阅读说明：本技术 单环β-内酰胺类化合物、单环内酰胺类化合物盐及其制备方法 (Monocyclic beta-lactam compound, monocyclic lactam compound salt and preparation method thereof ) 是由 高原雨 孙健 刘元柏 母养秀 翟丽娟 何丽丽 于 2020-06-04 设计创作，主要内容包括：本发明提出一种单环β-内酰胺类化合物、单环内酰胺类化合物盐及其制备方法,属于医药合成技术领域,该化合物及其盐具有式(Ⅷ)所示结构:<Image he="307" wi="504" file="DDA0002524690900000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中,R为氢、钠或钾。该新型单环β-内酰胺类化合物及其盐可作为中间体,用于单环β-内酰胺类抗生素的制备,该制备方法路线新颖,条件温和。(The invention provides a monocyclic β -lactam compound, a monocyclic lactam compound salt and a preparation method thereof, belonging to the technical field of medical synthesis, wherein the compound and the salt thereof have structures shown in a formula (VIII): the novel monocyclic β -lactam compound and the salts thereof can be used as intermediates for preparing monocyclic β -lactam antibiotics, and the preparation method has a novel route and mild conditions.)

1. A monocyclic beta-lactam compound and salts thereof, having a structure represented by formula (VIII):

wherein R is H, Na or K.

2. A preparation method of monocyclic beta-lactam compound and salt thereof comprises the following steps:

d) reacting the compound with the structure of formula (IV) with lithium diisopropylamide and acetaldehyde to obtain a compound with the structure of formula (V);

e) reacting a compound with a structure shown in a formula (V) with sodium 2-ethylhexanoate under the action of a catalyst to obtain a compound with a structure shown in a formula (VI);

f) reacting the compound with the structure of the formula (VI) with a sulfonic acid-pyridine complex to obtain a compound with the structure of the formula (VII);

g) reacting the compound with the structure of the formula (VII) with p-toluenesulfonic acid, and performing ion exchange treatment to obtain a compound with the structure of the formula (VIII);

wherein R is H, Na or K.

3. The method of claim 2,

the preparation method of the compound with the structure of the formula (IV) comprises the following steps:

a) reacting a compound with a structure shown in a formula (I) with allyl bromide under the action of a catalyst to obtain a compound with a structure shown in a formula (II);

b) reacting a compound with a structure shown in a formula (II) with trifluoroacetic acid to obtain a compound with a structure shown in a formula (III);

c) reacting a compound with a structure shown in a formula (III) with 4-nitro-benzaldehyde to obtain a compound with a structure shown in a formula (IV);

4. the method of claim 2,

in the step a), the mol ratio of the compound with the structure of formula (I) to allyl bromide is 1 (0.5-2); the catalyst is 1, 8-diazabicycloundecen-7-ene;

in the step b), the molar ratio of the compound with the structure of formula (II) to trifluoroacetic acid is 1 (2-4);

in the step c), the molar ratio of the compound with the structure of the formula (III) to the 4-nitro-benzaldehyde is 1 (0.5-2).

5. The method of claim 2,

in the step d), the molar ratio of the compound with the structure of formula (IV), lithium diisopropylamide and acetaldehyde is (12-15): (18-23): 100-150); the reaction temperature is-60 to-80 ℃.

6. The method of claim 2,

in the step e), the molar ratio of the compound with the structure of formula (V) to the sodium 2-ethylhexanoate is 1 (2-5); the catalyst for the reaction is 1,1' -bis diphenylphosphino ferrocene palladium dichloride; the molar ratio of the catalyst to the compound with the structure of the formula (V) is 1 (0.5-3); the reaction time is 20-80 h.

7. The method of claim 2,

in the step f), the molar ratio of the compound with the structure of the formula (VI) to the sulfonic acid-pyridine complex is 1 (1.5-3); the concentration of the compound with the structure of the formula (VI) in a reaction solvent is 0.1-0.2 mol/L; the reaction temperature is 25-35 ℃, and the reaction time is 40-80 h.

8. The method of claim 2,

in the step g), the molar ratio of the compound with the structure of the formula (VII) to the p-toluenesulfonic acid is 1 (0.5-2); the solvent for reaction is a mixed solution of ethyl acetate and water; wherein the volume ratio of the ethyl acetate to the water is 2: 1; the reaction time is 1-4 h; the reaction temperature is 0-40 ℃.

9. The method of claim 2,

in the step g), cation exchange chromatography is adopted for the ion exchange treatment; the cation exchange chromatography comprises hydrogen ion exchange chromatography, sodium ion exchange chromatography and potassium ion exchange chromatography.

10. The method of claim 2,

in the step f), the molar ratio of the compound with the structure of the formula (VI) to the sulfonic acid-pyridine complex is 1 (1.5-3); the reaction solvent is pyridine; the reaction temperature is 25-35 ℃; the reaction time is 40-80 h.

Technical Field

The invention belongs to the technical field of medicine synthesis, and particularly relates to a monocyclic beta-lactam compound, a monocyclic lactam compound salt and a preparation method thereof.

Background

The monocyclic beta-lactam antibiotics have simpler structures than penicillins and cephalosporins, are more stable in chemical properties than other types of beta-lactam antibiotics, have the characteristics of broad spectrum, strong efficacy, high safety and the like, and therefore, have an important position in clinic.

In 1986, CA524775C disclosed that monocyclic β -lactam antibiotics have antibacterial activity. Subsequently, aztreonam (formula I) is used as the first monocyclic beta-lactam antibiotic to be applied to clinic, has good stability to beta-lactam enzyme, simultaneously has good selectivity, has stronger antibacterial activity to gram-negative bacteria and the like, and is successfully marketed in 1997. In 2016, CN108137573 discloses a monocylic lactam antibiotic salt and solid forms (formula (R)). It is seen that researchers at home and abroad have been devoted to the research and development of monocyclic beta-lactam antibiotics due to their excellent properties.

The monocyclic beta-lactam antibiotics are lactam antibiotics with a quaternary lactam ring as a main ring. A series of inhibitors with antibacterial activity were investigated, for example by Swar en, P.et al [ emulsification of Mechanism of Inhibition and X-ray Structure of the TEM-1. beta. -lactase from Escherichia coli by aN-sulfo-xyloxy-beta-lactam. journal of the American Chemical Society,121(23), 5353-5359 ], in which Compound 5 containing a quaternary lactam ring exhibits inhibitory activity against E.coli. In CN107641119, yankee corporation et al developed a series of compounds containing quaternary lactam ring and showed good activity in treating bacterial infectious diseases.

The modification of the quaternary lactam ring in monocyclic β -lactam antibiotics is mainly concentrated on the 1, 2 and 3 positions (formula ③) of the main ring, wherein the 1 position is mainly-SO₃，-OSO₃Group modification, wherein the 2 and 3 positions are mainly modified by various substituents.

Disclosure of Invention

The invention provides a monocyclic beta-lactam compound, a monocyclic lactam compound salt and a preparation method thereof, wherein the 3 rd position of the main ring of the monocyclic beta-lactam is mainly modified to form a compound containing a hydroxyl branched chain and an amino branched chain.

The invention provides a monocyclic beta-lactam compound and a salt thereof, which have a structure shown in a formula (VIII):

wherein R is H, Na or K.

The invention also provides a preparation method of the monocyclic beta-lactam compound and the salt thereof, which comprises the following steps:

d) reacting the compound with the structure of formula (IV) with lithium diisopropylamide and acetaldehyde to obtain a compound with the structure of formula (V);

e) reacting a compound with a structure shown in a formula (V) with sodium 2-ethylhexanoate under the action of a catalyst to obtain a compound with a structure shown in a formula (VI);

f) reacting the compound with the structure of the formula (VI) with a sulfonic acid-pyridine complex to obtain a compound with the structure of the formula (VII);

g) reacting the compound with the structure of the formula (VII) with p-toluenesulfonic acid, and performing ion exchange treatment to obtain a compound with the structure of the formula (VIII);

wherein R is H, Na or K.

Further, the preparation of the compound with the structure of the formula (IV) comprises the following steps:

a) reacting a compound with a structure shown in a formula (I) with allyl bromide under the action of a catalyst to obtain a compound with a structure shown in a formula (II);

b) reacting a compound with a structure shown in a formula (II) with trifluoroacetic acid to obtain a compound with a structure shown in a formula (III);

c) reacting a compound with a structure shown in a formula (III) with 4-nitro-benzaldehyde to obtain a compound with a structure shown in a formula (IV);

further, in the step a), the molar ratio of the compound with the structure of formula (I) to allyl bromide is 1 (0.5-2); the catalyst is 1, 8-diazabicycloundecen-7-ene;

in the step b), the molar ratio of the compound with the structure of formula (II) to trifluoroacetic acid is 1 (2-4);

in the step c), the molar ratio of the compound with the structure of the formula (III) to the 4-nitro-benzaldehyde is 1 (0.5-2).

Further, in the step d), the molar ratio of the compound with the structure of the formula (IV), lithium diisopropylamide and acetaldehyde is (12-15): (18-23): 100-150); the reaction temperature is-60 to-80 ℃.

Further, in the step e), the molar ratio of the compound with the structure of the formula (V) to the sodium 2-ethylhexanoate is 1 (2-5); the catalyst for the reaction is 1,1' -bis diphenylphosphino ferrocene palladium dichloride; the molar ratio of the catalyst to the compound with the structure of the formula (V) is 1 (0.5-3); the reaction time is 20-80 h.

Further, in the step f), the molar ratio of the compound with the structure of the formula (VI) to the sulfonic acid-pyridine complex is 1 (1.5-3); the concentration of the compound with the structure of the formula (VI) in a reaction solvent is 0.1-0.2 mol/L; the reaction temperature is 25-35 ℃, and the reaction time is 40-80 h.

Further, in the step g), the molar ratio of the compound with the structure of the formula (VII) to the p-toluenesulfonic acid is 1 (0.5-2); the solvent for reaction is a mixed solution of ethyl acetate and water; wherein the volume ratio of the ethyl acetate to the water is 2: 1; the reaction time is 1-4 h; the reaction temperature is 0-40 ℃.

Further, in the step g), the ion exchange treatment adopts cation exchange chromatography; the cation exchange chromatography comprises hydrogen ion exchange chromatography, sodium ion exchange chromatography and potassium ion exchange chromatography.

Further, in the step f), the molar ratio of the compound with the structure of the formula (VI) to the sulfonic acid-pyridine complex is 1 (1.5-3); the reaction solvent is pyridine; the reaction temperature is 25-35 ℃; the reaction time is 40-80 h.

The invention has the following advantages:

the novel monocyclic beta-lactam compound and the salt thereof can be used as intermediates for preparing monocyclic beta-lactam antibiotics.

The research of calculating simulation sites finds that the hydroxyl introduced into the 3 rd position of the main ring of the monocyclic beta-lactam can interact with the hydrophilic group on the position of the target protein, and the inhibition effect of the monocyclic beta-lactam antibiotic taking the compound with the structure of formula (VIII) as a mother nucleus on bacteria can be expected to be enhanced.

The preparation method of the monocyclic beta-lactam compound and the salt thereof provided by the invention has the advantages of novel synthetic route and mild reaction conditions.

Detailed Description

It should be noted that the embodiments and features of the embodiments may be combined with each other without conflict. The source of the raw materials used in the present invention is not particularly limited.

One embodiment of the present invention provides a monocyclic β -lactam compound and a salt thereof, having a structure represented by formula (viii):

wherein R is H, Na or K.

The monocyclic beta-lactam compound and the salt thereof provided by the embodiment of the invention are the monocyclic beta-lactam compound and the sodium salt and the potassium salt thereof, the 3 rd position of the main ring of the monocyclic beta-lactam is mainly modified to form a compound containing a hydroxyl branched chain and an amino branched chain, and the novel monocyclic beta-lactam compound and the salt thereof can be used as intermediates for preparing the monocyclic beta-lactam antibiotic.

The research of calculating simulation sites finds that the hydroxyl introduced into the 3 rd position of the main ring of the monocyclic beta-lactam can interact with the hydrophilic group on the position of the target protein, and the inhibition effect of the monocyclic beta-lactam antibiotic taking the compound with the structure of formula (VIII) as a mother nucleus on bacteria can be expected to be enhanced.

One embodiment of the invention provides a preparation method of a monocyclic beta-lactam compound, which comprises the following steps:

d) reacting the compound with the structure of formula (IV) with lithium diisopropylamide and acetaldehyde to obtain a compound with the structure of formula (V);

e) reacting a compound with a structure shown in a formula (V) with sodium 2-ethylhexanoate under the action of a catalyst to obtain a compound with a structure shown in a formula (VI);

f) reacting the compound with the structure of the formula (VI) with a sulfonic acid-pyridine complex to obtain a compound with the structure of the formula (VII);

g) reacting the compound with the structure of the formula (VII) with p-toluenesulfonic acid, and performing ion exchange treatment to obtain a compound with the structure of the formula (VIII);

wherein R is H, Na or K.

Specifically, the preparation of the compound with the structure of the formula (IV) comprises the following steps:

a) reacting a compound with a structure shown in a formula (I) with allyl bromide under the action of a catalyst to obtain a compound with a structure shown in a formula (II);

b) reacting a compound with a structure shown in a formula (II) with trifluoroacetic acid to obtain a compound with a structure shown in a formula (III);

c) reacting a compound with a structure shown in a formula (III) with 4-nitro-benzaldehyde to obtain a compound with a structure shown in a formula (IV);

the preparation method of the monocyclic beta-lactam compound and the salt thereof provided by the invention has the advantages of novel synthetic route and mild reaction conditions.

In step a) of the embodiment of the present invention, a compound having a structure of formula (i) is reacted with allyl bromide under the action of a catalyst to obtain a compound having a structure of formula (ii), specifically:

the molar ratio of the compound with the structure of the formula (I) to the allyl bromide is 1 (0.5-2), and the preferred molar ratio of the compound with the structure of the formula (I) to the allyl bromide is 1 (1-1.2). In some embodiments of the invention, the compound having the structure of formula (I) is reacted with allyl bromide in a molar ratio of 50.72: 60.36. The solvent for the reaction is an organic solvent, and preferably, the solvent for the reaction is Dimethylformamide (DMF). The catalyst is 1, 8-diazabicycloundecen-7-ene (DBU); the molar ratio of the catalyst to the compound with the structure of the formula (I) is (2-3) to 1; in some embodiments of the invention, the molar ratio of the catalyst to the compound having the structure of formula (i) is 127.03: 50.72.

The reaction temperature is 0-40 ℃, preferably 15-30 ℃; in some embodiments of the invention, the temperature of the reaction is room temperature; the reaction time is 1-3 h; preferably, the reaction time is 1.5-2 h.

The post-treatment of the reaction comprises rotary evaporation and concentration of the reaction mixture, dilution with ethyl acetate, washing with brine, drying with anhydrous magnesium sulfate, filtration and concentration to obtain the compound with the structure of formula (II).

In step b), reacting a compound with a structure shown in a formula (II) with trifluoroacetic acid to obtain a compound with a structure shown in a formula (III); the method specifically comprises the following steps:

the molar ratio of the compound with the structure of formula (II) to trifluoroacetic acid is 1 (2-4); preferably, the molar ratio of the compound having the structure of formula (II) to trifluoroacetic acid is 1: 3; in some embodiments of the invention, the molar ratio of the compound having the structure of formula (ii) to trifluoroacetic acid is 33.34: 94.73. The solvent for the reaction is an organic solvent, preferably dichloromethane.

Preferably, the reaction time is 15-20 h; preferably, the reaction time is 17 h; the reaction temperature is 0-40 ℃; preferably, the reaction temperature is 15-30 ℃; in some embodiments of the invention, the temperature of the reaction is room temperature; mixing the raw materials for reaction under the condition of a cold water bath; the temperature of the cold water bath is 0-5 ℃.

The post-treatment of the reaction comprises adjusting the pH of the mixture obtained by the reaction to 14 with saturated sodium bicarbonate, washing the organic layer with saturated brine, drying over anhydrous magnesium sulfate, filtering and concentrating to obtain the compound having the structure of formula (III).

In step c), reacting a compound with a structure shown in a formula (III) with 4-nitro-benzaldehyde to obtain a compound with a structure shown in a formula (IV); the method specifically comprises the following steps:

the molar ratio of the compound with the structure of formula (III) to 4-nitro-benzaldehyde is 1 (0.5-2); preferably, the molar ratio of the compound having the structure of formula (iii) to 4-nitro-benzaldehyde is 1: 1; in some embodiments of the invention, the molar ratio of the compound having the structure of formula (iii) to 4-nitro-benzaldehyde is 22.64: 23.76. The solvent for reaction is organic solvent, preferably dichloromethane; anhydrous magnesium sulfate is added into the dichloromethane; wherein, the addition of anhydrous magnesium sulfate mainly plays a role in drying and water absorption.

The reaction is carried out under the protection of nitrogen; the reaction time is 15-20 h, preferably 17 h; the reaction temperature is 0-40 ℃, preferably 15-30 ℃; in some embodiments of the invention, the temperature of the reaction is room temperature.

The post-treatment of the reaction comprises reacting the obtained mixture, filtering and concentrating the filtrate to obtain the compound with the structure of the formula (IV) in a solid form.

In step d) of the embodiment of the invention, reacting a compound with a structure shown in formula (IV) with lithium diisopropylamide and acetaldehyde to obtain a compound with a structure shown in formula (V); the method specifically comprises the following steps:

the molar ratio of the compound with the structure of formula (IV), lithium diisopropylamide and acetaldehyde is (12-15): (18-23): 100-150); in some embodiments of the invention, the molar ratio of the compound having the structure of formula (IV), the lithium diisopropylamide solution, and acetaldehyde is 13.53:20.21: 136; wherein lithium diisopropylamide is added in the form of lithium diisopropylamide hexamethylphosphoramide solution; the concentration of the hexamethylphosphoramide solution of lithium diisopropylamide is 1-4 mol/L; in some embodiments of the invention, the lithium diisopropylamide solution in hexamethylphosphoramide has a concentration of 2.85 mol/L; the solvent for the reaction is an organic solvent, and preferably, the solvent for the reaction is anhydrous tetrahydrofuran.

The reaction is carried out under the protection of nitrogen; the reaction temperature is-60 to-80 ℃, and preferably-78 ℃.

The specific preparation method of the compound with the structure of the formula (V) comprises the steps of adding an anhydrous tetrahydrofuran solution of the compound with the structure of the formula (IV) into a hexamethylphosphoramide solution of lithium diisopropylamide and acetaldehyde at the reaction temperature, and carrying out post-treatment of the reaction after the reaction.

Preferably, the specific preparation method of the compound with the structure of the formula (V) comprises the following steps of adding an anhydrous tetrahydrofuran solution of the compound with the structure of the formula (IV) into a hexamethylphosphoramide solution of lithium diisopropylamide at the reaction temperature, reacting for 0.5-2 h, adding acetaldehyde, reacting for 0.5-2 h, heating to 8-12 ℃ within 1-2 h, and carrying out post-treatment of the reaction.

The post-treatment of the reaction comprises adding saturated ammonium chloride solution to the reaction mixture, quenching, extracting with ethyl acetate, washing with brine, drying with anhydrous magnesium sulfate, filtering, concentrating to obtain residue, and purifying with silica gel column chromatography to obtain the compound with the structure of formula (V).

Specifically, the lithium diisopropylamide hexamethylphosphoramide solution was prepared by adding a solution of butyllithium (2.5M) in hexane (10.1mL) to a solution of diisopropylamine (20.21mmol) in anhydrous tetrahydrofuran (95mL) at-78 deg.C under nitrogen, stirring for 1h, and adding hexamethylphosphoramide (7.04mL) to the reaction mixture.

In step e) of the embodiment of the invention, reacting a compound with a structure shown in formula (V) with sodium 2-ethylhexanoate under the action of a catalyst to obtain a compound with a structure shown in formula (VI); the method specifically comprises the following steps:

the molar ratio of the compound with the structure of formula (V) to the sodium 2-ethylhexanoate is 1 (2-5); preferably, the molar ratio of the compound with the structure of formula (V) to the sodium 2-ethylhexanoate is 1 (3-4); in some embodiments of the invention, the molar ratio of the compound having the structure of formula (v) to sodium 2-ethylhexanoate is 2.09: 8.27; the catalyst for the reaction is 1,1' -bis diphenylphosphino ferrocene palladium dichloride; the molar ratio of the catalyst to the compound with the structure of the formula (V) is 1 (0.5-3); in some embodiments of the invention, the molar ratio of the catalyst to the compound having the structure of formula (v) is 1.05: 2.09; the solvent for the reaction is an organic solvent, and preferably, the solvent for the reaction is anhydrous tetrahydrofuran.

The reaction was carried out under nitrogen. The reaction temperature is 0-40 ℃, preferably 15-30 ℃; in some embodiments of the invention, the temperature of the reaction is room temperature. The reaction time is 20-80 h; preferably, the reaction time is 30-60 h.

The specific preparation method of the compound with the structure of the formula (VI) comprises the steps of adding 1,1' -bis-diphenylphosphino ferrocene palladium dichloride into an anhydrous tetrahydrofuran solution of the compound with the structure of the formula (V) and 2-sodium ethyl hexanoate for reaction;

preferably, the specific preparation method of the compound with the structure of the formula (VI) comprises the steps of adding 1/3-1/2 (the total mass of 1,1' -bis-diphenylphosphine ferrocene palladium dichloride used for reaction) of 1,1' -bis-diphenylphosphine ferrocene palladium dichloride into an anhydrous tetrahydrofuran solution of the compound with the structure of the formula (V) and 1/3-1/2 (the total mass of 2-sodium ethylhexanoate used for reaction is in proportion), reacting, adding the rest of 2-sodium ethylhexanoate and the rest of 1,1' -bis-diphenylphosphine ferrocene palladium dichloride, and heating to 1-10 ℃ for reaction.

The post-treatment of the reaction comprises filtering the reaction mixture, collecting the filter residue, washing with ethyl acetate, drying to obtain the sodium salt of the compound with the structure of formula (VI), adjusting the pH value to 4 with formic acid, washing the organic layer with brine, drying with anhydrous magnesium sulfate, filtering and concentrating to obtain the compound with the structure of formula (VI).

In step f) of the embodiment of the invention, reacting a compound with a structure shown in a formula (VI) with a sulfonic acid-pyridine complex to obtain a compound with a structure shown in a formula (VII); the method specifically comprises the following steps:

the molar ratio of the compound with the structure of formula (VI) to the sulfonic acid-pyridine complex is 1 (1.5-3); preferably, the molar ratio of the compound having the structure of formula (vi) to the sulfonic acid-pyridine complex is 1: 2. The solvent for the reaction is an organic solvent, preferably pyridine; the concentration of the compound with the structure of the formula (VI) in a reaction solvent is 0.1-0.2 mol/L; in some embodiments of the invention, the concentration of the compound having the structure of formula (VI) in the reaction solvent is 0.12 mol/L;

the reaction temperature is 25-35 ℃, preferably 30 ℃; the reaction time is 40-80 h.

The specific preparation method of the compound with the structure of the formula (VII) comprises the steps of adding a sulfonic acid-pyridine complex into a pyridine solution of the compound with the structure of the formula (VI) and reacting.

Preferably, the specific preparation method of the compound with the structure of the formula (VII) comprises the steps of adding 1/3-1/2 (mass ratio of the sulfonic acid-pyridine complex used in the reaction) of the sulfonic acid-pyridine complex into a pyridine solution of the compound with the structure of the formula (VI), reacting for 30-50 h, then adding the rest of the sulfonic acid-pyridine complex, and reacting for 10-20 h.

The post-treatment of the reaction comprises concentrating the reaction mixture, adding methylene chloride, removing the resulting precipitate by filtration, and concentrating the filtrate to obtain a compound having the structure of formula (VII).

In step g) of the embodiment of the invention, after a compound with a structure of a formula (VII) reacts with p-toluenesulfonic acid, the compound with a structure of a formula (VIII) is obtained through ion exchange treatment; the method specifically comprises the following steps:

the molar ratio of the compound with the structure of formula (VII) to the p-toluenesulfonic acid is 1 (0.5-2); preferably, the molar ratio of the compound having the structure of formula (VII) to p-toluenesulfonic acid is 1: 1; the solvent for reaction is a mixed solution of ethyl acetate and water; wherein the volume ratio of the ethyl acetate to the water is 2: 1; the concentration of the compound with the structure of the formula (VII) in a solvent is 0.01-0.1 mmol/ml; preferably, the concentration of the compound having the structure of formula (VII) in the solvent is 0.06 mol/L.

The reaction time is 1-4 h, preferably 2.5 h; the reaction temperature is 0-40 ℃, preferably 15-30 ℃; in some embodiments of the invention, the temperature of the reaction is room temperature.

The post-treatment of the reaction comprises concentrating the obtained reaction mixture, adding deionized water, washing with diethyl ether, freeze-drying and freeze-drying the water phase, and treating with ion exchange chromatography to obtain the compound (3-amino-3- (1-hydroxyethyl) -2, 2-dimethyl-4-carbonyl-azetidin-1-yl sulfonate) with the structure of formula (VIII).

Specifically, the ion exchange treatment employs cation exchange chromatography; the cation exchange chromatography comprises hydrogen ion exchange chromatography, sodium ion exchange chromatography and potassium ion exchange chromatography. After the treatment of hydrogen ion exchange chromatography, the obtained product has a structure shown in a formula (VIII-1), and after the treatment of sodium ion exchange chromatography and potassium ion exchange chromatography, the obtained product has a structure shown in a formula (VIII-2) and a structure shown in a formula (VIII-3) respectively:

the present invention will be described in detail with reference to specific examples.