CN103058824A - Synthetic method for p-chlorobenzene alcohol - Google Patents
Synthetic method for p-chlorobenzene alcohol Download PDFInfo
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- CN103058824A CN103058824A CN2012105623762A CN201210562376A CN103058824A CN 103058824 A CN103058824 A CN 103058824A CN 2012105623762 A CN2012105623762 A CN 2012105623762A CN 201210562376 A CN201210562376 A CN 201210562376A CN 103058824 A CN103058824 A CN 103058824A
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- trifluoride diethyl
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Abstract
The invention discloses a synthetic method for p-chlorobenzene alcohol. The synthetic method for the p-chlorobenzene alcohol comprises the steps of serving tetrahydrofuran as a reaction solvent of p-chlorobenzene acetic acid, under the action of sodium borohydride and boron trifluoride diethyl etherate, stirring and reacting under room temperature, tracing and checking by thin layer chromatography (TLC) until completely reacting, and obtaining the p-chlorobenzene alcohol through after-treatment of the reaction solution. The ratio of the amount of substances of p-chlorobenzene acetic acid, sodium borohydride to boron trifluoride diethyl etherate is 1: 1.05-1.3: 1.1-1.3. The synthetic method is short in process route. The p-chlorobenzene alcohol can be synthesized by a one-step method. The reaction raw materials are low in price and easy to obtain. Reaction conditions are temperate, the reaction can be achieved under room temperature, and energy consumption is greatly saved in industrial production, production and operation are simple and easy to control, reaction yield is high, and production cost is low. Provided is a process route. The process route is quite suitable for industrial enlarged production.
Description
Technical field
The present invention relates to a kind of synthetic method to chlorophenethylol.
Background technology
Be the key intermediate of agricultural chemicals RH-7592 to chlorophenethylol, RH-7592 is usually used in the control of the leaf spot of the brown heart of peach and Banana tree as sterilant, it is again the starting raw material of synthesis material medicine green card look woods hydrochloride, food and drug administration is in the diet pill listing of approval on June 27th, 2012 commodity Belviq by name, this is that this office has ratified new diet pill listing first since 1999, green card look woods hydrochloride is the main component of this medicine, so predict future will further enlarge the market requirement of chlorophenethylol.Be summarized as follows about the synthetic main several method to chlorophenethylol at present: (1) Xu builds equality people (synthetic chemistry, 2007,15(5): the 595-596.) route of report: at first 4-Chlorophenylacetic acid is changed into the 4-Chlorophenylacetic acid ethyl ester, and then be reduced into chlorophenethylol, this route need to consume sulfur oxychloride, can produce the sour gas such as a large amount of sulfurous gas and hydrogenchloride in the production process, and the sodium borohydride consumption of this route is also larger, is unfavorable for the production control cost.(2) people such as Zhang Liguang (Chinese Journal of Pharmaceuticals, 2011,42(3) 174-175) mole dosage of sodium borohydride is 2 times of material quantity in the route of report, and will consume equimolar iodine, iodine expensive causes production cost very high like this.(3) people (CN 101250090A) such as Zhou Wengong report: anhydrous chlorides of rase benzene is under the effect of catalyzer, effect obtains product by processing with oxyethane, the lab scale yield is about 70%, although this technique reactions steps is few, but raw material needs Non-aqueous processing, and catalyst levels is very large, and actually operating control is difficulty a bit, yield is not high yet, and oxyethane belongs to inflammable and explosive compounds.
Summary of the invention
In order to solve existing, complicated operation high to production cost in the chlorophenethylol synthetic method, to be unfavorable for the technical problem of suitability for industrialized production, the invention provides a kind of new synthetic technological line to chlorophenethylol.
The technical solution used in the present invention is:
A kind of synthetic method to chlorophenethylol, described method is: 4-Chlorophenylacetic acid is take tetrahydrofuran (THF) as reaction solvent, under the effect of sodium borohydride and boron trifluoride diethyl etherate, stirring reaction under the room temperature, TLC follows the tracks of and detects to reacting completely, the reaction solution aftertreatment makes described to chlorophenethylol, and the ratio of the amount of substance of described 4-Chlorophenylacetic acid, sodium borohydride, boron trifluoride diethyl etherate is 1:1.05 ~ 1.3:1.1 ~ 1.3, is preferably 1:1.08 ~ 1.3:1.11 ~ 1.3.
The reaction formula of the present invention's reaction is as follows:
Further, the method of the invention may further comprise the steps: 4-Chlorophenylacetic acid is dissolved in the tetrahydrofuran (THF), slowly add sodium borohydride, 10 ~ 30 ℃ of control reacting liquid temperatures, add rear dropping boron trifluoride diethyl etherate, 10 ~ 30 ℃ of control reacting liquid temperatures add stirring reaction under the rear room temperature, TLC follows the tracks of and detects to reacting completely, and the reaction solution aftertreatment makes described to chlorophenethylol.
The volumetric usage of described tetrahydrofuran (THF) is counted 1.5 ~ 3mL/g with the quality of 4-Chlorophenylacetic acid usually, preferred 1.6 ~ 2mL/g.
Reaction times of the present invention is generally 6 ~ 10 hours.
Reaction solution post-treating method of the present invention is: after reaction finishes, reaction solution is added to the water, the control temperature is 15 ~ 35 ℃, add rear abundant stirring (usually stirring 0.5 ~ 1 hour), then organic solvent is removed in distillation, extracts with ethylene dichloride after the debris cooling, extraction phase is successively after the solution of potassium carbonate of 3 ~ 4wt%, water washing, get organic phase drying, concentrated, obtain weak yellow liquid, be described to chlorophenethylol.
Described reaction solution is added to the water, and the volumetric usage of water is generally 2 ~ 3 times of reaction solution volume.
Comparatively preferred, the recommendering folder inventive method is carried out according to the following steps:
4-Chlorophenylacetic acid is dissolved in the tetrahydrofuran (THF), slowly add sodium borohydride, 10 ~ 30 ℃ of control reacting liquid temperatures, add rear dropping boron trifluoride diethyl etherate, 10 ~ 30 ℃ of control reacting liquid temperatures, add stirring reaction under the rear room temperature, TLC follows the tracks of and detects to reacting completely, and reaction solution is added to the water, and the control temperature is 15 ~ 35 ℃, add rear abundant stirring, then organic solvent is removed in distillation, and with the ethylene dichloride extraction, extraction phase is successively after the solution of potassium carbonate of 3 ~ 4wt%, water washing after the debris cooling, get organic phase drying, concentrated, make described to chlorophenethylol; The ratio of the amount of substance of described 4-Chlorophenylacetic acid, sodium borohydride, boron trifluoride diethyl etherate is 1:1.05 ~ 1.3:1.1 ~ 1.3.
The beneficial effect of the inventive method is: (1) route is brief, single stage method can be synthesized chlorophenethylol, (2) reaction raw materials is cheap and easy to get, (3) reaction conditions is gentle, and at room temperature reaction gets final product, energy efficient greatly on the industrial production, (4) production operation is simple and easy to control, (5) yield is high, is more than 90%, and production cost is low.The invention provides an operational path that is fit to very much industrial amplification production.
Embodiment
The present invention will be further described with specific embodiment for the below, but protection scope of the present invention is not limited to this
Embodiment 1.
In the 250ml there-necked flask, add 4-Chlorophenylacetic acid 31g(0.18mol) and the 50ml tetrahydrofuran (THF), stirring and dissolving, under the water-bath cooling, slowly add sodium borohydride 7.6g(0.2mol), control reaction soln temperature is no more than 30 ℃, add about half an hour, after adding, slowly drips boron trifluoride diethyl etherate 28.8g(0.20mol), control reaction soln temperature is no more than 30 ℃, approximately added in 1 hour, add rear stirring reaction, TLC detects without behind the raw material, stopped reaction, the time is about 6 hours.Under stirring reaction solution is slowly joined in the 100ml water, the temperature of control solution is no more than 35 ℃, add rear stirring half an hour, organic solvent is removed in distillation under the normal pressure, and raffinate cools to about 30 ℃, with twice of dichloromethane extraction (75ml * 2), dichloromethane solution is used 100ml 3% left and right sides solution of potassium carbonate successively, and each washs 100ml water once, and dichloromethane solution is concentrated after drying, obtain weak yellow liquid 26.7g, yield 93.8%.Product characterizes through NMR (Nuclear Magnetic Resonance) spectrum, and the result is: 1HNMR(CDCl3), δ (ppm): 2H on the 7.28(phenyl ring), 2H on the 6.89(phenyl ring), 3.81(-CH2OH), 2.81(-CH2CH2OH), the data sheet mark product structure that makes eye bright is correct.(following same)
Embodiment 2.
In the 250ml there-necked flask, add 4-Chlorophenylacetic acid 31g(0.182mol) and the 60ml tetrahydrofuran (THF), stirring and dissolving, under the water-bath cooling, slowly add sodium borohydride 9.0g(0.237mol), control reaction soln temperature is no more than 30 ℃, add about half an hour, after adding, slowly drips boron trifluoride diethyl etherate 33.6g(0.237mol), control reaction soln temperature is no more than 30 ℃, approximately added in 1 hour, add rear stirring reaction, TLC detects without behind the raw material, stopped reaction, the time is about 6 hours.Under stirring reaction solution is slowly joined in the 150ml water, the temperature of control solution is no more than 35 ℃, add rear stirring half an hour, organic solvent is removed in distillation under the normal pressure, and raffinate cools to about 30 ℃, with twice of dichloromethane extraction (75ml * 2), dichloromethane solution is used 100ml 3 wt % solution of potassium carbonate successively, and each washs 100ml water once, and dichloromethane solution is concentrated after drying, obtain weak yellow liquid 26.2g, yield 92.0%.
Embodiment 3
In the 500ml there-necked flask, add 4-Chlorophenylacetic acid 62g(0.364mol) and the 120ml tetrahydrofuran (THF), stirring and dissolving, under the water-bath cooling, slowly add sodium borohydride 15.5g(0.408mol), control reaction soln temperature is no more than 30 ℃, add about half an hour, after adding, slowly drips boron trifluoride diethyl etherate 58.0g(0.408mol), control reaction soln temperature is no more than 30 ℃, approximately added in 1 hour, add rear stirring reaction, TLC detects without behind the raw material, stopped reaction, the time is about 8 hours.Under stirring reaction solution is slowly joined in the 250ml water, the temperature of control solution is no more than 35 ℃, add rear stirring half an hour, organic solvent is removed in distillation under the normal pressure, and raffinate cools to about 30 ℃, with twice of dichloromethane extraction (120ml * 2), dichloromethane solution is used 150ml 3 wt % solution of potassium carbonate successively, and each washs 200ml water once, and dichloromethane solution is concentrated after drying, obtain weak yellow liquid 53.6g, yield 94.0%.
Embodiment 4
In the 1000ml there-necked flask, add 4-Chlorophenylacetic acid 125g(0.733mol) and the 250ml tetrahydrofuran (THF), stirring and dissolving, under the water-bath cooling, slowly add sodium borohydride 30g(0.789mol), control reaction soln temperature is no more than 30 ℃, approximately added in 45 minutes, after adding, slowly drip boron trifluoride diethyl etherate 120g(0.845mol), control reaction soln temperature is no more than 30 ℃, approximately added in 1.5 hours, add rear stirring reaction, TLC detects without behind the raw material, stopped reaction, the time is about 9 hours.Under stirring reaction solution is slowly joined in the 500ml water, the temperature of control solution is no more than 35 ℃, add rear stirring half an hour, organic solvent is removed in distillation under the normal pressure, and raffinate cools to about 30 ℃, with twice of dichloromethane extraction (200ml * 2), dichloromethane solution is with 3 wt % solution of potassium carbonate washed twice (200ml * 2), twice of water washing (200ml * 2), and dichloromethane solution is concentrated after drying, obtain weak yellow liquid 107.0g, yield 93.3%.
Embodiment 5:
In the 2500ml there-necked flask, add 4-Chlorophenylacetic acid 256g(1.5mol) and the 450ml tetrahydrofuran (THF), stirring and dissolving, under the water-bath cooling, slowly add sodium borohydride 68.5g(1.8mol), control reaction soln temperature is no more than 30 ℃, approximately added in 1 hour, after adding, slowly drip boron trifluoride diethyl etherate 256.0g(1.8mol), control reaction soln temperature is no more than 30 ℃, approximately added in 1.5 hours, add rear stirring reaction, TLC detects without behind the raw material, stopped reaction, the time is about 10 hours.Under stirring reaction solution is slowly joined in the 800ml water, the temperature of control solution is being no more than 35 ℃, add rear stirring half an hour, organic solvent is removed in air distillation, and raffinate cools to about 30 ℃, with dichloromethane extraction three times (250ml * 3), dichloromethane solution 3wt% solution of potassium carbonate washed twice (250ml * 2), twice of water washing (250ml * 2), dichloromethane solution is concentrated after drying, obtain weak yellow liquid 210.0g, yield 89.4%.
Claims (5)
1. synthetic method to chlorophenethylol, it is characterized in that described method is: 4-Chlorophenylacetic acid is take tetrahydrofuran (THF) as reaction solvent, under the effect of sodium borohydride and boron trifluoride diethyl etherate, stirring reaction under the room temperature, TLC follows the tracks of and detects to reacting completely, the reaction solution aftertreatment makes described to chlorophenethylol, and the ratio of the amount of substance of described 4-Chlorophenylacetic acid, sodium borohydride, boron trifluoride diethyl etherate is 1:1.05 ~ 1.3:1.1 ~ 1.3.
2. the method for claim 1, it is characterized in that described method is: 4-Chlorophenylacetic acid is dissolved in the tetrahydrofuran (THF), slowly add sodium borohydride, 10 ~ 30 ℃ of control reacting liquid temperatures, add rear dropping boron trifluoride diethyl etherate, 10 ~ 30 ℃ of control reacting liquid temperatures add stirring reaction under the rear room temperature, TLC follows the tracks of and detects to reacting completely, and the reaction solution aftertreatment makes described to chlorophenethylol.
3. method as claimed in claim 1 or 2, it is characterized in that described reaction solution post-treating method is: after reaction finishes, reaction solution is added to the water, the control temperature is 15 ~ 35 ℃, adds rear abundant stirring, and then organic solvent is removed in distillation, extract with ethylene dichloride after the debris cooling, extraction phase after the solution of potassium carbonate of 3 ~ 4wt%, water washing, is got organic phase drying, concentrated successively, makes described to chlorophenethylol.
4. method as claimed in claim 1 or 2 is characterized in that the volumetric usage of described tetrahydrofuran (THF) is counted 1.5 ~ 3mL/g with the quality of 4-Chlorophenylacetic acid.
5. the method for claim 1, it is characterized in that described method carries out according to the following steps: 4-Chlorophenylacetic acid is dissolved in the tetrahydrofuran (THF), slowly add sodium borohydride, 10 ~ 30 ℃ of control reacting liquid temperatures, add rear dropping boron trifluoride diethyl etherate, 10 ~ 30 ℃ of control reacting liquid temperatures add stirring reaction under the rear room temperature, and TLC follows the tracks of and detects to reacting completely, reaction solution is added to the water, the control temperature is 15 ~ 35 ℃, adds rear abundant stirring, and then organic solvent is removed in distillation, extract with ethylene dichloride after the debris cooling, extraction phase is successively through the solution of potassium carbonate of 3 ~ 4wt%, after the water washing, get the organic phase drying, concentrated, make described to chlorophenethylol; The ratio of the amount of substance of described 4-Chlorophenylacetic acid, sodium borohydride, boron trifluoride diethyl etherate is 1:1.05 ~ 1.3:1.1 ~ 1.3.
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| CN2012105623762A CN103058824A (en) | 2012-12-21 | 2012-12-21 | Synthetic method for p-chlorobenzene alcohol |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110128244A (en) * | 2019-06-13 | 2019-08-16 | 安徽工大化工科技有限公司 | A kind of synthetic method of pair of chlorophenethylol |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000042043A1 (en) * | 1999-01-11 | 2000-07-20 | The Regents Of The University Of Michigan | PYRROLO[2,3-d]PYRIMIDINES AS ANTIVIRAL AGENTS |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000042043A1 (en) * | 1999-01-11 | 2000-07-20 | The Regents Of The University Of Michigan | PYRROLO[2,3-d]PYRIMIDINES AS ANTIVIRAL AGENTS |
Non-Patent Citations (2)
| Title |
|---|
| SU-DONG CHO，ET AL.: "Facile Reduction of Carboxylic Acids, Esters, Acid Chlorides, Amides and Nitriles to Alcohols or Amines Using NaBH4/BF3•Et2O", 《BULLETIN OF KOREAN CHEMICAL SOCIETY》, vol. 25, no. 3, 31 December 2004 (2004-12-31), pages 407 - 409 * |
| 张立光等: "4-氯苯乙醇的合成", 《中国医药工业杂志》, vol. 42, no. 3, 31 December 2011 (2011-12-31), pages 174 - 175 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110128244A (en) * | 2019-06-13 | 2019-08-16 | 安徽工大化工科技有限公司 | A kind of synthetic method of pair of chlorophenethylol |
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Application publication date: 20130424 |