CN105837624B - A kind of synthetic method of phosphine oxamate - Google Patents
A kind of synthetic method of phosphine oxamate Download PDFInfo
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- CN105837624B CN105837624B CN201610331162.2A CN201610331162A CN105837624B CN 105837624 B CN105837624 B CN 105837624B CN 201610331162 A CN201610331162 A CN 201610331162A CN 105837624 B CN105837624 B CN 105837624B
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- WTEJQBARPJSNLZ-UHFFFAOYSA-N C(C(=O)N)(=O)O.P Chemical compound C(C(=O)N)(=O)O.P WTEJQBARPJSNLZ-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 238000010189 synthetic method Methods 0.000 title claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- -1 Methyl dichloro phosphorus Chemical compound 0.000 claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 238000004176 ammonification Methods 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 54
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 238000010792 warming Methods 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000012065 filter cake Substances 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- CDPKWOKGVUHZFR-UHFFFAOYSA-N dichloro(methyl)phosphane Chemical compound CP(Cl)Cl CDPKWOKGVUHZFR-UHFFFAOYSA-N 0.000 claims description 9
- 229910021529 ammonia Inorganic materials 0.000 claims description 8
- 239000011230 binding agent Substances 0.000 claims description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 238000001556 precipitation Methods 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 4
- 235000019441 ethanol Nutrition 0.000 claims description 4
- 238000006845 Michael addition reaction Methods 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 2
- 230000000996 additive effect Effects 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 230000008859 change Effects 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical class [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 229910052698 phosphorus Inorganic materials 0.000 claims 1
- 239000011574 phosphorus Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 14
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 231100000004 severe toxicity Toxicity 0.000 abstract description 3
- SEJXNPFTEXQNOU-UHFFFAOYSA-N 2-(oxomethylidene)butanoic acid Chemical class CCC(=C=O)C(O)=O SEJXNPFTEXQNOU-UHFFFAOYSA-N 0.000 abstract description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 abstract description 2
- 238000007259 addition reaction Methods 0.000 abstract description 2
- 150000003863 ammonium salts Chemical class 0.000 abstract description 2
- 230000009467 reduction Effects 0.000 abstract description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 235000011121 sodium hydroxide Nutrition 0.000 description 6
- WAXMRVDZHXIAHQ-UHFFFAOYSA-N COP(=O)(OO)CCC(C(=O)O)=C=O Chemical compound COP(=O)(OO)CCC(C(=O)O)=C=O WAXMRVDZHXIAHQ-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- STNJBCKSHOAVAJ-UHFFFAOYSA-N Methacrolein Chemical compound CC(=C)C=O STNJBCKSHOAVAJ-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000002363 herbicidal effect Effects 0.000 description 3
- 239000004009 herbicide Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- IAJOBQBIJHVGMQ-UHFFFAOYSA-N Phosphinothricin Natural products CP(O)(=O)CCC(N)C(O)=O IAJOBQBIJHVGMQ-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- NSSMTQDEWVTEKN-UHFFFAOYSA-N diethoxy(methyl)phosphane Chemical compound CCOP(C)OCC NSSMTQDEWVTEKN-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 231100001231 less toxic Toxicity 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- TUJPSRWSOZCXPK-UHFFFAOYSA-N 2-(oxomethylidene)but-3-enoic acid Chemical class OC(=O)C(C=C)=C=O TUJPSRWSOZCXPK-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- HEGJOQDCIZEXLT-UHFFFAOYSA-N C(=O)=C(C(=O)OCC)C=C Chemical compound C(=O)=C(C(=O)OCC)C=C HEGJOQDCIZEXLT-UHFFFAOYSA-N 0.000 description 1
- ZTUVTQBAHLRCRV-UHFFFAOYSA-N COC(C(C=C)=C=O)=O Chemical class COC(C(C=C)=C=O)=O ZTUVTQBAHLRCRV-UHFFFAOYSA-N 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 238000007059 Strecker synthesis reaction Methods 0.000 description 1
- LUAMIGOADJTNQF-UHFFFAOYSA-N [Mg].[Cl-].C(=C)[N+]1=CNC=C1 Chemical compound [Mg].[Cl-].C(=C)[N+]1=CNC=C1 LUAMIGOADJTNQF-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 150000001912 cyanamides Chemical class 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 244000037671 genetically modified crops Species 0.000 description 1
- IAJOBQBIJHVGMQ-BYPYZUCNSA-N glufosinate-P Chemical compound CP(O)(=O)CC[C@H](N)C(O)=O IAJOBQBIJHVGMQ-BYPYZUCNSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- PMVVRSKJCGEFIY-UHFFFAOYSA-N methylphosphonous acid Chemical compound CP(O)O PMVVRSKJCGEFIY-UHFFFAOYSA-N 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical class O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
- XRBCRPZXSCBRTK-UHFFFAOYSA-N phosphonous acid Chemical compound OPO XRBCRPZXSCBRTK-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 229920002338 polyhydroxyethylmethacrylate Polymers 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000035943 smell Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 238000009333 weeding 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)
Abstract
The invention discloses a kind of synthetic methods of phosphine oxamate.Methyl dichloro phosphorus species and 2- carbonyl -3-butenoic acid ester type compound are subjected to addition reaction, carbonyl butyric acid analog derivative is made, using ammonification, reduction, phosphine oxamate compound can be obtained.This method not only can be to avoid the cyanide for using severe toxicity, hence it is evident that shortens reaction route, so that the processing step of synthesis phosphine oxamate is reduced, easy to operate, without recrystallizing away ammonium salt, and high income is at low cost, phosphine oxamate purity obtained is higher, especially suitable for industrialized production.
Description
Technical field
The invention belongs to chemosynthesis technical field, in particular to a kind of synthetic method of herbicide phosphinothricin.
Background technique
Phosphine oxamate (Glufosinafe) is efficient, less toxic, the non-selective weeding developed at first by Hoechest company
Agent, trade name Basta, molecular formula are：C5H12NO4P, structure are：
Phosphine oxamate as a kind of excellent herbicide, have the characteristics that efficiently, it is less toxic and non-selective, be current transgenosis
The ideal herbicide of resistance crop, market demand are greatly increased with the fast development of genetically modified crops.Have both at home and abroad
More the document report synthetic method of phosphine oxamate, tight Hydron etc. exist《The synthetic method of phosphine oxamate》[《Pesticide》, 2002,
The 9th phase of volume 43, the page number：46-48] common several synthetic methods both at home and abroad are reviewed at present in a text, mainly there is high pressure to urge
It is combined to method, low temperature controlled syntheses method, smells the phosphine oxamate method that is combined to, this spy tired Ke Er (Strecker) reaction synthesis phosphine oxamate
Method, closely that (Michael) addition process and microbe fermentation method.Li Yiming etc. exists《A kind of new method synthesizing phosphine oxamate》[《Agriculture
Medicine》, in January, 2012, the 1st phase of volume 51, the page number：11-12] it summarizes in document main three used by synthesis phosphine oxamate at present
Route, route 1：Using phosphonous acid trimethyl as starting material, pass through rearrangement, chlorination, grignard reaction, Michael addition, hydrolysis
5 steps react to obtain phosphine oxamate；Route 2：Using diethyl methyl-phosphonite as raw material, after rearrangement reaction occurs with methacrylaldehyde, then lead to
It crosses Strecker to react to obtain cyanamide derivative, obtains phosphine oxamate after hydrolysis；Route 3：It is original with diethyl methyl-phosphonite
Expect it is rearranged, replace, hydrolyze, smelling, decarboxylation, 6 step of ammonolysis react to obtain phosphine oxamate.Wherein the chemical synthesis process of route 2 is
The technique of comparative maturity, Hoechst AG (DE) Frankfurt/Main 80, Federsl Republic of Germany one give up self-employed tree cultivator's industry Development Co., Ltd and disclose a kind of grass in patent in CN1267305A
The synthetic method of amine phosphine and its intermediate, using the method for above-mentioned route 2, by methyl phosphine compound, such as methyl phosphonous acid two
Ethyl ester etc. and unsaturated ketone or aldehyde compound such as methacrylaldehyde, reaction generate adduct, apply special rake through subsequent
(Strecker) reaction and the hydrolysis of final cyanamide, needing to use raw material during synthesizing amino cyanogen is NH3、NaCN、
NH4C1, then by amino cyanogen compound, the U.S. that generation phosphine oxamate US6359162 is hydrolyzed using hydrochloric acid or sodium hydroxide is special
Amino cyanogen compound is obtained also with Strecker reaction synthesis in benefit, then hydrolysis obtains phosphine oxamate.Its technological reaction is such as
Under：
2 reaction process of route is short, and yield is relatively high, is the technique of current domestic synthesis phosphine oxamate comparative maturity, tool
Disadvantage of both having：On the one hand it is that amino cyanogen compound is hydrolyzed into generation phosphine oxamate using hydrochloric acid or sodium hydroxide, can produces
Raw a large amount of salt leads in industrial production that there is sodium chloride and product separating step wherein mainly sodium chloride, and by
There is similarity in phosphine oxamate and sodium chloride solubility property, such as is all dissolved in water, so that physical separation step is not easy to, mesh
Preceding is all with methanol come the sodium chloride in isolated product, this process occupies large number of equipment, has been doped into methanol in product；Separately
On the one hand, the more three wastes can be generated using the Cymag and concentrated hydrochloric acid of severe toxicity, is unfavorable for environmental protection.
Summary of the invention
In order to overcome the above problem, the object of the present invention is to provide a kind of synthetic methods of phosphine oxamate, by methyl dichloro
Phosphorus species and 2- carbonyl -3-butenoic acid ester type compound carry out addition reaction, and carbonyl butyric acid analog derivative is made, using
Phosphine oxamate compound can be obtained in ammonification, reduction.This method not only can be to avoid the cyanide for using severe toxicity, hence it is evident that shortens anti-
Answer route it is easy to operate so that the processing step of synthesis phosphine oxamate is reduced, without recrystallizing away ammonium salt, and high income at
This is low, and phosphine oxamate purity obtained is higher, especially suitable for industrialized production.
To achieve the above object, the present invention takes following technical scheme：A kind of synthetic method of phosphine oxamate, including walk as follows
Suddenly：
(1) 2- of acid binding agent and formula III carbonyl -3-butenoic acid ester type compound is added in organic solvent, -20~
The methyl hypophosphorous acid class compound of Formula II is slowly added dropwise under the conditions of 20 DEG C, stirs 0.5-2h, carries out Michael addition reaction, reaction
After add basic hydrolysis, be warming up to reflux 4-6h, be cooled to room temperature, washing filtering, the alpha-carbonyl acids of production IV spreads out
Biology, reaction equation are as follows：
(2) it takes alpha-carbonyl acid derivative (IV) obtained in step (1) in autoclave, is added thereto organic molten
Agent is passed through ammonia under normal pressure, carries out ammonification, controls reaction system pH, adds catalyst, be passed through hydrogen, and it is anti-to be warming up to reflux
4-6h is answered, there is solid precipitation in system, is filtered, the phosphine oxamate of production I, reaction equation is as follows：
It advanced optimizes, step (1), step (2) organic solvent are methanol or ethyl alcohol.
It advanced optimizes, R1 described in step (1) is the alkyl for having 1-4 carbon atom.
It advanced optimizes, acid binding agent described in step (1) is triethylamine, diethylamine, pyridine or ammonia.
It advanced optimizes, in step (1), the methyl-phosphinic acid ester type compound and 2- carbonyl -3-butenoic acid esters
The molar ratio of compound is 1：1-1.5.
It advanced optimizes, reaction system pH described in step (2) is 12 ± 0.5, and temperature is 0-20 DEG C.
It advanced optimizes, the catalyst of reduction reaction described in step (2) is Pt/C, and Pt/C additive amount is alpha-carbonyl acids
The 1~20% of derivative (IV) quality, temperature are 40-100 DEG C.
It advanced optimizes, further includes that resulting filter cake is dissolved step (2) to water, refilter, obtain clear filtrate,
Methanol is added thereto, methanol, water consumption ratio are 1：5~20, it is stirred overnight.
Compared with prior art, beneficial effect is：1), raw materials used oxalate diester, vinylimidazolium chloride magnesium are cheap, be easy to get,
It being readily synthesized, three-step reaction total recovery is high, and it is easy to operate, it is particularly suitable for industrial production；2), synthesized phosphine oxamate purity is high,
Ammonia salt is removed without repeated recrystallize.
Specific embodiment
Illustrated embodiment is to preferably be illustrated to the contents of the present invention, but is not that the contents of the present invention only limit
In illustrated embodiment.So those skilled in the art carry out nonessential change to embodiment according to foregoing invention content
Into and adjustment, still fall within protection scope of the present invention.
Methyl dichloro phosphorus in the invention patent can be made by phosphorus trichloride and methane reaction, and for details, reference can be made to Baeyer public affairs
The synthetic method of the dichloromethyl phosphine proposed in US4521348 is taken charge of, the synthesis of dichloromethyl phosphine is as follows：
Embodiment 1
A kind of synthetic method of phosphine oxamate, includes the following steps：
1) 2- carbonyl -3-butenoic acid methyl esters 45.6g (0.4mol), acid binding agent triethylamine 60.6g (0.6mol) is taken to be added to
In 50ml methanol solution, under the conditions of 0 DEG C, methyl dichloro phosphorus 47.5g (0.41mol) slowly is added dropwise thereto, 1h is added dropwise and completes,
After low temperature stirs 1h, 1mol/l sodium hydrate aqueous solution 100ml is added thereto, is warming up to reflux 5h, is down to room temperature filtering, filter
Cake is washed with water three times, obtains white solid 68.1g, yield 93.8%；
2) it takes 4- (methylhydroxy phosphono) -2- carbonyl-butyric acid 54.0g (0.3mol) in autoclave, is added thereto
Methanol 300ml, 20 DEG C, be passed through ammonia to 0.5Mpa under normal pressure, controlling reaction system pH is 12, and alpha-carbonyl is then added thereto
The Pt/C of acid derivative (IV) 5% is passed through hydrogen to 1Mpa, is warming up to 60 DEG C of back flow reaction 5h, has solid precipitation in system,
Filtering refilters after dissolving resulting filter cake with 50ml water, obtains clear filtrate, and 500ml methanol is added thereto, stirs
It mixes overnight, obtains white crystal 50.5g, yield 86.2%, surveying purity with liquid phase normalization method is 98.1%.
Embodiment 2
A kind of synthetic method of phosphine oxamate, includes the following steps：
1) 2- carbonyl -3-butenoic acid ethyl ester 51.2g (0.4mol), acid binding agent triethylamine 60.6g (0.6mol) is taken to be added to
In 50ml methanol solution, under the conditions of -10 DEG C, methyl dichloro phosphorus 47.5g (0.41mol) slowly is added dropwise thereto, it is complete that 1h is added dropwise
At, after low temperature stirs 1h, 1M sodium hydrate aqueous solution 100ml is added thereto, is warming up to reflux 5h, is down to room temperature and filters, filter
Cake is washed with water three times, obtains white solid 64.8g, yield 90.6%；
2) it takes 4- (methylhydroxy phosphono) -2- carbonyl-butyric acid 54.0g (0.3mol) in autoclave, is added thereto
Methanol 300ml is passed through ammonia under normal pressure to 0.5Mpa, and controlling reaction system pH is 12.5, and alpha-carbonyl acid is then added thereto
The Pt/C of analog derivative (IV) 10% is passed through hydrogen to 1Mpa, is warming up to 80 DEG C of back flow reaction 5h, has solid precipitation in system,
Filtering refilters after dissolving resulting filter cake with 50ml water, obtains clear filtrate, and 500ml methanol is added thereto, stirs
It mixes overnight, obtains white crystal 50.9g, yield 85.6%, surveying purity with liquid phase normalization method is 98.4%.
Embodiment 3
A kind of synthetic method of phosphine oxamate, includes the following steps：
1) the 2- carbonyl taken -3-butenoic acid ethyl ester 51.2g (0.4mol), acid binding agent triethylamine 60.6g (0.6mol) are added
Into 50ml ethanol solution, under the conditions of 10 DEG C, methyl dichloro phosphorus 47.5g (0.41mol) slowly is added dropwise thereto, it is complete that 1h is added dropwise
At, after low temperature stirs 1h, 1M sodium hydrate aqueous solution 100ml is added thereto, is warming up to reflux 5h, is down to room temperature and filters, filter
Cake is washed with water three times, obtains white solid 68.7g, yield 94.6%；
2) it takes 4- (methylhydroxy phosphono) -2- carbonyl-butyric acid 54.0g (0.3mol) in autoclave, is added thereto
Methanol 300ml is passed through ammonia under normal pressure to 0.5Mpa, and controlling reaction system pH is 12.5, and alpha-carbonyl acid is then added thereto
The Pt/C of analog derivative (IV) 20% is passed through hydrogen to 1Mpa, is warming up to 100 DEG C of back flow reaction 5h, has solid precipitation in system,
Filtering refilters after dissolving resulting filter cake with 50ml water, obtains clear filtrate, and 500ml methanol is added thereto, stirs
It mixes overnight, obtains white phosphine oxamate crystal 53.8g, yield 91.3%, HPLC purity is greater than 99%, and largest single impurity is less than 0.1%.
Embodiment 4
A kind of synthetic method of phosphine oxamate, includes the following steps：
The 2- carbonyl taken -3-butenoic acid ethyl ester 51.2g (0.4mol), acid binding agent pyridine 47.4g (0.6mol) are added to
In 50ml ethanol solution, under the conditions of 10 DEG C, methyl dichloro phosphorus 47.5g (0.41mol) slowly is added dropwise thereto, it is complete that 1h is added dropwise
At, after low temperature stirs 1h, 1M sodium hydrate aqueous solution 100ml is added thereto, is warming up to reflux 5h, is down to room temperature and filters, filter
Cake is washed with water three times, obtains white solid 67.7g, yield 94.2%；
2) it takes 4- (methylhydroxy phosphono) -2- carbonyl-butyric acid 54.0g (0.3mol) in autoclave, is added thereto
Methanol 300ml is passed through ammonia under normal pressure to 0.5Mpa, and controlling reaction system pH is 12.5, and alpha-carbonyl acid is then added thereto
The Pt/C of analog derivative (IV) 20% is passed through hydrogen to 1Mpa, is warming up to 100 DEG C of back flow reaction 5h, has solid precipitation in system,
Filtering refilters after dissolving resulting filter cake with 50ml water, obtains clear filtrate, and 500ml methanol is added thereto, stirs
It mixes overnight, obtains white phosphine oxamate crystal 55.3g, yield 94.3%, HPLC purity is greater than 99%, and largest single impurity is less than 0.1%.
Claims (5)
1. a kind of synthetic method of phosphine oxamate, which is characterized in that include the following steps：
(1) 2- of acid binding agent and formula III carbonyl -3-butenoic acid ester type compound is added in organic solvent, at -20~20 DEG C
Under the conditions of the dichloromethylphosphine of Formula II is slowly added dropwise, stir 0.5-2h, carry out Michael addition reaction, after reaction again plus
Enter basic hydrolysis, is warming up to reflux 4-6h, is cooled to room temperature, washing filtering, the alpha-carbonyl acid derivative of production IV, reaction equation
It is as follows：
(2) alpha-carbonyl acid derivative (IV) obtained in step (1) is taken organic solvent to be added thereto, often in autoclave
Pressure is passed through ammonia, carries out ammonification, controls reaction system pH, adds catalyst, be passed through hydrogen, be warming up to back flow reaction 4-
6h has solid precipitation in system, filters, the phosphine oxamate of production I, and reaction equation is as follows：
,
R1 described in step (1) is the alkyl for having 1-4 carbon atom；Organic solvent described in step (1), step (2) is methanol
Or ethyl alcohol；Acid binding agent described in step (1) is triethylamine, diethylamine, pyridine or ammonia.
2. the synthetic method of phosphine oxamate according to claim 1, which is characterized in that in step (1), the methyl dichloro
Change phosphorus and 2- carbonyl -3-butenoic acid ester type compound molar ratio is 1：1-1.5.
3. the synthetic method of phosphine oxamate according to claim 2, which is characterized in that reaction system pH described in step (2)
It is 12 ± 0.5, temperature is 0-20 DEG C.
4. the synthetic method of phosphine oxamate according to claim 3, which is characterized in that catalyst described in step (2) is
Pt/C, Pt/C additive amount are the 1~20% of alpha-carbonyl acid derivative (IV) quality, and temperature is 40-100 DEG C.
5. the synthetic method of phosphine oxamate according to claim 4, which is characterized in that further including will be resulting by step (2)
Filter cake is dissolved with water, is refiltered, and clear filtrate is obtained, and methanol is added thereto, and methanol, water consumption volume ratio are 1：5~
20, it is stirred overnight.
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