CN109369711A - A kind of new synthetic method of L- phosphine oxamate key intermediate - Google Patents
A kind of new synthetic method of L- phosphine oxamate key intermediate Download PDFInfo
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- CN109369711A CN109369711A CN201811258596.XA CN201811258596A CN109369711A CN 109369711 A CN109369711 A CN 109369711A CN 201811258596 A CN201811258596 A CN 201811258596A CN 109369711 A CN109369711 A CN 109369711A
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- 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 System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids R2P(=O)(OH); Thiophosphinic acids, i.e. R2P(=X)(XH) (X = S, Se)
- C07F9/301—Acyclic saturated acids which can have further substituents on alkyl
Abstract
The present invention provides a kind of new synthetic method of L- phosphine oxamate key intermediate, and steps are as follows: the compound of Formula II structure being mixed with the compound of formula III structure, distills, obtains the compound of formula IV structure；The compound of formula IV structure is mixed with organic acid, distills, obtains the compound of Formula V structure；The compound of Formula V structure, glycolylurea are mixed with weak base, the first acid solution is added after reaction and adjusts pH value, is then filtered, washed, dries, obtain the compound of Formula IV structure；Strong base solution is added into the compound of Formula IV structure; the compound of Formula VII structure is obtained after reaction: the second acid solution being added into the compound of Formula VII structure and adjusts pH value; then it is evaporated water and obtains solids; using third solvent dissolved solid object, filtering, cooling, the 4th solvent of addition; it filters again; washing, drying are to get the compound for arriving Formulas I structure, i.e. key intermediate 4- (hydroxymethyl phosphono)-ALPHA-ketobutyric acid of L- phosphine oxamate.At low cost, high income of the invention.
Description
Technical field
It is crucial intermediate that the present invention relates to the synthesis technical fields of herbicide organic intermediate more particularly to a kind of L- phosphine oxamate
The new synthetic method of body.
Background technique
Phosphine oxamate (glufosinate-ammonium) is a kind of wide spectrum, low toxicity, nonselective herbicide, by Hoechest
Company is in the development and production eighties in last century.Phosphine oxamate is world's second largest genetically modified crops herbicide-tolerant, application prospect ten
Divide wide.There are two types of enantiomters for glufosinate-ammonium tool, but only L- configuration has activity of weeding, 4- (hydroxymethyl phosphono)-
ALPHA-ketobutyric acid is the key intermediate of chemical method synthesis L- configuration glufosinate-ammonium.In recent years, chemical method and bioanalysis synthesis L- grass
The method of amine phosphine developed in succession, but being required to using key intermediate 4- (hydroxymethyl phosphono)-without exception
ALPHA-ketobutyric acid.
Patent US06936444 discloses Process for the Preparation of L-
Phosphinothricine by Enzymatic Transamination with Aspartate is (logical using aspartate
Cross enzyme and turn the method that amination prepares L- phosphine ester), the preparation process of this method are as follows: in bioanalysis, 4- (hydroxymethyl phosphono)-
ALPHA-ketobutyric acid converts amino for carbonyl using transaminase effect and selectivity obtains L- phosphine oxamate；Hoechest company exists
1991 (J.Org.Chem, Vol.56, No.5 1991) report the change of 4- (hydroxymethyl phosphono)-ALPHA-ketobutyric acid at first
It learns synthetic method: Michael's addition occurs under the action of sodium ethoxide using methyl phosphonous acid mono ethyl ester and ethyl acrylate and is first made
3- (ethoxyl methyl phosphono)-ethyl propionate, then in subzero 50 degree and diethy-aceto oxalate generation gram under sodium ethoxide effect
The gloomy ester condensation of Lay, then with after hydrochloric acid hydrolysis decarboxylation be made 4- (hydroxymethyl phosphono)-ALPHA-ketobutyric acid.Anhui state star bioid
It learns Co., Ltd and discloses a kind of phosphine oxamate intermediate 4- (hydroxymethyl phosphoryl) -2- carbonyl in patent CN106008596
The preparation method of butyric acid, Jiangsu Qizhou Green Chemical Co., Ltd disclose a kind of careless ammonium in patent CN103665032
The preparation method of phosphine, both methods are using ring phosphonic acid anhydrides and diethy-aceto oxalate or Cymag preparation 4- (hydroxymethyl phosphine
Acyl group)-ALPHA-ketobutyric acid.
In existing preparation method, Hoechest method needs deep cooling to subzero 50 DEG C, and needs using expensive second
Sodium alkoxide, overall yield of reaction are low；The preparation of ring phosphonic acid anhydrides used in ring phosphonic acid anhydrides method is not easy, at high cost, and purification difficult, is easy to lead
It causes its acidity value higher, causes sodium alkoxide to cause reaction system complicated by additional consumption in Claisen condensation, total recovery is low, and makes
It will cause huge security risk when being reacted with the higher cycli phosphate acid anhydride of acidity value with Cymag, and Cymag sheet is as severe toxicity,
Should avoid as far as possible using.
Summary of the invention
In view of this, the present invention provides a kind of new synthetic method of L- phosphine oxamate key intermediate, this method operation letter
Just, at low cost, process environments are friendly, party's legal system is utilized especially suitable for industrialized production without particular/special requirement to production equipment
The crystallized precipitation of product obtained, HPLC purity is up to 98% or more.
The present invention provides a kind of new synthetic method of L- phosphine oxamate key intermediate, comprising the following steps:
S101 mixes the compound of Formula II structure and the compound of formula III structure under the first solvent or condition of no solvent
It closes, is distilled after reaction, obtain the compound of formula IV structure:
The compound of formula IV structure is mixed with organic acid, is distilled after reaction, obtained under conditions of the second solvent by S102
To the compound of Formula V structure:
The compound of Formula V structure, glycolylurea are mixed with weak base, are added after reaction under conditions of protonic solvent by S103
First acid solution adjusts pH value, is then filtered, washed, dries, obtains the compound of Formula IV structure:
Strong base solution is added into the compound of Formula IV structure, the compound of Formula VII structure is obtained after reaction by S104:
The second acid solution is added into the compound of Formula VII structure and adjusts pH value, is then evaporated water and obtains solid by S105
Object, using third solvent dissolved solid object, filtering, cooling are added the 4th solvent, filter again, wash, dry to get Formulas I is arrived
The compound of structure:
Formula II, formula IV, Formula V, in Formula IV, R1For C1-C4Alkyl；In formula III, X is chlorine, bromine or iodine.
Further, in step S101, the compound of the Formula II structure mixed with the compound of formula III structure after
5-12h is reacted at 80-130 DEG C.
Further, in step S101, the molar ratio of the compound and the compound of formula III structure of the Formula II structure is
1:1-1.5, first solvent select any in acetonitrile, Isosorbide-5-Nitrae-dioxane, 1,2- dichloropropane, toluene or dimethylbenzene
Kind.
Further, in step S102, the compound of the formula IV structure reacts at 30-90 DEG C with after organic acid mixing
2-12h, the compound of the formula IV structure and the molar ratio of organic acid are 1:0.1-0.5.
Further, in step S102, the second solvent selection methylene chloride, toluene, acetonitrile, Isosorbide-5-Nitrae-dioxane or
Any one of tetrahydrofuran, the organic acid are selected as appointing in trifluoromethanesulfonic acid, oxalic acid, p-methyl benzenesulfonic acid or methane sulfonic acid
It is a kind of.
Further, in step S103, compound, the glycolylurea of the Formula V structure mixed with weak base after at 50-100 DEG C
8-12h is reacted, the molar ratio of the compound of the Formula V structure, glycolylurea and weak base is 1:1:0.8-1.
Further, in step S103, any one of the protonic solvent selection water, ethyl alcohol, methanol or isopropanol,
Any one of the weak base selection sodium bicarbonate, saleratus, ethanol amine or triethylamine, first acid solution is hydrochloric acid.
Further, anti-at 50-100 DEG C after strong base solution is added into the compound of Formula IV structure in step S104
1-12h is answered, the compound of the Formula IV structure and the molar ratio of strong base solution are 1:2-3.
Further, in step S104, the strong base solution selects sodium hydroxide solution.
Further, in step S105, any, third solvent of the second acid solution selection hydrochloric acid or sulfuric acid
Select acetone, the 4th solvent selection methyl iso-butyl ketone (MIBK).
Technical solution provided by the invention has the benefit that L- phosphine oxamate key intermediate provided by the invention
New synthetic method first passes through Arbuzov rearrangement reaction production IV with the compound of Formula II structure and the compound of formula III structure
The compound of structure, then solve contracting to it with organic acid and obtain the compound of Formula V structure, the compound and glycolylurea ring of Formula V structure exist
Condensation reaction is carried out under catalyst action and obtains the compound of Formula IV structure, and the compound of Formula IV structure obtains formula by basic hydrolysis
The compound of VII structure finally obtains the compound of Formulas I structure, i.e. 4- (hydroxyl to crystallization after the compound tune acid of Formula VII structure
Ylmethyl phosphono)-ALPHA-ketobutyric acid；Compared to existing synthetic route, synthetic route provided by the invention is popular response,
Raw material is easy to get, at low cost, and reaction condition is mild, high income and environmental-friendly, has very big industrial prospect, utilizes the present invention
The crystallized precipitation of (hydroxymethyl the phosphono)-ALPHA-ketobutyric acid of 4- made from the method for offer, HPLC purity is up to 98% or more.
Detailed description of the invention
Fig. 1 is a kind of flow diagram of the new synthetic method of the L- phosphine oxamate key intermediate of the embodiment of the present invention 2.
Specific embodiment
To make the object, technical solutions and advantages of the present invention clearer, below in conjunction with attached drawing to embodiment party of the present invention
Formula is further described.
The embodiment provides a kind of new synthetic methods of L- phosphine oxamate key intermediate, comprising the following steps:
Step S101, under the first solvent or condition of no solvent, by the chemical combination of the compound of Formula II structure and formula III structure
Object mixing, reacts 5-12h at 80-130 DEG C, and vacuum distillation removal low-boiling-point substance, obtains the compound of formula IV structure after reaction；
The structural formula of the compound of Formula II structure are as follows:
The structural formula of the compound of formula III structure are as follows:
The structural formula of the compound of formula IV structure are as follows:
In step S101, the molar ratio of the compound of the compound and formula III structure of Formula II structure is 1:1-1.5, first
Solvent selects any one of acetonitrile, 1,4- dioxane, 1,2- dichloropropane, toluene or dimethylbenzene.
Step S102 mixes the compound of formula IV structure with organic acid, under conditions of the second solvent at 30-90 DEG C
Lower reaction 2-12h, is evaporated under reduced pressure after reaction, obtains the compound of Formula V structure；
The structural formula of the compound of Formula V structure are as follows:
In step S102, the compound of formula IV structure and the molar ratio of organic acid are 1:0.1-0.5, the second solvent selection two
Chloromethanes, toluene, acetonitrile, Isosorbide-5-Nitrae-any one of dioxane or tetrahydrofuran, organic acid are selected as trifluoromethanesulfonic acid, grass
Any one of acid, p-methyl benzenesulfonic acid or methane sulfonic acid.
Step S103 mixes the compound of Formula V structure and glycolylurea (hydantoins, No. CAS: 461-72-3), then plus
Enter weak base, add protonic solvent, 8-12h is reacted at 50-100 DEG C, be added after reaction the first acid solution adjust pH value to
4, it is then filtered, washed, dries, obtain the compound of Formula IV structure；
The structural formula of the compound of Formula IV structure are as follows:
In step S103, the molar ratio of the compound of Formula V structure, glycolylurea and weak base is 1:1:0.8-1, protonic solvent choosing
Any one of water, ethyl alcohol, methanol or isopropanol are selected, weak base selects in sodium bicarbonate, saleratus, ethanol amine or triethylamine
Any, the first acid solution is hydrochloric acid.
Strong base solution is added into the compound of Formula IV structure in step S104, and 1-12h is reacted at 50-100 DEG C, reaction
The compound of Formula VII structure is obtained afterwards；
The structural formula of the compound of Formula VII structure are as follows:
In step S104, the compound of Formula IV structure and the molar ratio of strong base solution are 1:2-3, strong base solution selection 20%
Sodium hydroxide solution.
The second acid solution is added into the aqueous solution of the compound of Formula VII structure and adjusts pH value to 1-2, so by step S105
It is evaporated water afterwards and obtains the solids in clear yellow viscous object shape, using third solvent dissolved solid object, filtering, obtained filtrate is cooling
It to 0 DEG C or so, is slowly stirred, the 4th solvent is then slowly added dropwise until reaction system starts to become cloudy, crystallization at this temperature
It is filtered again after 5-12h, the filter cake being obtained by filtration again is washed using the 4th solvent, be dried in vacuo to get the change of Formulas I structure is arrived
Close object, i.e. key intermediate 4- (hydroxymethyl phosphono)-ALPHA-ketobutyric acid of L- phosphine oxamate；
The structural formula of the compound of Formulas I structure are as follows:
In step S105, the second acid solution selects any, third solvent selection acetone of hydrochloric acid or sulfuric acid, the 4th solvent
Select methyl iso-butyl ketone (MIBK).
Formula II, formula IV, Formula V, in Formula IV, R1For C1-C4Alkyl, two R in Formula II1Can be identical, it can also not
Together；In formula III, X is chlorine, bromine or iodine.
The synthetic route of above-mentioned L- phosphine oxamate key intermediate are as follows:
It is detailed to a kind of new synthetic method progress of L- phosphine oxamate key intermediate provided by the invention below with reference to embodiment
It describes in detail bright.
Embodiment 1:
Methyl dimethyl phosphite 108g (1mol), bromoacetaldehyde condensed ethandiol are added in the four-hole boiling flask of 500ml
167g (1mol) is heated under nitrogen protection, and back flow reaction 5h (GC detects reaction end), is cooled to room temperature at 120 DEG C, will be anti-
It answers liquid to be evaporated under reduced pressure, 120 DEG C of fractions is collected under 10mmHg, obtain 2- (o- methyl methylphosphine acyl group) ethylidene ether 164g, produce
Rate 91.1%；
2- (o- methyl methylphosphine acyl group) ethylidene ether 36g (0.2mol), trifluoro is added in the three-necked flask of 250ml
Methanesulfonic acid 3g (0.02mol), acetonitrile 100ml react 5h (GC detects reaction end) at 30 DEG C, reaction solution are evaporated under reduced pressure,
110 DEG C of fractions are collected under 15mmHg, obtain 2- (o- methyl methylphosphine acyl group) acetaldehyde 26g in colourless liquid, yield 95.6%, 2-
The analysis result of (o- methyl methylphosphine acyl group) acetaldehyde are as follows: 1HNMR (400MHz, CDCl3, δ ppm): 1.28 (t, J=7.2Hz,
3H), 1.53 (d, J=14.5Hz, 3H), 3.12 (d, J=17.6Hz, 2H), 4.08 (t, J=7.4Hz, 2H), 9.70 (s, 1H)
,31PNMR(400MHz,CDCl3,δppm):45.18；
Glycolylurea 15g (0.15mol) and saleratus 12g (0.12mol) are added in the three-necked flask of 250ml, adds
100ml water, oil bath are slowly warming up to 70 DEG C, while 2- (o- methyl methylphosphine acyl group) acetaldehyde 20.4g being at the uniform velocity added dropwise in 1h
(0.15mol), solid is gradually dissolved to clarification during dropwise addition, is stirred at reflux, and keeps 90 DEG C of reaction 8h, reaction solution is in yellowish
Color is cooled to room temperature after stopping reaction, has a small amount of solid to be precipitated, and adjusts PH to 4 with 6N hydrochloric acid, a large amount of solids are precipitated, filter, water
It washes, it is dry, obtain 5- (o- methyl methylphosphine acyl group) propylene glycolylurea 30g of white, yield 91.7%；
5- (o- methyl methylphosphine acyl group) propylene glycolylurea 22g (0.1mol) and 20% are added in the three-necked flask of 100ml
Sodium hydroxide solution 50ml is stirred at reflux 7h at 65 DEG C, obtains 4- (hydroxymethyl phosphono)-ALPHA-ketobutyric acid double sodium salt water
Solution；
Concentrated hydrochloric acid is added in 4- (hydroxymethyl phosphono)-ALPHA-ketobutyric acid double sodium salt aqueous solution and adjusts pH value to 1.5,
Water is evaporated to obtain yellow, viscous substance, a small amount of acetone solution is added, filters out inorganic salts, obtained acetone soln is at 0 DEG C
Left and right is slowly stirred, and is slow added into methyl iso-butyl ketone (MIBK) until system becomes cloudy, is filtered after persistently stirring 8h, utilize first
Base isobutyl ketone washs the filter cake being obtained by filtration, and vacuum drying obtains 4- (hydroxymethyl phosphono) -2- carbonyl of white powder
Base butyric acid 13.3g, yield 73.9%.
Embodiment 2:
Fig. 1 is the flow diagram that the embodiment of the present invention 2 prepares 4- (hydroxymethyl phosphono)-ALPHA-ketobutyric acid.
Diethyl methyl-phosphonite 136g (1mol), bromoacetaldehyde condensed ethandiol 167g are added in the four-hole boiling flask of 1L
(1mol) and toluene 400ml is heated under nitrogen protection, and back flow reaction 5h (GC detects reaction end), is cooled to room at 110 DEG C
Reaction solution is evaporated under reduced pressure by temperature, and 120 DEG C of fractions are collected under 10mmHg, obtain 2- (o- ethyl methylphosphine acyl group) ethylidene ether
182g, yield 93.8%；
2- (o- ethyl methylphosphine acyl group) ethylidene ether 38.8g (0.2mol), right is added in the three-necked flask of 250ml
Toluenesulfonic acid 6.88g (0.04mol), toluene 100ml react 6h (GC detects reaction end) at 50 DEG C, reaction solution are depressurized
It distills, 108 DEG C of fractions is collected under 12mmHg, obtain 2- (o- ethyl methylphosphine acyl group) acetaldehyde 29g in colourless liquid, yield
96.7%；
Glycolylurea 15g (0.15mol) and triethylamine 15.2g (0.15mol) are added in the three-necked flask of 250ml, adds
100ml ethyl alcohol, oil bath are slowly warming up to 60 DEG C, while 2- (o- ethyl methylphosphine acyl group) acetaldehyde 22.5g being at the uniform velocity added dropwise in 1h
(0.15mol), solid is gradually dissolved to clarification during dropwise addition, is stirred at reflux, and keeps 75 DEG C of reaction 10h, reaction solution is in yellowish
Solvent is evaporated off after reaction for color, is cooled to room temperature, and with 6N hydrochloric acid regulation system PH to 4, a large amount of solids are precipitated, and filters, water
It washes, it is dry, obtain white 5- (o- ethyl methylphosphine acyl group) propylene glycolylurea 32g, yield 92%；
5- (o- ethyl methylphosphine acyl group) propylene glycolylurea 23.2g (0.1mol) and 20% is added in the three-necked flask of 100ml
Sodium hydroxide solution 50ml, be stirred at reflux 6h at 85 DEG C, obtain 4- (hydroxymethyl phosphono)-ALPHA-ketobutyric acid double sodium salt
Aqueous solution；
Concentrated hydrochloric acid is added in 4- (hydroxymethyl phosphono)-ALPHA-ketobutyric acid double sodium salt aqueous solution and adjusts pH value to 1-2,
Water is evaporated to obtain yellow, viscous substance, a small amount of acetone solution is added, filters out inorganic salts, obtained acetone soln is at 0 DEG C
Left and right is slowly stirred, and is slow added into methyl iso-butyl ketone (MIBK) until system becomes cloudy, is filtered after persistently stirring 8h, utilize first
Base isobutyl ketone washs the filter cake being obtained by filtration, and vacuum drying obtains 4- (hydroxymethyl phosphono) -2- carbonyl of white powder
Base butyric acid 12g, yield 66.7%.
The analysis detection result of 4- made from embodiment 2 (hydroxymethyl phosphono)-ALPHA-ketobutyric acid is as follows:
1HNMR(400MHz,DMSO-d6) keto-acid: δ 10.93 (s, 2H, OH), 3.00 (dt, J=10.5,7.6Hz, 2H,
PCH2CH2CO),1.86-1.76(m,2H,PCH2CH2), CO 1.31 (dd, J=22.7,14.0Hz, 3H, PCH3)；Enol form: δ
10.93(s,2H,OH),5.52(dt,1H,PCH2), CH=C 2.56 (dd, 2H, PCH2), CH=1.29 (d, 3H, PCH3)。
31PNMR(400MHz,DMSO-d6, δ ppm) and keto-acid: 46.81, enol form 44.82.HPLC purity 98.2%.
HPLC condition: chromatographic column Ultimate XB-C18,5 μm, 4.6X250mm；Column temperature: 30 DEG C；Detection wavelength:
205nm, 6 μ l of sample volume, target compound retention time: 10.0min.
Embodiment 3:
Methyl phosphonous acid di-n-propyl ester 164g (1mol) is added in the four-hole boiling flask of 500ml, chloroacetaldehyde condensed ethandiol
123g (1mol) is heated under nitrogen protection, and back flow reaction 9h (GC detects reaction end), is cooled to room temperature at 120 DEG C, will be anti-
It answers liquid to be evaporated under reduced pressure, 125 fractions is collected under 10mmHg, obtain 2- (o- n-propyl methylphosphine acyl group) ethylidene ether 176g, produce
Rate 84.6%；
In the three-necked flask of 250ml be added 2- (o- n-propyl methylphosphine acyl group) ethylidene ether 41.6g (0.2mol),
Oxalic acid 7.56g (0.06mol), tetrahydrofuran 100ml react 8h (GC detects reaction end) at 70 DEG C, reaction solution are depressurized
It distills, 120 DEG C of fractions is collected under 12mmHg, obtain 2- (o- n-propyl methylphosphine acyl group) acetaldehyde 28g in colourless liquid, yield
85.4%；
Addition glycolylurea 15g (0.15mol) and sodium bicarbonate 11.8g (0.14mol) in the three-necked flask of 250ml, then plus
Enter 100ml water, oil bath is slowly warming up to 65 DEG C, while 2- (o- n-propyl methylphosphine acyl group) acetaldehyde 24.8g being at the uniform velocity added dropwise in 1h
(0.15mol), solid is gradually dissolved to clarification during dropwise addition, is stirred at reflux, and keeps 85 DEG C of reaction 8.5h, reaction solution is in yellowish
Color is cooled to room temperature after stopping reaction, has a small amount of solid to be precipitated, and adjusts PH to 4 with 6N hydrochloric acid, a large amount of solids are precipitated, filter, water
It washes, it is dry, obtain 5- (o- propyl methylphosphine acyl group) propylene glycolylurea 35.6g of white, yield 95.7%；
5- (o- propyl methylphosphine acyl group) propylene glycolylurea 24.8g (0.1mol) and 20% is added in the three-necked flask of 100ml
Sodium hydroxide solution 50ml, be stirred at reflux 7h at 95 DEG C, obtain 4- (hydroxymethyl phosphono)-ALPHA-ketobutyric acid double sodium salt
Aqueous solution；
Concentrated hydrochloric acid is added in 4- (hydroxymethyl phosphono)-ALPHA-ketobutyric acid double sodium salt aqueous solution and adjusts pH value to 1-2,
Water is evaporated to obtain yellow, viscous substance, a small amount of acetone solution is added, filters out inorganic salts, obtained acetone soln is at 0 DEG C
Left and right is slowly stirred, and is slow added into methyl iso-butyl ketone (MIBK) until system becomes cloudy, is filtered after persistently stirring 9h, utilize first
Base isobutyl ketone washs the filter cake being obtained by filtration, and vacuum drying obtains 4- (hydroxymethyl phosphono) -2- carbonyl of white powder
Base butyric acid 12.7g, yield 70.5%.
Embodiment 4:
Methyl phosphonous acid di-n-butyl 192g (1mol), chloroacetaldehyde condensed ethandiol are added in the four-hole boiling flask of 500ml
123g (1mol), acetonitrile 400ml are heated under nitrogen protection, and back flow reaction 12h (GC detects reaction end), cooling at 80 DEG C
To room temperature, reaction solution is evaporated under reduced pressure, 130 DEG C of fractions are collected under 8mmHg, obtain 2- (o- normal-butyl methylphosphine acyl group) acetaldehyde contracting second
Glycol 175g, yield 78.8%；
In the three-necked flask of 250ml be added 2- (o- normal-butyl methylphosphine acyl group) ethylidene ether 44.4g (0.2mol),
Methane sulfonic acid 7.68g (0.08mol), Isosorbide-5-Nitrae-dioxane 100ml react 12h (GC detects reaction end) at 90 DEG C, will be anti-
It answers liquid to be evaporated under reduced pressure, 125 DEG C of fractions is collected under 10mmHg, obtain 2- (o- normal-butyl methylphosphine acyl group) acetaldehyde in colourless liquid
29g, yield 81.5%；
Glycolylurea 15g (0.15mol) and ethanol amine 7.9g (0.13mol) are added in the three-necked flask of 250ml, adds
100ml water, oil bath are slowly warming up to 90 DEG C, while 2- (o- normal-butyl methylphosphine acyl group) acetaldehyde 26.6g being at the uniform velocity added dropwise in 1h
(0.15mol), solid is gradually dissolved to clarification during dropwise addition, is stirred at reflux, and keeps 95 DEG C of reaction 6h, reaction solution is in yellowish
Color is cooled to room temperature after stopping reaction, has a small amount of solid to be precipitated, and adjusts PH to 4 with 6N hydrochloric acid, a large amount of solids are precipitated, filter, water
It washes, it is dry, obtain 5- (o- butyl methylphosphine acyl group) propylene glycolylurea 36.0g of white, yield 92.3%；
5- (o- butyl methylphosphine acyl group) propylene glycolylurea 26g (0.1mol) and 20% are added in the three-necked flask of 100ml
Sodium hydroxide solution 50ml is stirred at reflux 4h at 95 DEG C, obtains 4- (hydroxymethyl phosphono)-ALPHA-ketobutyric acid double sodium salt water
Solution；
Concentrated hydrochloric acid is added in 4- (hydroxymethyl phosphono)-ALPHA-ketobutyric acid double sodium salt aqueous solution and adjusts pH value to 1.8,
Water is evaporated to obtain yellow, viscous substance, a small amount of acetone solution is added, filters out inorganic salts, obtained acetone soln is at 0 DEG C
Left and right is slowly stirred, and is slow added into methyl iso-butyl ketone (MIBK) until system becomes cloudy, is filtered after persistently stirring 6h, utilize first
Base isobutyl ketone washs the filter cake being obtained by filtration, and vacuum drying obtains 4- (hydroxymethyl phosphono) -2- carbonyl of white powder
Base butyric acid 14.1g, yield 78.4%.
The synthesis of L- phosphine oxamate key intermediate 4- (hydroxymethyl phosphono)-ALPHA-ketobutyric acid provided by the invention is newly square
Method passes through the change of Arbuzov rearrangement reaction production IV structure first with the compound of Formula II structure and the compound of formula III structure
Object is closed, then solves contracting to it with organic acid and obtains the compound of Formula V structure, the compound and glycolylurea ring of Formula V structure are made in catalyst
It is carried out condensation reaction with lower and is obtained the compound of Formula IV structure, the compound of Formula IV structure obtains Formula VII structure by basic hydrolysis
Compound, the compound of Formulas I structure, i.e. 4- (hydroxymethyl phosphine finally are obtained to crystallization after the compound tune acid of Formula VII structure
Acyl group)-ALPHA-ketobutyric acid；Compared to existing synthetic route, synthetic route provided by the invention is popular response, and raw material is easy
, at low cost, reaction condition is mild, high income and environmental-friendly, has very big industrial prospect, and utilization is provided by the invention
The crystallized precipitation of (hydroxymethyl the phosphono)-ALPHA-ketobutyric acid of 4- made from method, HPLC purity is up to 98% or more.
In the absence of conflict, the feature in embodiment and embodiment herein-above set forth can be combined with each other.
The foregoing is merely presently preferred embodiments of the present invention, is not intended to limit the invention, it is all in spirit of the invention and
Within principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of new synthetic method of L- phosphine oxamate key intermediate, which comprises the following steps:
S101 mixes the compound of Formula II structure with the compound of formula III structure under the first solvent or condition of no solvent,
It is distilled after reaction, obtains the compound of formula IV structure:
The compound of formula IV structure is mixed with organic acid, is distilled after reaction, obtain Formula V under conditions of the second solvent by S102
The compound of structure:
The compound of Formula V structure, glycolylurea are mixed with weak base under conditions of protonic solvent, first are added after reaction by S103
Acid solution adjusts pH value, is then filtered, washed, dries, obtains the compound of Formula IV structure:
Strong base solution is added into the compound of Formula IV structure, the compound of Formula VII structure is obtained after reaction by S104:
The second acid solution is added into the compound of Formula VII structure and adjusts pH value, is then evaporated water and obtains solids by S105, benefit
With third solvent dissolved solid object, filtering, cooling are added the 4th solvent, filter again, wash, dry to get Formulas I structure is arrived
Compound:
Formula II, formula IV, Formula V, in Formula IV, R1For C1-C4Alkyl；In formula III, X is chlorine, bromine or iodine.
2. the new synthetic method of L- phosphine oxamate key intermediate as described in claim 1, which is characterized in that in step S101,
The compound of the Formula II structure reacts 5-12h at 80-130 DEG C with after the mixing of the compound of formula III structure.
3. the new synthetic method of L- phosphine oxamate key intermediate as described in claim 1, which is characterized in that in step S101,
The molar ratio of the compound of the compound and formula III structure of the Formula II structure is 1:1-1.5, and first solvent selects second
Any one of nitrile, 1,4- dioxane, 1,2- dichloropropane, toluene or dimethylbenzene.
4. the new synthetic method of L- phosphine oxamate key intermediate as described in claim 1, which is characterized in that in step S102,
React 2-12h at 30-90 DEG C after the compound of the formula IV structure and organic acid mixing, the compound of the formula IV structure with
The molar ratio of organic acid is 1:0.1-0.5.
5. the new synthetic method of L- phosphine oxamate key intermediate as described in claim 1, which is characterized in that in step S102,
The second solvent selection methylene chloride, toluene, acetonitrile, Isosorbide-5-Nitrae-any one of dioxane or tetrahydrofuran, it is described organic
Acid is selected as any one of trifluoromethanesulfonic acid, oxalic acid, p-methyl benzenesulfonic acid or methane sulfonic acid.
6. the new synthetic method of L- phosphine oxamate key intermediate as described in claim 1, which is characterized in that in step S103,
Compound, the glycolylurea of the Formula V structure react 8-12h, the chemical combination of the Formula V structure after mixing with weak base at 50-100 DEG C
The molar ratio of object, glycolylurea and weak base is 1:1:0.8-1.
7. the new synthetic method of L- phosphine oxamate key intermediate as described in claim 1, which is characterized in that in step S103,
Any one of the protonic solvent selection water, ethyl alcohol, methanol or isopropanol, the weak base selects sodium bicarbonate, bicarbonate
Any one of potassium, ethanol amine or triethylamine, first acid solution are hydrochloric acid.
8. the new synthetic method of L- phosphine oxamate key intermediate as described in claim 1, which is characterized in that in step S104,
After strong base solution is added into the compound of Formula IV structure, 1-12h, the compound of the Formula IV structure are reacted at 50-100 DEG C
Molar ratio with strong base solution is 1:2-3.
9. the new synthetic method of L- phosphine oxamate key intermediate as described in claim 1, which is characterized in that in step S104,
The strong base solution selects sodium hydroxide solution.
10. the new synthetic method of L- phosphine oxamate key intermediate as described in claim 1, which is characterized in that in step S105,
Any, third solvent selection acetone of the second acid solution selection hydrochloric acid or sulfuric acid, the 4th solvent selection first
Base isobutyl ketone.
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| US6936444B1 (en) * | 1999-04-30 | 2005-08-30 | Aventis Cropscience Gmbh | Process for the preparation of L-phosphinothricine by enzymatic transamination with aspartate |
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| CN107434812A (en) * | 2017-09-08 | 2017-12-05 | 南京工业大学 | One kind synthesis 2- amide groups -4-（O- alkyl methylphosphine acyl groups）The method of -2- butenoic acids and its ester |
| CN108250186A (en) * | 2018-02-07 | 2018-07-06 | 杭州科巢生物科技有限公司 | The synthetic method of Acalabrutinib and its intermediate |
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2018
- 2018-10-26 CN CN201811258596.XA patent/CN109369711A/en not_active Withdrawn
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US6936444B1 (en) * | 1999-04-30 | 2005-08-30 | Aventis Cropscience Gmbh | Process for the preparation of L-phosphinothricine by enzymatic transamination with aspartate |
| CN103665032A (en) * | 2013-12-09 | 2014-03-26 | 江苏七洲绿色化工股份有限公司 | Preparation method of glufosinate |
| CN106008596A (en) * | 2016-05-17 | 2016-10-12 | 安徽国星生物化学有限公司 | Preparation method of 4-[hydroxy(methyl)phosphoryl]-2-oxobutanoic acid as glufosinate intermediate |
| CN107434812A (en) * | 2017-09-08 | 2017-12-05 | 南京工业大学 | One kind synthesis 2- amide groups -4-（O- alkyl methylphosphine acyl groups）The method of -2- butenoic acids and its ester |
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