H),6.15-6.13(m,2H),3.82(d,J＝4.0Hz,1H),2.88(dd,J1＝4.0Hz,J2＝4.0Hz,4H)；2.66(s,6H),2.43-2.41(m,2H),1.96-1.94(m,8H).13C NMR(100M,DMSO-d6):154.6,142.9,133.2,119.5,111.7,55.4,47.2,35.8；MS(ESI)m/z:451.2[M+H]+.Anal.Calcd forC13H28N10O4P2:C,34.67；H,6.27；N,31.10.Found:C,34.75；H,6.22；N,31.36。
example 18
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％ | 13.9％ | 17.6％ | 26.3％ |
| 2 | 0％ | 29.4％ | 36.1％ | 43.2％ |
| 4 | 0％ | 38.2％ | 47.5％ | 51.6％ |
| 6 | 0％ | 45.3％ | 56.7％ | 62.6％ |
| 8 | 0％ | 52.4％ | 64.6％ | 74.5％ |
Example 19
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 taken by oral drenching at intervals of 4h, the administration dose is 16.0g/kg, the administration volume is 0.2mL/10g of body weight, the result shows that the animals normally eat, drink water, excrement and act within 14d, no toxic reaction is seen, and the novel feed additive orally takes LD (laser diode) for the mice and the 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 (6)
1. A preparation method of a phosphoramide cattle feed additive is characterized in that the molecular structure of the phosphoramide cattle feed additive is as follows:
the preparation method of the phosphoramide cattle feed additive comprises the following specific preparation steps:
(1) in a high-pressure reaction kettle, under the protection of argon, starting cooling, adding 3-chlorobenzonitrile into a mixed solution of halogenated methane and dimethyl sulfoxide at an internal temperature of 5-10 ℃, keeping the temperature unchanged, adding a certain amount of catalyst combination, adding a certain amount of sodium hydride, stirring for a period of time at the internal temperature of 10-20 ℃, and then introducing ammonia gas into the reaction kettle to ensure that the pressure in the kettle reaches a certain pressure; keeping the pressure unchanged, slowly raising the temperature to 45 ℃, adding ice water to quench the reaction solution after the reaction is finished, standing, separating a lower organic phase, extracting a water phase for multiple times by using dichloromethane, combining the organic phases, drying by using anhydrous magnesium sulfate, and concentrating to obtain 2- (3-chlorphenyl) -2-cyanoethylamine;
(2) adding 2- (3-chlorphenyl) -2-cyanoethylamine into sulfuric acid at a certain temperature, adding potassium nitrate, reacting at room temperature for a period of time, pouring the reaction liquid into an ice-water mixed solution, uniformly stirring, extracting the reaction liquid for multiple times by using ethyl acetate, combining organic phases, washing the reaction liquid twice by using a saturated sodium carbonate solution, drying by using anhydrous magnesium sulfate, and concentrating to obtain a mixture of 2- (3-chloro-5-nitrophenyl) -2-amidoethylamine and 2- (3-chloro-5-nitrophenyl) -2-cyanoethylamine;
(3) adding 2- (3-chloro-5-nitrophenyl) -2-acylaminoethylamine into 1, 4-dioxane, adding trifluoroacetic anhydride and triethylamine, heating to 90 ℃ under the protection of nitrogen, cooling the reaction liquid to room temperature after the raw materials completely react, 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- (3-chloro-5-nitrophenyl) -2-cyanoethylamine;
(4) adding 2- (3-chloro-5-nitrophenyl) -2-cyanoethylamine and benzylamine into N, N-dimethylformamide, heating to 100 ℃, reacting until the raw materials disappear, cooling the reaction liquid to room temperature, and pouring into water; extracting the reaction liquid with ethyl acetate for three times, combining organic phases, drying the organic phases with anhydrous magnesium sulfate, and concentrating to obtain 2- (3-benzylamino-5-nitrophenyl) -2-cyanoethylamine;
(5) dissolving 2- (3-benzylamino-5-nitrophenyl) -2-cyanoethylamine in methanol, adding a mixed solution of triethanolamine and di-tert-butyl dicarbonate under the protection of nitrogen, performing reflux reaction until the raw materials react completely, evaporating to remove methanol, adding dichloromethane, washing with a certain amount of water, separating an organic phase, and evaporating the organic phase to obtain N-Boc-2- (3-benzylamino-5-nitrophenyl) -2-cyanoethylamine;
(6) adding N-Boc-2- (3-benzylamino-5-nitrophenyl) -2-cyanoethylamine and a catalyst palladium carbon into methanol, introducing hydrogen into an autoclave, reacting until the raw materials react completely when the pressure reaches 0.2MPa and the reaction temperature is 40 ℃, filtering reaction liquid, and concentrating filtrate to obtain N-Boc-2- (3, 5-diaminophenyl) -2-cyanoethylamine;
(7) adding N-Boc-2- (3, 5-diaminophenyl) -2-cyanoethylamine into dichloromethane, slowly dropwise adding methyl isocyanate at 0 ℃, slowly heating to room temperature after dropwise adding, and concentrating a reaction solution after the reaction is finished to obtain N-Boc-2- (3, 5-dimethylureidophenyl) -2-cyanoethylamine;
(8) adding N-Boc-2- (3, 5-dimethylureidophenyl) -2-cyanoethylamine and a catalyst Raney nickel into ethanol, introducing ammonia gas into a high-pressure kettle to ensure that the pressure reaches 0.1MPa, keeping the pressure, stirring for a period of time, introducing hydrogen to ensure that the pressure reaches 0.3MPa, keeping the reaction temperature at 40 ℃, reducing the pressure to 0.1MPa for a period of time, introducing ammonia gas to ensure that the pressure reaches 0.2MPa, keeping the pressure and stirring for a period of time, introducing hydrogen again to ensure that the pressure reaches 0.3MPa, continuing to react until the raw materials completely react, filtering reaction liquid, and concentrating filtrate to obtain 1-Boc-amino-2- (3, 5-dimethylureidophenyl) -propylamine;
(9) adding 1-Boc-amino-2- (3, 5-dimethylureidophenyl) -propylamine and trifluoroacetic acid into dichloromethane, stirring at room temperature for reaction until the raw materials react completely, adding a certain amount of water to wash the reaction solution, separating an organic phase, and distilling the organic phase to obtain 1-amino-2- (3, 5-dimethylureidophenyl) -propylamine;
(10) adding phosphorus oxychloride into dichloromethane, adding a dichloromethane mixed solution dissolved with 1-amino-2- (3, 5-dimethylureidophenyl) -propylamine into a constant-pressure dropping funnel, dropwise adding the mixed solution at room temperature under the protection of nitrogen, continuously stirring to react 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 is decreased to room temperature, filtering the reaction solution, drying an organic phase by anhydrous magnesium sulfate, and concentrating to obtain the 1, 3-diphosphotriamide-2- (3, 5-dimethylureidophenyl) -propane.
2. The process for preparing a phosphoramide bovine feed additive as claimed in claim 1, wherein the halomethane in step (1) is dibromomethane or diiodomethane; the catalyst combination is palladium acetate, silver acetate and sodium trifluoroacetate; the feeding amount molar ratio of the 3-chlorobenzeneacetonitrile to the palladium acetate, the silver acetate and the sodium trifluoroacetate is 1:0.01:0.01: 0.02; the feeding amount molar ratio of the 3-chlorobenzonitrile to the sodium hydride is 1: 2-4; the pressure in the reaction kettle is 0.05-0.15 MPa.
3. The method for preparing a phosphoramide cattle feed additive according to claim 1, wherein the reaction temperature in the step (2) is-5 to 10 ℃.
4. The method for preparing phosphoramide cattle feed additive according to claim 1, wherein the molar ratio of the 2- (3-chloro-5-nitrophenyl) -2-amidoethylamine to the trifluoroacetic anhydride and triethylamine in step (3) is 1:1: 1.
5. The preparation method of phosphoramide cattle feed additive according to claim 1, wherein the mass ratio of the N-Boc-2- (3-benzylamino-5-nitrophenyl) -2-cyanoethylamine to the palladium on carbon in step (6) is 100: 2-5.
6. The preparation method of phosphoramide cattle feed additive according to claim 1, wherein the specific synthetic route in the preparation process is as follows:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811182526.0A CN109232643B (en) | 2018-10-11 | 2018-10-11 | Preparation method of phosphamide cattle feed additive |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811182526.0A CN109232643B (en) | 2018-10-11 | 2018-10-11 | Preparation method of phosphamide cattle feed additive |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109232643A CN109232643A (en) | 2019-01-18 |
| CN109232643B true CN109232643B (en) | 2020-08-21 |
Family
ID=65052166
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811182526.0A Active CN109232643B (en) | 2018-10-11 | 2018-10-11 | Preparation method of phosphamide cattle feed additive |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109232643B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1451293A (en) * | 2002-04-19 | 2003-10-29 | 四川大学 | Non-protein nitrogen feed, preparing method and use thereof |
| CN101731459A (en) * | 2008-11-17 | 2010-06-16 | 唐祯 | Method for using non-protein nitrogen feed additives |
| CN102391155A (en) * | 2011-10-25 | 2012-03-28 | 贵州川恒化工有限责任公司 | Urea phosphate production method |
| WO2015016829A1 (en) * | 2013-07-30 | 2015-02-05 | Benemilk Oy | Feed for lactating ruminants |
-
2018
- 2018-10-11 CN CN201811182526.0A patent/CN109232643B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1451293A (en) * | 2002-04-19 | 2003-10-29 | 四川大学 | Non-protein nitrogen feed, preparing method and use thereof |
| CN101731459A (en) * | 2008-11-17 | 2010-06-16 | 唐祯 | Method for using non-protein nitrogen feed additives |
| CN102391155A (en) * | 2011-10-25 | 2012-03-28 | 贵州川恒化工有限责任公司 | Urea phosphate production method |
| WO2015016829A1 (en) * | 2013-07-30 | 2015-02-05 | Benemilk Oy | Feed for lactating ruminants |
Non-Patent Citations (2)
| Title |
|---|
| Complementary-addressed site-directed spin labeling of long natural RNAs;Elena G. Bagryanskaya et al.;《Nucleic Acids Research》;20160606;第44卷(第16期);第7935-7943页 * |
| 磷酸脲产品的开发研究现状;张宏;《青海大学学报( 自然科学版)》;20000430;第18卷(第2期);第17-20页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109232643A (en) | 2019-01-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6106798B2 (en) | Triazine compounds having anti-chicken coccidiosis activity | |
| EP0035393A1 (en) | Poultry feeds containing and methods of using anovulatory compounds, and novel anovulatory imidazolines | |
| CN109651274A (en) | Thiocarbamide composite feed additive with urease inhibiting activity and preparation method thereof | |
| CN109232643B (en) | Preparation method of phosphamide cattle feed additive | |
| SK279258B6 (en) | (-)-1-(4'-amino-3'-cyanophenyl)-2-isopropylaminoethanol and additive salts thereof, method of preparation thereof, pharmaceutical compositions containing thereof and their use | |
| CN101402612A (en) | Synthesis of quinocetone | |
| WO2015113321A1 (en) | Diamino guanidine derivative and application in preparing animal feed growth promoter | |
| EP0017309B1 (en) | Cyclic hexapeptide and dipeptide and compositions containing them | |
| US3715375A (en) | New diphenyl sulfones | |
| CN102093467A (en) | Dipeptide iron chelate for feed additives and preparation method thereof | |
| CN111072508B (en) | Preparation method and application of zinc valine | |
| CN109053805B (en) | Preparation method of thiazine feed additive | |
| GB2034704A (en) | 2,6-daiminonebularines | |
| CN101585796A (en) | Preparation method of piglet intestinal canal nutrition controlling substance-alpha-pyrrole formic acid | |
| CN101704779B (en) | Preparation method for feed additive dihydropyridine | |
| CN103319416A (en) | Novel veterinary drug triclabendazole sulfoxide and preparation method thereof | |
| CN109601739B (en) | Compound amino acid feed additive and preparation method thereof | |
| CN1390213A (en) | Aryloxy propanolamines for improving livestock production | |
| CN111533742A (en) | Method for synthesizing 2-methoxy trimethylpurine diketone by taking cyanamide as raw material | |
| CN109232646B (en) | Triazole urease inhibitor type feed additive and preparation method thereof | |
| JP2022502487A (en) | Compound 2,2-difluoro-N-((1R, 2S) -3-fluoro-1-hydroxy-1- (4- (6- (S-methylsulfonimideyl) pyridin-3-yl) phenyl) propane- 2-Il) Process for preparing acetamide | |
| US3775403A (en) | Diphenyl sulfones | |
| US4461914A (en) | Method for the preparation of 1-(4'-amino-3',5'-dichlorophenyl)-2-alkyl(or dialkyl)aminoethanols | |
| CN109232649B (en) | Tetrazole urease inhibitor type feed additive and preparation method thereof | |
| CN101759652B (en) | Method for synthesizing spirocyclic compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB03 | Change of inventor or designer information | ||
| CB03 | Change of inventor or designer information |
Inventor after: Yang Weixiao Inventor after: Li Hui Inventor after: Hou Yansheng Inventor before: Yang Weixiao Inventor before: Hou Yansheng |
|
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20200727 Address after: No. 161, Punan Road, shenbeixin District, Shenyang, Liaoning 110000 Applicant after: SHENYANG FUSHI DATONG TECHNOLOGY Co.,Ltd. Address before: 471002 Qiming Road, Luoyang, Henan Applicant before: HENAN WANLIU BIOTECHNOLOGY Co.,Ltd. |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant |