阅读说明：本技术 一种苯肾上腺素杂质及其制备方法和应用 (Phenyladrenaline impurity and preparation method and application thereof ) 是由 梁大成 李慧敏 刘泽华 冯伟钊 于 2021-09-28 设计创作，主要内容包括：本发明公开了一种苯肾上腺素杂质及其制备方法和应用,涉及化学合成技术领域。本发明提供的苯肾上腺素杂质的制备方法,以苯肾上腺素为起始原料,在碱性条件下与马来酸酯缩合,再经水解即可快速得到目标产物,即(R)-2-[N-甲基-N-[[2-羟基-2-(3-羟基)苯基]乙基]氨基-丁二酸。本发明方法操作简单,成本低廉,具有很高的商业价值；通过本发明制备方法所得到的苯肾上腺素杂质为苯肾上腺素的质量控制提供了合格、廉价、高质量的杂质对照品,解决了该杂质合成过程中路线长、收率低、操作危险等技术问题,对苯肾上腺素用药安全有重要意义。(The invention discloses phenylephrine impurities and a preparation method and application thereof, and relates to the technical field of chemical synthesis. The invention provides a preparation method of phenylephrine impurities, which takes phenylephrine as an initial raw material, condenses with maleic acid ester under alkaline condition, and quickly obtains a target product, namely (R) -2- [ N-methyl-N- [ [ 2-hydroxy-2- (3-hydroxy) phenyl ] ethyl ] amino-succinic acid through hydrolysis. The method has the advantages of simple operation, low cost and high commercial value; the phenylephrine impurity obtained by the preparation method provides a qualified, cheap and high-quality impurity reference substance for the quality control of phenylephrine, solves the technical problems of long route, low yield, dangerous operation and the like in the impurity synthesis process, and has important significance for the safety of phenylephrine medication.)

1. A preparation method of phenylephrine impurities is characterized by comprising the following steps:

(1) dissolving a compound with a structure shown in a formula I in a mixed phase of an organic solvent and water, adding alkali, reacting with maleic ester at room temperature, and after the reaction is finished, rotationally evaporating the organic solvent to obtain an aqueous phase solution;

(2) extracting the aqueous phase solution obtained in the step (1) by using an organic solvent, combining organic phases, drying, performing rotary evaporation to obtain colorless oily liquid, and performing column chromatography purification by using petroleum ether and ethyl acetate as mobile phases to obtain a compound with a structure shown in a formula II;

(3) hydrolyzing the compound with the structure shown in the formula II obtained in the step (2) in an organic solvent by using alkali liquor, then acidifying and adjusting the pH value, extracting by using the organic solvent, combining organic phases, drying the organic phases, then carrying out rotary evaporation to obtain a crude product of the compound with the structure shown in the formula III, and finally purifying to obtain the compound with the structure shown in the formula III;

wherein, the synthetic reaction route is as follows:

2. the method of claim 1, wherein: in the step (1), the organic solvent includes any one of methanol, ethanol, and isopropanol.

3. The method of claim 2, wherein: in the step (1), the volume ratio of the organic solvent to water is 1: 0.2 to 1.

4. The method of claim 1, wherein: in the step (1), the base is any one of trimethylamine, triethylamine, N-diisopropylethylamine, 1, 8-diazohetero-bis-spiro [5.4.0] undec-7-ene and pyridine.

5. The method of claim 1, wherein: in the step (1), the maleate is any one of cis-or trans-dimethyl maleate, diethyl maleate and diallyl maleate.

6. The method of claim 1, wherein: in the step (2), the organic solvent used for extraction is any one of ethyl acetate, dichloromethane, methyl tert-butyl ether, isopropyl ether and toluene.

7. The method of claim 1, wherein: in the step (2), the mobile phase used for column chromatography is a mixed mobile phase of petroleum ether and ethyl acetate, wherein the volume ratio of the petroleum ether to the ethyl acetate is 1: 0.2 to 0.5.

8. The method of claim 1, wherein: in the step (3), the organic solvent used for the hydrolysis reaction of the compound with the structure shown in the formula II is any one of tetrahydrofuran, dioxane and isopropyl ether.

9. The method of claim 1, wherein: in the step (3), the alkali liquor used for hydrolysis is any one of sodium hydroxide aqueous solution and potassium hydroxide aqueous solution, and the concentration of the alkali liquor is 0.2-4 mol/L.

10. The method of claim 1, wherein: in the step (3), the organic solvent used for extraction is any one of ethyl acetate, dichloromethane, methyl tert-butyl ether, isopropyl ether and toluene.

11. The method of claim 1, wherein: in the step (3), the acid used for acidification is any one of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid and citric acid.

12. The method of claim 1, wherein: in the step (3), the end point of the acidification is 1 to 4.

13. The method of claim 1, wherein: in step (3), the purification method is C₁₈And (5) performing column chromatography.

14. Phenylephrine impurity prepared by the preparation method of any one of claims 1 to 13, wherein the chemical name of the phenylephrine impurity is (R) -2- [ N-methyl-N- [ 2-hydroxy-2- (3-hydroxy) phenyl ] ethyl ] amino-succinic acid.

15. Use of (R) -2- [ N-methyl-N- [ 2-hydroxy-2- (3-hydroxy) phenyl ] ethyl ] amino-succinic acid prepared by the preparation method of any one of claims 1 to 13 in a phenylephrine impurity reference substance.

Technical Field

The invention relates to the technical field of chemical synthesis, in particular to phenylephrine impurities and a preparation method and application thereof

Background

Phenylephrine, also known as phenylephrine, has significant vasoconstrictive effects, increases peripheral vascular resistance, increases systolic and diastolic blood pressure, and is weaker than norepinephrine, but has a lasting effect. Phenylephrine has no direct cardiac stimulation effect, can reflectively slow down heart rate, and has no drug resistance after continuous use. Meanwhile, phenylephrine has mydriatic effect, and has quick and short duration of action, and does not raise intraocular pressure and cause regulatory paralysis. Is clinically suitable for raising blood pressure, treating toxic shock and anaphylactic shock in infection and controlling paroxysmal supraventricular tachycardia.

The target compound (R) -2- [ N-methyl-N- [ 2-hydroxy-2- (3-hydroxy) phenyl ] ethyl ] amino-succinic acid is a diastereoisomer mixture, is an important impurity of phenylephrine, and is recorded in European pharmacopoeia.

The synthetic preparation method of the compound has few reports, and only the documents [1 and 2] report at present.

The first document is: chan, T. -M., Kong, J., McNamara, P., & Wong, J.K. (2008). Synthesis of functional degradation products of phenyl ephrine in OTC products. Synthesis Communications,38(13), 2252-2260. doi: 10.1080/00397910802026188. The synthesis method is reported in the literature:

document two: wong, J., Wiseman, L., Al-mamon, S., Cooper, T., Zhang, L. -K., & Chan, T. -M. (2006.) Major Degradation Product Identified in general Pharmaceutical Formulations of the Common Cold, analytical Chemistry,78 (22); 7891-7895. doi:10.1021/ac 0611263. The second literature reports synthetic methods:

among them, the first literature uses phenylephrine hydrochloride as a starting material, and the product can be obtained by six steps of reaction, with many steps and low yield.

The method reported in the second document is basically consistent with the method reported in the first document, benzyl protected phenylephrine is used as a starting material, and the product is obtained by condensation with dibenzyl maleate and then hydro-hydrolysis.

Disclosure of Invention

The invention aims to provide phenylephrine impurities and a preparation method and application thereof, and solves the problems of complex operation, low yield, potential safety hazard, high cost and the like of the impurities prepared by the prior art by providing the preparation method of the phenylephrine impurities, so that cheap and easily-obtained high-quality impurity reference substances are provided for the quality control related research of phenylephrine, and the medication safety is promoted.

In order to achieve the purpose, the invention adopts the following technical scheme:

in a first aspect, the invention provides a preparation method of phenylephrine impurities, which comprises the following steps:

(1) dissolving a compound with a structure shown in a formula I in a mixed phase of an organic solvent and water, adding alkali, reacting with maleic ester at room temperature, and after the reaction is finished, rotationally evaporating the organic solvent to obtain an aqueous phase solution;

(2) extracting the aqueous phase solution obtained in the step (1) by using an organic solvent, combining organic phases, drying, performing rotary evaporation to obtain colorless oily liquid, and performing column chromatography purification by using petroleum ether and ethyl acetate as mobile phases to obtain a compound with a structure shown in a formula II;

(3) hydrolyzing the compound with the structure shown in the formula II obtained in the step (2) in an organic solvent by using alkali liquor, then acidifying and adjusting the pH value, extracting by using the organic solvent, combining organic phases, drying the organic phases, then carrying out rotary evaporation to obtain a crude product of the compound with the structure shown in the formula III, and finally purifying to obtain the compound with the structure shown in the formula III;

wherein, the compound with the structure shown in formula I, the compound with the structure shown in formula II and the compound with the structure shown in formula III are as follows:

the synthetic reaction route is as follows:

further, in the step (1), the organic solvent includes any one of methanol, ethanol and isopropanol.

Preferably, in step (1), the organic solvent used is methanol.

Further, in the step (1), the volume ratio of the organic solvent to the water is 1: 0.2 to 1.

Preferably, in step (1), the volume ratio of methanol to water is 1: 0.3.

further, in the step (1), the base is any one of trimethylamine, triethylamine, N-diisopropylethylamine, 1, 8-diazohetero-bis-spiro [5.4.0] undec-7-ene and pyridine.

Preferably, in step (1), the base used is triethylamine.

Further, in the step (1), the maleate is any one of cis-or trans-dimethyl maleate, diethyl maleate and diallyl maleate.

Preferably, in step (1), the maleate used is cis-dimethyl maleate.

Further, in the step (2), the organic solvent used for extraction is any one of ethyl acetate, dichloromethane, methyl tert-butyl ether, isopropyl ether and toluene.

Preferably, in step (2), the organic solvent used for extraction is ethyl acetate.

Further, in the step (2), the mobile phase used for column chromatography is a mixed mobile phase of petroleum ether and ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate is 1: 0.2 to 0.5.

Preferably, in the step (2), the column chromatography uses a mobile phase of a mixed mobile phase of petroleum ether and ethyl acetate, wherein the volume ratio of the petroleum ether to the ethyl acetate is 1: 0.3.

further, in the step (3), the organic solvent used for the hydrolysis reaction of the compound with the structure shown in formula II is any one of tetrahydrofuran, dioxane and isopropyl ether.

Preferably, in step (3), the organic solvent used for the hydrolysis reaction of the compound with the structure of formula II is tetrahydrofuran.

Further, in the step (3), the alkali solution used for hydrolysis is any one of an aqueous sodium hydroxide solution and an aqueous potassium hydroxide solution, and the concentration of the alkali solution is 0.2-4 mol/l.

Preferably, in step (3), the alkali solution used for the hydrolysis is an aqueous sodium hydroxide solution having a concentration of 1.0 mol/l.

Further, in the step (3), the organic solvent used for extraction is any one of ethyl acetate, dichloromethane, methyl tert-butyl ether, isopropyl ether and toluene.

Preferably, in step (3), the organic solvent used for the extraction is ethyl acetate.

Further, in the step (3), the acid used for acidification is any one of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid and citric acid.

Preferably, in step (3), the acid used to effect acidification is hydrochloric acid.

Further, in the step (3), the end point of the acidification is 1 to 4.

Preferably, in step (3), the end point of acidification is pH 3.

Further, in the step (3), the purification method is to use C₁₈And (5) performing column chromatography.

In a second aspect, the present invention provides a phenylephrine impurity having the chemical name (R) -2- [ N-methyl-N- [ 2-hydroxy-2- (3-hydroxy) phenyl ] ethyl ] amino-succinic acid prepared by the above preparation method.

In a third aspect, the invention also provides an application of the (R) -2- [ N-methyl-N- [ 2-hydroxy-2- (3-hydroxy) phenyl ] ethyl ] amino-succinic acid prepared by the preparation method in a phenylephrine impurity reference substance.

Compared with the prior art, the invention has the following beneficial effects:

the invention provides a new synthetic route, which takes phenylephrine as a starting material, and can obtain a product through two steps of condensation and hydrolysis with maleic acid ester. The preparation method greatly reduces the preparation cost of the product, has higher economic value, can provide cheap and high-quality impurity reference substances for the quality research of phenylephrine, and has important significance for the safe medication of phenylephrine.

In addition, the phenylephrine impurities prepared by the invention provide qualified and cheap impurity reference substances for the quality control of phenylephrine, and simultaneously solve the technical problems of complex operation, low yield, potential safety hazard, high cost and the like in the synthesis of phenylephrine impurities.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to these drawings without creative efforts.

FIG. 1 is a one-dimensional nuclear magnetic hydrogen spectrum of a product synthesized in example 1 of the present invention;

FIG. 2 is a mass spectrum of a product synthesized in example 1 of the present invention;

FIG. 3 is a first page of HPLC of the product synthesized in example 1 of the present invention;

FIG. 4 is the second page of the HPLC chart of the product synthesized in example 1 of the present invention.

Detailed Description

The technical solutions of the present invention will be described clearly and completely below, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The invention provides a preparation method of phenylephrine impurities, which comprises the following steps:

(1) dissolving a compound with a structure shown in a formula I in a mixed phase of an organic solvent and water, adding alkali, reacting with maleic ester at room temperature, and after the reaction is finished, rotationally evaporating the organic solvent to obtain an aqueous phase solution;

(2) extracting the aqueous phase solution obtained in the step (1) by using an organic solvent, combining organic phases, drying, performing rotary evaporation to obtain colorless oily liquid, and performing column chromatography purification by using petroleum ether and ethyl acetate as mobile phases to obtain a compound with a structure shown in a formula II;

(3) hydrolyzing the compound with the structure shown in the formula II obtained in the step (2) in an organic solvent by using alkali liquor, then acidifying and adjusting the pH value, extracting by using the organic solvent, combining organic phases, drying the organic phases, then carrying out rotary evaporation to obtain a crude product of the compound with the structure shown in the formula III, and finally purifying to obtain the compound with the structure shown in the formula III;

wherein, the compound with the structure shown in formula I, the compound with the structure shown in formula II and the compound with the structure shown in formula III are as follows:

the synthetic reaction route is as follows:

wherein, the compound with the structure shown in the formula I is phenylephrine, and the chemical name of the phenylephrine is (R) -3- [ (1-hydroxy-2-methylamino) ethyl ] phenol; a compound having the structure of formula II, wherein the chemical name is (R) -2- [ N-methyl-N- [ 2-hydroxy-2- (3-hydroxy) phenyl ] ethyl ] amino-succinic acid diester; the chemical name of the compound with the structure shown in the formula III is (R) -2- [ N-methyl-N- [ 2-hydroxy-2- (3-hydroxy) phenyl ] ethyl ] amino-succinic acid.

In a preferred embodiment, in step (1), the compound of formula I is dissolved in methanol and water in a ratio of 1g of compound of formula I to methanol and water: 15 ml: 10 ml.

In a preferred embodiment, the base used in the reaction system is triethylamine, and the molar ratio of the triethylamine to the compound having the structure of formula I is 2: 1.

In a preferred embodiment, in step (1), the maleic acid ester added to the reaction system at room temperature is cis-dimethyl maleate in a molar ratio of 2:1 to the compound having the structure of formula I.

In a preferred embodiment, in step (1), the reaction time is 2 hours.

In a preferred embodiment, in step (2) and step (3), the aqueous solution is extracted three times, the organic solvent used for extraction is ethyl acetate, and the volume ratio of the organic solvent to the aqueous solution used for single extraction is 1: 2.

In a preferred embodiment, in step (2), the column chromatography purification process uses a mixed mobile phase system of petroleum ether and ethyl acetate as a mobile phase, wherein the volume ratio of petroleum ether to ethyl acetate is 3: 1.

in a preferred embodiment, in step (3), the organic solvent used for the hydrolysis of the compound having the structure of formula II is tetrahydrofuran in a ratio of 1: 5.

in a preferred embodiment, in step (3), the lye used for the hydrolysis is an aqueous sodium hydroxide solution having a concentration of 1.0 mol/l and the compound of the formula II is used in a ratio to the aqueous sodium hydroxide solution of 1: 7.5.

in a preferred embodiment, in step (3), acidification is carried out with hydrochloric acid, with the end point of acidification being pH 3.

In a preferred embodiment, in step (3)Purified using C₁₈And (5) performing column chromatography.

The raw materials used in the invention are as follows: the compound with the structure shown in the formula I is phenylephrine, which is a commercially available raw material; the compound with the structure of formula IIa is synthesized by the inventor independently, and the synthetic route of the compound with the structure of formula IIa is shown as follows:

the preparation method comprises the following specific operations: dissolving 1.00g of the compound with the structure shown in the formula I in 15ml of methanol, adding 10ml of purified water, dropwise adding 1.67ml of triethylamine and 1.73g of dimethyl maleate, reacting for two hours at room temperature, and evaporating organic components in a reaction solution; then extracting with 25ml ethyl acetate for 3 times, combining organic phases, washing with 50ml saturated saline solution, drying with 0.5g anhydrous sodium sulfate, evaporating to dryness to obtain 1.76g of light yellow oily liquid which is a crude product of the structural compound of the formula IIa; the crude product was then purified by column chromatography, mobile phase (petroleum ether: ethyl acetate: 3:1), yielding 1.31g of a colorless oily liquid in 70.00% yield.

In order to facilitate a clearer understanding of the present disclosure, the present disclosure will now be described in further detail with reference to specific embodiments and the accompanying drawings.

The reagents used according to the invention are, unless otherwise specified, all customary reagents available on the market, the operating temperatures involved, unless otherwise stated, being those at room temperature of 25 ℃.

Example 1

The synthetic route is as follows:

the preparation method comprises the following specific operations:

dissolving 2.00g of the compound with the structure shown in the formula I in 30ml of methanol, adding 20ml of purified water, dropwise adding 3.35ml of triethylamine and 3.46g of dimethyl maleate, reacting for two hours at room temperature, and evaporating organic components in a reaction solution; then extracting with 50ml ethyl acetate for 3 times, combining organic phases, washing with 100ml saturated saline solution, drying with 1.0g anhydrous sodium sulfate, evaporating to dryness to obtain a light yellow oily liquid 3.52g, which is a crude product of the structural compound of formula IIa; the crude product was purified by column chromatography with mobile phase (petroleum ether: ethyl acetate: 3:1) to give 2.59g of a colorless oily liquid as pure compound of formula IIa.

Dissolving 2.59g of the compound with the structure IIa in 20ml of tetrahydrofuran, adding 32.5ml of 1M sodium hydroxide aqueous solution, and reacting for one hour at room temperature; after mass spectrometry monitoring shows that no raw material is left, slowly dropwise adding concentrated hydrochloric acid to adjust the pH value to 4, extracting for 3 times by using 50ml of ethyl acetate, combining organic phases, and performing rotary evaporation to obtain a light yellow oily liquid, namely a crude product of the structural compound of the formula III, purifying the crude product by C18 column chromatography, and performing freeze-drying to obtain 2.68g of a colorless oily liquid, namely the pure structural compound of the formula III, wherein the purity of the pure structural compound of the formula III is 96.53%, and the yield of the pure structural compound of the formula III is 79%.

Example 2

The synthetic route is as follows:

the preparation method comprises the following specific operations:

dissolving 5.00g of the compound with the structure shown in the formula I in 75ml of methanol, adding 50ml of purified water, dropwise adding 8.34ml of triethylamine and 11.98g of diisopropyl maleate, reacting for two hours at room temperature, and distilling out organic components in a reaction solution; extracting with 120ml ethyl acetate for 3 times, combining organic phases, washing with 200ml saturated saline solution, drying with 3.0g anhydrous sodium sulfate, and evaporating to obtain a light yellow oily liquid 7.91g, which is a crude product of the structural compound of formula IIb; the crude product was purified by column chromatography with mobile phase (petroleum ether: ethyl acetate: 3:1) to give 5.98g of a colourless oily liquid as pure compound of formula lib.

Dissolving 5.98g of the compound with the structure of the formula IIb in 40ml of tetrahydrofuran, adding 65ml of 1M sodium hydroxide aqueous solution, and reacting for one hour at room temperature; after mass spectrometry monitoring shows that no raw material is left, slowly dropwise adding concentrated hydrochloric acid to adjust the pH value to 4, extracting for 3 times by using 100ml of ethyl acetate, combining organic phases, and performing rotary evaporation to obtain a light yellow oily liquid, namely a crude product of the structural compound of the formula III, purifying the crude product by C18 column chromatography, and performing freeze-drying to obtain 6.44g of a colorless oily liquid, namely the pure structural compound of the formula III, wherein the purity of the pure structural compound of the formula III is 97.24%, and the yield of the pure structural compound of the formula III is 76%.

Example 3

The synthetic route is as follows:

the preparation method comprises the following specific operations:

dissolving 2.00g of the compound with the structure shown in the formula I in 30ml of methanol, adding 20ml of purified water, dropwise adding 3.07g of diisopropylethylamine and 4.02g of diisopropyl maleate, reacting for two hours at room temperature, and distilling out organic components in a reaction solution; extracting with 50ml ethyl acetate for 3 times, mixing organic phases, washing with 100ml saturated saline solution, drying with 1.0g anhydrous sodium sulfate, and evaporating to obtain a light yellow oily liquid 3.46g, which is a crude product of the structural compound of formula IIc; the crude product was purified by column chromatography with mobile phase (petroleum ether: ethyl acetate: 3:1) to give 3.21g of a colourless oily liquid as pure compound of formula IIc.

Dissolving 3.21g of the compound with the structure of the formula IIc in 20ml of tetrahydrofuran, adding 32ml of 1M sodium hydroxide aqueous solution, and reacting for one hour at room temperature; after mass spectrometry monitoring shows that no raw material is left, slowly dropwise adding concentrated hydrochloric acid to adjust the pH value to 4, extracting for 3 times by using 50ml of ethyl acetate, combining organic phases, and performing rotary evaporation to obtain a light yellow oily liquid, namely a crude product of the structural compound of the formula III, purifying the crude product by C18 column chromatography, and performing freeze-drying to obtain 6.18g of a colorless oily liquid, namely the pure structural compound of the formula III, wherein the purity of the pure structural compound of the formula III is 98.27%, and the yield of the pure structural compound of the formula III is 73%.

Example 4

The synthetic route is as follows:

the preparation method comprises the following specific operations:

dissolving 2.00g of a compound with a structure shown in the formula I in 30ml of methanol, adding 20ml of purified water, dropwise adding 3.35ml of triethylamine and 3.46g of trans-maleic acid dimethyl ester, reacting for two hours at room temperature, and evaporating organic components in a reaction solution; then extracting with 50ml ethyl acetate for 3 times, combining organic phases, washing with 100ml saturated saline solution, drying with 1.0g anhydrous sodium sulfate, evaporating to dryness to obtain a light yellow oily liquid 3.26g, which is a crude product of the structural compound of formula IIa; the crude product was purified by column chromatography with mobile phase (petroleum ether: ethyl acetate: 3:1) to give 2.22g of a colorless oily liquid as pure compound of formula IIa.

Dissolving 2.22g of the compound with the structure IIa in 20ml of tetrahydrofuran, adding 32.5ml of 1M sodium hydroxide aqueous solution, and reacting for one hour at room temperature; monitoring by mass spectrometry, slowly dropwise adding concentrated hydrochloric acid to adjust pH to 4, extracting with 50ml ethyl acetate for 3 times, mixing organic phases, and rotary evaporating to obtain yellowish oily liquid as the crude product of the compound with the structure of formula III₁₈Purifying by column chromatography, and lyophilizing to obtain colorless oily liquid 2.27g, which is pure compound of formula III with purity of 95.58% and yield of 67%.

Example 5

The synthetic route is as follows:

the preparation method comprises the following specific operations:

dissolving 3.00g of the compound with the structure shown in the formula I in 45ml of methanol, adding 30ml of purified water, dropwise adding 2.84g of pyridine and 6.18g of trans-diethyl maleate, reacting for two hours at room temperature, and evaporating organic components of a reaction solution; extracting with 75ml ethyl acetate for 3 times, combining organic phases, washing with 150ml saturated saline solution, drying with 2.0g anhydrous sodium sulfate, and evaporating to obtain a light yellow oily liquid 4.51g, which is a crude product of the compound with the structure of the formula IId; the crude product was purified by column chromatography with mobile phase (petroleum ether: ethyl acetate: 3:1) to give 4.32g of a colourless oily liquid as pure compound of formula IId.

4.32g of the compound of formula IId are dissolved in 30ml of tetrahydrofuran, and 45ml of 1M aqueous sodium hydroxide solution are added and reacted at room temperature for one hour(ii) a Monitoring by mass spectrometry, slowly dropwise adding concentrated hydrochloric acid to adjust pH to 4, extracting with 75ml ethyl acetate for 3 times, mixing organic phases, and rotary evaporating to obtain yellowish oily liquid as the crude product of the compound with the structure of formula III₁₈And (3) performing column chromatography purification and freeze-drying to obtain 3.66g of colorless oily liquid, namely the pure compound with the structure of the formula III, wherein the purity is 96.01%, and the yield is 72%.

FIG. 1 confirms that the product of example 1 has a correct structure by means of one-dimensional nuclear magnetic hydrogen spectrum.

FIG. 2 is a diagram for further assisting in confirming the correct structure of the product of example 1 by the information of the combined molecular weight of mass spectra.

The high performance liquid chromatography in FIG. 3 and FIG. 4 proves that the purity of the product in example 1 reaches 96.53%.

The above examples show that the phenylephrine impurities provided by the invention are prepared by condensing phenylephrine serving as a raw material with maleate under an alkaline condition, and hydrolyzing to obtain a target product quickly. The method has the advantages of simple operation, low cost and high commercial value.

The phenylephrine impurity obtained by the preparation method provides a qualified, cheap and high-quality impurity reference substance for the quality control of phenylephrine, solves the technical problems of long route, low yield, dangerous operation and the like in the impurity synthesis process, and has important significance for the safety of phenylephrine medication.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the present invention. It will be appreciated by those skilled in the art that any modification, equivalent replacement, simplification, improvement or the like that comes within the spirit and principle of the invention should be included in the scope of the invention.