CN111876448A - Synthesis method of 4-cyano-3-hydroxy ethyl butyrate - Google Patents
Synthesis method of 4-cyano-3-hydroxy ethyl butyrate Download PDFInfo
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Abstract
The invention provides a method for synthesizing 4-cyano-3-hydroxy ethyl butyrate, which relates to the technical field of ethyl butyrate synthesis and comprises the following steps: reaction synthesis: adding deionized water into a reaction bottle, adding 4-chloro-3-hydroxybutyric acid ethyl ester, adding a buffering agent to regulate the pH value to 6.9-7.1, adding dehalogenase, introducing hydrocyanic acid, adding a buffering agent to regulate the pH value to 6.9-7.1 again, reacting at the temperature of 40-55 ℃ until the content of the 4-chloro-3-hydroxybutyric acid ethyl ester is analyzed to be less than or equal to 1%, then, counting the plates again to confirm the complete reaction, and confirming the reaction end point to obtain a reaction solution; compared with the prior art, the synthesis method reduces the cost of three-waste treatment, equipment investment, manual investment and other links, and increases the technical advancement of the product.
Description
Technical Field
The invention relates to the technical field of ethyl butyrate synthesis, and particularly relates to a synthesis method of 4-cyano-3-hydroxy ethyl butyrate.
Background
Ethyl 4-cyano-3-hydroxybutyrate is a key intermediate of atorvastatin, which is an HMG-CoA reductase selective inhibitor and is mainly used for reducing plasma cholesterol and lipoprotein levels and can be a common medicine for regulating blood fat of lower cardiovascular systems by increasing the level of low-density lipoprotein (LDL) on the surfaces of liver cells.
The prior synthesis process of ethyl cyano-3-hydroxybutyrate comprises the following steps:
the prior synthesis process has the following disadvantages:
(1) the synthetic route has large sodium cyanide consumption, low utilization rate, 1.6 to 1.8 times of the molar ratio of 4-chloro-3-hydroxy ethyl butyrate, generates a large amount of cyanide-containing wastewater and has high treatment cost;
(2) the synthetic route has the advantages of large using amount of an extracting agent, more extraction times and high operation cost;
(3) the synthesis route requires a pH value of 6.9 +/-0.1 for reaction control, and has high reaction control requirement and high operation cost;
(4) the synthetic route reacts to generate a large amount of salt, and is mixed salt of sodium chloride and sodium sulfate, and in addition, the cyanide-containing wastewater is treated to generate a large amount of salt and wastewater, so that the environment-friendly treatment cost is high.
Therefore, a new synthesis method which has mild reaction, stable yield, lower operation cost and environmental protection cost during the synthesis of ethyl 4-cyano-3-hydroxybutyrate is provided, which is a technical problem to be solved in the field at present.
Disclosure of Invention
Technical problem to be solved
Aiming at the defects of the prior art, the invention provides a method for synthesizing 4-cyano-3-hydroxy ethyl butyrate, which reduces the cost of three-waste treatment, equipment investment, manual investment and other links and increases the technical advancement of the product compared with the prior art.
(II) technical scheme
In order to achieve the purpose, the invention is realized by the following technical scheme:
a method for synthesizing 4-cyano-3-hydroxy ethyl butyrate comprises the following steps:
1) reaction synthesis: adding deionized water into a reaction bottle, adding 4-chloro-3-hydroxybutyric acid ethyl ester, adding a buffering agent to regulate the pH value to 6.9-7.1, adding dehalogenase, introducing hydrocyanic acid, adding a buffering agent to regulate the pH value to 6.9-7.1 again, reacting at the temperature of 40-55 ℃ until the content of the 4-chloro-3-hydroxybutyric acid ethyl ester is analyzed to be less than or equal to 1%, then, counting the plates again to confirm the complete reaction, and confirming the reaction end point to obtain a reaction solution;
2) desolventizing and dewatering: concentrating and dehydrating the reaction liquid, controlling the temperature below 60 ℃ and the vacuum degree at 15Kpa, and concentrating to 35-45% of the volume of the reaction liquid to obtain a feed liquid;
3) filtering and desalting: adding an extracting agent into the desolventized feed liquid, uniformly stirring, filtering salt, washing a filter cake by using the same extracting agent, combining and collecting filtrate;
4) extraction and washing: layering the filtrate, collecting organic phase, washing the organic phase with saturated sodium chloride aqueous solution, adjusting pH to 7-8 with sodium bicarbonate aqueous solution, layering, collecting organic phase, extracting the water layer with the same extractant as in step 3), and mixing the organic phases;
5) desolventizing and rectifying: and (3) carrying out decompression desolventizing on the organic phase, controlling the temperature below 70 ℃, continuously desolventizing, and carrying out vacuum till the organic phase does not flow out to obtain a crude product of the 4-cyano-3-hydroxy ethyl butyrate, and carrying out decompression rectification on the crude product to obtain a finished product of the 4-cyano-3-hydroxy ethyl butyrate.
Further, the buffer is ammonia water or an organic alkali aqueous solution.
Further, the organic base is one of methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine and triethylamine.
Further, in the step 1), the dosage of the dehalogenase is 3-8% of that of the ethyl 4-chloro-3-hydroxybutyrate.
Further, in the step 3), the extracting agent is ethyl acetate or dichloroethane.
Further, in the step 5), the temperature during rectification is 125-135 ℃, the recovery content is not less than 96%, the yield of the finished product of the 4-cyano-3-hydroxy ethyl butyrate is 85-92%, and the purity is not less than 98.5%.
The synthetic process route of the invention is as follows:
(III) advantageous effects
The invention provides a method for synthesizing 4-cyano-3-hydroxy ethyl butyrate, which has the following beneficial effects:
1. in the synthetic method, hydrocyanic acid replaces sodium cyanide and sulfuric acid in the original process, ammonia water or organic alkali is used as a buffer of a reaction system, and the hydrocyanic acid can be dissolved by the ammonia water or the organic alkali water, so that the hydrocyanic acid is slowly released in the reaction process, the reaction is mild, the yield is more stable, and the pH value of the system is 6.9-7.1.
2. The synthetic route of the invention finally generates the single waste ammonium chloride salt without other waste salts, thereby greatly reducing the environmental protection cost.
3. After the reaction is finished, the ammonium chloride or the organic ammonium salt is filtered and separated out after part of water is removed (the removed water can be used in the process), and then the extracting agent is used for washing and extraction, so that the using amount of the extracting agent is reduced by about 40 percent compared with that of the original process, wastewater is not generated basically, and the environmental protection cost is greatly reduced.
4. Compared with the prior art, the synthesis process method reduces the cost of three-waste treatment, equipment investment, manual investment and other links, and increases the technical advancement of the product.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1:
a method for synthesizing 4-cyano-3-hydroxy ethyl butyrate comprises the following steps:
(1) reaction synthesis: adding 80ml of deionized water into a reaction bottle, adding 17.3g (0.1mol) of 4-chloro-3-hydroxybutyric acid ethyl ester (the purity is 96%), adding ammonia water (25%) to adjust the pH value to be 6.9-7.1, adding 0.85g of dehalogenase, introducing hydrocyanic acid, simultaneously adding an ammonia water (25%) solution to adjust the pH value to be 6.9-7.1, controlling the temperature to be 40-55 ℃, reacting until the content of the 4-chloro-3-hydroxybutyric acid ethyl ester is analyzed to be less than or equal to 1%, then, dotting the plate again to confirm the reaction is complete, and confirming the reaction end point to obtain a reaction solution;
(2) desolventizing and dewatering: concentrating and dehydrating the reaction liquid, controlling the temperature below 60 ℃ and the vacuum degree at 15Kpa, and concentrating to 35-45% of the volume of the liquid to obtain liquid;
(3) filtering and desalting: adding 250ml of ethyl acetate into the desolventized feed liquid, uniformly stirring, filtering, washing a filter cake by using 50ml of ethyl acetate, combining and collecting filtrate;
(4) extraction and washing: collecting organic phase by separating the filtrate, washing the organic phase with 80ml saturated sodium chloride aqueous solution, adjusting pH to 7-8 with sodium bicarbonate aqueous solution, separating the organic phase, collecting the organic phase, extracting the water layer with 80ml ethyl acetate once, and combining the organic phase;
(5) desolventizing and rectifying: the organic layer was desolventized under reduced pressure at a temperature of 70 ℃ or lower, and the desolventization was continued until no flow out was observed under vacuum to obtain about 15.6g (purity 92%, yield 90%) of crude ethyl 4-cyano-3-hydroxybutyrate. The obtained crude product of the ethyl 4-cyano-3-hydroxybutyrate is rectified under reduced pressure, the temperature at the top of the tower is controlled to be 135 ℃, the vacuum degree is-0.097 MPa, the extracted content is more than or equal to 96 percent, 13.69g of the finished product of the ethyl 4-cyano-3-hydroxybutyrate is obtained, the rectification yield is about 95 percent, and the purity is more than or equal to 98.5 percent.
Example 2:
a method for synthesizing 4-cyano-3-hydroxy ethyl butyrate comprises the following steps:
(1) reaction synthesis: adding 80ml of deionized water into a reaction bottle, adding 17.3g (0.1mol) of 4-chloro-3-hydroxy ethyl butyrate (the purity is 96%), adding a methylamine water (40%) solution to adjust the pH value to be 6.9-7.1, adding 0.85g of dehalogenase, introducing hydrocyanic acid, simultaneously adding a methylamine water (40%) solution to adjust the pH value to be 6.9-7.1, controlling the temperature to be 40-55 ℃, reacting until the content of the 4-chloro-3-hydroxy ethyl butyrate is analyzed to be less than or equal to 1%, then, carrying out plate counting again to confirm the reaction is complete, and confirming the reaction end point to obtain a reaction solution;
(2) desolventizing and dewatering: concentrating and dehydrating the reaction liquid, controlling the temperature below 60 ℃ and the vacuum degree at 15Kpa, and concentrating each batch until the volume of the reaction liquid is 35-45% of that of the feed liquid to obtain the feed liquid;
(3) filtering and desalting: adding 350ml of dichloroethane into the desolventized feed liquid, uniformly stirring, filtering salt, washing a filter cake by using 80ml of dichloroethane, combining and collecting filtrate;
(4) extraction and washing: collecting organic phase by layering, washing the organic phase with 80ml saturated sodium chloride aqueous solution, adjusting pH to 7-8 with sodium bicarbonate aqueous solution, layering, collecting organic phase, extracting water layer with 80ml dichloroethane, and mixing organic phases;
(5) desolventizing and rectifying: the organic layer was desolventized under reduced pressure at a temperature of 70 ℃ or lower, and the desolventization was continued until no flow out was observed under vacuum to obtain about 15.3g (purity 91%, yield 89%) of crude ethyl 4-cyano-3-hydroxybutyrate. The obtained crude product of the ethyl 4-cyano-3-hydroxybutyrate is rectified under reduced pressure, the temperature at the top of the tower is controlled to be 135 ℃, the vacuum degree is-0.097 MPa, the extracted content is more than or equal to 96 percent, 13.42g of the finished product of the ethyl 4-cyano-3-hydroxybutyrate is obtained, the rectification yield is about 95 percent, and the purity is more than or equal to 98.5 percent.
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.
Claims (6)
1. A method for synthesizing 4-cyano-3-hydroxy ethyl butyrate is characterized by comprising the following steps:
1) reaction synthesis: adding deionized water into a reaction bottle, adding 4-chloro-3-hydroxybutyric acid ethyl ester, adding a buffering agent to regulate the pH value to 6.9-7.1, adding dehalogenase, introducing hydrocyanic acid, adding a buffering agent to regulate the pH value to 6.9-7.1 again, reacting at the temperature of 40-55 ℃ until the content of the 4-chloro-3-hydroxybutyric acid ethyl ester is analyzed to be less than or equal to 1%, then, counting the plates again to confirm the complete reaction, and confirming the reaction end point to obtain a reaction solution;
2) desolventizing and dewatering: concentrating and dehydrating the reaction liquid, controlling the temperature below 60 ℃ and the vacuum degree at 15KPa, and concentrating to 35-45% of the volume of the reaction liquid to obtain a feed liquid;
3) filtering and desalting: adding an extracting agent into the desolventized feed liquid, uniformly stirring, filtering salt, washing a filter cake by using the same extracting agent, combining and collecting filtrate;
4) extraction and washing: layering the filtrate, collecting organic phase, washing the organic phase with saturated sodium chloride aqueous solution, adjusting pH to 7-8 with sodium bicarbonate aqueous solution, layering, collecting organic phase, extracting the water layer with the same extractant as in step 3), and mixing the organic phases;
5) desolventizing and rectifying: and (3) carrying out decompression desolventizing on the organic phase, controlling the temperature below 70 ℃, continuously desolventizing, and carrying out vacuum till the organic phase does not flow out to obtain a crude product of the 4-cyano-3-hydroxy ethyl butyrate, and carrying out decompression rectification on the crude product to obtain a finished product of the 4-cyano-3-hydroxy ethyl butyrate.
2. The method for synthesizing ethyl 4-cyano-3-hydroxybutyrate according to claim 1, wherein in the step 1), the buffer is aqueous ammonia or an aqueous organic base.
3. The method of synthesizing ethyl 4-cyano-3-hydroxybutyrate of claim 2, wherein the organic base is one of methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine and triethylamine.
4. The method for synthesizing ethyl 4-cyano-3-hydroxybutyrate according to claim 1, wherein the amount of the dehalogenase used in the step 1) is 3 to 8% of the amount of the ethyl 4-chloro-3-hydroxybutyrate.
5. The method for synthesizing ethyl 4-cyano-3-hydroxybutyrate of claim 1, wherein in step 3), the extractant is ethyl acetate or dichloroethane.
6. The method for synthesizing ethyl 4-cyano-3-hydroxybutyrate according to claim 1, wherein in the step 5), the distillation temperature is 125-135 ℃, the recovery content is not less than 96%, the yield of the ethyl 4-cyano-3-hydroxybutyrate product is 85-92%, and the purity is not less than 98.5%.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1537222A2 (en) * | 2002-08-09 | 2005-06-08 | Codexis, Inc. | Enzymatic processes for the production of 4-substituted 3-hydroxybutyric acid derivatives |
| CN102168117A (en) * | 2011-01-12 | 2011-08-31 | 江苏阿尔法药业有限公司 | Method for preparing ethyl (R)-4-cyano-3-hydroxybutyate |
| CN106065409A (en) * | 2016-08-22 | 2016-11-02 | 江苏理工学院 | A kind of preparation method of synthesis (R) 4 cyano group 3 3-hydroxyethyl butyrate of circulation continuously |
| CN109628511A (en) * | 2019-01-16 | 2019-04-16 | 抚顺顺能化工有限公司 | The environmentally protective preparation method of one kind (R)-(-) -4- cyano-3-hydroxy ethyl butyrate |
-
2020
- 2020-08-03 CN CN202010766722.3A patent/CN111876448A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1537222A2 (en) * | 2002-08-09 | 2005-06-08 | Codexis, Inc. | Enzymatic processes for the production of 4-substituted 3-hydroxybutyric acid derivatives |
| CN102168117A (en) * | 2011-01-12 | 2011-08-31 | 江苏阿尔法药业有限公司 | Method for preparing ethyl (R)-4-cyano-3-hydroxybutyate |
| CN106065409A (en) * | 2016-08-22 | 2016-11-02 | 江苏理工学院 | A kind of preparation method of synthesis (R) 4 cyano group 3 3-hydroxyethyl butyrate of circulation continuously |
| CN109628511A (en) * | 2019-01-16 | 2019-04-16 | 抚顺顺能化工有限公司 | The environmentally protective preparation method of one kind (R)-(-) -4- cyano-3-hydroxy ethyl butyrate |
Non-Patent Citations (2)
| Title |
|---|
| STEVEN K. MA等: "A green-by-design biocatalytic process for atorvastatin intermediate", 《GREEN CHEMISTRY》 * |
| 王雷等: "一种来源于运动替斯崔纳菌KA081020-065的新型卤", 《生物工程学报》 * |
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Effective date of registration: 20210423 Address after: 222523 Jiangsu city of Lianyungang province guannaxian heap ditch town (Chemical Industrial Park) Applicant after: JIANGSU DIPU TECHNOLOGY Co.,Ltd. Address before: 222523 Jiangsu city of Lianyungang province guannaxian heap ditch town Industrial Park Applicant before: LIANYUNGANG HONGYE CHEMICAL Co.,Ltd. |
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Application publication date: 20201103 |