Stereoselective synthesis method of R and S-4-chloro-3-hydroxybutyronitrile
By using anhydrous methanol as a solvent and combining falling film evaporation and multi-stage condensation technology, the problems of large wastewater volume and high energy consumption in the hydrogen cyanide process were solved, and high yield and high purity production of R/S-4-chloro-3-hydroxybutyronitrile were achieved.
Patent Information
- Application Number
- CN202511101165.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-08-07
- Publication Date
- 2025-10-31
AI Technical Summary
The existing hydrogen cyanide process uses water as a solvent, which leads to problems such as large wastewater volume and high energy consumption, affecting the production efficiency and cost of R/S-4-chloro-3-hydroxybutyronitrile.
Anhydrous methanol is used as the reaction solvent, and combined with falling film evaporation and multi-stage condensation technology, the reaction temperature is controlled by a jacket and built-in coil to efficiently recover the solvent, avoid side reactions, and improve product yield and purity.
It significantly improved the yield and purity of R/S-4-chloro-3-hydroxybutyronitrile, reduced energy and material consumption, and simplified the subsequent purification process.
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Figure CN120865019A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of chemical synthesis technology, specifically to a stereoselective synthesis method of R and S-4-chloro-3-hydroxybutyronitrile. Background Technology
[0002] Both the R-configuration and S-configuration of 4-chloro-3-hydroxybutyronitrile are important pharmaceutical intermediates. S-4-chloro-3-hydroxybutyronitrile can be used to synthesize the chiral side chains of the lipid-lowering drugs atorvastatin calcium and rosuvastatin calcium, while R-4-chloro-3-hydroxybutyronitrile can be used to synthesize L-carnitine.
[0003] Currently, there are two production processes for the R / S-configuration of 4-chloro-3-hydroxybutyronitrile: the sodium cyanide method and the hydrogen cyanide method. The sodium cyanide method is gradually being phased out due to its large waste volume, relatively low yield, and high cost. The hydrogen cyanide method, on the other hand, has become the mainstream process due to its advantages of less waste and better controllability. However, the hydrogen cyanide method currently uses water as a solvent, which still results in problems such as large wastewater volume and high energy consumption. Summary of the Invention
[0004] To address the shortcomings of existing technologies, this invention provides a stereoselective synthesis method for R and S-4-chloro-3-hydroxybutyronitrile. This method overcomes the problem that while the hydrogen cyanide process has become the mainstream process due to its advantages of low waste and good controllability, the current hydrogen cyanide process uses water as a solvent, which still results in problems such as large wastewater volume and high energy consumption.
[0005] To achieve the above objectives, the present invention provides a stereoselective synthesis method for R and S-4-chloro-3-hydroxybutyronitrile, comprising the following steps:
[0006] S1. First, the entire system is purged with nitrogen, and epichlorohydrin and methanol are pumped into the synthesis reactor through the pumping pipeline. After the pumping is completed, stirring is started.
[0007] S2. Diethylamine is added through a diethylamine dropper while stirring. The temperature during the reaction is controlled by the jacket outside the reactor and the built-in coil. After the reaction is qualified by sampling and testing, the material can be transferred to the reaction liquid tank.
[0008] S3. After the reaction liquid is transferred, start the circulation pump to circulate it. The reaction liquid enters from the top of the falling film evaporator. Open the hot water regulating valve of the falling film evaporator. The concentrated liquid comes out from the bottom and returns to the reaction liquid tank.
[0009] S4. Start the screw vacuum pump. The vapor phase after methanol vaporization enters the receiving tank after primary and secondary condensation. After dissolution is completed, take a sample of the reaction liquid to test the solvent. After passing the test, transfer the material to the subsequent distillation process.
[0010] S5. Transfer the desolventized crude product to the distillation column. After the transfer is completed, start the shielded pump to circulate the product, open the reboiler steam regulating valve, and start the vacuum unit step by step to begin the distillation process.
[0011] By adopting the above technical solution, and using anhydrous methanol as the reaction solvent combined with falling film evaporation and multi-stage condensation technology for efficient recovery and reuse, the large amount of process wastewater generated by the traditional aqueous phase method is avoided from the source. By using a jacket and built-in coil to precisely control the exothermic process of the nucleophilic ring-opening reaction, the occurrence of side reactions is effectively suppressed, ensuring high product selectivity. Furthermore, gas chromatography analysis is used to accurately determine the fraction switching point in the vacuum distillation process. Therefore, this method significantly improves the yield and purity of the final product R / S-4-chloro-3-hydroxybutyronitrile, while reducing energy and material consumption.
[0012] Preferably, in step S1, the amount of R or S-epoxychloropropane added into the pumping pipeline is 500-1500 kg, and the amount of anhydrous methanol is 1000-2000 kg.
[0013] Preferably, in step S2, the amount of diethylamine added is 25-30 kg, and the temperature is controlled at 15-20°C during the addition by the jacket outside the reactor and the built-in coil.
[0014] Preferably, in step S2, after the diethylamine has been added, the following steps are performed:
[0015] After the process is complete, add hydrogen cyanide dropwise. The amount of hydrogen cyanide added is 300-400 kg. After the addition is complete, stir the mixture and control the temperature at 15-20℃.
[0016] After the addition is complete, keep the mixture warm for 7-9 hours and take a sample for gas chromatography analysis of the raw material epichlorohydrin;
[0017] During testing, the content of epichlorohydrin in the raw material was <0.5%, and the reaction was qualified, so the material was transferred to the reaction tank.
[0018] Preferably, in step S3, the hot water regulating valve of the falling film evaporator is opened. When the boiling point of methanol is low, hot water can be introduced under vacuum conditions to meet its vaporization conditions, thereby controlling the temperature of the falling film evaporator to be >80°C.
[0019] Preferably, in step S4, in order to prevent the solvent from being drawn away by the vacuum pump, a condenser is installed on the receiving tank, and a collection tank is added after the vacuum pump.
[0020] Preferably, the temperature of the primary condenser is controlled to be <30℃, the temperature of the secondary condenser is <10℃, the condenser is circulated with chilled water and the temperature is controlled to be <5℃, and the solvent residue in the reaction solution is considered qualified if the solvent residue is <2%.
[0021] Preferably, in step S5, when the crude product is transferred to the distillation column, the two batches of materials are combined, and the distillation process controls the column bottom temperature to be 110-120°C, initially collecting light components in receiving tank 1.
[0022] Preferably, when receiving tank 1 collects light components, it samples and tests the gas phase content of R / S-4-chloro-3-hydroxybutyronitrile product to ensure it is >98%.
[0023] Preferably, after detecting that the gas phase content of the product is >98%, the following steps are performed:
[0024] Switch to receiving tank 2 to collect the product;
[0025] After distillation is complete, stop steaming and then shut down the vacuum units in stages.
[0026] After restoring to normal pressure with nitrogen, the product in receiving tank 2 is packed into barrels, and the light components are collected and returned for re-refining.
[0027] This invention provides a stereoselective synthesis method for R and S-4-chloro-3-hydroxybutyronitrile. It has the following beneficial effects:
[0028] This invention utilizes methanol as a solvent to induce a nucleophilic addition reaction between the R-configuration / S-configuration 4-chloro-3-hydroxybutyronitrile and diethylamine, a catalyst in which the R-configuration / S-configuration reacts with hydrogen cyanide to obtain the R / S-configuration 4-chloro-3-hydroxybutyronitrile. After the reaction, the methanol solvent is removed and can be recycled. The crude product is further purified to obtain a high-purity R / S-configuration 4-chloro-3-hydroxybutyronitrile. This invention solves the problem of high wastewater volume and high energy consumption caused by the inability to recycle water as a solvent in existing technologies. Attached Figure Description
[0029] Figure 1 This is a flowchart of a stereoselective synthesis method of R and S-4-chloro-3-hydroxybutyronitrile according to the present invention;
[0030] Figure 2 This is a flowchart of the synthesis process of a stereoselective synthesis method for R and S-4-chloro-3-hydroxybutyronitrile according to the present invention;
[0031] Figure 3 This is a flow chart of the solvent removal process in the stereoselective synthesis method of R and S-4-chloro-3-hydroxybutyronitrile according to the present invention;
[0032] Figure 4 This is a flow chart of the distillation process in a stereoselective synthesis method for R and S-4-chloro-3-hydroxybutyronitrile according to the present invention. Detailed Implementation
[0033] The technical solution of the present invention will now be clearly and completely described with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.
[0034] Please see the appendix Figure 1 - Appendix Figure 4 This invention provides a stereoselective synthesis method for R and S-4-chloro-3-hydroxybutyronitrile, comprising the following steps:
[0035] S1. First, the entire system is purged with nitrogen, and epichlorohydrin and methanol are pumped into the synthesis reactor through the pumping pipeline. After the pumping is completed, stirring is started.
[0036] S2. Diethylamine is added through a diethylamine dropper while stirring. The temperature during the reaction is controlled by the jacket outside the reactor and the built-in coil. After the reaction is qualified by sampling and testing, the material can be transferred to the reaction liquid tank.
[0037] S3. After the reaction liquid is transferred, start the circulation pump to circulate it. The reaction liquid enters from the top of the falling film evaporator. Open the hot water regulating valve of the falling film evaporator. The concentrated liquid comes out from the bottom and returns to the reaction liquid tank.
[0038] S4. Start the screw vacuum pump. The vapor phase after methanol vaporization enters the receiving tank after primary and secondary condensation. After dissolution is completed, take a sample of the reaction liquid to test the solvent. After passing the test, transfer the material to the subsequent distillation process.
[0039] S5. Transfer the desolventized crude product to the distillation column. After the transfer is completed, start the shielded pump to circulate the product, open the reboiler steam regulating valve, and start the vacuum unit step by step to begin the distillation process.
[0040] In step S1, the amount of R or S-epoxychloropropane added to the pumping pipeline is 500-1500 kg, and the amount of anhydrous methanol is 1000-2000 kg.
[0041] Specifically, by constructing a non-aqueous homogeneous organic solvent system, the inherent defects of existing aqueous phase processes are overcome. Firstly, anhydrous methanol is chosen as the reaction solvent, instead of water in traditional processes. The fundamental purpose is to create a completely homogeneous non-aqueous reaction environment. Chiral epichlorohydrin and the subsequently added hydrocyanic acid both exhibit excellent solubility in this organic solvent, enabling the formation of a single-phase solution. This homogeneous system ensures sufficient contact between reactant molecules, avoiding problems such as uneven reaction rates and increased side reactions caused by interphase mass transfer resistance.
[0042] In the ring-opening reaction of epoxy resins using anhydrous methanol as the medium, water molecules are nucleophiles. In an aqueous system, water inevitably competes with cyanide ions to attack the epoxy ring, generating uneconomical byproducts such as 3-chloro-1,2-propanediol. This invention eliminates water, the main competing nucleophile, from the reaction system by using anhydrous methanol as the organic solvent, thereby improving the selectivity of cyanide ion attack on the epoxy ring. This allows the reaction pathway to be highly specific towards the formation of the target product, 4-chloro-3-hydroxybutyronitrile, achieving both high raw material utilization and product purity, thus simplifying the subsequent purification process.
[0043] In step S2, the amount of diethylamine added is 25-30 kg, and the temperature is controlled at 15-20℃ during the addition by the jacket outside the reactor and the built-in coil.
[0044] Specifically, firstly, diethylamine acts as an organic base catalyst in this reaction. It does not react directly with epichlorohydrin, but rather serves as a highly efficient proton shuttle to activate the subsequently added nucleophile, hydrogen cyanide. As a moderately strong base, diethylamine can reversibly react with the weakly acidic hydrogen cyanide, abstracting its protons and thus continuously generating the highly reactive nucleophile cyanide ion (CN-) in situ within the reaction system. Compared to molecular hydrogen cyanide, the exposed cyanide ion exhibits stronger nucleophilicity, enabling it to attack the epoxide carbon atom of the chiral epichlorohydrin at a higher rate and with greater selectivity, initiating a ring-opening reaction.
[0045] In step S2, after the diethylamine has been added, the following steps are performed:
[0046] After that, add hydrogen cyanide dropwise. The amount of hydrogen cyanide added is 300-400 kg. After the addition is complete, stir and control the temperature at 15-20℃.
[0047] After the addition is complete, keep the mixture warm for 7-9 hours and take a sample for gas chromatography analysis of the raw material epichlorohydrin;
[0048] During testing, the content of epichlorohydrin in the raw material was <0.5%, and the reaction was qualified, so the material was transferred to the reaction tank.
[0049] Specifically, the cyanide ion CN- generated by diethylamine activation in the preceding step acts as the core nucleophile. The cyanide ion selectively breaks the carbon atom with less steric hindrance on the epoxy ring, i.e., the carbon atom with the -CH2Cl group, from the back side, causing the chemical bond between the carbon atom and the epoxy oxygen to break. Since the break point is not the chiral center, and the stereochemical characteristics of the SN2 reaction ensure that the configuration of the chiral center, i.e. the carbon atom connected to the hydroxyl group, is completely preserved, the R-epoxychloropropane provides the optimal energy environment for this highly selective reaction pathway, ensuring nucleophilic efficiency.
[0050] Secondly, the heat preservation stage after the drop addition provides ample opportunity for the remaining small amount of epichlorohydrin and cyanide ions to collide and react. This not only directly increases the yield of the target product but also reduces the burden on subsequent purification steps. If there is a large amount of residual epichlorohydrin, its boiling point is close to that of the target product, which will cause difficulties in distillation separation and affect the purity and yield of the product.
[0051] In step S3, the hot water regulating valve of the falling film evaporator is opened. When the boiling point of methanol is low, hot water can be introduced under vacuum conditions to meet its vaporization conditions, and the temperature of the falling film evaporator is controlled to be >80℃.
[0052] Specifically, under an inert atmosphere protected by nitrogen, metered chiral epichlorohydrin and anhydrous methanol as solvent are first added to a reaction vessel. Diethylamine, the catalyst, is then added dropwise, followed by the addition of hydrogen cyanide. The reaction temperature is precisely controlled using the reaction vessel's jacket and built-in coils to carry out the nucleophilic ring-opening reaction. Gas chromatography is used to monitor the conversion of the raw materials. The synthesis step is complete when the residual epichlorohydrin content is detected to be <0.5%. This step uses an organic solvent instead of the traditional aqueous phase system, thus avoiding the generation of large amounts of process wastewater at the source.
[0053] The synthesis reaction solution then enters the solvent removal process. This step uses a falling film evaporator to circulate and evaporate the reaction solution under vacuum conditions to remove the solvent methanol. Falling film evaporation technology utilizes the principle of thin-film evaporation, increasing the gas-liquid contact area and shortening the heating time of the material, making it suitable for processing heat-sensitive target products. The evaporated methanol vapor is condensed and collected through a multi-stage condensation system, including primary, secondary, and safety condensers after the receiving tank, enabling solvent recovery and reuse. Solvent removal ends when the residual methanol content in the concentrate is <2%.
[0054] Finally, the crude product obtained after solvent removal is purified by vacuum distillation. The material is pumped into the bottom of a distillation column and fractionated under high vacuum and a bottom temperature of 110-120°C. During the operation, residual solvent and other light components are distilled off first. Once the vapor content of the top product stabilizes above 98%, the fraction is switched and the target product is collected. The light components obtained from distillation can be collected and returned to previous batches for reprocessing, ultimately yielding high-purity R / S-4-chloro-3-hydroxybutyronitrile.
[0055] In step S4, a condenser was installed on the receiving tank to prevent the solvent from being drawn away by the vacuum pump, and a collection tank was added after the vacuum pump.
[0056] The temperature of the first-stage condenser should be controlled below 30℃, the temperature of the second-stage condenser below 10℃, and chilled water should be circulated through the condenser. The temperature should be controlled below 5℃. The reaction solution is considered qualified if the solvent residue is less than 2% when sampled and tested.
[0057] Specifically, the first step is the synthesis reaction. Under an inert atmosphere protected by nitrogen, a measured amount of chiral epichlorohydrin and anhydrous methanol as a solvent are added to a reaction vessel. At a temperature of 15-20°C, diethylamine, a catalyst, is added first, followed by the dropwise addition of hydrogen cyanide. The reaction is precisely controlled using the jacket and built-in coils of the reaction vessel to carry out a nucleophilic ring-opening reaction. The conversion of the raw materials is monitored by gas chromatography. When the residual amount of epichlorohydrin is <0.5%, the synthesis step is complete. This step uses an organic solvent to replace the traditional aqueous phase system, avoiding the generation of a large amount of process wastewater at the source and creating conditions for subsequent solvent recovery.
[0058] After the synthesis reaction solution is transferred, a falling film evaporator is used to circulate and evaporate the reaction solution under vacuum conditions to remove the solvent methanol. The falling film evaporation technology utilizes the thin film evaporation principle, which increases the heat and mass transfer area and shortens the heating time of the material. This is beneficial for protecting the heat-sensitive target product. The evaporated methanol vapor is condensed and collected by a multi-stage condensation system, including the first stage, the second stage and the safety condenser after the receiving tank. This allows for the recovery and reuse of the solvent. When the residual methanol content in the concentrate is <2%, the solvent removal is completed.
[0059] The crude product obtained by desolventizing is finally purified by vacuum distillation. The material is pumped into the bottom of the distillation column and fractionated under high vacuum and bottom temperature of 110-120℃. During the operation, the residual solvent and other light components are distilled off first. When the vapor content of the product at the top of the column is stable above 98%, the fraction is switched and the target product is collected. The light components obtained by distillation can be collected and returned to the previous batch for reprocessing, and finally high-purity R / S-4-chloro-3-hydroxybutyronitrile product is obtained.
[0060] In step S5, when the crude product is transferred to the distillation column, the two batches of materials are combined. The distillation process controls the temperature of the column bottom at 110-120℃. Initially, the light components are collected in receiving tank 1.
[0061] Specifically, at the start of the operation, the crude products obtained from the two batches of solvent removal are usually combined and transferred together into the distillation column to improve the efficiency of a single run. After the distillation is started, the temperature of the material is maintained at 110-120°C by heating the column bottom. Under this temperature and vacuum conditions, impurities with lower boiling points, including residual solvents, will be distilled off first. These initial distillates are called light components and are collected separately in the first receiving tank. The purpose is to remove impurities in advance in preparation for the subsequent collection of high-purity products.
[0062] When receiving tank 1 collects light components, it is sampled and tested. The gas phase content of R / S-4-chloro-3-hydroxybutyronitrile product is >98%.
[0063] Once the gas phase content of the tested product is >98%, proceed with the following steps:
[0064] Switch to receiving tank 2 to collect the product;
[0065] After distillation is complete, stop steaming and then shut down the vacuum units in stages.
[0066] After restoring to normal pressure with nitrogen, the product in receiving tank 2 is packed into barrels, and the light components are collected and returned for re-refining.
[0067] Specifically, the process is monitored by sampling and analyzing the distillate in the first receiving tank. When gas chromatography shows that the product content exceeds 98%, it indicates that the light component impurities have been basically removed. At this point, the fraction collection is switched to the second receiving tank to start collecting the high-purity final product.
[0068] After distillation, the system is safely shut down in the order of stopping heating first and then stopping vacuum. After the system cools down, nitrogen is used to restore the equipment to atmospheric pressure to prevent the product from being oxidized by contact with air. Finally, the qualified product in the second receiving tank is barreled, while the light components containing a small amount of product collected in the first receiving tank are collected and sent back to subsequent batches for re-distillation to improve the overall utilization rate of the material.
[0069] Example 1
[0070] Under nitrogen protection, 500 kg of S-epoxychloropropane and 1000 kg of anhydrous methanol were added to the reactor. 25 kg of diethylamine was added dropwise at 15 °C, followed by 300 kg of hydrogen cyanide. The reaction was maintained at 15 °C for 7 hours. The reaction ended when the residual S-epoxychloropropane content was <0.5%.
[0071] The reaction solution is circulated and evaporated under vacuum through a falling film evaporator at >80℃ to remove methanol. The methanol vapor is recovered by three-stage condensation. When the methanol residue in the concentrate is <2%, the desolvation is completed.
[0072] Two batches of crude product were combined for vacuum distillation, with the bottom temperature controlled at 110°C. Initially, the light components were collected separately. When the content of the top product was >98%, the receiving tank was switched to collect the product. After the process was completed, the light components were returned for re-purification.
[0073] Example 2
[0074] Under nitrogen protection, 1000 kg of R-epoxychloropropane and 1500 kg of anhydrous methanol were added to the reactor. At 18°C, 27.5 kg of diethylamine was added dropwise, followed by 350 kg of hydrogen cyanide. The reaction was maintained at 18°C for 8 hours. The reaction ended when the residual R-epoxychloropropane content was <0.5%.
[0075] The reaction solution is circulated and evaporated under vacuum through a falling film evaporator at >80℃ to remove methanol. The methanol vapor is recovered by three-stage condensation. Desolvation is completed when the methanol residue in the concentrate is <2%.
[0076] Two batches of crude product were combined and subjected to vacuum distillation. The temperature of the bottom of the column was controlled at 115°C. The initial fraction was collected separately. When the content of the top product was >98%, the receiving tank was switched to collect the product. After the process was completed, the light components were returned for re-purification.
[0077] Example 3
[0078] Under nitrogen protection, 1500 kg of S-epoxychloropropane and 2000 kg of anhydrous methanol were added to the reactor. At 20°C, 30 kg of diethylamine was added dropwise, followed by 400 kg of hydrogen cyanide. The reaction was maintained at 20°C for 9 hours. The reaction ended when the residual amount of the raw material S-epoxychloropropane was <0.5%.
[0079] The reaction solution is circulated and evaporated under vacuum through a falling film evaporator at >80℃ to remove methanol. The methanol vapor is recovered by three-stage condensation. When the methanol residue in the concentrate is <2%, the desolvation is completed.
[0080] Two batches of crude product were combined and subjected to vacuum distillation. The temperature of the distillate column was controlled at 120°C. The initial fraction was collected separately. When the content of the product at the top of the column was >98%, the receiving tank was switched to collect the product. After the process was completed, the light components were returned for re-purification.
[0081] Comparative Example 1:
[0082] The difference from Example 1 is that diethylamine, which is used as a catalyst, is not added in step S2; all other steps are the same.
[0083] Comparative Example 2:
[0084] Compared with Example 1, the difference is that in step S2, when diethylamine and hydrogen cyanide are added dropwise, the temperature is not controlled by the external jacket and internal coil of the reactor to make the reaction temperature exceed the range of 15-20°C. All other aspects are the same.
[0085] Comparative Example 3:
[0086] Compared with Example 2, the difference is that in the vacuum solvent removal process of step S4, only the primary condenser is used to control the temperature at <30°C for solvent recovery, and the secondary condenser and the safety condenser located after the receiving tank are not installed. All other aspects are the same.
[0087] Comparative Example 4:
[0088] The difference from Example 2 is that in the vacuum distillation of step S5, the temperature of the reboiler is controlled at 150°C, which is outside the range of 110-120°C, but the rest are the same.
[0089] Comparative Example 5:
[0090] Compared with Example 3, the difference is that in step S2, the heat preservation time after the addition of hydrogen cyanide is 2 hours, which does not meet the requirement of 7-9 hours, but the rest are the same.
[0091] Comparative Example 6:
[0092] Compared with Example 3, the difference is that in the distillation process of step S5, the content of the top product of the column is not sampled and tested. Instead, one hour after the start of distillation, the sample is switched from receiving tank 1 to receiving tank 2. All other steps are the same.
[0093] Table 1: Results Comparison Table
[0094]
[0095]
[0096]
[0097] As can be seen from Table 1:
[0098] Comparing Example 1 and Comparative Example 1, the nucleophilic ring-opening reaction could hardly proceed without the addition of the catalyst diethylamine, proving that the catalyst is essential in this reaction system.
[0099] Comparing Example 1 and Comparative Example 2, it can be seen that strictly controlling the reaction temperature at 15-20℃ is the key to ensuring high yield and high purity. If the temperature is not controlled, the violent exothermic reaction will cause side reactions and seriously affect the product quality.
[0100] Comparing the results of Example 2 with those of Comparative Example 3 demonstrates that the use of a three-stage series condensation system is crucial for the complete recovery of solvents, while using only a single-stage condensation system would result in significant solvent loss and environmental pollution.
[0101] Comparing Example 2 and Comparative Example 4, it can be seen that the target product R / S-4-chloro-3-hydroxybutyronitrile is a heat-sensitive substance, and the temperature of the distillation column reboiler must be strictly controlled within the range of 110-120℃. Excessive temperature will lead to severe decomposition of the product, making it impossible to obtain a qualified product.
[0102] The results of comparing Example 3 and Comparative Example 5 show that a heat preservation reaction time of 7-9 hours is a prerequisite for ensuring the full conversion of raw materials. Insufficient heat preservation time will lead to incomplete reaction and directly reduce the process yield.
[0103] Comparing Example 3 and Comparative Example 6, it can be seen that the analytical control method using online gas chromatography detection and product content as the basis for fraction switching ensures high final product quality and consistent batch-to-batch stability. Traditional switching methods based on fixed time intervals cannot guarantee product purity.
[0104] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.
Claims
1. A stereoselective synthesis method for R and S-4-chloro-3-hydroxybutyronitrile, characterized in that, Includes the following steps: S1. First, the entire system is purged with nitrogen, and epichlorohydrin and methanol are pumped into the synthesis reactor through the pumping pipeline. After the pumping is completed, stirring is started. S2. Diethylamine is added through a diethylamine dropper while stirring. The temperature during the reaction is controlled by the jacket outside the reactor and the built-in coil. After the reaction is tested and found to be qualified, the material can be transferred to the reaction liquid tank. S3. After the reaction liquid is transferred, start the circulation pump to circulate it. The reaction liquid enters from the top of the falling film evaporator. Open the hot water regulating valve of the falling film evaporator. The concentrated liquid comes out from the bottom and returns to the reaction liquid tank. S4. Start the screw vacuum pump. The vapor phase after methanol vaporization enters the receiving tank after primary and secondary condensation. After dissolution is completed, take a sample of the reaction liquid to test the solvent. After passing the test, transfer the material to the subsequent distillation process. S5. Transfer the desolventized crude product to the distillation column. After the transfer is completed, start the shielded pump to circulate the product, open the reboiler steam regulating valve, and start the vacuum unit step by step to begin the distillation process.
2. The stereoselective synthesis method of R and S-4-chloro-3-hydroxybutyronitrile according to claim 1, characterized in that, In step S1, the amount of R or S-epoxychloropropane added to the pumping pipeline is 500-1500 kg, and the amount of anhydrous methanol is 1000-2000 kg.
3. The stereoselective synthesis method of R and S-4-chloro-3-hydroxybutyronitrile according to claim 1, characterized in that, In step S2, the amount of diethylamine added is 25-30 kg, and the temperature is controlled at 15-20°C during the addition by the jacket outside the reactor and the built-in coil.
4. The stereoselective synthesis method of R and S-4-chloro-3-hydroxybutyronitrile according to claim 1, characterized in that, In step S2, after the diethylamine has been added, the following steps are performed: After the process is complete, add hydrogen cyanide dropwise. The amount of hydrogen cyanide added is 300-400 kg. After the addition is complete, stir the mixture and control the temperature at 15-20℃. After the addition is complete, keep the mixture warm for 7-9 hours and take a sample for gas chromatography analysis of the raw material epichlorohydrin; During testing, the content of epichlorohydrin in the raw material was <0.5%, and the reaction was qualified, so the material was transferred to the reaction tank.
5. The stereoselective synthesis method of R and S-4-chloro-3-hydroxybutyronitrile according to claim 1, characterized in that, In step S3, the hot water regulating valve of the falling film evaporator is opened. When the boiling point of methanol is low, hot water can be introduced under vacuum conditions to meet its vaporization conditions, and the temperature of the falling film evaporator is controlled to be >80°C.
6. The stereoselective synthesis method of R and S-4-chloro-3-hydroxybutyronitrile according to claim 1, characterized in that, In step S4, to prevent the solvent from being drawn away by the vacuum pump, a condenser was installed on the receiving tank, and a collection tank was added after the vacuum pump.
7. The stereoselective synthesis method of R and S-4-chloro-3-hydroxybutyronitrile according to claim 6, characterized in that, The temperature of the first-stage condenser is controlled to be <30℃, the temperature of the second-stage condenser is <10℃, the condensers are circulated with chilled water and the temperature is controlled to be <5℃, and the solvent residue of the reaction solution is qualified if the sample test shows <2%.
8. The stereoselective synthesis method of R and S-4-chloro-3-hydroxybutyronitrile according to claim 1, characterized in that, In step S5, when the crude product is transferred to the distillation column, the two batches of materials are combined. The distillation process controls the temperature of the column bottom to be 110-120°C. Initially, the light components are collected in receiving tank 1.
9. The stereoselective synthesis method of R and S-4-chloro-3-hydroxybutyronitrile according to claim 8, characterized in that, When receiving tank 1 collects light components, it is sampled and tested to determine that the gas phase content of R / S-4-chloro-3-hydroxybutyronitrile product is >98%.
10. The stereoselective synthesis method of R and S-4-chloro-3-hydroxybutyronitrile according to claim 9, characterized in that, Once the gas phase content of the detected product is >98%, the following steps are performed: Switch to receiving tank 2 to collect the product; After distillation is complete, stop steaming and then shut down the vacuum units in stages. After restoring to normal pressure with nitrogen, the product in receiving tank 2 is packed into barrels, and the light components are collected and returned for re-refining.