CN112898234A - Preparation method of landiolol hydrochloride intermediate - Google Patents
Preparation method of landiolol hydrochloride intermediate Download PDFInfo
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- CN112898234A CN112898234A CN201911218730.8A CN201911218730A CN112898234A CN 112898234 A CN112898234 A CN 112898234A CN 201911218730 A CN201911218730 A CN 201911218730A CN 112898234 A CN112898234 A CN 112898234A
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- ethylenediamine
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- C07—ORGANIC CHEMISTRY
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
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- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
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- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D317/24—Radicals substituted by singly bound oxygen or sulfur atoms esterified
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Abstract
The invention discloses a preparation method of a high-purity landiolol hydrochloride intermediate N- (2-aminoethyl) -4-morpholine formamide oxalate. Reacting N-phenoxyl carbonyl morpholine with ethylenediamine, concentrating a reaction solution, adding a solvent to dissolve the reaction solution, adjusting the pH value to 9-14 by using alkali, filtering to remove a solid byproduct, concentrating a filtrate to obtain N- (2-aminoethyl) -4-morpholine formamide, adding water to dissolve the N- (2-aminoethyl) -4-morpholine formamide, adjusting the pH value to 1-6 by using oxalic acid, filtering to remove a small amount of ethylenediamine oxalate solid, concentrating the filtrate, adding the solvent to recrystallize to obtain the high-purity N- (2-aminoethyl) -4-morpholine formamide oxalate. The method can obtain the high-purity landiolol hydrochloride intermediate, overcomes the defects that the byproduct sodium phenolate is difficult to filter, the ethylenediamine is easy to remain and the like, has stable and controllable process, can recycle the solvent, and is more suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines and medical intermediates, and relates to a preparation method of landiolol hydrochloride intermediate N- (2-aminoethyl) -4-morpholine formamide oxalate.
Background
Landiolol hydrochloride, CAS number: 144481-98-1, Chinese cultural name: [ (4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] methyl 3- [4- [ (2S) -2-hydroxy-3- [2- (morpholine-4-carboxamido) ethylamino ] propoxy ] phenyl ] propanoate hydrochloride. Structural formula is
The landiolol hydrochloride is a selective beta 1 receptor blocker and has an ultra-broad spectrum effect. It can inhibit increase of heart rate caused by catecholamine, and is an indispensable emergency drug for emergency treatment of arrhythmia in perioperative period, dynamic monitoring of arrhythmia after operation, etc. However, the landiolol hydrochloride has a complex chemical structure, complicated preparation process steps, difficulty in controlling impurities and difficulty in mass preparation, so that no factory in China currently forms large-scale production. N- (2-aminoethyl) -4-morpholine formamide oxalate is a key intermediate for preparing landiolol hydrochloride, so that an advanced high-purity preparation method suitable for industrialization needs to be researched.
N- (2-aminoethyl) -4-morpholinecarboxamide oxalate, CAS number: 154467-16-0, chemical name: n- (2-aminoethyl) -4-morpholinocarboxamide oxalate of the formula:
at present, the existing preparation method is as follows:
japanese patent JPH05306281 discloses a preparation method of N- (2-aminoethyl) -4-morpholine formamide oxalate. Adding N-phenoxycarbonylmorpholine into ethylenediamine, stirring for one day, concentrating under reduced pressure after the reaction is finished, adding N-pentane into the residue for azeotropic concentration, adding methanol for dissolving, dropwise adding a methanol solution of oxalic acid to the pH value of 2, separating out a solid, and filtering to obtain a filtrate. Concentrating the filtrate, evaporating to dryness, adding ethyl acetate, pulping, filtering, and drying to obtain N- (2-aminoethyl) -4-morpholine formamide oxalate solid. In the process of concentrating the ethylenediamine, although n-pentane is used for drawing the tape for multiple times, the ethylenediamine still remains in large quantity, and the operation process is complicated; after the alkali is adjusted, the sodium phenolate is filtered, so that the conditions of sticky solid and difficulty in filtering exist in the process of filtering the sodium phenolate, and the sodium phenolate is not suitable for industrial production; the crude product is pulped by ethyl acetate, the refining effect is poor, and the purity of the obtained product is low.
U.S. Pat. No. 4,106456649 discloses a process for preparing N- (2-aminoethyl) -4-morpholinecarboxamide hydrogensulfate by stirring N-phenoxycarbonylmorpholine and ethylenediamine at room temperature for 3 days and evaporating the excess ethylenediamine under reduced pressure. The residue was dissolved in methanol, concentrated sulfuric acid was added to pH2, celite was added, and filtration was performed. The filtrate is concentrated under reduced pressure, and the residue is pulped with ethyl acetate and filtered to obtain N- (2-aminoethyl) -4-morpholinecarboxamide hydrogen sulfate. The method is characterized in that the bisulfate is prepared, the problem that ethylenediamine is difficult to remove exists, diatomite is required to be added for assisting filtration during filtration, and the operation is complicated; in addition, the reaction of the second step needs room temperature for 3 days, the reaction period is long, and the industrialization difficulty is large.
Chinese patent CN106608863 discloses a method for preparing N- (2-aminoethyl) -4-morpholinecarboxamide oxalate, the route is as follows:
the method comprises the step of reacting N, N' -Carbonyl Diimidazole (CDI) with morpholine in dichloromethane to prepare N-imidazole-4-morpholine formamide. Dropwise adding a dichloromethane solution of N-imidazole-4-morpholine formamide into ethylenediamine under stirring, heating to reflux for 35h, concentrating under reduced pressure, dissolving residues with methanol, slowly dropwise adding a methanol solution of oxalic acid, and adjusting the pH to 4-5. Filtering, concentrating, adding ethyl acetate into the residue for crystallization to obtain N- (2-aminoethyl) -4-morpholine formamide oxalate. N, N' -carbonyl diimidazole is used in the route, and raw materials are not easy to obtain; the method also has the problems of large quantity of residual ethylenediamine and long reaction time, and the operation process is complicated; the crude product is pulped by ethyl acetate, the refining effect is poor, and the purity of the obtained product is low.
Therefore, there is still a need in the art to provide a novel synthesis method of high purity N- (2-aminoethyl) -4-morpholinecarboxamide oxalate suitable for industrialization.
Disclosure of Invention
The invention aims to overcome the defects that sodium phenolate is difficult to filter, ethylenediamine is easy to remain, the purity of a prepared product is poor, and the preparation method is not suitable for industrial production in the process of preparing a landiolol hydrochloride intermediate in the prior art, and provides a preparation method of a high-purity landiolol hydrochloride intermediate. The preparation method provided by the invention has the advantages that the purity of the prepared product is high, the process is stable and controllable, the solvent can be recycled, the preparation method is more suitable for industrial production, and the requirements of the landiolol hydrochloride raw material medicine are met.
In order to achieve the purpose, the invention adopts the following technical scheme:
a preparation method of a high-purity landiolol hydrochloride intermediate N- (2-aminoethyl) -4-morpholine formamide oxalate is characterized by comprising the following steps: reacting N-phenoxycarbonylmorpholine with ethylenediamine, concentrating the reaction solution, adding a solvent to dissolve, adjusting the pH value to 9-14 with alkali, filtering to remove a solid byproduct, concentrating the filtrate to obtain N- (2-aminoethyl) -4-morpholinecarboxamide, adding water to dissolve, adjusting the pH value to 1-6 with oxalic acid, filtering to remove solids, concentrating the filtrate to obtain a crude product of N- (2-aminoethyl) -4-morpholinecarboxamide oxalate, adding the solvent to recrystallize, and obtaining the high-purity N- (2-aminoethyl) -4-morpholinecarboxamide oxalate.
Further, the reaction of N-phenoxycarbonylmorpholine and ethylenediamine can be carried out with or without a solvent, wherein the solvent can be: toluene, acetone, acetonitrile, preferably toluene.
Further, N-phenoxycarbonylmorpholine reacts with ethylenediamine, and the reaction solution is concentrated and then added with a dissolving solvent which is: acetone, toluene, acetonitrile, tetrahydrofuran, and the solvent is preferably acetone.
Further, adjusting pH and using alkali as aqueous solution of sodium hydroxide and potassium hydroxide; the pH is adjusted to 9-14, preferably 11-12.
Further, oxalic acid may be added in solid form or may be dissolved in water; adjusting the pH value to 1-6, preferably 2-3, by oxalic acid.
Further, the recrystallization solvent of the crude N- (2-aminoethyl) -4-morpholinecarboxamide oxalate is: ethanol, methanol, acetone, preferably ethanol.
Compared with the prior art, the preparation method of the landiolol hydrochloride intermediate disclosed by the invention has the positive effects that:
(1) in the prior art, the removal effect of the ethylenediamine is poor, and the ethylenediamine is easy to remain. The invention carries out the salt forming reaction in water, the ethylenediamine oxalate is difficult to dissolve in water, and after filtration, the residual quantity of ethylenediamine in the product is little, thus greatly improving the product quality.
(2) In the prior art, after the reaction is finished, alkali is adjusted in alcohol to generate a sodium phenolate byproduct, the solid is sticky, the problem of difficult filtration exists during filtration, and the effect is poor after filter aids such as kieselguhr, silica gel and the like are added. The invention selects to adjust alkali in aprotic solvent, and the precipitated solid is crystal, so the filtration is very good. Thoroughly solves the problem of difficult filtration in the prior art and does not need filter aid.
(3) The prior art is basically at the laboratory level, and many links are not suitable for industrial production. The invention has been verified by enlarged production, and the used solvent can be recycled, and the production process meets the requirement of environmental protection. The content of ethylenediamine in the produced landiolol hydrochloride intermediate N- (2-aminoethyl) -4-morpholine formamide oxalate is only 0.02%, and the quality of the landiolol hydrochloride intermediate N- (2-aminoethyl) -4-morpholine formamide oxalate meets the requirements of raw material medicines.
Detailed Description
The invention is described below by means of specific embodiments. Unless otherwise specified, the technical means used in the present invention are well known to those skilled in the art. In addition, the embodiments should be considered illustrative, and not restrictive, of the scope of the invention, which is defined solely by the claims. It will be apparent to those skilled in the art that various changes or modifications in the components and amounts of the materials used in these embodiments can be made without departing from the spirit and scope of the invention. The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention. The experimental methods in the following examples, which are not specified under specific conditions, are generally performed according to conventional methods. The starting materials, reagents and the like used in the following examples are, unless otherwise specified, commercially available products, for example, N-phenoxycarbonylmorpholine.
Experimental instrument and method for experiment
Content and purity chromatographic conditions: a chromatographic column: YMC Hydrosphere C18, 150X 4.6mm,5 μm or similar chromatography column; column temperature: 30 ℃; detection wavelength: 200 nm; mobile phase: water-methanol (75: 25) +1.5g/L sodium pentane sulfonate +0.5% (v/v) 85% phosphoric acid; isocratic elution: running for 20 minutes; sample introduction volume: 5 mu l of the solution; flow rate: 1.0 ml/min.
Detection conditions of ethylenediamine: a chromatographic column: waters ACQUITY UPLC BEH C18, 50mm × 2.1mm,1.7 μm or similar chromatography column; a detector: LC-MS Quadrupole; mobile phase: 0.1% aqueous formic acid-0.1% acetonitrile formic acid solution (98: 2, v/v); isocratic elution: the running time is 3 minutes; flow rate: 0.6 ml/min; sample introduction volume: 5 mu l of the solution; column temperature: 40 ℃; sample injector temperature: 10 ℃.
Detection conditions of the residual solvent: a chromatographic column: DB-624, 30m × 0.53mm,3.0 μm, helium as carrier gas (constant flow 1.85 ml/min); a detector: FID; detector temperature: 250 ℃; air flow rate: 400 ml/min; h2Flow rate: 40 ml/min.
Example 1
Preparation of N- (2-aminoethyl) -4-morpholinecarboxamide oxalate
Adding 230.0kg of ethylenediamine into a reaction kettle, adding 93.0kg of N-phenoxycarbonylmorpholine while stirring, heating to 64-70 ℃, and reacting for 6 hours. Distilling under reduced pressure to recover ethylenediamine, controlling temperature at 70 + -2 deg.C until no liquid drops, and continuing distilling under reduced pressure for 1 hr. Cooling to room temperature, adding 370.0kg of acetone, dropwise adding 30% sodium hydroxide solution while stirring, adjusting the pH to 11-12, separating out a large amount of solids, filtering, concentrating the filtrate, and recovering the acetone. And adding 350.0kg of water into the residue, stirring and dissolving the mixture to be clear, controlling the temperature to be 20-40 ℃, adding oxalic acid solid in batches to adjust the pH to be 2-3, and separating out a small amount of solid. Filtering by throwing, concentrating the filtrate into slurry, adding 600kg of ethanol, heating and refluxing for 0.5 hour, and carrying out filter pressing to a crystallizing tank. Cooling and crystallizing, keeping the temperature at 0-10 ℃ for 4 hours, filtering, and drying a filter cake for 8 hours at 50-60 ℃ by using a hot air circulation oven to obtain 106.1kg of white-like N- (2-aminoethyl) -4-morpholine formamide oxalate solid with the yield of 89.8 percent. HPLC purity: 99.97%, moisture: 0.7%, ethylenediamine: 0.02%, ethanol: 7 ppm.
Example 2
Preparation of N- (2-aminoethyl) -4-morpholinecarboxamide oxalate
200ml of toluene and 81.0g of ethylenediamine (3 equivalents) are added into a reaction flask, and 93g of N-phenoxycarbonylmorpholine are added while stirring, and the temperature is raised to 64-70 ℃ for reaction for 6 hours. Distilling under reduced pressure to recover ethylenediamine, controlling temperature at 70 + -2 deg.C until no liquid drops, and continuing distilling under reduced pressure for 1 hr. Cooling to room temperature, adding 460ml of acetone, dropwise adding a 30% sodium hydroxide solution while stirring, adjusting the pH to 11-12, separating out a large amount of solids, filtering, and concentrating the filtrate to recover the acetone. And adding 350g of water into the residue, stirring and dissolving, controlling the temperature to be 20-40 ℃, adding oxalic acid solid in batches to adjust the pH value to be 2-3, and separating out a small amount of solid. Filtering, concentrating the filtrate to slurry, adding 770ml ethanol, heating and refluxing for 0.5 h. Cooling and crystallizing, preserving heat for 4 hours at 0-10 ℃, filtering, and drying a filter cake for 8 hours at 50-60 ℃ by a hot air circulation oven to obtain 87.8g of white-like N- (2-aminoethyl) -4-morpholine formamide oxalate solid with the yield of 74.3%. HPLC purity: 99.12%, moisture: 0.7%, ethylenediamine: 0.03%, ethanol: 8 ppm.
Example 3
Preparation of N- (2-aminoethyl) -4-morpholinecarboxamide oxalate
Adding 230g of ethylenediamine into a reaction bottle, adding 93g of N-phenoxycarbonylmorpholine while stirring, heating to 64-70 ℃, and reacting for 6 hours. Distilling under reduced pressure to recover ethylenediamine, controlling temperature at 70 + -2 deg.C until no liquid drops, and continuing distilling under reduced pressure for 1 hr. Cooling to room temperature, adding 460ml of tetrahydrofuran, dropwise adding a 30% sodium hydroxide solution while stirring, adjusting the pH to 11-12, separating out a large amount of solids, filtering, and concentrating the filtrate to recover tetrahydrofuran. And adding 350g of water into the residue, stirring and dissolving, controlling the temperature to be 20-40 ℃, adding oxalic acid solid in batches to adjust the pH value to be 2-3, and separating out a small amount of solid. Filtering, concentrating the filtrate to slurry, adding 770ml ethanol, heating and refluxing for 0.5 h. Cooling and crystallizing, keeping the temperature at 0-10 ℃ for 4 hours, filtering, and drying a filter cake in a hot air circulating oven at 50-60 ℃ for 8 hours to obtain 102.3g of off-white N- (2-aminoethyl) -4-morpholine formamide oxalate with the yield of 86.6%. HPLC purity: 99.88%, moisture: 0.6%, ethylenediamine: 0.03%, ethanol: 8 ppm.
EXAMPLE 4 preparation of N- (2-aminoethyl) -4-morpholinecarboxamide oxalate
Adding 230g of ethylenediamine into a reaction bottle, adding 93g of N-phenoxycarbonylmorpholine while stirring, heating to 64-70 ℃, and reacting for 6 hours. Distilling under reduced pressure to recover ethylenediamine, controlling temperature at 70 + -2 deg.C until no liquid drops, and continuing distilling under reduced pressure for 1 hr. Cooling to room temperature, adding 460ml of acetone, dropwise adding a 30% sodium hydroxide solution while stirring, adjusting the pH to 11-12, separating out a large amount of solids, filtering, and concentrating the filtrate to recover the acetone. And adding 350g of water into the residue, stirring and dissolving, controlling the temperature to be 20-40 ℃, adding oxalic acid solid in batches to adjust the pH value to be 2-3, and separating out a small amount of solid. Filtering, concentrating the filtrate to slurry, adding 580ml of methanol, heating and refluxing for 0.5 h. Cooling and crystallizing, keeping the temperature at 0-10 ℃ for 4 hours, filtering, and drying a filter cake in a hot air circulating oven at 50-60 ℃ for 8 hours to obtain 96.3g of off-white N- (2-aminoethyl) -4-morpholine formamide oxalate with the yield of 81.5%. HPLC purity: 99.92%, moisture: 0.7%, ethylenediamine: 0.01%, methanol: 6 ppm.
EXAMPLE 5 preparation of N- (2-aminoethyl) -4-morpholinecarboxamide oxalate
Adding 230g of ethylenediamine into a reaction bottle, adding 93g of N-phenoxycarbonylmorpholine while stirring, heating to 64-70 ℃, and reacting for 6 hours. Distilling under reduced pressure to recover ethylenediamine, controlling temperature at 70 + -2 deg.C until no liquid drops, and continuing distilling under reduced pressure for 1 hr. Cooling to room temperature, adding 460ml of acetone, dropwise adding a 30% sodium hydroxide solution while stirring, adjusting the pH to 11-12, separating out a large amount of solids, filtering, and concentrating the filtrate to recover the acetone. And adding 100ml of water into the residue, stirring and dissolving the water clearly, controlling the temperature to be 20-40 ℃, dropwise adding 10% oxalic acid water solution to adjust the pH value to be 2-3, and separating out a small amount of solid. Filtering, concentrating the filtrate to slurry, adding 770ml ethanol, heating and refluxing for 0.5 h. Cooling and crystallizing, keeping the temperature at 0-10 ℃ for 4 hours, filtering, and drying a filter cake in a hot air circulating oven at 50-60 ℃ for 8 hours to obtain 102.3g of off-white N- (2-aminoethyl) -4-morpholine formamide oxalate with the yield of 86.6%. HPLC purity: 99.88%, moisture: 0.8%, ethylenediamine: 0.02%, ethanol: 5 ppm.
Example 6
80g of N- (2-aminoethyl) -4-morpholinecarboxamide oxalate obtained in example 1 above were dissolved in 350ml of water, the pH was adjusted to 40 ℃ with 40% sodium hydroxide and filtered to remove the sodium oxalate, and then 56g of an isopropanol solution of methyl 4- [ (2S) -3-cyclopropoxy ] phenylpropionate [ (4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl) was added to 600ml of ice bath. The reaction was stirred at 30 ℃ for 8 hours, filtered and concentrated under reduced pressure to remove isopropanol. Then adding sodium chloride to saturation, extracting with 1L ethyl acetate, drying with anhydrous sodium sulfate, and filtering to obtain ethyl acetate solution of crude landiolol product.
600ml of a saturated aqueous ammonium chloride solution was added to the organic phase, and the mixture was stirred for 2 hours, extracted, and the operation was repeated 2 times. The organic phase was concentrated to dryness under reduced pressure to give a pale yellow solid. And then adding the mixture into a reaction bottle, adding ethyl acetate for dissolving, dropwise adding a 14% ethyl acetate hydrochloride solution, adjusting the pH value to 4-4.5, and separating out floccules. Heating to dissolve, naturally cooling to separate out a solid, filtering, washing a filter cake for 3 times by using ethyl acetate, and drying in a vacuum drying oven at the temperature of 35-40 ℃ to obtain 71.3g of landiolol hydrochloride, wherein the yield is 78.4% and the purity is 99.7%. The obtained finished product has high yield and good quality, and meets the requirements of raw material medicaments.
Example 7
And (3) comparison test: the process of Japanese patent JPH05306281 was repeated by adding 52.89g of N-phenoxycarbonylmorpholine and 122.6g of ethylenediamine to the reaction flask and stirring at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure and the residue was concentrated azeotropically with n-pentane. Dissolving the residue in 200ml methanol, cooling to below 0 deg.C, adding dropwise oxalic acid methanol solution to pH2, separating out crystal with viscosity, not easy to filter, and washing the filter cake with methanol to obtain filtrate. The filtrate was concentrated to dryness, and 400ml of ethyl acetate was added thereto, followed by stirring and then standing overnight to precipitate 18.3g of a solid in 27% yield.
Conventional methods are compared with the present invention
And (4) conclusion: compared with the conventional method, the method has the advantages of short reaction time, high yield and no problem of difficult filtration. In addition, the residual quantity of the ethylenediamine in the product is very small, and the product purity is greatly improved.
Claims (5)
1. A preparation method of a high-purity landiolol hydrochloride intermediate N- (2-aminoethyl) -4-morpholine formamide oxalate is characterized by comprising the following steps: reacting N-phenoxycarbonylmorpholine with ethylenediamine, concentrating the reaction solution, adding a solvent to dissolve, adjusting the pH value to 9-14 with alkali, filtering to remove a solid byproduct, concentrating the filtrate to obtain N- (2-aminoethyl) -4-morpholinecarboxamide, adding water to dissolve, adjusting the pH value to 1-6 with oxalic acid, filtering to remove solids, concentrating the filtrate to obtain a crude product of oxalate of N- (2-aminoethyl) -4-morpholinecarboxamide, adding the solvent to recrystallize to obtain high-purity oxalate of N- (2-aminoethyl) -4-morpholinecarboxamide; the weight ratio of the N-phenoxycarbonylmorpholine to the ethylenediamine in the reaction is 1: 2-10; the recrystallization solvent is ethanol, methanol or acetone.
2. The process according to claim 1, wherein the reaction of N-phenoxycarbonylmorpholine with ethylenediamine is carried out with or without a solvent; the solvent is as follows: toluene, acetone or acetonitrile.
3. The process according to claim 1, wherein N-phenoxycarbonylmorpholine is reacted with ethylenediamine, and the reaction solution is concentrated and then dissolved in the following solvent: acetone, toluene, acetonitrile or tetrahydrofuran.
4. The process according to claim 1 or 3, wherein the solvent is acetone.
5. The production method of claim 1, wherein the recrystallization solvent is: and (3) ethanol.
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