The preparation method of 2- hydroxymethylacrylate methyl esterTechnical field
The present invention relates to a kind of preparation method of 2- hydroxymethylacrylate methyl ester.
Background technology
2- hydroxymethylacrylate methyl ester is a kind of important medicine intermediate, can be used for new anti-hepatitis B medicament Telbivudine, 2-The structure of hydroxymethylacrylate methyl ester is as follows:
The structure of 2- hydroxymethylacrylate methyl ester is as follows:
The preparation method of phenylalaninol is a lot.Wherein main preparation method has following two:
Method one (organic letters 2006, vol.83359-3362):.
The method raw material is easy to get, but reaction is very slow, and side reaction is a lot, is not suitable for industrialized production.
Method 2 (organic synthesis)
The method simple process, but " three wastes " amount is big, and product purity is low, and impurity is more.
Content of the invention
It is an object of the invention to provide a kind of raw material is easy to get, production cost is relatively low, is suitable for the 2- hydroxyl of industrialized productionThe preparation method of methyl methacrylate.
The technical solution of the present invention is:
A kind of preparation method of 2- hydroxymethylacrylate methyl ester, is characterized in that: comprise the following steps:
(1) triphenyl phosphorus, catalysts and solvents mixing, 2- methyl bromoacetate are added drop-wise in mixed liquor, temperature reaction；
(2) after reaction terminates, stand split-phase, divide and go toluene phase；
(3) Deca sodium hydrate aqueous solution, crystallisation by cooling；
(4) sucking filtration, rinses filter cake with normal heptane, prepared methoxycarbonylmethylene triphenylphosphonium chloride, machine wittig reagent；
(5) wittig reagent is added to the water, adds formalin, Deca wet chemical reacts；
(6) it is filtered to remove triphenyl phosphorus；
(7) filtrate adds solvent extraction；
(8) organic faciess concentrate, and remove vacuum distillation after solvent, obtain 2- hydroxymethylacrylate methyl ester.
The molar ratio of 2- methyl bromoacetate and triphenyl phosphorus is 1:0.9～1:1.1.
2- methyl bromoacetate and molecular proportion of catalyst are 1:0.1～1:0.5.
2- methyl bromoacetate and molecular proportion of catalyst are 1:1.9～1:2.5.
Catalyst is sodium iodide or potassium iodide.
The concentration of formalin is 20-30%.
Reaction dissolvent is toluene, dimethylbenzene, dichloromethane or chloroform.
Raw material of the present invention is easy to get, and production cost is relatively low, is suitable for industrialized production；Product yield is high.
With reference to embodiment, the invention will be further described.
Specific embodiment
Embodiment 1:
First, the preparation of methoxycarbonylmethylene tri-phenyl-phosphorus bromide:
Add 88g (0.29mol) triphenylphosphine in there-necked flask, add 200ml toluene molten clear, then by 4.8g(0.029mol) ki is dissolved in 200ml water and adds in toluene, Deca 44.4g (0.29mol) 2- methyl bromoacetate.Nitrogen is protectedUnder be warming up to 65～75 DEG C, be incubated 20h.After insulation terminates, it is cooled to 50～60 DEG C, add 350ml water, split-phase.Aqueous phase is protectedTemperature, at 40 DEG C, is slowly added dropwise 268.4 gram of 10% sodium hydroxide solution, drips and is incubated 30min after finishing, sucking filtration, and filter cake is with 40ml positive heptanAlkane rinses, and 50 DEG C of decompression dryings obtain 119.2 grams of yellow solid, yield 90%.
2nd, the preparation of 2- hydroxyethyl methacrylate:
119.2 grams of methoxycarbonylmethylene tri-phenyl-phosphorus bromides, 300ml water and 58 gram of 30% formalin is added in there-necked flaskSolution, slowly 266.8 grams of Deca 30% wet chemical at controlling 10-15 DEG C, drips and is incubated 6 hours at finishing 15-20 DEG C, filterRemove insoluble matter (triphenyl phosphorus).Filtrate adds dichloromethane 500ml extraction, and organic faciess concentrate, and controls 70-90 after removing solventDEG C, vacuum distillation under vacuum 0.098mpa, obtain 25.7 grams of 2- hydroxymethylacrylate methyl ester (yield 85%).
Embodiment 2:
A kind of preparation method of 2- hydroxymethylacrylate methyl ester, comprises the following steps:
(1) triphenyl phosphorus, catalysts and solvents mixing, 2- methyl bromoacetate are added drop-wise in mixed liquor, temperature reaction；
(2) after reaction terminates, stand split-phase, divide and go toluene phase；
(3) Deca sodium hydrate aqueous solution, crystallisation by cooling；
(4) sucking filtration, rinses filter cake with normal heptane, prepared methoxycarbonylmethylene triphenylphosphonium chloride, machine wittig reagent；
(5) wittig reagent is added to the water, adds formalin, Deca wet chemical reacts；
(6) it is filtered to remove triphenyl phosphorus；
(7) filtrate adds solvent extraction；
(8) organic faciess concentrate, and remove vacuum distillation after solvent, obtain 2- hydroxymethylacrylate methyl ester.
The molar ratio of 2- methyl bromoacetate and triphenyl phosphorus is 1:0.9～1:1.1 (example 1:0.9,1:1,1:1.1).
2- methyl bromoacetate and molecular proportion of catalyst are 1:0.1～1:0.5 (example 1:0.1,1:0.3,1:0.5)；Or2- methyl bromoacetate and molecular proportion of catalyst are 1:1.9～1:2.5 (example 1:1.9,1:2.3,1:2.5).
Catalyst is sodium iodide or potassium iodide.
The concentration of formalin is 20-30% (example 20%, 25%, 30%).
Reaction dissolvent is toluene, dimethylbenzene, dichloromethane or chloroform.