CN104003850B - A kind of preparation method of 2-chloroethoxy-2-oxyethyl group di-alcohol - Google Patents
A kind of preparation method of 2-chloroethoxy-2-oxyethyl group di-alcohol Download PDFInfo
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- CN104003850B CN104003850B CN201410212574.5A CN201410212574A CN104003850B CN 104003850 B CN104003850 B CN 104003850B CN 201410212574 A CN201410212574 A CN 201410212574A CN 104003850 B CN104003850 B CN 104003850B
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- oxyethyl group
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/02—Preparation of ethers from oxiranes
- C07C41/03—Preparation of ethers from oxiranes by reaction of oxirane rings with hydroxy groups
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Abstract
The invention discloses a kind of preparation method of 2-chloroethoxy-2-oxyethyl group di-alcohol, with ethylene chlorhydrin and oxyethane for raw material, react under catalyzer existence condition, first 2-chloroethoxyethanol is obtained, after sloughing remaining solvent and reactant ethylene chlorhydrin, 2-chloroethoxyethanol continues to be obtained by reacting target product 2-chloroethoxy-2-oxyethyl group di-alcohol with the oxyethane again added.Reaction of the present invention is easy to operate, and system is gentle, and side reaction is few, product content and yield high, the pollutent that reaction produces is few.
Description
Technical field
The invention belongs to chemical field, particularly relate to a kind of medicine intermediate 2-chloroethoxy-2-oxyethyl group di-alcohol, specifically a kind of preparation method of 2-chloroethoxy-2-oxyethyl group di-alcohol.
Background technology
2-chloroethoxy-2-oxyethyl group di-alcohol, be called for short CEEE, outward appearance is colourless transparent liquid, and CAS registration number is [5197-62-6], and structural formula is:
2-chloroethoxy-2-oxyethyl group di-alcohol, as the intermediate of the medicines such as PranedipineTartrate and LJP-920, is a kind of important intermediate of medication chemistry.
Its synthetic method mainly contains following three kinds:
A: directly carry out etherification reaction by triethylene glycol and HCl and prepare 2-chloroethoxy-2-oxyethyl group di-alcohol, synthetic route is as follows:
The method raw material is easy to get, but side reaction is many, poor selectivity, and yield is low, and cost is higher, is therefore difficult to application and suitability for industrialized production.
B: reacted by glycol ether and HCl, first obtained 2-chloroethoxyethanol, then carry out second step reaction with oxyethane, preparation 2-chloroethoxy-2-oxyethyl group di-alcohol, synthetic route is as follows:
The method raw material is easy to get, but there is reaction preference difference, and side reaction is many, and yield is low, high in cost of production problem.
C: with Isosorbide-5-Nitrae-dioxane for 2-chloroethoxy-2-oxyethyl group di-alcohol prepared by raw material, synthetic route is as follows:
The method is in theoretical research stage at present, is not suitable for suitability for industrialized production.
The subject matter of above-mentioned various method is poor selectivity, and yield is low, and preparation difficulty, is unfavorable for suitability for industrialized production.
Summary of the invention
For the defect existed in above-mentioned prior art, technical problem to be solved by this invention is to provide a kind of preparation method of 2-chloroethoxy-2-oxyethyl group di-alcohol, and described this method will solve preparation method's poor selectivity of the prior art, yield is low, preparation is difficult, be unfavorable for the technical problem of suitability for industrialized production.
The preparation method of a kind of 2-chloroethoxy of the present invention-2-oxyethyl group di-alcohol, comprises the following steps:
1) take reactant ethylene chlorhydrin and first oxyethane, the mol ratio of ethylene chlorhydrin and first oxyethane is 7 ~ 9:1, and ethylene chlorhydrin and first oxyethane react under catalyzer existence condition, generates intermediate product 2-chloroethoxyethanol;
2) material reacting end in step 1) is sloughed excessive ethylene chlorhydrin under vacuum decompression condition;
3) by step 2) in slough ethylene chlorhydrin after material continue to react with second batch oxyethane under catalyzer existence condition, described 2-chloroethoxyethanol and the mol ratio of second batch oxyethane are 1:1.0 ~ 1.4;
4) material reacting end in step 3) is distilled under vacuum decompression condition, collect middle runnings, obtain 2-chloroethoxy-2-oxyethyl group di-alcohol crude product;
5) the 2-chloroethoxy-2-oxyethyl group di-alcohol crude product will obtained in step 4), carries out rectifying under vacuum decompression condition, collects 2-chloroethoxy-2-oxyethyl group di-alcohol cut, namely obtains 2-chloroethoxy-2-oxyethyl group di-alcohol product.
Concrete, in step 1), ethylene chlorhydrin both as reactant, again as solvent.
Further, in described step 1), step 3), used catalyst is boron trifluoride diethyl etherate, and catalyst charge is 0.3% ~ 0.6% of material system total mass, and the add-on of described catalyzer is preferably 0.45%.
Further, in described step 1), temperature of reaction is 35-55 DEG C, and the reaction times is 1.5 ~ 2 hours; Preferable temperature is 40-50 DEG C.
Further, described step 2) in vacuum tightness be 10-15mmHg, precipitation temperature is 100 ~ 110 DEG C.
Further, in described step 3), temperature of reaction is 40-55 DEG C, and the reaction times is 1.5-2 hour; Preferable temperature is 45-55 DEG C.
Further, in described step 4), vacuum distillation temperature is 105-130 DEG C, and vacuum tightness is 5-10mmHg.
Further, in described step 5), vacuum distillation temperature is 108-125 DEG C, and vacuum tightness is 5-10mmHg.
The reaction equation that the present invention relates to is as follows:
The present invention take ethylene chlorhydrin as raw material, prepares 2-chloroethoxy-2-oxyethyl group di-alcohol by two step etherification reactions, efficiently solves the many and problem that content is high of dopant species that direct chlorination method brings.The crude product purity of its 2-chloroethoxy of preparation method provided by the invention-2-oxyethyl group di-alcohol can reach more than 93%, and improve the purity of product, meanwhile, the transformation efficiency of reaction and yield, yield can reach more than 70%, and process costs is significantly reduced.Because namely reactant can be used as solvent, and solvent can be recycled, and so there is no extra solvent reclamation cost; Without waste water and other pollutent in reaction process, three-protection design cost is reduced greatly, and technique is environmental protection more.
The present invention compares with prior art, and its technical progress is significant.Namely method of the present invention improves content and the yield of product, again reduces pollution, is applicable to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is the infrared spectrogram of 2-chloroethoxy-2-oxyethyl group di-alcohol prepared by the present invention.
Fig. 2 is the hydrogen nuclear magnetic spectrogram of 2-chloroethoxy-2-oxyethyl group di-alcohol prepared by the present invention.
Fig. 3 is the mass spectrum of 2-chloroethoxy-2-oxyethyl group di-alcohol prepared by the present invention.
Embodiment
Embodiment 1
In 1000ml there-necked flask, add ethylene chlorhydrin 685g (8.5mol), catalyzer 3.3g, start agitator and well heater, be warming up to 40 DEG C (for making temperature of reaction maintain 40-50 DEG C, gate ring oxidative ethane to pass into speed, water-bath temperature control can be adopted if desired), in flask, slowly pass into 44g oxyethane, the time of passing into is 1.5-2h.For making to react completely, after logical oxyethane terminates, continue stirring reaction 0.5h.Stir and terminate, heat up, under reduced pressure, slough excessive ethylene chlorhydrin, vacuum tightness 0.075mPa(water rushes pump), last precipitation temperature is 105 DEG C, collects ethylene chlorhydrin and is about 592g(and can recycles), obtain in flask based on the material of intermediate product 2-chloroethoxyethanol.
Material in there-necked flask is cooled to 45-50 DEG C, adds 0.7g boron trifluoride diethyl etherate, under stirring, pass into 46.2g(1.05mol) oxyethane, the time of passing into is 1.5-2h, for making temperature of reaction maintain 45-55 DEG C, gate ring oxidative ethane to pass into speed, water-bath temperature control can be adopted if desired.Meanwhile, for making to react completely, after logical oxyethane terminates, continue stirring reaction 0.5h.After reaction terminates, heat up, distill under vacuum decompression, getting middle runnings (cut temperature 115-123 DEG C, vacuum tightness 10mmHg) is colourless transparent liquid.By rectifying under the middle runnings vacuum decompression condition of collection, getting middle runnings (cut temperature 118-121 DEG C, vacuum tightness 10mmHg) is colourless transparent liquid, 123.6g, gas phase content 97.7%, total 73.3%.
Product structure confirms: in annex 1 infrared spectrogram, the absorption peak at 3416 places is hydroxyl (-OH), and the absorption peak at 1105 places is ehter bond (C-O-C), and 2871 places are C-H bond (-CH), and 1064 places are-CH
2-OH.In annex 2 proton magnetic spectrum, 3.685 is the peak-to-peak signals of hydrogen on two methylene radical in the middle of 2-chloroethoxy-2-oxyethyl group di-alcohol structural formula, 3.763 is the peak-to-peak signals of hydrogen on the methylene radical adjacent with C-Cl, 3.735 is the peak-to-peak signals of hydrogen on the methylene radical that connects with hydroxyl, 3.643 is the peak-to-peak signals of hydrogen on the methylene radical that connects with chlorine, and 3.613 is the peak-to-peak signals of hydrogen on the methylene radical adjacent with C-0H.In annex 3 mass spectrum, the molecular ion peak of 169 obviously can confirm the molecular weight of this material.The structure that can obtain 2-chloroethoxy-2-oxyethyl group di-alcohol thus meets the conclusion of collection of illustrative plates.
Embodiment 2
In 1000ml there-necked flask, add ethylene chlorhydrin 685g (recycling 592g+93g new) (8.5mol), catalyzer 3.3g, start agitator and well heater, be warming up to 40 DEG C (for making temperature of reaction maintain 40-50 DEG C, gate ring oxidative ethane to pass into speed, water-bath temperature control can be adopted if desired), in flask, slowly pass into 44g oxyethane, the time of passing into is 1.5-2h.For making to react completely, after logical oxyethane terminates, continue stirring reaction 0.5h.Stir and terminate, start to heat up, under reduced pressure, slough excessive ethylene chlorhydrin, vacuum tightness 0.075mPa(water rushes pump), last precipitation temperature is 105 DEG C, collects ethylene chlorhydrin and is about 587g, can continue to apply mechanically, be based on the material of intermediate product 2-chloroethoxyethanol in flask.
Material in there-necked flask is cooled to 45-50 DEG C, adds 0.7g boron trifluoride diethyl etherate, under stirring, pass into 46.2g(1.05mol) oxyethane, the time of passing into is 1.5-2h, for making temperature of reaction maintain 45-55 DEG C, gate ring oxidative ethane to pass into speed, water-bath temperature control can be adopted if desired.For making to react completely, after logical oxyethane terminates, continue stirring reaction 0.5h.After reaction terminates, start to heat up, distill under vacuum decompression, getting middle runnings (cut temperature 115-123 DEG C, vacuum tightness 10mmHg) is colourless transparent liquid.By middle runnings rectifying under vacuum decompression condition, getting middle runnings (cut temperature 118-121 DEG C, vacuum tightness 10mmHg) is colourless transparent liquid, 122.3g, gas phase content 97.8%, total recovery 72.5%.
Embodiment 3
Catalyst levels in embodiment 2 is turned down 0.3% to material total amount, charge ratio and reaction conditions in the same manner as in Example 2, obtain product 116.7g after rectifying, gas phase content 97.6%, total recovery 69.2%.
Claims (1)
1. a preparation method for 2-chloroethoxy-2-oxyethyl group di-alcohol, is characterized in that comprising the following steps:
1) reactant ethylene chlorhydrin and first oxyethane is taken, the mol ratio of ethylene chlorhydrin and first oxyethane is 7 ~ 9:1, ethylene chlorhydrin and first oxyethane react under catalyzer existence condition, generate intermediate product 2-chloroethoxyethanol, used catalyst is boron trifluoride diethyl etherate, catalyst charge is the 0.3%-0.6% of material system total mass, and temperature of reaction is 35-55 DEG C, and the reaction times is 1.5-2 hour;
2) material reacting end in step 1) is steamed excessive ethylene chlorhydrin under vacuum decompression condition;
3) by step 2) in slough ethylene chlorhydrin after material continue to react with second batch oxyethane under catalyzer existence condition, described 2-chloroethoxyethanol and the mol ratio of second batch oxyethane are 1:1.0 ~ 1.4, used catalyst is boron trifluoride diethyl etherate, catalyst charge is the 0.3%-0.6% of material system total mass, temperature of reaction is 40-55 DEG C, and the reaction times is 1.5-2 hour;
4) distilled under vacuum decompression condition by the material reacting end in step 3), collect middle runnings, obtain 2-chloroethoxy-2-oxyethyl group di-alcohol crude product, vacuum distillation temperature is 105-130 DEG C, and vacuum tightness is 5-10mmHg;
5) the 2-chloroethoxy-2-oxyethyl group di-alcohol crude product will obtained in step 4), rectifying is carried out under vacuum decompression condition, collect 2-chloroethoxy-2-oxyethyl group di-alcohol cut, namely 2-chloroethoxy-2-oxyethyl group di-alcohol is obtained, vacuum distillation temperature is 108-125 DEG C, and vacuum tightness is 5-10mmHg.
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| JPS5967235A (en) * | 1982-10-07 | 1984-04-16 | Mitsui Toatsu Chem Inc | Preparation of 2-(2'-chloroethoxy)ethanol |
| JP2577627B2 (en) * | 1988-12-05 | 1997-02-05 | 日曹丸善ケミカル株式会社 | Method for producing high-purity 2- (2'-chloroethoxy) ethanol |
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Inventor after: Jiang Jibo Inventor after: Huang Qi Inventor after: He Huihong Inventor after: Zhu Jun Inventor after: Ma Peng Inventor after: Han Sheng Inventor after: Ye Fengying Inventor after: Yu Fei Inventor after: Liu Cheng Inventor after: Chen Yongyue Inventor after: Liu Yafeng Inventor after: Liu Fan Inventor before: Han Sheng Inventor before: Ma Peng Inventor before: Yu Fei Inventor before: Liu Cheng Inventor before: Chen Yongyue Inventor before: Liu Yafeng Inventor before: He Huihong Inventor before: Zhu Jun |
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Effective date of registration: 20181129 Address after: Room 3270, Building 1, 215 Union North Road, Fengxian District, Shanghai, 201417 Patentee after: Shanghai wisdom Medical Technology Service Co., Ltd. Address before: 200235 No. 120, Xuhui District, Shanghai, Caobao Road Patentee before: Shanghai Institute of Technology |
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Effective date of registration: 20210128 Address after: Room 301, 965 Halley Road, Zhangjiang hi tech park, Pudong New Area, Shanghai 201203 Patentee after: SHANGHAI CHEMPARTNER Co.,Ltd. Address before: Room 3270, Building 1, 215 Union North Road, Fengxian District, Shanghai, 201417 Patentee before: Shanghai wisdom Medical Technology Service Co.,Ltd. |
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