CN109232644A - The synthetic method of glufosinate-ammonium - Google Patents
The synthetic method of glufosinate-ammonium Download PDFInfo
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- CN109232644A CN109232644A CN201811159960.7A CN201811159960A CN109232644A CN 109232644 A CN109232644 A CN 109232644A CN 201811159960 A CN201811159960 A CN 201811159960A CN 109232644 A CN109232644 A CN 109232644A
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- Prior art keywords
- butyrolacton
- gamma
- glufosinate
- ammonium
- bromine
- Prior art date
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 16
- IAJOBQBIJHVGMQ-UHFFFAOYSA-N 2-amino-4-[hydroxy(methyl)phosphoryl]butanoic acid Chemical compound CP(O)(=O)CCC(N)C(O)=O IAJOBQBIJHVGMQ-UHFFFAOYSA-N 0.000 title abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 52
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 33
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 27
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 claims abstract description 24
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000000908 ammonium hydroxide Substances 0.000 claims abstract description 21
- LFJJGHGXHXXDFT-UHFFFAOYSA-N 3-bromooxolan-2-one Chemical compound BrC1CCOC1=O LFJJGHGXHXXDFT-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000005576 amination reaction Methods 0.000 claims abstract description 11
- 125000001246 bromo group Chemical group Br* 0.000 claims abstract description 9
- 125000003368 amide group Chemical group 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 7
- 238000006467 substitution reaction Methods 0.000 claims abstract description 6
- 238000004176 ammonification Methods 0.000 claims abstract description 5
- 230000020477 pH reduction Effects 0.000 claims abstract description 5
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical group CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims abstract description 3
- 208000021302 gastroesophageal reflux disease Diseases 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- ZBMRKNMTMPPMMK-UHFFFAOYSA-N 2-amino-4-[hydroxy(methyl)phosphoryl]butanoic acid;azane Chemical compound [NH4+].CP(O)(=O)CCC(N)C([O-])=O ZBMRKNMTMPPMMK-UHFFFAOYSA-N 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- -1 dicarbonyl chloride Chemical compound 0.000 claims description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 230000006837 decompression Effects 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 claims description 3
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims description 3
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 150000003673 urethanes Chemical class 0.000 claims 2
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 claims 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical group OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 claims 1
- 125000004494 ethyl ester group Chemical group 0.000 claims 1
- 238000005292 vacuum distillation Methods 0.000 abstract description 17
- 239000002994 raw material Substances 0.000 abstract description 10
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 230000003321 amplification Effects 0.000 abstract description 2
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 25
- 239000007787 solid Substances 0.000 description 20
- 238000002360 preparation method Methods 0.000 description 17
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- 239000007788 liquid Substances 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 238000000967 suction filtration Methods 0.000 description 8
- 238000010792 warming Methods 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000031709 bromination Effects 0.000 description 6
- 238000005893 bromination reaction Methods 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- NSWQJASYEPJGJA-UHFFFAOYSA-N CCOP(C)(O)OCC.CNC(S)=N Chemical compound CCOP(C)(O)OCC.CNC(S)=N NSWQJASYEPJGJA-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- KFSKXIGXKIMRHM-UHFFFAOYSA-N 2-amino-4-[hydroxy(hydroxymethoxy)phosphoryl]butanoic acid Chemical compound NC(C(=O)O)CCP(=O)(OCO)O KFSKXIGXKIMRHM-UHFFFAOYSA-N 0.000 description 3
- 238000004679 31P NMR spectroscopy Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 230000000116 mitigating effect Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- STNJBCKSHOAVAJ-UHFFFAOYSA-N Methacrolein Chemical compound CC(=C)C=O STNJBCKSHOAVAJ-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 244000025254 Cannabis sativa Species 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 239000005561 Glufosinate Substances 0.000 description 1
- 239000005562 Glyphosate Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000005654 Michaelis-Arbuzov synthesis reaction Methods 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 238000007059 Strecker synthesis reaction Methods 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- WJEIYVAPNMUNIU-UHFFFAOYSA-N [Na].OC(O)=O Chemical compound [Na].OC(O)=O WJEIYVAPNMUNIU-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- QLULGSLAHXLKSR-UHFFFAOYSA-N azane;phosphane Chemical compound N.P QLULGSLAHXLKSR-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 244000037671 genetically modified crops Species 0.000 description 1
- 102000005396 glutamine synthetase Human genes 0.000 description 1
- 108020002326 glutamine synthetase Proteins 0.000 description 1
- XDDAORKBJWWYJS-UHFFFAOYSA-N glyphosate Chemical compound OC(=O)CNCP(O)(O)=O XDDAORKBJWWYJS-UHFFFAOYSA-N 0.000 description 1
- 229940097068 glyphosate Drugs 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- APNSGVMLAYLYCT-UHFFFAOYSA-N isobutyl nitrite Chemical compound CC(C)CON=O APNSGVMLAYLYCT-UHFFFAOYSA-N 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000006146 oximation reaction Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 125000002467 phosphate group Chemical class [H]OP(=O)(O[H])O[*] 0.000 description 1
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 1
- 230000029553 photosynthesis Effects 0.000 description 1
- 238000010672 photosynthesis Methods 0.000 description 1
- 230000005080 plant death Effects 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000197 pyrolysis Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 238000005059 solid analysis Methods 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/301—Acyclic saturated acids which can have further substituents on alkyl
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of synthetic methods of glufosinate-ammonium; it include that single bromine replaces; amination, amido protecting, chlorination open loop; A Erbuzuofu reaction; acidification hydrolization ammonification, single bromine substitution are that gamma-butyrolacton I replaces through catalyst and the single bromines of bromine generation α, and vacuum distillation obtains pure intermediate II α-bromo- gamma-butyrolacton; wherein, the catalyst is phosphorus tribromide;The amination is the bromo- gamma-butyrolacton II of α-and ammonium hydroxide generation ammoxidation, and then plus hydrochloric acid reflux obtains III alpha-amido of intermediate-gamma-butyrolacton hydrochloride.The beneficial effects of the present invention are: 1) using cheap gamma-butyrolacton as raw material, it is acted on bromine and single bromine substitution occurs, then carry out ammoxidation with ammonium hydroxide, used raw material is cheap and easily-available, reaction condition is mild, simple to operation, highly-safe, amplification production is feasible, and reaction yield is high, product purity is high, greatly reduces cost, is suitble to industrialized production.
Description
Technical field
The present invention relates to technical field of pesticide, in particular to a kind of synthetic method of glufosinate-ammonium.
Background technique
Glufosinate-ammonium (glufosinate-ammonium), chemical name are 4- [hydroxyl (methyl) phosphono] third ammonia of-DL-
Acid, structure are as follows:
Glufosinate-ammonium (glufosinate) is a kind of high-efficiency low-toxicity broad-spectrum touch-out type organic phosphates herbicide, it be earliest by
Hirst company (belongs to Bayer AG's development and production) afterwards.It is a kind of glutamine synthetase inhibitor, leads to plant
Interior nitrogen metabolism disorder, the excess accumulation of ammonia, chloroplaset disintegrate, and inhibit its photosynthesis so as to cause Plant death.In those early years, conspicuous
Si Te company has successfully imported the resistant gene of glufosinate-ammonium in 20 various crop such as rice, wheat, corn.Glufosinate-ammonium is only second to
Glyphosate becomes second-biggest-in-the-world genetically modified crops herbicide-tolerant.Glufosinate-ammonium toxicity is low, safer, is easy to drop in the soil
Solution, to crop safety, environmental pressure is small.The market prospects of glufosinate-ammonium are very good.
The primary synthetic methods of glufosinate-ammonium are Si Chuikefa in industrial production at present, while being also the tradition side of comparative maturity
After methylisothiouronium methylphosphite ester and methacrylaldehyde addition Strecker reaction, hydrolysis, the grass for obtaining high-purity after purification occur for method
Ammonium phosphine.But its route of synthesis is long, and the hypertoxic raw material such as Cymag has been used in raw material, has been unfavorable for environmental protection, and produce
Raw three-protection design is more complicated, at high cost.
Therefore low raw-material cost is provided, the method for short, conducive to environmental protection preparation glufosinate-ammonium reaction time has important meaning
Justice.
There is document to be reported for the first time using gamma-butyrolacton as raw material at present, through oximate, restores, amido protecting, chlorination open loop, with
Methylisothiouronium methylphosphite diethylester, which carries out arbuzov reaction, can be obtained the higher glufosinate-ammonium of purity, and reaction yield is high, have certain
Industrialization potential.But potassium tert-butoxide and isobutyl nitrite that its oximation reaction uses, expensive cost are very high and not
It is easy to get, reduction reaction is related to hydrogen and Pd/C catalyst, and at high cost and safety is defective.Its synthetic route is as follows:
Summary of the invention
The present invention provides a kind of method for preparing glufosinate-ammonium, and using cheap gamma-butyrolacton as raw material, reaction yield is higher,
Product purity is high, mild condition and simple and convenient, and safety is good, meets green chemical industry trend, is suitable for industrialized production.
The technical proposal adopted by the invention to solve the above technical problems is that: the synthetic method of glufosinate-ammonium includes single bromine
Replace, amination, amido protecting, chlorination open loop, A Erbuzuofu reaction, acidification hydrolization ammonification, single bromine substitution is γ-
Butyrolactone I occurs α single bromines through catalyst and bromine and replaces, and vacuum distillation (b.p.120~125 DEG C/1.6kPa) obtains pure
Intermediate II α-bromo- gamma-butyrolacton, wherein the catalyst is phosphorus tribromide;The amination is the bromo- gamma-butyrolacton of α-
II occurs ammoxidation with ammonium hydroxide, and then plus hydrochloric acid reflux obtains III alpha-amido of intermediate-gamma-butyrolacton hydrochloride.
According to the above scheme: the amido protecting is III alpha-amido of intermediate-gamma-butyrolacton hydrochloride for will obtaining molten
In the presence of agent, suitable alkali is added, reacts to obtain intermediate IV (2- oxo-tetrahydrofuran -3- base) amino first with alcoxyl dicarbonyl chloride
Acetoacetic ester.
According to the above scheme: the chlorination open loop is intermediate IV (2- oxo-tetrahydrofuran -3- base) amino that will be obtained
Ethyl formate reacts to obtain the chloro- 2- ethoxycarbonylamino ethyl butyrate of V 4- of intermediate with the HCl ethanol solution of saturation;Described
A Erbuzuofu reaction is the chloro- 2- ethoxycarbonylamino ethyl butyrate of V 4- of intermediate and methylisothiouronium methylphosphite diethylester that will be obtained
It is reacted by Arbuzov, obtains VI 4- ethyoxyl -4- methyl phosphono -2- ethoxycarbonylamino ethyl butyrate of intermediate;It is described
Acidification hydrolization ammonification be the VI 4- ethyoxyl -4- methyl phosphono -2- ethoxycarbonylamino ethyl butyrate of intermediate that will be obtained
Hydrochloric acid hydrolysis is first passed through, then plus ammonium hydroxide reacts to obtain product glufosinate-ammonium ammonium salt.
According to the above scheme: the molar ratio of the bromine and gamma-butyrolacton is 1-2:1.
According to the above scheme: the molar ratio of the bromine and gamma-butyrolacton is 2:1.
According to the above scheme: the molar ratio of the intermediate II and ammonium hydroxide is 1:3-9, the molar ratio of intermediate II and hydrochloric acid
For 1:1-2.5.
According to the above scheme: the molar ratio of the intermediate II and ammonium hydroxide is 1:6, and the molar ratio of intermediate II and hydrochloric acid is
1:1.5。
According to the above scheme: the alkali is Na2CO3Or triethylamine.
According to the above scheme: the alcoxyl dicarbonyl chloride is appointing in ethyl chloroformate, methylchloroformate and carbobenzoxy chloride
It anticipates one kind.
According to the above scheme: the solvent is methylene chloride and one of water and the mixed liquor of tetrahydrofuran.
Reaction equation according to the present invention are as follows:
Wherein R1For the alkyl or Bn of C1-C2.
The beneficial effects of the present invention are:
1) it using cheap gamma-butyrolacton as raw material, is acted on bromine and single bromine substitution occurs, then carry out amination with ammonium hydroxide
Reaction, used raw material is cheap and easily-available, and reaction condition is mild, simple to operation, highly-safe, and amplification production is feasible, and anti-
High income is answered, product purity is high, greatly reduces cost, is suitble to industrialized production;
2) present invention use cheap and easily-available bromine as bromine source, selectively single bromine substitution reaction yield 88% or more,
Product purity is high after vacuum distillation, and gamma-butyrolacton is both raw material and solvent in bromo-reaction, after reducing costs and reducing
The step of processing;
3) ammoxidation of the present invention generates III alpha-amido of intermediate-gamma-butyrolacton hydrochloride mild condition, and reaction is received
Rate is 70% or more, and post-processing is simple and to obtain product purity very high;
4) present invention has used the mixed solvent body of tetrahydrofuran and water in the reaction that amido protecting generates intermediate IV
System, and select to use inorganic base system, reaction yield is 85% or more;
5) present invention selects the ethanol solution of saturation HCl in the reaction that chlorination open loop generates intermediate V, and the system is green
Colour circle is protected, and yield is 65% or more.
Detailed description of the invention
Fig. 1 is V compound 4-chloro -2- ethoxycarbonylamino ethyl butyrate of formula prepared by the present invention1H-NMR figure;
Fig. 2 is formula VII compound 2- amino -4- (hydroxymethyl phosphono) butyric acid prepared by the present invention1H-NMR figure;
Fig. 3 is formula VII compound 2- amino -4- (hydroxymethyl phosphono) butyric acid prepared by the present invention13C-NMR figure;
Fig. 4 is formula VII compound 2- amino -4- (hydroxymethyl phosphono) butyric acid prepared by the present invention31P-NMR figure.
Specific embodiment
The present invention is further described in detail below by specific embodiment:
Embodiment 1: intermediate II α-bromo- gamma-butyrolacton preparation method:
Under ice bath, 330mL bromine is slowly added dropwise into the mixture of 500g gamma-butyrolacton and 31g red phosphorus in there-necked flask,
70 DEG C are then heated to, continues that 330mL bromine is added dropwise.After being added dropwise, it is warming up to 80 DEG C of reaction 3h.Stopping is heated to cooling down,
It is persistently blown into air, the hydrogen bromide of excessive bromine and generation is blown away.Then it is warming up to 80 DEG C again, 100mL water is slowly added dropwise,
Equal reactions add 700mL water after mitigating, and flow back 4h.It is layered after cooling, water layer is extracted with dichloromethane, and merges organic layer, nothing
Water magnesium sulfate is dry.Decompression obtains crude product (b.p.120~125 DEG C/1.6kPa) after boiling off solvent, after vacuum distillation purification,
Obtain pale yellow oily liquid 850g, yield 88.7%.
Embodiment 2: intermediate II α-bromo- gamma-butyrolacton preparation method:
Under ice bath, 330mL bromine is slowly added dropwise into the mixture of 500g gamma-butyrolacton and 31g red phosphorus in there-necked flask,
70 DEG C are then heated to, continues that 250mL bromine is added dropwise.After being added dropwise, it is warming up to 80 DEG C of reaction 3h.Stopping is heated to cooling down,
It is persistently blown into air, the hydrogen bromide of excessive bromine and generation is blown away.Then it is warming up to 80 DEG C again, 100mL water is slowly added dropwise,
Equal reactions add 750mL water after mitigating, and flow back 4h.It is layered after cooling, water layer is extracted with dichloromethane, and merges organic layer, nothing
Water magnesium sulfate is dry.Decompression obtains crude product after boiling off solvent, and vacuum distillation purification obtains pale yellow oily liquid 760g, yield
80%.
Embodiment 3: intermediate II α-bromo- gamma-butyrolacton preparation method:
Under ice bath, 330mL bromine is slowly added dropwise into the mixture of 500g gamma-butyrolacton and 31g red phosphorus in there-necked flask,
70 DEG C are then heated to, continues that 150mL bromine is added dropwise.After being added dropwise, it is warming up to 80 DEG C of reaction 3h.Stopping is heated to cooling down,
It is persistently blown into air, the hydrogen bromide of excessive bromine and generation is blown away.Then it is warming up to 80 DEG C again, 100mL water is slowly added dropwise,
Equal reactions add 750mL water after mitigating, and flow back 4h.It is layered after cooling, water layer is extracted with dichloromethane, and merges organic layer, nothing
Water magnesium sulfate is dry.Decompression obtains crude product after boiling off solvent, and vacuum distillation purification obtains pale yellow oily liquid 610g, yield
64.2%.
1H NMR(600MHz,CDCl3)δ:4.48(td,1H),4.41(ddd,2H),2.84–2.74(m,1H),2.47
(ddt,1H).
In embodiment 1, the bromine of addition and the equivalent proportion of gamma-butyrolacton are 2, finally obtain pale yellow oily liquid
850g, yield is up to 88.7%;In embodiment 2, the bromine of addition and the equivalent proportion of gamma-butyrolacton are 1.8, are finally obtained faint yellow
Oily liquids 760g, yield is up to 80%;In embodiment 3, the bromine of addition and the equivalent proportion of gamma-butyrolacton are 1.5, are finally obtained
Pale yellow oily liquid 610g, yield is up to 64.2%.Therefore when the equivalent proportion of the bromine and gamma-butyrolacton that are added is 2, yield reaches
88.7%, effect is best.
Embodiment 4: III alpha-amido of intermediate-gamma-butyrolacton hydrochloride preparation method:
Under condition of ice bath, (similarly hereinafter) bromination product of the embodiment 1 of 50g is slowly added drop-wise to 136mL 25wt%'s
In ammonium hydroxide, after reacting 48h, vacuum distillation removes solvent, and subsequent enriching hydrochloric acid, flow back 1h at 110 DEG C, and suction filtration obtains 39.4g
White solid, yield 50.3%.
Embodiment 5: III alpha-amido of intermediate-gamma-butyrolacton hydrochloride preparation method:
Under condition of ice bath, the bromination product of 50g is slowly added drop-wise in the ammonium hydroxide of 270mL 25wt%, reacts 48h
Afterwards, vacuum distillation removes solvent, and subsequent enriching hydrochloric acid, flow back 1h at 110 DEG C, and suction filtration obtains the white solid of 48.25g, receives
Rate 70.6%.
Embodiment 6: III alpha-amido of intermediate-gamma-butyrolacton hydrochloride preparation method:
Under condition of ice bath, the bromination product of 50g is slowly added drop-wise in the ammonium hydroxide of 46mL 25wt%, reacts 48h
Afterwards, vacuum distillation removes solvent, and subsequent enriching hydrochloric acid, flow back 1h at 110 DEG C, and suction filtration obtains the white solid of 18.5g, yield
10.2%.
In embodiment 4, when the equivalent proportion of ammonium hydroxide and the bromo- gamma-butyrolacton of α-is 3eq, it is solid to obtain III white of product Intermediate
Body has a 39.4g, and yield is up to 50.3%;In embodiment 5, when the equivalent proportion of ammonium hydroxide and the bromo- gamma-butyrolacton of α-is 6eq, product is obtained
III white solid of intermediate has a 48.25g, and yield is up to 70.6%;In embodiment 6, the equivalent proportion of ammonium hydroxide and the bromo- gamma-butyrolacton of α-
When for 1eq, obtaining III white solid of product Intermediate has 18.5g, and yield is up to 10.2%. therefore when ammonium hydroxide and the bromo- gamma-butyrolacton of α-
Equivalent proportion be 6eq when, for yield up to 70.6%, effect is best.
Embodiment 7: III alpha-amido of intermediate-gamma-butyrolacton hydrochloride preparation method:
Under condition of ice bath, the bromination product of 50g is slowly added drop-wise in the ammonium hydroxide of 270mL 25wt%, reacts 48h
Afterwards, vacuum distillation removes solvent, and subsequent enriching hydrochloric acid 26mL, flow back 1h at 110 DEG C, and the white that suction filtration obtains 40.96g is solid
Body, yield 42.8%.
Embodiment 8: III alpha-amido of intermediate-gamma-butyrolacton hydrochloride preparation method:
Under condition of ice bath, the bromination product of 50g is slowly added drop-wise in the ammonium hydroxide of 270mL 25wt%, reacts 48h
Afterwards, vacuum distillation removes solvent, and subsequent enriching hydrochloric acid 39mL, flow back 1h at 110 DEG C, and suction filtration obtains the white solid of 46g, receives
Rate 68.3%.
Embodiment 9: III alpha-amido of intermediate-gamma-butyrolacton hydrochloride preparation method:
Under condition of ice bath, the bromination product of 50g is slowly added drop-wise in the ammonium hydroxide of 270mL 25wt%, reacts 48h
Afterwards, vacuum distillation removes solvent, and subsequent enriching hydrochloric acid 65mL, flow back 1h at 110 DEG C, and the white that suction filtration obtains 36.17g is solid
Body, yield 40.3%.1H NMR(600MHz,DMSO)δ8.89(s,2H),4.46–4.25(m,3H),2.59–2.52(m,1H),
2.36–2.26(m,1H).
In embodiment 7, when the equivalent proportion of hydrochloric acid and the bromo- gamma-butyrolacton of α-is 1, III white solid of product Intermediate is obtained
There are 40.96g, yield 42.8%;In embodiment 8, when the equivalent proportion of hydrochloric acid and the bromo- gamma-butyrolacton of α-is 1.5, product is obtained
III white solid of intermediate has 46g, yield 68.3%;In embodiment 9, the equivalent proportion of hydrochloric acid and the bromo- gamma-butyrolacton of α-is
When 2.0, obtaining III white solid of product Intermediate has 36.17g, yield 40.3%;Therefore when hydrochloric acid and the bromo- gamma-butyrolacton of α-
Equivalent proportion be 1.5eq when, obtaining III white solid of product Intermediate has 46g, and yield 68.3%, effect is best.
Embodiment 10: the preparation method of intermediate IV:
Under condition of ice bath, amination product as white solid 20g is taken to mix with 100mL tetrahydrofuran and 200mL water, toward it
Middle addition sodium carbonate, then after reaction half an hour is slowly added dropwise into the ethyl chloroformate of 19g, the reaction was continued after restoring to room temperature
2h, vacuum distillation remove solvent, adjust pH to acidity, are extracted with dichloromethane to obtain thick IV compound of formula, have solid after cooling
It is precipitated, suction filtration obtains colourless oil liquid 13.08g.Yield is 87%.1H NMR(600MHz,CDCl3)δ:5.20(s,1H),
4.47–4.12(m,5H),2.79(s,1H),2.27–2.15(m,1H),1.60(s,2H),0.87(s,1H).
Embodiment 11: the preparation method of intermediate IV:
Under condition of ice bath, takes amination product as white solid 20g to mix with tetrahydrofuran and water, be charged with carbonic acid
Sodium, then after reaction half an hour is slowly added dropwise into the benzyl chloroformate of 30g, the reaction was continued after restoring to room temperature 2h, decompression are steamed
Solvent is removed in distillation, adjusts pH to acidity, is extracted with dichloromethane to obtain thick IV compound of formula, there is solid precipitation after cooling, take out
Filter obtains product colourless oil liquid 13.54g, yield 90%.1H NMR(600MHz,CDCl3) δ: 7.36~7.25 (m,
5H), 5.34 (s, 1H), 5.13 (s, 2H), 4.48~4.21 (m, 3H), 2.80~2.75 (m, 1H), 2.27~2.18 (m, 1H)
Embodiment 12: the preparation method of intermediate IV:
Under condition of ice bath, amination product as white solid 20g is taken to mix with 100mL tetrahydrofuran and 200mL water, toward it
Middle addition sodium carbonate, then after reaction half an hour is slowly added dropwise into the methylchloroformate of 16.5g, continue after restoring to room temperature anti-
2h is answered, vacuum distillation removes solvent, adjusts pH to acidity, is extracted with dichloromethane to obtain thick IV compound of formula, have after cooling
Solid is precipitated, and suction filtration obtains colourless oil liquid 9.0g.Two step yields are 60%.1H NMR(600MHz,CDCl3)δ:5.52(s,
1H), 4.49~4.23 (m, 3H), 3.71 (s, 3H), 2.79~2.70 (m, 1H), 2.28-2.21 (m, 1H)
Embodiment 13: the preparation method of intermediate IV:
Under condition of ice bath, amination product as white solid 20g is taken to be added to the CH of the triethylamine containing 20mL2Cl2
(300mL), then after reaction half an hour is slowly added dropwise into the benzyl chloroformate of 30g, the reaction was continued after restoring to room temperature 2h subtract
Solvent is distilled off in pressure, adjusts pH to acidity, is extracted with dichloromethane to obtain thick IV compound of formula, there is solid analysis after cooling
Out, it filters and obtains product colourless oil liquid 3.0g.Two step yields are 20%.
Embodiment 14: the preparation method of intermediate V:
IV compound of 10g formula is taken, is added in the pressure pipe of 200ml, then by the HCl ethanol solution of the saturation of 150mL
It is added thereto, after being warming up to 65 DEG C of reaction 12h, rotates alcohol solvent therein, a small amount of water is added, extract with ethyl acetate
It takes three times, after spinning off solvent, then uses petroleum ether, obtain colourless oil liquid 8.12g i.e. V compound of formula, yield and exist
60% or more.1H NMR(400MHz,CDCl3)δ:5.29(s,1H),4.47(s,1H),4.27–4.18(m,2H),4.13(d,
2H), 3.60 (t, 2H), 2.34 (s, 1H), 2.16 (s, 1H), 1.32-1.23 (m, 6H),1H-NMR is as shown in Figure 1.
Embodiment 15: the preparation method of intermediate VI:
10.0g such as the intermediate of formula V 4 is taken to mix in 150mL dry toluene with 6.9g methylisothiouronium methylphosphite diethylester, nitrogen
Under gas shielded, back flow reaction 10h.Vacuum distillation removal toluene and superfluous methylisothiouronium methylphosphite diethylester, residue are dissolved in acetic acid second
After ester, salt water washing 3 times, organic layer is dry, and vacuum distillation removal solvent obtains 5 yield of intermediate of 9.6g such as formula VI
75.87%.1HNMR(400MHz,DMSO-d6) δ: 7.49 (s, 1H), 4.17-3.97 (m, 6H), 2.14~1.91 (m, 2H),
1.65–1.07(m,13H).
Embodiment 16: the preparation method of VII product of formula:
The intermediate for weighing 10.0g such as formula VI is added in 100mL 6mol/L HCl solution, and flow back 8h.Again with 28% ammonia
PH value is transferred to 9 by water, is continued the 6h that flows back, after vacuum distillation, with recrystallizing methanol, is obtained white glufosinate-ammonium crystal 5.2g, yield
80.96%.1H NMR(400MHz,D2O) δ: 3.67 (dd, 1H), 2.04~1.87 (m, 2H), 1.58-1.41 (m, 2H), 1.14
(d,3H).13C NMR(101MHz,D2O)δ:172.3,53.7(d,JC-P=14.1Hz), 25.9 (d, JC-P=92.0Hz), 23.2
(d,JC-P=2.3Hz), 14.1 (d, JC-P=93.2Hz)31P NMR(162MHz,D2O) δ: 49.04,1H-NMR is as shown in Figure 2
,13C-NMR as shown in figure 3,31P-NMR is as shown in Figure 4.
Although the embodiments of the present invention have been disclosed as above, but its is not only in the description and the implementation listed
With it can be fully applied to various fields suitable for the present invention, for those skilled in the art, can be easily
Realize other modification, therefore without departing from the general concept defined in the claims and the equivalent scope, the present invention is simultaneously unlimited
In specific details and embodiment shown and described herein.
Claims (10)
1. the synthetic method of glufosinate-ammonium includes that single bromine replaces, amination, amido protecting, chlorination open loop, A Erbuzuofu reaction
With acidification hydrolization ammonification, single bromine substitution is that gamma-butyrolacton I replaces through catalyst and the single bromines of bromine generation α, and decompression is steamed
It evaporates to obtain pure intermediate II α-bromo- gamma-butyrolacton, wherein the catalyst is phosphorus tribromide;The amination is α-
With ammonium hydroxide ammoxidation occurs for bromo- gamma-butyrolacton II, and then plus hydrochloric acid reflux obtains III alpha-amido of intermediate-gamma-butyrolacton
Hydrochloride.
2. the synthetic method of glufosinate-ammonium according to claim 1, it is characterised in that: the amido protecting will obtain
In the presence of solvent, suitable alkali is added in III alpha-amido of intermediate-gamma-butyrolacton hydrochloride, reacts to obtain with alcoxyl dicarbonyl chloride
Intermediate IV (2- oxo-tetrahydrofuran -3- base) urethanes.
3. the synthetic method of glufosinate-ammonium according to claim 1, it is characterised in that:
The chlorination open loop is (2- oxo-tetrahydrofuran -3- base) urethanes of intermediate IV that will be obtained and saturation
HCl ethanol solution reacts to obtain the chloro- 2- ethoxycarbonylamino ethyl butyrate of V 4- of intermediate;
The A Erbuzuofu reaction is that the chloro- 2- ethoxycarbonylamino ethyl butyrate of V 4- of intermediate that will be obtained and methyl are sub-
Diethyl phosphate is reacted by Arbuzov, obtains VI 4- ethyoxyl -4- methyl phosphono -2- ethoxycarbonylamino fourth of intermediate
Acetoacetic ester;
The acidification hydrolization ammonification is the VI 4- ethyoxyl -4- methyl phosphono -2- ethoxycarbonylamino of intermediate that will be obtained
Ethyl butyrate first passes through hydrochloric acid hydrolysis, and then plus ammonium hydroxide reacts to obtain product glufosinate-ammonium ammonium salt.
4. the synthetic method of glufosinate-ammonium according to claim 1, it is characterised in that: the bromine and gamma-butyrolacton
Molar ratio is 1-2:1.
5. the synthetic method of glufosinate-ammonium according to claim 4, it is characterised in that: the bromine and gamma-butyrolacton
Molar ratio is 2:1.
6. the synthetic method of glufosinate-ammonium according to claim 1, it is characterised in that: the intermediate II and ammonium hydroxide is rubbed
, than being 1:3-9, the molar ratio of intermediate II and hydrochloric acid is 1:1-2.5 for you.
7. the synthetic method of glufosinate-ammonium according to claim 6, it is characterised in that: the intermediate II and ammonium hydroxide is rubbed
, than being 1:6, the molar ratio of intermediate II and hydrochloric acid is 1:1.5 for you.
8. the synthetic method of glufosinate-ammonium according to claim 2, it is characterised in that: the alkali is Na2CO3Or triethylamine.
9. the synthetic method of glufosinate-ammonium according to claim 2, it is characterised in that: the alcoxyl dicarbonyl chloride is chloro-carbonic acid
Any one in ethyl ester, methylchloroformate and carbobenzoxy chloride.
10. the synthetic method of glufosinate-ammonium according to claim 2, it is characterised in that: the solvent is methylene chloride, with
And one of water and the mixed liquor of tetrahydrofuran.
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