Process for the production of vitamin b6 intermediate n-ethoxyoxalyl-l-alanine ethyl ester

Abstract

The application provides a production process of a vitamin B6 intermediate N-ethoxyoxalyl-L-alanine ethyl ester and belongs to the technical field of compound synthesis. Alanine 1 and oxalic acid diethyl ester 2 are stirred under heating at 110 DEG C for 15-20 hours, and the reaction solution is completely dissolved. 80% of product 4 is generated, and 20% of intermediate product 3 is generated. The intermediate product 3 is subjected to hydroxyl esterification by adding a catalyst (concentrated phosphoric acid) and anhydrous ethanol to generate the product 4. The route generates most of the product through acylation reaction, and a small amount of intermediate is subjected to esterification reaction to generate the product. The application has the advantages of short reaction time, high production efficiency and the like, and does not need harmful benzene as a solvent.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of compound synthesis, and relates to a production process of vitamin B6 intermediate N-ethoxyoxalyl-L-alanine ethyl ester. BACKGROUND

[0002] At present, the production process of vitamin B6 intermediate N-ethoxyoxalyl-L-alanine ethyl ester generally uses the reaction of alanine and oxalic acid under the conditions of heating and water separation of phenol and oxalic acid diethyl ester to prepare oxalate. The reaction formula is as follows:

[0003]

[0004] The process has a reversible esterification reaction, which leads to a long reaction time, and the reaction is difficult to complete due to the presence of water, and the energy consumption is high, and the product molar yield is generally about 90%. The solvent benzene is a high-stability solvent with strong carcinogenicity, and is generally not accepted by pharmaceutical and chemical production, and government regulatory departments also repeatedly advocate avoiding the use of solvent benzene in drug production. The present application aims to solve this problem. SUMMARY

[0005] The present application aims to solve the above problems existing in the prior art, and provides a production process of vitamin B6 intermediate N-ethoxyoxalyl-L-alanine ethyl ester, and the technical problem to be solved by the present application is how to shorten the reaction time and avoid the use of solvent benzene.

[0006] The object of the present application can be achieved by the following technical scheme:

[0007] The present application is a new production process of N-oxalate, which completely eliminates the solvent benzene, and the main route of the process is as follows:

[0008]

[0009] The route is that alanine 1 and oxalic acid diethyl ester 2 are stirred at 110 DEG C for 15-20 hours under heating conditions, and the reaction liquid is completely dissolved. 80% of the product 4 is generated, and 20% of the intermediate product 3 is generated. The intermediate product 3 is subjected to hydroxyl esterification with a catalyst (concentrated phosphoric acid) and anhydrous ethanol to generate the product 4. The route first acylates to obtain most of the product, and a small amount of intermediate state is subjected to esterification reaction to obtain the product. In this way, the reaction time is greatly shortened, the production efficiency is improved, and the solvent benzene is eliminated.

[0010] The specific steps are as follows:

[0011] 1) Add oxalic acid diethyl ester 15 kg to a 50 L reaction kettle, stir in alanine 3 kg, and then start heating, and the material temperature is kept at 108-112 DEG C, and the reaction is kept for 15-20 hours until the alanine is completely dissolved;

[0012] 2) confirm whether the alanine is completely reacted by the way of indantrione coloration;

[0013] 3) after the alanine is completely reacted, the material is slightly cooled to 97-105°C, and the recovery of diethyl oxalate is started under reduced pressure. The vacuum and temperature are continuously increased until the material temperature is 145°C and the vacuum degree is -0.1 MPa, and the recovery of diethyl oxalate is completed. The whole operation time is 7 hours;

[0014] 4) the material is started to be cooled to 65-75°C, and 3 kg of anhydrous ethanol is added. After the material temperature is reduced to 45-50°C, 250 g of concentrated phosphoric acid is started to be added;

[0015] 5) after the addition of the concentrated phosphoric acid is completed, the material is stirred for 10 minutes, and then the temperature is gradually increased. The heating temperature is set to 90°C, and the material is started to be refluxed at 80°C. After the material is kept at 80°C for 22 hours, the recovery of ethanol is started;

[0016] 6) diethyl oxalate is recovered again. The vacuum is continuously reduced to -0.1 MPa, and the temperature is slowly increased until the material temperature is 140°C. The recovery of diethyl oxalate is completed, and the remaining material is the target product. The material is cooled and discharged.

[0017] In the traditional process, alanine and oxalic acid are reacted to prepare oxalate under the conditions of benzene alcohol, diethyl oxalate, and water separation. The reaction kettle does not require high vacuum degree. However, in the present scheme, the core is to use excess diethyl oxalate to react with alanine to ensure complete reaction of alanine and irreversibility. Therefore, after the reaction is completed, the excess diethyl oxalate needs to be recovered. Since the boiling point of diethyl oxalate is high, and the product will produce impurities at high temperature, the high vacuum method is needed to reduce the boiling point of diethyl oxalate, that is, the temperature in the kettle is controlled to be lower than the boiling point of diethyl oxalate under normal pressure to recover diethyl oxalate. Generally, a vacuum of -0.1 MPa needs to be formed in the kettle, and at least two high-quality Roots vacuum pumps need to be connected in series to achieve this. Therefore, the strength of the reaction kettle also has higher requirements for high vacuum degree. Therefore, based on the equipment in the traditional process, if the new way in the present scheme is used to produce N-ethoxyoxalyl-L-alanine ethyl ester, which is an intermediate of vitamin B6, not only the vacuum degree needs to be adjusted, but also the strength of the reaction kettle itself is not enough to support the safe production. Therefore, the applicant makes small adjustments to the existing process equipment to adapt to the new production process, as follows:

[0018] When diethyl oxalate begins to vaporize and be recovered, a first vacuum pump evacuates the gaseous diethyl oxalate into the jacket of the reactor body. Then, a second vacuum pump controls the pressure within the jacket to be between atmospheric pressure and the internal pressure of the reactor. This solves several problems: First, the pressure within the jacket is between atmospheric pressure and the internal pressure of the reactor. The pressure difference between the inner and outer shells of the reactor is the difference between the internal pressure and the pressure within the jacket, while the pressure difference between the outer shell and the external pressure is the difference between atmospheric pressure and the pressure within the jacket. Compared to traditional reaction... Regarding the reactor, both the inner and outer shells experience a smaller pressure difference, whereas traditional reactor bodies require pressure equal to the difference between atmospheric pressure and the internal pressure. Secondly, the temperature of the reactor can be controlled using diethyl oxalate extracted from the vessel. After entering the jacket, the extracted diethyl oxalate transforms from a gaseous state to a liquid state, resulting in a smaller temperature difference between it and the internal temperature of the reactor. During the diethyl oxalate recovery process, the reactor needs continuous heating, while the liquefaction process of diethyl oxalate in the jacket is exothermic. Therefore, energy consumption can be reduced, and the waste heat from the recovered diethyl oxalate can be fully utilized. Thirdly, because the pressure inside the jacket is much lower than atmospheric pressure, the pressure difference between the inlet and outlet of the first vacuum pump is not large, at least much smaller than the pressure at the outlet connected to atmospheric pressure. This will significantly improve the operating efficiency and actual effect of the first vacuum pump. As is well known, the reason why multiple vacuum pumps are connected in series to achieve a high vacuum environment is that the pressure difference between the inlet and outlet of a single vacuum pump cannot be too large. An excessive pressure difference will cause backflow and increase the operating resistance of the equipment. In this scheme, the outlet of the first vacuum pump is connected to the jacket of the reactor, not the external atmospheric pressure. This significantly reduces the pressure difference between the inlet and outlet of the first vacuum pump, and the pressure difference between the inlet and outlet of the second vacuum pump is also not very large. Thus, the traditional method of directly connecting multiple vacuum pumps in series is replaced by connecting them to the jacket of the reactor, which can still achieve the high vacuum environment required inside the reactor. Moreover, diethyl oxalate does not need to pass through multiple vacuum pumps, but only through the first vacuum pump. This will greatly reduce the residue of diethyl oxalate in the equipment after liquefaction and improve the recovery rate of diethyl oxalate. At the same time, as is well known, the residue of liquid in the vacuum pump will reduce the efficiency of the vacuum pump. Attached Figure Description

[0019] Figure 1 This is a schematic diagram of the equipment connections during the recovery of diethyl oxalate.

[0020] In the diagram, 1 is the interlayer; 2 is the first vacuum pump; and 3 is the second vacuum pump. Detailed Implementation

[0021] The following are specific embodiments of the present invention, which are described in conjunction with the accompanying drawings to further illustrate the technical solutions of the present invention. However, the present invention is not limited to these embodiments.

[0022] The existing process route is: oxalic acid and ethanol esterification reaction to generate diethyl oxalate. Alanine and ethanol reaction to generate alanine ethyl ester. Then diethyl oxalate and alanine ethyl ester acylation reaction to generate our intermediate product N-ethoxyoxalyl-L-alanine ethyl ester. The main reaction formula is as follows:

[0023]

[0024] The current process has the following disadvantages:

[0025] 1. There is solvent benzene. Benzene is a primary carcinogen, which is not conducive to the market competitiveness of the final product.

[0026] 2. Due to the reversibility of esterification reaction, the esterification reaction time is longer, and the esterification reaction of alanine and ethanol has certain difficulty. The entire water separation reaction time reaches 70 hours, and the reaction is difficult to complete. The entire process operation time is more than 120 hours, which brings high energy consumption to production and increases production cost. Due to the long reaction time, the quality of the final product is also affected.

[0027] Our current approach is to overcome the above solvent benzene and shorten the reaction time. Directly using diethyl oxalate and alanine to perform acylation reaction to generate intermediate product N-ethoxyoxalyl-L-alanine ethyl ester. The main reaction formula is as follows:

[0028]

[0029] The route is that alanine 1 and diethyl oxalate 2 are stirred at 110°C under heating for 15-20 hours, and the reaction liquid is completely dissolved. 80% of the product 4 is generated, and 20% of the intermediate product 3 is generated. The intermediate product 3 (N-ethoxyoxalyl-L-alanine) is subjected to hydroxyl site esterification with a catalyst (concentrated phosphoric acid) and anhydrous ethanol to generate product 4 (N-ethoxyoxalyl-L-alanine). Continue to react with ethanol under the catalysis of concentrated phosphoric acid to generate product N-ethoxyoxalyl-L-alanine ethyl ester. This route first acylates to obtain most of the product, and a small amount of intermediate state is subjected to esterification reaction to obtain the product. This greatly shortens the reaction time, improves the production efficiency, and eliminates the solvent benzene.

[0030] The specific steps are as follows:

[0031] 1) Add diethyl oxalate 15 kg to a 50 L reaction kettle, stir in alanine 3 kg, and start heating. The material temperature is maintained at 110°C, and the reaction is maintained for 15-20 hours until the alanine is completely dissolved.

[0032] 2) Confirm whether the alanine is completely reacted by using ninhydrin coloration;

[0033] 3) After the complete reaction of alanine, the material is slightly cooled to 100°C, and the recovery of diethyl oxalate is started under reduced pressure. The vacuum and temperature are continuously increased until the material temperature is 145°C and the vacuum is -0.1 MPa. The recovery of diethyl oxalate is completed. The whole operation time is 7 hours;

[0034] 4) The material is started to be cooled to 70°C, and 3 kg of anhydrous ethanol is added. After the temperature of the material is reduced to 48°C, 250 g of concentrated phosphoric acid is added;

[0035] 5) After the addition of the concentrated phosphoric acid, the material is stirred for 10 minutes, and then gradually heated to 90°C. The material is refluxed at 80°C, and the reaction is kept for 22 hours. Then, the ethanol is recovered;

[0036] 6) The diethyl oxalate is recovered again under reduced pressure to -0.1 MPa, and slowly heated to 140°C. The second recovery of diethyl oxalate is completed, and the remaining material is oxalate mainly composed of the target product. The material is cooled and weighed as 8 kg.

[0037] 7) The sample is sent for detection. The gas chromatography results are as follows: (main impurities)

[0038]

[0039] Molar yield: about 94.5%, and the whole operation time is about 55 hours. The yield is improved, and the energy consumption is reduced.

[0040] In steps 3) and 6), the structure shown in Figure 1 is adopted. On the basis of the prior art, a small range adjustment can be realized. Simply speaking, the original multiple vacuum pumps in series are replaced by a first vacuum pump 2 connected to the reaction kettle jacket 1 and the reaction kettle inner cavity, and a second vacuum pump 3 connected to the outside and the reaction kettle jacket 1. The distilled diethyl oxalate is stored in the original fluid temperature control jacket 1, instead of the traditional reaction kettle temperature control medium. The waste heat of diethyl oxalate is recovered, and the disadvantages caused by the series connection of vacuum pumps are reduced.

[0041] Specifically: when diethyl oxalate starts to vaporize and recover, use the first vacuum pump 2 to extract gaseous diethyl oxalate into the interlayer 1 of the reactor body, and then use the second vacuum pump 3 to control the gas pressure value in the interlayer 1 of the reactor body to be between atmospheric pressure and the gas pressure in the reactor, so that the following problems can be solved: 1. The gas pressure in the interlayer 1 of the reactor body is between atmospheric pressure and the gas pressure in the reactor body, the pressure difference received by the inner shell of the reactor body is the difference between the gas pressure in the reactor and the gas pressure in the interlayer 1, and the pressure difference received by the outer shell is the difference between atmospheric pressure and the gas pressure in the interlayer 1. Compared with traditional reactors, both the inner shell and the outer shell bear smaller pressure difference, and the traditional reactor body needs to bear the pressure difference between atmospheric pressure and the gas pressure in the reactor body; 2. The temperature of the reactor can be controlled by using the extracted diethyl oxalate. The extracted diethyl oxalate from the reactor changes from gas to liquid after entering the interlayer 1, and the temperature difference between the extracted diethyl oxalate and the internal temperature of the reactor is small. During the recovery of diethyl oxalate, the reactor needs to be continuously heated, while the liquefaction of diethyl oxalate in the interlayer 1 is exothermic, so the energy consumption can be reduced and the waste heat of diethyl oxalate recovery can be fully utilized; 3. Because the pressure in the interlayer 1 is much lower than atmospheric pressure, the pressure difference between the inlet and outlet of the first vacuum pump 2 is not large, at least much smaller than the outlet connected to atmospheric pressure, which will greatly improve the operating efficiency and actual effect of the first vacuum pump 2. As we all know, the reason why multiple vacuum pumps are connected in series to achieve high vacuum environment is that the pressure difference between the inlet and outlet of a single vacuum pump cannot be too large. A large pressure difference will cause backflow and increase the operating resistance of the equipment. In this scheme, the outlet of the first vacuum pump 2 is connected to the interlayer 1 of the reactor, not to the outside atmospheric pressure, so the pressure difference between the inlet and outlet of the first vacuum pump 2 is much smaller, and the pressure difference between the inlet and outlet of the second vacuum pump is also not large. In this way, the traditional method of directly connecting multiple vacuum pumps in series is changed to connecting the interlayer 1 of the reactor, which can also achieve the requirement of high vacuum environment in the reactor, and diethyl oxalate does not need to pass through multiple vacuum pumps, only through the first vacuum pump. This will greatly reduce the residue of diethyl oxalate in the equipment after liquefaction, improve the recovery rate of diethyl oxalate, and at the same time, as we all know, the residue of liquid in the vacuum pump will reduce the efficiency of the vacuum pump; finally, the diethyl oxalate liquid is recovered from the bottom of the interlayer 1. The extraction pressure of the second vacuum pump 3 is different during the two recoveries of diethyl oxalate. The first recovery of diethyl oxalate is greater than the second recovery, because the recovery amount of diethyl oxalate during the second recovery is very small, and the second vacuum pump 3 can be closed during the second recovery of diethyl oxalate. Even during the first recovery of diethyl oxalate, the second vacuum pump 3 is intermittently started according to the pressure difference and the liquefaction of diethyl oxalate.

[0042] The specific embodiments described herein are merely illustrative of the spirit of the application. Various modifications or changes in the specific embodiments described herein can occur to those skilled in the art to which the application pertains without departing from the spirit of the application, and it is understood that such modifications or changes are to be considered as within the scope of the application as defined by the appended claims.

Claims

1. A production process for N-ethoxyoxaloyl-L-alanine ethyl ester, an intermediate of vitamin B6, characterized in that, Includes the following steps: 1) Add 15 kg of diethyl oxalate to a 50 L reactor, stir and add 3 kg of alanine, then start heating. Keep the material temperature between 108 and 112 °C and keep the reaction at this temperature for 15 to 20 hours until the alanine is completely dissolved. 2) Use ninhydrin to determine if the alanine has reacted completely; 3) After the alanine has completely reacted, the material is cooled slightly to between 97 and 105°C, and the diethyl oxalate is recovered under reduced pressure. Vacuuming and heating are continued until the material temperature reaches 145°C and the vacuum degree is -0.1 MPa to complete the recovery of diethyl oxalate. The entire operation takes 7 hours. 4) Start cooling the material to between 65 and 75°C, add 3 kg of anhydrous ethanol. After the material temperature drops to 45 to 50°C after adding anhydrous ethanol, start adding 250 g of concentrated phosphoric acid. 5) After adding concentrated phosphoric acid, stir for 10 minutes and then gradually increase the temperature to 90°C. When the material temperature reaches 80°C, start the reflux reaction and keep the reaction at this temperature for 22 hours before starting to recover ethanol. 6) Recover diethyl oxalate again by continuously reducing the pressure to -0.1 MPa and slowly raising the temperature until the material temperature reaches 140°C. The second recovery of diethyl oxalate is completed, and the residue is the target product. Cool down and release the material. In steps 3) and 6), the recovery system used for recovering diethyl oxalate includes a reaction vessel, a jacket (1) set outside the reaction vessel, a first vacuum pump (2) and a second vacuum pump (3). The inlet of the first vacuum pump (2) is connected to the inner cavity of the reaction vessel, the outlet of the first vacuum pump (2) is connected to the jacket (1), the inlet of the second vacuum pump is connected to the jacket (1), and the outlet of the second vacuum pump (3) is connected to the atmosphere. The gas pressure inside the jacket (1) is greater than the pressure inside the reaction vessel, and the gas pressure inside the jacket (1) is less than the atmospheric pressure.

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