CN114671823A - Preparation method of 4-methyl-5-ethoxy oxazole acid ethyl ester - Google Patents
Preparation method of 4-methyl-5-ethoxy oxazole acid ethyl ester Download PDFInfo
- Publication number
- CN114671823A CN114671823A CN202210442034.0A CN202210442034A CN114671823A CN 114671823 A CN114671823 A CN 114671823A CN 202210442034 A CN202210442034 A CN 202210442034A CN 114671823 A CN114671823 A CN 114671823A
- Authority
- CN
- China
- Prior art keywords
- toluene
- reaction
- temperature
- ethyl ester
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/36—One oxygen atom
- C07D263/42—One oxygen atom attached in position 5
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention provides a preparation method of 4-methyl-5-ethoxy oxazole, which adopts a composite cyclization agent of phosphorus oxychloride and triphosgene, greatly reduces the usage amount of the phosphorus oxychloride, improves the reaction yield from less than 80 percent to more than 90 percent, and has the advantages of reduced production cost and reduced phosphorus-containing wastewater.
Description
Technical Field
The invention relates to synthesis of vitamin B6, in particular to a preparation method of an intermediate 4-methyl-5-ethoxy oxazole acid ethyl ester thereof.
Background
Vitamin B6(Vitamin B6), also known as pyridoxine, includes pyridoxine, pyridoxal and pyridoxamine, exists in vivo in the form of phosphate, is a water-soluble Vitamin, is easily destroyed by light or alkali, and is not resistant to high temperature. Pyridoxine is thermostable, and pyridoxal and pyridoxamine are not. Vitamin B6 is marketed primarily as pyridoxine hydrochloride.
Vitamin B6 is a component of some coenzymes in human body, participates in various metabolic reactions, and especially has close relation with amino acid metabolism. The vitamin B6 preparation is clinically applied to prevent and treat vomiting of pregnancy and vomiting of radiation sickness. It can also be used for treating arteriosclerosis, alopecia, hypercholesterolemia, cystitis, hypoglycemia, mental disorder, muscular disorder, neurological disorder, emesis in early stage of pregnancy, overweight, postoperative emesis, and photosensitivity to sunlight. In recent years, vitamin B6 has been found to be useful in rescuing isoniazid poisoning, treating anemia, treating leukopenia, treating mental retardation, treating canker sore, treating arteriosclerosis and thromboembolic disease, delactation, treating Parkinson's disease, etc.
Vitamin B6 is usually produced industrially by chemical synthesis methods, mainly by the pyridone method, the oxazole method and other microbiological methods.
The pyridone method is a method for synthesizing vitamin B6 by using chloroacetic acid as a starting material and carrying out esterification, substitution, cyclization and other reactions, vitamin B6 is synthesized for the first time in 1936, and the vitamin B6 is proved to have the same chemical structure and biological activity as natural extracts, and then, the research on the synthesis of vitamin B6 is actively carried out in all countries in the world, so that the rapid development of the vitamin B6 industry is promoted.
In the 60 s of the 20 th century, Firestone RA and the like, on the basis of research results of scholars, a key intermediate 4-methyl-5-ethoxy oxazole is obtained by cyclization with N-formyl alanine ethyl ester as a starting material, then the key intermediate is subjected to Diels-Alder reaction with a dienophile, and vitamin B6 is obtained after conversion treatment. This synthetic route has the advantages of readily available starting materials, high yields, etc., and this process has been referred to hereafter as the "oxazole process". The oxazole method is applied to production, so that the production cost is obviously reduced, and the sale price of the vitamin B6 is greatly reduced.
Compared with the pyridone method, the oxazole method has great progress, but has certain defects. For example, a toxic solvent benzene and strong corrosive phosphorus oxychloride are used in the synthesis process of the oxazole intermediate, and the refining process of the vitamin B6 crude product is complex.
In the oxazole process for vitamin B6, there are two important intermediate compounds: ethyl N-ethoxyoxalylalaninate and ethyl 4-methyl-5-ethoxyoxazoloate.
The reaction process of the 4-methyl-5-ethoxy oxazole acid ethyl ester is generally to carry out cyclization reaction on N-ethoxy oxalyl alanine ethyl ester, and add the N-ethoxy oxalyl alanine ethyl ester, phosphorus oxychloride and triethylamine into a reaction vessel to carry out reaction to prepare the 4-methyl-5-ethoxy oxazole acid ethyl ester. In this preparation step, the yield reported in the literature (journal of Chinese medicine industry, 2004,35(1), pages 1-2) was 76.5%.
The synthesis process mainly adopts phosphorus oxychloride as a cyclization dehydration solvent, and has the defects of generating a large amount of phosphate and phosphorus-containing wastewater in the production process and low yield. The water layer and the oil layer need to be extracted and extracted for many times after the cyclization is finished, the process is complex, and more equipment is occupied.
The preparation method of N-ethoxyoxalyl alanine ethyl ester reports that: adding alpha-aminopropionic acid, industrial oxalic acid, hydrochloric acid, ethanol and benzene into a reaction vessel, and heating, rectifying, dehydrating and esterifying; adding diethyl oxalate and alkali into the esterification reaction liquid for reaction to prepare the N-ethoxy oxalyl alanine ethyl ester. The reaction path is as follows:
the toxic solvent benzene is used in the reaction, so that the subsequent reaction and the treatment of waste water and waste liquid are very complicated, and the method has great harm to the health of staff.
The Roche (Shanghai) vitamin Co Ltd adopts a solvent substitution technology, eliminates water-carrying agent benzene in the alanine esterification stage, and develops the first benzene-free vitamin B6 production process in China. The new benzene-free production process reduces the influence of production on the environment and improves the operation conditions, but the cost of the substitute solvent is relatively high, the process complexity is increased, and the production cost is increased.
How to avoid generating a large amount of phosphate and phosphorus-containing wastewater; how to avoid using toxic solvent benzene, reduce the harm to the health of staff and reduce the pollution and damage to the environment, and the realization of simple and feasible process without increasing the cost is an urgent problem to be solved.
Disclosure of Invention
The invention provides a preparation method of N-ethoxy oxalyl alanine ethyl ester and a preparation method of 4-methyl-5-ethoxy oxazole acid ethyl ester.
The invention adopts the composite cyclization agent of phosphorus oxychloride and triphosgene, greatly reduces the usage amount of the phosphorus oxychloride, simultaneously improves the reaction yield from less than 80 percent to more than 90 percent, and has the advantages of reduced production cost and reduced phosphorus-containing wastewater. The dosage of the phosphorus oxychloride can be reduced by 2/3, the yield is greatly improved, and the reaction process is milder. The water layer is extracted by toluene, can be continuously extracted by an extraction tower, can be combined with engineering optimization, and is applied to large-scale industrial mass production.
The invention provides a preparation method of 4-methyl-5-ethoxy oxazole acid ethyl ester, which is characterized by comprising the following steps: adding 250 weight parts of N-ethoxyoxalyl alanine ethyl ester 180-plus, 600 weight parts of triethylamine 400-plus and toluene into a reaction vessel, and cooling to-5-0 ℃; dissolving 80-150 parts by weight of solid phosgene in toluene, then dropwise adding the mixed solution into a reaction container, controlling the temperature to be below 6 ℃ in the dropwise adding process, cooling the temperature in the reaction container to room temperature after the dropwise adding is finished, and stirring while keeping the temperature; then dropping 20-50 parts by weight of phosphorus oxychloride, slowly heating to 40-60 ℃ after dropping, reacting for 2-6 hours, then heating to 80-100 ℃, and reacting for 0.5-4 hours under heat preservation; after the reaction is finished, cooling the reaction solution to 50-60 ℃, and adding water; washing the lower layer with toluene, mixing the toluene layer with the upper layer, recovering toluene, and distilling the substrate to obtain 4-methyl-5-ethoxy-oxazole acid ethyl ester.
The preparation method of the ethyl 4-methyl-5-ethoxy oxazole acid is characterized by comprising the following steps: 230 parts of N-ethoxy oxalyl alanine ethyl ester 200-plus, 520 parts of triethylamine 450-plus and toluene are added into a reaction vessel and cooled to-5 ℃ to 0 ℃; dissolving 130 parts by weight of solid phosgene 110-containing liquid in toluene, then dropwise adding the mixed liquid into a reaction container, controlling the temperature below 6 ℃ in the dropwise adding process, after the dropwise adding is finished, cooling the temperature in the reaction container to room temperature, and stirring while keeping the temperature; then dropping 20-30 parts by weight of phosphorus oxychloride, slowly heating to 40-60 ℃ after dropping, reacting for 4 hours, then heating to 80-100 ℃, and reacting for 1 hour under heat preservation; after the reaction is finished, cooling the reaction solution to 50-60 ℃, and adding water; washing the lower layer with toluene, mixing the toluene layer with the upper layer, recovering toluene, and distilling the substrate to obtain 4-methyl-5-ethoxy-oxazole acid ethyl ester.
The preparation method of the ethyl 4-methyl-5-ethoxy oxazole acid is characterized by comprising the following steps: 230g of N-ethoxyoxalyl alanine ethyl ester, 520g of triethylamine and 400ml of toluene are added into a 2L reaction kettle and cooled to-5-0 ℃; dissolving 110g of solid phosgene in 300ml of toluene, then dropwise adding the mixed solution into a reaction kettle, controlling the temperature to be below 6 ℃ in the dropwise adding process, after the dropwise adding is finished, cooling the temperature in the reaction kettle to room temperature, and stirring for 2 hours while keeping the temperature; then dropping 30g of phosphorus oxychloride, slowly heating to 40-60 ℃ after dropping, reacting for 4 hours, then heating to 80-100 ℃, and reacting for 1 hour under heat preservation; after the reaction is finished, cooling the reaction solution to 50-60 ℃, and adding 500mL of water; washing the lower layer of water with 400ml of toluene for 2 times, mixing the toluene layer with the upper layer of materials, recovering the toluene at the temperature of 80-100 ℃ under the vacuum condition of 0.1-3 kpa, and distilling the substrate to obtain the 4-methyl-5-ethoxy-oxazole acid ethyl ester.
The invention also provides a preparation method of N-ethoxy oxalyl alanine ethyl ester, and a large number of experiments and innovative researches find that benzene with high toxicity can be successfully replaced by a solvent with low toxicity by using absolute ethyl alcohol and toluene, and steam can be recycled for the second time by using a steam compressor, so that the energy consumption is greatly reduced, and the energy conservation and environmental protection are realized.
The synthesis process adopts toluene for esterification and rectification to carry water, but due to the difference of physicochemical properties of the toluene and the benzene, the reaction time is prolonged, the energy consumption is increased, therefore, in order to reduce the production energy consumption and shorten the reaction time, the invention carries out various attempts, finally discovers that the benzene can be replaced by using absolute ethyl alcohol and the toluene, and ensures that the yield is not reduced. Through the use of the steam compressor, the steam can be recycled for the second time, so that the energy consumption is greatly reduced, and the energy conservation and environmental protection are realized. And provides a brand-new reaction system for preparing the N-ethoxyoxalyl alanine ethyl ester.
The invention provides a reaction system (or reaction equipment) of N-ethoxy oxalyl alanine ethyl ester, which comprises the following components: the device comprises a reaction container, a rectifying tower, a water separator and a vapor compressor; heating the reaction vessel so that the vapor enters the rectification column; the vapor phase enters a vapor compressor from the top of the rectifying tower, the vapor compressor increases the temperature of the vapor by compressing hot vapor, the compressed vapor is input into a reaction container, the condensed solvent enters a water separator to continuously separate a water layer, and the toluene layer is pumped into the tower by a pump.
Preferably, the reaction vessel is an esterification rectifying still.
Preferably, the reaction system further comprises a superheater, and the vapor compressor raises the temperature of the vapor by compressing the hot vapor, and then delivers the vapor to the reaction vessel through the superheater.
Preferably, the reaction system further comprises a centrifugal pump, and the vapor compressor increases the temperature of the vapor by compressing the hot vapor, and then passes the vapor through the superheater and the centrifugal pump to feed the vapor into the reaction vessel.
Preferably, the water separator is a delayer, and a condensation recoverer is arranged at the upper end of the delayer; the condensed solvent enters a demixer to continuously separate a water layer, and a toluene layer is pumped into the tower.
Preferably, a centrifugal pump is arranged behind the water separator, and the toluene layer is pumped into the tower after passing through the centrifugal pump.
Most preferably, the reaction system comprises: the device comprises a reaction vessel 1, a rectifying tower 2, a vapor compressor 3, a superheater 4, a centrifugal pump 5, a delayer 6, a condensation recoverer 7 and a centrifugal pump 8.
The upper end of the reaction vessel 1 is provided with a rectifying tower 2, vapor phase enters a vapor compressor 3 from the top of the rectifying tower 2, the vapor compressor 3 compresses hot vapor to increase the temperature of the vapor, and then the vapor passes through a superheater 4 and a centrifugal pump 5 to be input into the reaction vessel. The lower end of the reaction vessel 1 is provided with a delayer 6, the delayer 6 is provided with a condensation recoverer 7, condensed solvent enters the delayer 6 to continuously separate a water layer, and a toluene layer is pumped into the tower through a centrifugal pump 8.
The reaction vessel is preferably an esterification rectifying still.
The invention provides a preparation method of N-ethoxy oxalyl alanine ethyl ester, which is characterized by comprising the following steps: respectively adding 20-50 parts by mass of L-alanine, 30-80 parts by mass of oxalic acid and absolute ethyl alcohol into a mixing container, heating to 90-100 ℃ for dissolving, transferring the dissolved solution into an esterification rectifying kettle, adding 50-100 parts by mass of toluene and diethyl oxalate, heating for reacting, introducing a vapor phase into a vapor compressor from the top of a rectifying tower, compressing hot vapor by the vapor compressor to increase the temperature of the vapor, inputting the compressed vapor into the reaction container, introducing the condensed solvent into a water separator to continuously separate a water layer, and pumping the toluene layer into the tower through a pump; when the reaction is carried out for 20-60 hours, adding toluene and ethanol into the esterification rectifying kettle again for reaction rectification until the water separator is basically separated out and the moisture of the materials in the esterification rectifying kettle is less than 0.1 percent, and stopping the reaction; evaporating toluene and ethanol at normal pressure; vacuum decompression steaming to eliminate diethyl oxalate and obtain N-ethoxy oxalyl alanine ethyl ester;
the reaction system used in the preparation method comprises: the device comprises a reaction container, a rectifying tower, a water separator and a vapor compressor; heating the reaction vessel so that the vapor enters the rectification column; the vapor phase enters a vapor compressor from the top of the rectifying tower, the vapor compressor increases the temperature of the vapor by compressing hot vapor, the compressed vapor is input into a reaction container, the condensed solvent enters a water separator to continuously separate a water layer, and the toluene layer is pumped into the tower by a pump.
Preferably, the reaction vessel is an esterification rectifying still.
Preferably, the reaction system further comprises a superheater, and the vapor compressor raises the temperature of the vapor by compressing the hot vapor, and then delivers the vapor to the reaction vessel through the superheater.
Preferably, the reaction system further comprises a centrifugal pump, and the vapor compressor increases the temperature of the vapor by compressing the hot vapor, and then passes the vapor through the superheater and the centrifugal pump to feed the vapor into the reaction vessel.
Preferably, the water separator is a delayer, and a condensation recoverer is arranged at the upper end of the delayer; the condensed solvent enters a demixer to continuously separate a water layer, and a toluene layer is pumped into the tower.
Preferably, a centrifugal pump is arranged behind the water separator, and the toluene layer is pumped into the tower after passing through the centrifugal pump.
Most preferably, the reaction system comprises: the device comprises a reaction vessel 1, a rectifying tower 2, a vapor compressor 3, a superheater 4, a centrifugal pump 5, a delayer 6, a condensation recoverer 7 and a centrifugal pump 8.
The upper end of the reaction vessel 1 is provided with a rectifying tower 2, vapor phase enters a vapor compressor 3 from the top of the rectifying tower 2, the vapor compressor 3 compresses hot vapor to increase the temperature of the vapor, and then the vapor passes through a superheater 4 and a centrifugal pump 5 to be input into the reaction vessel. The lower end of the reaction vessel 1 is provided with a delayer 6, the delayer 6 is provided with a condensation recoverer 7, condensed solvent enters the delayer 6 to continuously separate a water layer, and a toluene layer is pumped into the tower through a centrifugal pump 8.
The reaction vessel is preferably an esterification rectifying still.
The preparation method of N-ethoxy oxalyl alanine ethyl ester is characterized by comprising the following steps: the reaction system used in the preparation method comprises: the device comprises an esterification rectifying kettle 1, a rectifying tower 2, a vapor compressor 3, a superheater 4, a centrifugal pump 5, a delayer 6, a condensation recoverer 7 and a centrifugal pump 8; a rectifying tower 2 is arranged at the upper end of an esterification rectifying kettle 1, vapor phase enters a vapor compressor 3 from the top of the rectifying tower 2, the vapor compressor 3 compresses hot vapor to increase the temperature of the vapor, and then the vapor passes through a superheater 4 and a centrifugal pump 5 and is input into a reaction container; the lower end of the esterification rectifying kettle 1 is provided with a delayer 6, the delayer 6 is provided with a condensation recoverer 7, condensed solvent enters the delayer 6 to continuously separate a water layer, and a toluene layer is pumped into the tower through a centrifugal pump 8.
The preparation method of N-ethoxy oxalyl alanine ethyl ester is characterized by comprising the following steps: respectively adding 35 parts by mass of L-alanine, 58 parts by mass of oxalic acid and absolute ethyl alcohol into a mixing container, heating to 90-100 ℃ for dissolving, transferring the dissolved solution into an esterification rectifying kettle, adding 65 parts by mass of toluene and diethyl oxalate, heating for reacting, allowing a vapor phase to enter a vapor compressor from the top of a rectifying tower, compressing hot vapor by the vapor compressor to increase the temperature of the vapor, inputting the compressed vapor into a reaction container, allowing the condensed solvent to enter a water separator for continuously separating a water layer, and pumping the toluene layer into the tower through a pump; when the reaction is carried out for 40 hours, adding toluene and ethanol into the esterification rectifying kettle again for reaction rectification, and stopping the reaction when the water separator is basically separated out and the moisture of the materials in the esterification rectifying kettle is less than 0.1%; evaporating toluene and ethanol at normal pressure; and (3) evaporating diethyl oxalate at the temperature of between 100 and 130 ℃ at the speed of between 10 and 200pa in vacuum and reducing pressure to obtain the N-ethoxy oxalyl alanine ethyl ester.
The preparation method of N-ethoxy oxalyl alanine ethyl ester is characterized by comprising the following steps: adding 35kg of L-alanine, 58kg of oxalic acid and 60L of absolute ethyl alcohol into a mixing container respectively, heating to 90-100 ℃ for heating and dissolving, transferring the dissolved solution into an esterification rectifying kettle, adding 50L of toluene and 65kg of diethyl oxalate, heating for reaction, introducing a vapor phase into a vapor compressor from the top of a rectifying tower, compressing hot vapor by the vapor compressor to increase the temperature of the vapor, inputting the compressed vapor into the reaction container, introducing the condensed solvent into a water separator to continuously separate a water layer, and pumping the toluene layer into the tower through a pump; when the reaction is carried out for 40 hours, adding 20 liters of toluene and 30 liters of ethanol into the esterification rectifying kettle again for reaction rectification until the water separator is basically separated out and the moisture of the materials in the esterification rectifying kettle is less than 0.1 percent, and stopping the reaction; evaporating toluene and ethanol at normal pressure; and (3) evaporating diethyl oxalate at the temperature of between 100 and 130 ℃ at the speed of between 10 and 200pa in vacuum and reducing pressure to obtain the N-ethoxy oxalyl alanine ethyl ester.
The invention realizes the successful replacement of benzene and the effects of environmental protection and energy saving.
The invention also relates to a preparation method of the 4-methyl-5-ethoxy oxazole acid ethyl ester, which comprises the preparation method of the N-ethoxy oxalyl alanine ethyl ester and the preparation method of the 4-methyl-5-ethoxy oxazole acid ethyl ester. Namely, the ethyl N-ethoxyoxalyl-alaninate prepared by the preparation method of the ethyl N-ethoxyoxalyl-alaninate is used as a raw material, and the ethyl 4-methyl-5-ethoxyoxazoloate is further prepared according to the method.
The invention successfully improves the preparation methods of N-ethoxy oxalyl alanine ethyl ester and 4-methyl-5-ethoxy oxazole acid ethyl ester in the prior art; so that the prepared N-ethoxyoxalyl alanine ethyl ester directly serves as a substrate to participate in the synthesis of 4-methyl-5-ethoxyoxazole acid ethyl ester. The two steps are closely linked, the synthesis of two key intermediates in the synthesis of vitamin B6 is solved, the process steps are simple, toxic benzene is not used, the usage amount of phosphorus oxychloride is greatly reduced, the yield of the intermediates is improved, and the whole preparation process is environment-friendly, energy-saving and pollution-free. The dosage of the phosphorus oxychloride can be reduced by 2/3, the yield is greatly improved, and the reaction process is milder. The water layer is extracted by toluene, can be continuously extracted by an extraction tower, can be combined with engineering optimization, and is applied to large-scale industrial mass production.
Drawings
FIG. 1: schematic diagram of reaction equipment
1 is an esterification rectifying kettle 2, a rectifying tower 3, a vapor compressor 4, a superheater 5, a centrifugal pump 6, a delayer 7, a condensation recoverer 8 and a centrifugal pump.
Detailed Description
Example 1:
respectively adding 35 kgL-alanine, 58kg of industrial oxalic acid and 40L of 95% ethanol into a mixing container, heating to 80 ℃ for dissolving, transferring the dissolved solution into an esterification rectifying kettle, adding 30L of benzene and 65kg of diethyl oxalate, heating for reacting, continuously separating a water layer from a water separator at the top of a rectifying tower, and allowing the benzene layer to flow into the tower. When the reaction is carried out for 40 hours, adding 10L of benzene and 20L of 95 percent ethanol into the esterification rectifying still again for reaction rectification until the water separator is basically separated out and the moisture of the materials in the esterification rectifying still is less than 0.1 percent, and stopping the reaction. Distilling off benzene and alcohol under normal pressure; and (3) distilling the diethyl oxalate at the temperature of between 100 and 130 ℃ and under the vacuum pressure of between 10 and 200pa to remove the diethyl oxalate to obtain the N-ethoxyoxalyl alanine ethyl ester with the yield of 91 percent.
Example 2:
adding 35kg of L-alanine, 58kg of industrial oxalic acid and 40L of 95% ethanol into a mixing container respectively, heating to 80 ℃ for heating and dissolving, transferring the dissolved solution into an esterification rectifying kettle, adding 30L of toluene and 65kg of diethyl oxalate, heating to raise the temperature for reaction, continuously separating a water layer from a water separator at the top of a rectifying tower, and flowing the toluene layer into the tower. When the reaction is carried out for 40 hours, 10L of methylbenzene and 20L of 95% ethanol are added into the esterification rectifying still again for reaction rectification until the water separator is basically separated out and the moisture of the materials in the esterification rectifying still is less than 0.1%, and the reaction is stopped. Evaporating toluene and ethanol at normal pressure; and (3) distilling the diethyl oxalate at the temperature of between 100 and 130 ℃ and under the vacuum pressure of between 10 and 200pa to remove the diethyl oxalate to obtain the N-ethoxyoxalyl alanine ethyl ester, wherein the yield is 89 percent.
Because toluene toxicity is much lower than benzene, it is less harmful to staff and environment. After the solvent was replaced by toluene in example 2, the yield was found to be reduced, and the energy consumption was increased by 26% compared to example 1. Therefore, there is a need to screen methods that ensure yield and reduce energy consumption.
Example 3:
adding 35kg of L-alanine, 58kg of oxalic acid and 60L of absolute ethyl alcohol into a mixing container respectively, heating to 90-100 ℃ for heating and dissolving, transferring the dissolved solution into an esterification rectifying kettle, adding 50L of toluene and 65kg of diethyl oxalate, heating for reacting, continuously separating a water layer from a water separator at the top of a rectifying tower, and allowing the toluene layer to flow into the tower. And when the reaction is carried out for 40 hours, adding 20L of methylbenzene and 30L of ethanol into the esterification rectifying still again for reaction rectification until the water separator is basically separated out and the moisture of the materials in the three-opening container is less than 0.1 percent, and stopping the reaction. Distilling off toluene and alcohol under normal pressure; and (3) distilling the diethyl oxalate at the temperature of between 100 and 130 ℃ and under the vacuum pressure of between 10 and 200pa to remove the diethyl oxalate to obtain the N-ethoxyoxalyl alanine ethyl ester, wherein the yield is 92 percent.
Through experiments, the yield of the reaction can be kept above 90% by using absolute ethyl alcohol and increasing the using amount of the absolute ethyl alcohol and the toluene. But the energy consumption was still increased by 33% compared to example 1.
Example 4:
adding 35kg of L-alanine, 58kg of oxalic acid and 60 liters of absolute ethyl alcohol into a mixing container respectively, heating to 90-100 ℃ for heating and dissolving, transferring the dissolved solution into an esterification rectifying kettle, adding 50L of toluene and 65kg of diethyl oxalate, heating and heating for reacting. The upper end of an esterification rectifying kettle 1 is provided with a rectifying tower 2, a vapor phase enters a vapor compressor 3 from the top of the rectifying tower 2, the vapor compressor 3 compresses hot vapor to increase the temperature of the vapor, and the vapor passes through a superheater 4 and a centrifugal pump 5 to be input into a reaction vessel. The lower end of the esterification rectifying kettle 1 is provided with a delayer 6, the delayer 6 is provided with a condensation recoverer 7, condensed solvent enters the delayer 6 to continuously separate a water layer, and a toluene layer is pumped into the tower through a centrifugal pump 8. And when the reaction is carried out for 40 hours, adding 20L of methylbenzene and 30L of ethanol into the esterification rectifying still again for reaction rectification until the water separator is basically separated out and the water content of the materials in the esterification rectifying still is less than 0.1 percent, and stopping the reaction. Distilling off toluene and alcohol under normal pressure; and (3) distilling the diethyl oxalate at the temperature of between 100 and 130 ℃ and under the vacuum pressure of between 10 and 200pa to remove the diethyl oxalate to obtain the N-ethoxyoxalyl alanine ethyl ester with the yield of 93 percent. The secondary utilization of the steam by the steam compressor resulted in no decrease in yield, but in a 21% decrease in energy consumption, as compared to example 1.
Therefore, it was confirmed that the production method for N-ethoxyoxalyl-alanine ethyl ester, in which benzene was replaced with toluene only, increased the yield and energy consumption. Although the yield is improved by using absolute ethyl alcohol and increasing the amount of toluene, the energy consumption is increased. Through reutilization steam, the residual steam that gets into the water knockout drum with the rectifying column compresses through the hot gas compressor, recycles, has greatly reduced the energy consumption. Therefore, by combined use, the benzene is successfully replaced by the toluene with lower toxicity, the energy consumption is reduced, and the energy conservation and environmental protection are realized.
EXAMPLE 54 preparation of ethyl methyl-5-ethoxyoxazolate
230g of N-ethoxyoxalyl alanine ethyl ester, 520g of triethylamine and 400ml of toluene are added into a 2L reaction kettle and cooled to-5 ℃ to 0 ℃. 110g of solid phosgene is dissolved in 300ml of toluene, then the mixed solution is dripped into a reaction kettle, the temperature is controlled below 6 ℃ in the dripping process, and after the dripping is finished, the temperature in the reaction kettle is cooled to room temperature, and the mixture is stirred for 2 hours under heat preservation. Then 30g of phosphorus oxychloride is dripped, the temperature is slowly raised to 40-60 ℃ after the dripping is finished, the reaction is carried out for 4 hours, then the temperature is raised to 80-100 ℃, and the heat preservation reaction is carried out for 1 hour. After the reaction is finished, the temperature of the reaction solution is reduced to 50-60 ℃, and 500mL of water is added. Washing the lower layer of water with 400ml of toluene for 2 times, mixing the toluene layer with the upper layer of materials, recovering the toluene at the temperature of 80-100 ℃ under the vacuum condition of 0.1-3 kpa, and distilling the substrate to obtain the 4-methyl-5-ethoxy-oxazole acid ethyl ester, wherein the yield is 96 percent, and the content is 95 percent.
The invention adopts the composite cyclization agent of phosphorus oxychloride and triphosgene, greatly reduces the usage amount of the phosphorus oxychloride, simultaneously improves the reaction yield from less than 80 percent to more than 90 percent, and has the advantages of reduced production cost and reduced phosphorus-containing wastewater. The dosage of the phosphorus oxychloride can be reduced by 2/3, the yield is greatly improved, and the reaction process is milder. The water layer is extracted by toluene, can be continuously extracted by an extraction tower, can be combined with engineering optimization, and is applied to large-scale industrial mass production.
The foregoing description is a general description of the invention. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation, as form changes and equivalents may be employed. Various changes or modifications may be effected therein by one skilled in the art and equivalents may be made thereto without departing from the scope of the invention as defined in the claims appended hereto.
Claims (3)
1. A preparation method of 4-methyl-5-ethoxy oxazole acid ethyl ester is characterized in that: adding 250 weight parts of N-ethoxyoxalyl alanine ethyl ester 180-plus, 600 weight parts of triethylamine 400-plus and toluene into a reaction vessel, and cooling to-5-0 ℃; dissolving 80-150 parts by weight of solid phosgene in toluene, then dropwise adding the mixed solution into a reaction container, controlling the temperature to be below 6 ℃ in the dropwise adding process, cooling the temperature in the reaction container to room temperature after the dropwise adding is finished, and stirring while keeping the temperature; then dropping 20-50 parts by weight of phosphorus oxychloride, slowly heating to 40-60 ℃ after dropping, reacting for 2-6 hours, then heating to 80-100 ℃, and reacting for 0.5-4 hours under heat preservation; after the reaction is finished, cooling the reaction solution to 50-60 ℃, and adding water; washing the lower layer with toluene, mixing the toluene layer with the upper layer, recovering toluene, and distilling the substrate to obtain 4-methyl-5-ethoxy-oxazole acid ethyl ester.
2. The process for preparing ethyl 4-methyl-5-ethoxyoxazolate according to claim 1, characterized in that: 230 parts of N-ethoxy oxalyl alanine ethyl ester 200-plus, 520 parts of triethylamine 450-plus and toluene are added into a reaction vessel and cooled to-5 ℃ to 0 ℃; dissolving 130 parts by weight of solid phosgene 110-containing liquid in toluene, then dropwise adding the mixed liquid into a reaction container, controlling the temperature below 6 ℃ in the dropwise adding process, after the dropwise adding is finished, cooling the temperature in the reaction container to room temperature, and stirring while keeping the temperature; then dropping 20-30 parts by weight of phosphorus oxychloride, slowly heating to 40-60 ℃ after dropping, reacting for 4 hours, then heating to 80-100 ℃, and reacting for 1 hour under heat preservation; after the reaction is finished, cooling the reaction solution to 50-60 ℃, and adding water; washing the lower layer with toluene, mixing the toluene layer with the upper layer, recovering toluene, and distilling the substrate to obtain 4-methyl-5-ethoxy-oxazole acid ethyl ester.
3. The process for preparing ethyl 4-methyl-5-ethoxyoxazolate according to claim 1, characterized in that: 230g of N-ethoxyoxalyl alanine ethyl ester, 520g of triethylamine and 400ml of toluene are added into a 2L reaction kettle and cooled to-5-0 ℃; dissolving 110g of solid phosgene in 300ml of toluene, then dropwise adding the mixed solution into a reaction kettle, controlling the temperature to be below 6 ℃ in the dropwise adding process, after the dropwise adding is finished, cooling the temperature in the reaction kettle to room temperature, and stirring for 2 hours while keeping the temperature; then dropping 30g of phosphorus oxychloride, slowly heating to 40-60 ℃ after dropping, reacting for 4 hours, then heating to 80-100 ℃, and reacting for 1 hour under heat preservation; after the reaction is finished, cooling the reaction solution to 50-60 ℃, and adding 500mL of water; washing the lower layer of water with 400ml of toluene for 2 times, mixing the toluene layer with the upper layer of materials, recovering the toluene at the temperature of 80-100 ℃ under the vacuum condition of 0.1-3 kpa, and distilling the substrate to obtain the 4-methyl-5-ethoxy-oxazole acid ethyl ester.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210442034.0A CN114671823A (en) | 2022-04-25 | 2022-04-25 | Preparation method of 4-methyl-5-ethoxy oxazole acid ethyl ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210442034.0A CN114671823A (en) | 2022-04-25 | 2022-04-25 | Preparation method of 4-methyl-5-ethoxy oxazole acid ethyl ester |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114671823A true CN114671823A (en) | 2022-06-28 |
Family
ID=82079231
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210442034.0A Pending CN114671823A (en) | 2022-04-25 | 2022-04-25 | Preparation method of 4-methyl-5-ethoxy oxazole acid ethyl ester |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114671823A (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1194578A (en) * | 1966-11-12 | 1970-06-10 | Basf Ag | Production of 4-Methyloxazole-5-Carboxylic Alkyl Esters |
| CN85109641A (en) * | 1984-10-19 | 1986-06-10 | 武田药品工业株式会社 | Carry out the method and the device thereof of chemical dehydration reaction |
| CN101830821A (en) * | 2010-05-12 | 2010-09-15 | 浙江工业大学 | Chemical synthesis method of N-alcoxyloxalyl alanine ester |
| CN103435568A (en) * | 2013-08-30 | 2013-12-11 | 大丰海嘉诺药业有限公司 | Preparation method of 4-methyl-5-ethoxy oxazole acid ethyl |
| CN104725262A (en) * | 2013-12-23 | 2015-06-24 | 大丰海嘉诺药业有限公司 | Method for continuously preparing N-ethyloxyl oxalyl alanine ethyl ester |
| CN110240573A (en) * | 2019-07-04 | 2019-09-17 | 山东新和成精化科技有限公司 | A method of preparing polysubstituted evil azole compounds |
-
2022
- 2022-04-25 CN CN202210442034.0A patent/CN114671823A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1194578A (en) * | 1966-11-12 | 1970-06-10 | Basf Ag | Production of 4-Methyloxazole-5-Carboxylic Alkyl Esters |
| CN85109641A (en) * | 1984-10-19 | 1986-06-10 | 武田药品工业株式会社 | Carry out the method and the device thereof of chemical dehydration reaction |
| CN101830821A (en) * | 2010-05-12 | 2010-09-15 | 浙江工业大学 | Chemical synthesis method of N-alcoxyloxalyl alanine ester |
| CN103435568A (en) * | 2013-08-30 | 2013-12-11 | 大丰海嘉诺药业有限公司 | Preparation method of 4-methyl-5-ethoxy oxazole acid ethyl |
| CN104725262A (en) * | 2013-12-23 | 2015-06-24 | 大丰海嘉诺药业有限公司 | Method for continuously preparing N-ethyloxyl oxalyl alanine ethyl ester |
| CN110240573A (en) * | 2019-07-04 | 2019-09-17 | 山东新和成精化科技有限公司 | A method of preparing polysubstituted evil azole compounds |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101862443B (en) | Preparation method of enramycin premix | |
| CN106117072B (en) | A kind of levodopa crystalline powder and its manufacture method | |
| CN111718391B (en) | Residual oil treatment method for recovering sterol | |
| CN101759574B (en) | Synthesizing method of 3-methylamino-1, 2-propanediol | |
| CN102050822B (en) | Method for extracting tabersonine from Voacanga chalotiana | |
| CN102351933A (en) | Method for preparing hydroxycobalamin salt | |
| CN114671823A (en) | Preparation method of 4-methyl-5-ethoxy oxazole acid ethyl ester | |
| CN102320953A (en) | Method for preparing natural alpha-linolenic acid from crude oil of idesia polycarpa var.vestita diels | |
| CN110105195A (en) | A method of extracting dihydroartemisinic acid from sweet wormwood wax oil | |
| CN115057784B (en) | Method for treating waste water of octaworking | |
| CN109369749B (en) | Preparation method of astilbin | |
| CN114702405A (en) | Preparation method of N-ethoxy oxalyl alanine ethyl ester | |
| CN102924362B (en) | Preparation method of hexahydro-2-cyclopentyl-pyrryl amine hydrochloride | |
| CN100376519C (en) | A kind of method for preparing squalene | |
| CN102993009A (en) | Preparation method of glycerin monostearate alpha crystal | |
| CN1091106C (en) | Supercritical fluid extraction process for extracting concentrated natural vitamin E | |
| CN101492412B (en) | Synthesis of carprofen | |
| CN103304821B (en) | A kind of process for purification of xylogen | |
| CN112110796A (en) | Resorcinol refining method and concentration distillation equipment | |
| CN104402801A (en) | Methods for separating DNJ (1-deoxynojirimycin) and preparing DNJ nanometer suspension | |
| CN116655941B (en) | Method for preparing gutta-percha with high efficiency and high yield | |
| CN112457235B (en) | Preparation method of 7-methylindole | |
| CN113355369B (en) | Method for preparing conjugated linoleic acid by using immobilized lipase catalysis in fed-batch mode and application | |
| CN1252036C (en) | Method for producing chloropropham | |
| CN105769761B (en) | The method for preparing DNJ nano suspensions |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20220628 |
|
| RJ01 | Rejection of invention patent application after publication |