CN101838249B - A kind of method preparing high-purity guaiacol glycidyl ether - Google Patents
A kind of method preparing high-purity guaiacol glycidyl ether Download PDFInfo
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- CN101838249B CN101838249B CN201010144102.2A CN201010144102A CN101838249B CN 101838249 B CN101838249 B CN 101838249B CN 201010144102 A CN201010144102 A CN 201010144102A CN 101838249 B CN101838249 B CN 101838249B
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- glycidyl ether
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- guaiacol glycidyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/27—Condensation of epihalohydrins or halohydrins with compounds containing active hydrogen atoms
- C07D301/28—Condensation of epihalohydrins or halohydrins with compounds containing active hydrogen atoms by reaction with hydroxyl radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/24—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds
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Abstract
The invention discloses a kind of method preparing high-purity guaiacol glycidyl ether, i.e. methyl catechol and epoxy chloropropane condensation under the effect of alkali, reaction terminates rear underpressure distillation and obtains guaiacol glycidyl ether crude product.This crude product C1 ~ C4 lower alcohols solvent recrystallization is obtained purity (GC) higher than 99.5% guaiacol glycidyl ether.Present method yield is high, and quality is good, easy to operate, low for equipment requirements, is a kind of method preparing high-purity guaiacol glycidyl ether being applicable to very much suitability for industrialized production.
Description
(1) technical field
The present invention relates to the method that one prepares high purity 1-(2-methoxyphenoxy)-2,3-propylene oxide (being called guaiacol glycidyl ether in the present invention).
(2) background technology
Guaiacol glycidyl ether is widely used as the intermediate of ranolazine and moprolol, and its structural formula is as follows:
This product mainly by methyl catechol and epoxy chloropropane in the presence of base condensation form, reaction formula is as follows:
Two-step reaction is through in real reaction; The first open loop of epoxy chloropropane and methyl catechol condensation, and then under the effect of alkali, slough a hydrogenchloride formation oxirane ring.
Report in patent GB2216520, epoxy chloropropane and methyl catechol first use dchloromethane after completion of the reaction, then extract, and first distillation obtains crude product, and then fractionation obtains product under a high vacuum.Adopt the method, need to consume a large amount of methylene dichloride, very large to environmental influence, and in purification process, adopt vacuum fractionation under high temperature, harsh to equipment requirements.
Describe in WO2008047388, adopt toluene as solvent in reaction process, epoxy chloropropane and methyl catechol reaction, wash with water with methylbenzene extraction after completion of the reaction, then in 130 ~ 150 DEG C of (3bar) situations, distillation obtains product again.Relate to the large problem of quantity of solvent in this method equally, and due to product density larger than water, do solvent easily emulsification in the process extracted with toluene.Also do not mention purification process in this patent, the product purity obtained only has about 96%.
Except underpressure distillation under high temperature, other process for purification is not all mentioned at present in other document disclosed.And product is easily polymerized under high temperature, adopt in this way, the purity of product is difficult to improve, and yield is also lower.
(3) summary of the invention
The object of the present invention is to provide the preparation method that a kind of product purity is high, be conducive to industrialization, low cost guaiacol glycidyl ether.
In order to obtain highly purified product, have several key point in the building-up process of this product: (1) raw material needs to add alkali in reaction process, in order to control alkali in the product residual, the alkali selected well should be separated with product.(2) impurity formed in the raw material that after completion of the reaction, unreacted is complete and reaction process well should be separated with product.
In order to control the cost of product, first should choose cheap material, the input secondly on production unit should be well controlled as far as possible, and technique should handled easily, and the complete raw material of unreacted is wanted reclaim, and solvent is tried not use.
Comprehensive above two aspects, the alkali used in reaction selects inorganic base to have obvious advantage in this respect; Use inorganic base in reaction, use two phase reaction, effectively can control alkaloids in the product residual; Because the major impurity formed in two raw materials and reaction process is at room temperature all liquid, and product is at room temperature solid, therefore adopts the mode of crystallization to have extraordinary effect to the purity improving product; Directly adopt epoxy chloropropane as solvent in reaction, solvent can direct recovery after completion of the reaction, and environmental pollution is little, and cost is also low.
According to more than, the guaiacol glycidyl ether preparation method related in the present invention carries out as follows:
(1) methyl catechol is dissolved in excessive epoxy chloropropane.Then under the aqueous solution of mineral alkali and the effect of phase-transfer catalyst, carry out condensation reaction, after reaction terminates, branch vibration layer, reclaims excessive epoxy chloropropane by underpressure distillation.The cut continuing concentrated collection 148 ~ 153 DEG C/1.33KPa obtains guaiacol glycidyl ether crude product.
(2) the crude product organic solvent recrystallization that step (1) obtains is obtained highly purified guaiacol glycidyl ether.
In step (1), the amount of epoxy chloropropane can be chosen as 1 ~ 8 equivalent of methyl catechol, is preferably 2 ~ 5 equivalents.Mineral alkali can select sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide etc., preferred sodium hydroxide and potassium hydroxide.The concentration of aqueous solution of alkali can select 10% ~ 50%.Phase-transfer catalyst can select Tetrabutyl amonium bromide, benzyltriethylammoinium chloride, 4-butyl ammonium hydrogen sulfate, tetrabutylammonium chloride etc.Temperature of reaction is 20 DEG C ~ 80 DEG C, and wherein preferable temperature is 30 ~ 60 DEG C.Reaction times is 1 ~ 10 hour, and preferable range is 2 ~ 5 hours.
In step (2), organic solvent class can select alcohols, ester class and ethers, wherein preferred lower alcohols.More preferably C1 ~ C4 lower alcohols solvent such as methyl alcohol, ethanol, n-propyl alcohol, Virahol, butanols.The quantity of solvent of crystallization is 1 ~ 10ml/g (guaiacol glycidyl ether crude product), wherein preferred 2 ~ 5ml/g (guaiacol glycidyl ether crude product).Crystallization natural stirring and crystallizing also can add crystal seed induction crystallization, in order to crystallization control speed ensures the purity of product, preferably adds crystal seed induction crystallization.
Present method yield is high, and quality is good, easy to operate, low for equipment requirements, is a kind of method preparing high-purity guaiacol glycidyl ether being applicable to very much suitability for industrialized production.
(4) embodiment
Following implementations can contribute to understanding the present invention, but protection scope of the present invention is not limited thereto.
Embodiment 1: prepare guaiacol glycidyl ether crude product
Methyl catechol 44.4g drops in 250ml reaction flask, then adds epoxy chloropropane 99.8g, Tetrabutyl amonium bromide 1.16g, stirs.Drip the sodium hydroxide solution 64g of 25%, drip and finish, control temperature 50 ~ 55 DEG C reaction 2 hours.After completion of the reaction, wash with water once, then layering, the epoxy chloropropane that organic phase reclaim under reduced pressure is excessive.After recovery, heat up and continue distillation, the cut collecting 148 ~ 153 DEG C/1.33KPa obtains colourless transparent liquid 45.1g, yield 70%, purity: 98% (GC mensuration)
Embodiment 2: prepare high-purity guaiacol glycidyl ether
30g guaiacol glycidyl ether crude product adds in 90ml ethanol, is heated to 40 DEG C, is stirred to solution clearly molten.Filter, filtrate slow cooling to 20 DEG C, adds crystal seed, stirring and crystallizing 2 hours at maintaining the temperature at 18 ~ 20 DEG C, then temperature is slowly down to 0 ~ 5 DEG C and stirs 1 hour, filter.Filter cake 25 DEG C of vacuum-dryings obtain white solid 25.5g, yield 85%, purity: 99.8% (GC mensuration) in 12 hours.
Embodiment 3: prepare high-purity guaiacol glycidyl ether
30g guaiacol glycidyl ether crude product adds in 90ml methyl alcohol, is heated to 40 DEG C, is stirred to solution clearly molten.Filter, filtrate slow cooling to 14 DEG C, to add after crystal seed at 14 ~ 16 DEG C stirring and crystallizing 2 hours, then temperature is slowly down to 0 ~ 5 DEG C to stir 1 hour, filters, filter cake 25 DEG C of vacuum-dryings obtain white solid 24g in 12 hours, yield 80%, purity: 99.6% (GC mensuration).
Embodiment 4: prepare high-purity guaiacol glycidyl ether
30g guaiacol glycidyl ether crude product adds in 120ml Virahol, is heated to 50 DEG C, is stirred to solution clearly molten.Filter, filtrate slow cooling to 20 DEG C, to add after crystal seed at 15 ~ 20 DEG C stirring and crystallizing 2 hours, then temperature is slowly down to 0 ~ 5 DEG C to stir 1 hour, filters, filter cake 25 DEG C of vacuum-dryings obtain white solid 26.4g in 12 hours, yield 88%, purity: 99.5% (GC mensuration).
Embodiment 5: prepare high-purity guaiacol glycidyl ether
30g guaiacol glycidyl ether crude product adds in 120ml n-propyl alcohol, is heated to 50 DEG C, is stirred to solution clearly molten.Filter, filtrate slow cooling to 20 DEG C, to add after crystal seed at 15 ~ 20 DEG C stirring and crystallizing 2 hours, then temperature is slowly down to 0 ~ 5 DEG C to stir 1 hour, filters, filter cake 25 DEG C of vacuum-dryings obtain white solid 26.1g in 12 hours, yield 87%, purity: 99.7% (GC mensuration).
Claims (1)
1. prepare the method for guaiacol glycidyl ether for one kind, it is characterized in that described method is: methyl catechol and epoxy chloropropane condensation under the aqueous solution of mineral alkali and the effect of phase-transfer catalyst, reaction terminates rear underpressure distillation and obtains guaiacol glycidyl ether crude product, this crude product lower alcohols solvent recrystallization is obtained guaiacol glycidyl ether, described lower alcohol is methyl alcohol, ethanol, n-propyl alcohol, Virahol, butanols, and the quantity of solvent of crystallization is 1 ~ 10ml/g guaiacol glycidyl ether crude product; Described alkali is aqueous sodium hydroxide solution, potassium hydroxide aqueous solution, aqueous sodium carbonate; Described phase-transfer catalyst is Tetrabutyl amonium bromide, benzyltriethylammoinium chloride, 4-butyl ammonium hydrogen sulfate, tetrabutylammonium chloride.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
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| CN201010144102.2A CN101838249B (en) | 2010-03-19 | 2010-03-19 | A kind of method preparing high-purity guaiacol glycidyl ether |
| PCT/CN2010/073337 WO2011113228A1 (en) | 2010-03-19 | 2010-05-28 | A process for preparing guaiacol glycidyl |
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| CN201010144102.2A CN101838249B (en) | 2010-03-19 | 2010-03-19 | A kind of method preparing high-purity guaiacol glycidyl ether |
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| CN101838249B true CN101838249B (en) | 2015-08-19 |
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Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101838249B (en) * | 2010-03-19 | 2015-08-19 | 浙江华海药业股份有限公司 | A kind of method preparing high-purity guaiacol glycidyl ether |
| CN102558097B (en) * | 2011-12-27 | 2014-05-28 | 辅仁药业集团有限公司 | Improved method for synthesizing ranolazine |
| CN102964259A (en) * | 2012-12-11 | 2013-03-13 | 上海奥博生物医药技术有限公司 | Preparation method of related substance E of metoprolol |
| CN104262586B (en) * | 2014-10-22 | 2017-03-01 | 中国科学院上海有机化学研究所 | A kind of high-moduluss and high glass-transition temperature epoxy resin and its preparation and application |
| WO2016065576A1 (en) * | 2014-10-30 | 2016-05-06 | Tianjin Weijie Pharmaceutical Co., Ltd. | Process for preparation of high purity guaiacol glycidyl ether |
| CN106957426B (en) * | 2017-04-12 | 2019-01-25 | 浩力森化学科技（江苏）有限公司 | A kind of functional resin and preparation method thereof promoting cation-type water-thinned anticorrosion with coat covering power |
| CN111440131B (en) * | 2020-04-27 | 2021-12-28 | 江苏惠利生物科技有限公司 | Method for refining easy-to-decompose guaiacol glycidyl ether |
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| JPH07145101A (en) * | 1993-11-25 | 1995-06-06 | Natl Sci Council | New compound with guaiacol structure, its production, and adrenalin beta blocking drug containing it as effective component |
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| WO2010023687A2 (en) * | 2008-08-28 | 2010-03-04 | Shodhana Laboratories Limited | Preparation of ranolazine, its salts and intermediates thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101838249B (en) * | 2010-03-19 | 2015-08-19 | 浙江华海药业股份有限公司 | A kind of method preparing high-purity guaiacol glycidyl ether |
-
2010
- 2010-03-19 CN CN201010144102.2A patent/CN101838249B/en active Active
- 2010-05-28 WO PCT/CN2010/073337 patent/WO2011113228A1/en active Application Filing
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| DE3807522C1 (en) * | 1988-03-08 | 1989-03-30 | Boehringer Ingelheim Kg, 6507 Ingelheim, De | |
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| WO2008047388A2 (en) * | 2006-10-20 | 2008-04-24 | Ind-Swift Laboratories Limited | Improved process for the preparation of ranolazine |
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| WO2011113228A1 (en) | 2011-09-22 |
| CN101838249A (en) | 2010-09-22 |
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