CN111333553B - Synthetic method of florfenicol dimer impurity - Google Patents
Synthetic method of florfenicol dimer impurity Download PDFInfo
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Abstract
The invention discloses a method for synthesizing florfenicol dimer impurities, which comprises the following steps: (1) carrying out imidization reaction on the compound I and the compound II to obtain an intermediate III; (2) carrying out reduction reaction on the intermediate III obtained in the step (1) and a reducing agent to obtain an intermediate IV; (3) carrying out deprotection reaction on the intermediate IV obtained in the step (2) to obtain an intermediate V; (4) and (4) carrying out acylation reaction on the intermediate V obtained in the step (3) and dichloroacetyl chloride under the action of alkali to obtain the florfenicol dimer impurity. The synthesis method can synthesize a large amount of florfenicol dimer impurities with high purity, has great significance for the research on the quality and the impurities of the florfenicol, can be used for qualitative and quantitative analysis of the impurities in the production of the florfenicol, and provides guarantee for the medication safety of the florfenicol.
Description
Technical Field
The invention belongs to the technical field of chemical pharmacy, and particularly relates to a synthetic method of florfenicol dimer impurities.
Background
Florfenicol (Florfenicol), chemically known as 2, 2-dichloro-N- { (1S,2R) -1-fluoromethyl-2-hydroxy-2- [4- (methylsulfonyl) phenyl ] ethyl } acetamide, is a veterinary antibacterial agent developed by Schering-Plough, usa and first marketed in japan in 1990 under the trade name of Nuflor. Because of wide antibacterial spectrum, good absorption and low residual quantity in vivo, the traditional Chinese medicine composition is widely applied to the treatment of bacterial diseases of pigs, cows, fishes and poultry.
2, 2-dichloro-N- [3- (1, 3-dihydroxy-1- [4- (methylsulfonyl) phenyl ] -propyl-2-amino) ] -1-hydroxy-1- [4- (methylsulfonyl) phenyl ] propyl acetamide (VI-a) and 2, 2-dichloro-N- [3- (3-fluoro-1-hydroxy-1- [4- (methylsulfonyl) phenyl ] -propyl-2-amino) ] -1-hydroxy-1- [4- (methylsulfonyl) phenyl ] propyl acetamide are dimeric impurities of florfenicol (VI-b) with similar backbone structures. To date, the prior art has not reported the preparation of these two impurities.
Therefore, the two impurities are synthesized, the method has great significance for the research on the quality and the impurities of the florfenicol, can be used for qualitative and quantitative analysis of the impurities in the production of the florfenicol, and provides guarantee for the medication safety of the florfenicol.
Disclosure of Invention
The invention aims to provide a synthesis method of a florfenicol dimer impurity, which can synthesize a large amount of florfenicol impurities, namely 2, 2-dichloro-N- [3- (1, 3-dihydroxy-1- [4- (methylsulfonyl) phenyl ] -propyl-2-amino) ] -1-hydroxy-1- [4- (methylsulfonyl) phenyl ] propyl acetamide and 2, 2-dichloro-N- [3- (3-fluoro-1-hydroxy-1- [4- (methylsulfonyl) phenyl ] -propyl-2-amino) ] -1-hydroxy-1- [4- (methylsulfonyl) phenyl ] propyl acetamide, and the obtained florfenicol dimer impurity has high purity.
The technical scheme of the invention is as follows:
a method for synthesizing florfenicol dimer impurities comprises the following steps:
(1) carrying out imidization reaction on the compound I and the compound II to obtain an intermediate III;
the structure of the compound I is shown as the formula (I):
the structure of the compound II is shown as the formula (II):
the structure of the intermediate III is shown as the formula (III):
(2) carrying out reduction reaction on the intermediate III obtained in the step (1) under the condition of a reducing agent to obtain an intermediate IV, wherein the reaction formula is as follows:
the structure of the intermediate IV is shown as a formula (IV):
(3) carrying out deprotection reaction on the intermediate IV obtained in the step (2) to obtain an intermediate V;
the structure of the intermediate V is shown as the formula (V):
(4) carrying out acylation reaction on the intermediate V obtained in the step (3) and dichloroacetyl chloride under the action of alkali to obtain the florfenicol dimer impurity;
the structure of the florfenicol dimer impurity is shown as a formula (VI):
wherein R in the compounds II, III, IV and V has the same definition and is hydroxyl or fluorine.
In the step (1), the reaction formula is as follows:
in the step (1), the reaction solvent and the reaction temperature may have a large influence on the yield of the reaction, and the solvent for the imidization reaction is at least one of methanol, ethanol, ethyl acetate, and tetrahydrofuran, and preferably ethanol.
In the step (1), the reaction temperature is 0-80 ℃, preferably 60-80 ℃, the reaction time is prolonged due to the reduction of the temperature, and the yield is obviously reduced.
In the step (1), the reaction liquid obtained by the imidization reaction is directly subjected to the step (2) for reaction without post-treatment.
In the step (2), the reaction formula is as follows:
in the step (2), the kind of the reducing agent can greatly affect the conversion rate and selectivity of the reaction, and the reducing agent is at least one of hydrogen/palladium carbon, hydrogen/raney nickel, lithium aluminum hydride, sodium borohydride and potassium borohydride; preferably hydrogen/palladium carbon, and the pressure of the hydrogen is preferably 1.0-2.0 MPa.
In the step (2), the solvent for the reduction reaction is selected from at least one of methanol, ethanol, ethyl acetate and tetrahydrofuran. Ethanol is preferred.
In the step (2), the reaction temperature is 0-80 ℃, preferably 50-60 ℃.
The reaction is carried out under the preferable conditions of the step (1) and the step (2), the reaction has higher conversion rate and selectivity, and the obtained intermediate product has higher purity, and in this case, the post-treatment does not need to be carried out through column chromatography operation. Preferably, in step (2), after the reaction is completed, the obtained reaction solution is filtered, the filtrate is concentrated under reduced pressure until no fraction is obtained, and the obtained concentrate of intermediate IV is subjected to step (3) for reaction.
In the step (3), the reaction formula is as follows:
in the step (3), the reagent used for the deprotection reaction is selected from one of hydrochloric acid, HCl/methanol, HCl/ethanol, HCl/dioxane, HCl/ethyl acetate, HCl/tetrahydrofuran or trifluoroacetic acid, and preferably trifluoroacetic acid.
In the step (3), the solvent used for the deprotection reaction is selected from one of methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate and dichloromethane, and dichloromethane is preferred.
In the step (3), the reaction temperature is 0-80 ℃, and preferably 30-50 ℃.
In the step (3), the post-treatment process is as follows: after the reaction is finished, concentrating until no fraction is obtained, adding a solvent and a sodium hydroxide solution, stirring for 10-40 minutes, filtering or layering, and concentrating an organic phase to obtain a crude intermediate V;
the solvent is dichloromethane or isopropanol.
In the step (4), the reaction formula is as follows:
in the step (4), the alkali is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, triethylamine, diisopropylamine and diisopropylethylamine, and preferably potassium carbonate.
In the step (4), the solvent for the acylation reaction is selected from methanol, ethanol, tetrahydrofuran, dichloromethane and ethyl acetate. Tetrahydrofuran or dichloromethane is preferred.
In the step (4), the reaction temperature is 0-80 ℃, and preferably 20-40 ℃.
In the step (4), the post-treatment comprises extraction with dichloromethane, concentration and column chromatography.
The reaction end point is detected by TLC method in each step of the invention.
In the present invention, the amount of the raw materials for the reaction is not particularly limited, and the reaction may be carried out in a stoichiometric ratio or in an excess amount.
The dosage of the reaction solvent and the catalyst in the invention is not strictly limited, and can be adjusted according to the dosage of the reaction raw materials: the reaction raw materials are more, the dosage of the reaction solvent and the catalyst is increased, and the dosage of the reaction solvent and the dosage of the catalyst are less.
The invention has the following beneficial effects:
(1) provides a general method for preparing florfenicol dimer impurity 2, 2-dichloro-N- [3- (1, 3-dihydroxy-1- [4- (methylsulfonyl) phenyl ] -propyl-2-amino) ] -1-hydroxy-1- [4- (methylsulfonyl) phenyl ] propyl acetamide and 2, 2-dichloro-N- [3- (3-fluoro-1-hydroxy-1- [4- (methylsulfonyl) phenyl ] -propyl-2-amino) ] -1-hydroxy-1- [4- (methylsulfonyl) phenyl ] propyl acetamide in large quantity, which can be used for qualitative and quantitative analysis of impurities in florfenicol production, and the safety of the florfenicol is guaranteed.
(2) The method has the advantages of high conversion rate of each step, less side reaction, no need of column chromatography in the middle step, simpler operation and suitability for mass preparation.
Detailed Description
For better understanding of the technical solutions of the present invention, the following embodiments are further described, but those skilled in the art should recognize that the present invention is not limited to these embodiments.
Example 1
Preparation of 2, 2-dichloro-N- (3- ((1, 3-dihydroxy-1- [4- (methylsulfonyl) phenyl ] propyl) -2-amino) -1-hydroxy-1- [4- (methylsulfonyl) phenyl ] propyl) acetamide (compound VI-a):
a100 mL single-neck flask was charged with 30g of ethanol, 0.92g of 4-formyl-2, 2-dimethyl-5- [4- (methylsulfonyl) phenyl ] oxazolidine-3-t-butoxycarbonate (Compound I) and 0.62g of 2-amino-1- [4- (methylsulfonyl) phenyl ] -1, 3-propanediol (Compound II-a), stirred and heated to 60 to 70 ℃ to react for 8 hours, TLC monitored complete conversion of starting material to give 4- {1, 3-dihydroxy-1- [4- (methylsulfonyl) phenyl ] -2-methyleneaminopropyl } -2, 2-dimethyl-5- [4- (methylsulfonyl) phenyl ] oxazolidine-3-tert-butoxycarbonate as an ethanolic solution (Compound III-a).
Transferring the ethanol solution of the 4- {1, 3-dihydroxy-1- [4- (methylsulfonyl) phenyl ] -2-methyleneaminopropyl } -2, 2-dimethyl-5- [4- (methylsulfonyl) phenyl ] oxazolidine-3-tert-butoxycarbonate (compound III-a) into an autoclave, adding 0.1g of 5% palladium carbon, introducing hydrogen to a pressure of 2.0MPa, heating to 50-60 ℃ for reaction for 10 hours, monitoring by TLC (thin layer chromatography) that the raw material is completely converted, reducing the temperature and performing suction filtration, and concentrating the filtrate under reduced pressure until no fraction is obtained to obtain 4- {1, 3-dihydroxy-1- [4- (methylsulfonyl) phenyl ] -2-methylaminopropyl } -2, 2-dimethyl-5- [4- (methylsulfonyl) phenyl ] oxazolidine-3-tert-butoxycarbonate (compound IV) A) 1.5g of concentrate.
A reaction flask was charged with 1.3g of the above concentrate of 4- {1, 3-dihydroxy-1- [4- (methylsulfonyl) phenyl ] -2-methylaminopropyl } -2, 2-dimethyl-5- [4- (methylsulfonyl) phenyl ] oxazolidine-3-tert-butoxycarbonate (Compound IV-a), 20g of methylene chloride and 10g of trifluoroacetic acid, and the reaction was stirred at 30-40 ℃ for 20 hours with TLC monitoring for complete conversion of the starting material. The reaction mixture was concentrated under reduced pressure to give no distillate, and 30g of methylene chloride and 30g of 5% sodium hydroxide solution were added, and the mixture was stirred for 30 minutes, allowed to stand for separation, and the organic phase was concentrated to give 0.85g of a concentrate of 2- { 2-amino-3-hydroxy-3- [4- (methylsulfonyl) phenyl ] propylamino } -1- [4- (methylsulfonyl) phenyl ] -1, 3-propanediol (Compound V-a).
To a reaction flask were added 0.8g of the above concentrate of 2- { 2-amino-3-hydroxy-3- [4- (methylsulfonyl) phenyl ] propylamino } -1- [4- (methylsulfonyl) phenyl ] -1, 3-propanediol (Compound V-a), 24g of tetrahydrofuran and 0.8g of potassium carbonate, and a solution of dichloroacetyl chloride in tetrahydrofuran was added dropwise with stirring at 20 to 25 ℃ (0.26g of dichloroacetyl chloride added to 4g of tetrahydrofuran). And (3) after the dropwise addition, stirring and reacting for 3 hours at 20-25 ℃, and monitoring by TLC (thin layer chromatography) to show that the raw materials are basically completely converted. 40g of methylene chloride and 10g of water were added thereto, and the mixture was stirred for separation, the organic phase was concentrated, and the mixture was purified by column chromatography to obtain 0.6g of 2, 2-dichloro-N- [3- (1, 3-dihydroxy-1- [4- (methylsulfonyl) phenyl ] -propyl-2-amino) ] -1-hydroxy-1- [4- (methylsulfonyl) phenyl ] propyl acetamide (compound VI-a), which was obtained in a total yield of 52.5% in four steps and had a HPLC purity of > 98%.
2, 2-dichloro-N- [3- (1, 3-dihydroxy-1- [4- (methylsulfonyl) phenyl)]-propyl-2-aminoBase)]-1-hydroxy-1- [4- (methylsulfonyl) phenyl]The characterization data for propylacetamide are as follows:1H NMR(DMSO-d6)δ：2.44-2.48,2.83-2.86(m,2H),2.65-2.66(m,1H),3.14-3.15(m,6H),3.22-3.45(m,2H),3.75-3.76(m,1H),4.60-4.62(m,1H),5.45(d,1H),4.79,4.84,5.91(br s,3H),6.44(s,1H),7.35(d,2H),7.65(d,2H),7.79(d,2H),7.84(d,2H),8.27(d,1H).13C NMR(DMSO-d6)δ：43.60，43.63,48.00,55.13,60.14,64.90,66.49,69.92,70.85,126.31,126.39,126.89,127.34,138.93,139.04,149.07,150.65,163.20.MS：(M+H)+＝583，(M-H)+＝581.
example 2
Preparation of 2, 2-dichloro-N- (3- ((1, 3-dihydroxy-1- [4- (methylsulfonyl) phenyl ] propyl) -2-amino) -1-hydroxy-1- [4- (methylsulfonyl) phenyl ] propyl) acetamide (compound VI-a):
a100 mL single neck flask was charged with 30g of methanol, 0.92g of 4-formyl-2, 2-dimethyl-5- [4- (methylsulfonyl) phenyl ] oxazolidine-3-t-butoxycarbonate (Compound I) and 0.62g of 2-amino-1- [4- (methylsulfonyl) phenyl ] -1, 3-propanediol (Compound II-a), stirred and warmed to 30-40 ℃ for reaction for 24h, TLC monitored for complete conversion of starting material, this gave a methanol solution of 4- {1, 3-dihydroxy-1- [4- (methylsulfonyl) phenyl ] -2-methyleneaminopropyl } -2, 2-dimethyl-5- [4- (methylsulfonyl) phenyl ] oxazolidine-3-tert-butoxycarbonate (compound III-a).
Adding 1.5g of sodium borohydride to a methanol solution of the above 4- {1, 3-dihydroxy-1- [4- (methylsulfonyl) phenyl ] -2-methyleneaminopropyl } -2, 2-dimethyl-5- [4- (methylsulfonyl) phenyl ] oxazolidine-3-tert-butoxycarbonate (Compound III-a), heating to 50-60 ℃ for 24 hours, monitoring by TLC that the conversion of the starting material is complete, cooling and suction-filtering, concentrating the filtrate under reduced pressure until no fraction is formed, and purifying by column chromatography to obtain 0.7g of a concentrate of 4- {1, 3-dihydroxy-1- [4- (methylsulfonyl) phenyl ] -2-methylaminopropyl } -2, 2-dimethyl-5- [4- (methylsulfonyl) phenyl ] oxazolidine-3-tert-butoxycarbonate (Compound IV-a) .
A reaction flask was charged with 0.7g of the above concentrate of 4- {1, 3-dihydroxy-1- [4- (methylsulfonyl) phenyl ] -2-methylaminopropyl } -2, 2-dimethyl-5- [4- (methylsulfonyl) phenyl ] oxazolidine-3-tert-butoxycarbonate (Compound IV-a) and 10g of hydrogen chloride/ethyl acetate solution, and the reaction was stirred at 30-40 ℃ for 24 hours with TLC to monitor the completion of the conversion of the starting material. The reaction mixture was concentrated under reduced pressure to give no distillate, and 20g of methylene chloride and 30g of 5% sodium hydroxide solution were added, and the mixture was stirred for 30 minutes, allowed to stand for separation, and the organic phase was concentrated to give 0.5g of a concentrate of 2- { 2-amino-3-hydroxy-3- [4- (methylsulfonyl) phenyl ] propylamino } -1- [4- (methylsulfonyl) phenyl ] -1, 3-propanediol (Compound V-a).
To a reaction flask were added 0.5g of the above concentrate of 2- { 2-amino-3-hydroxy-3- [4- (methylsulfonyl) phenyl ] propylamino } -1- [4- (methylsulfonyl) phenyl ] -1, 3-propanediol (compound V-a), 15g of tetrahydrofuran and 0.4g of potassium carbonate, and a solution of dichloroacetyl chloride in tetrahydrofuran was added dropwise with stirring at 20 to 25 ℃ (0.1g of dichloroacetyl chloride added to 4g of tetrahydrofuran). And (3) after the dropwise addition, stirring and reacting for 3 hours at 20-25 ℃, and monitoring by TLC (thin layer chromatography) to show that the raw materials are basically completely converted. 20g of methylene chloride and 10g of water were added, the mixture was stirred and separated, the organic phase was concentrated, and the mixture was purified by preparative column to give 0.2g of 2, 2-dichloro-N- [3- (1, 3-dihydroxy-1- [4- (methylsulfonyl) phenyl ] -propyl-2-amino) ] -1-hydroxy-1- [4- (methylsulfonyl) phenyl ] propylacetamide (Compound VI-a) in a total yield of 17.5% in four steps and a purity by HPLC of > 97%.
Example 3
Preparation of 2, 2-dichloro-N- [3- (3-fluoro-1-hydroxy-1- [4- (methylsulfonyl) phenyl ] -propyl-2-amino) ] -1-hydroxy-1- [4- (methylsulfonyl) phenyl ] propyl acetamide (compound VI-b):
a100 mL single-neck flask was charged with 30g of methanol, 2g of 4-formyl-2, 2-dimethyl-5- [4- (methylsulfonyl) phenyl ] oxazolidine-3-t-butoxycarbonate (Compound I) and 1.35g of 2-amino-3-fluoro-1- [4- (methylsulfonyl) phenyl ] -1-propanol (Compound II-b), stirred and heated to 55 to 60 ℃ for reaction for 8 hours, TLC monitored complete conversion of starting material to give 4- { 3-fluoro-1-hydroxy-1- [4- (methylsulfonyl) phenyl ] -2-methyleneaminopropyl } -2, 2-dimethyl-5- [4- (methylsulfonyl) phenyl ] oxazolidine-3-tert-butoxycarbonate in methanol (Compound III-b).
Transferring the methanol solution of the 4- { 3-fluoro-1-hydroxy-1- [4- (methylsulfonyl) phenyl ] -2-methyleneaminopropyl } -2, 2-dimethyl-5- [4- (methylsulfonyl) phenyl ] oxazolidine-3-tert-butoxycarbonate (compound III-b) into an autoclave, adding 0.2g of 5% palladium carbon, introducing hydrogen to the pressure of 1.5-2.0 MPa, heating to 50-55 ℃ for reaction for 6 hours, monitoring the complete conversion of the raw material by TLC, cooling and filtering, and concentrating the filtrate under reduced pressure until no fraction is obtained to obtain 4- { 3-fluoro-1-hydroxy-1- [4- (methylsulfonyl) phenyl ] -2-methylaminopropyl } -2, 2-dimethyl-5- [4- (methylsulfonyl) phenyl ] oxazolidine-3- Tert-butoxycarbonate (Compound IV-b) concentrate 3 g.
A reaction flask was charged with 3g of the above concentrate of 4- { 3-fluoro-1-hydroxy-1- [4- (methylsulfonyl) phenyl ] -2-methylaminopropyl } -2, 2-dimethyl-5- [4- (methylsulfonyl) phenyl ] oxazolidine-3-tert-butoxycarbonate (Compound IV-b), 30g of methanol and 20g of 12% hydrochloric acid, and the reaction was stirred at 40-50 ℃ for 24 hours, and TLC monitored for substantial conversion completion of the starting material. The reaction solution was concentrated under reduced pressure until no fraction was obtained, 30g of isopropanol was added, the pH of the system was adjusted to >11 with 30% sodium hydroxide solution, and the mixture was filtered, and the organic phase was concentrated to obtain 2g of a concentrate of 2-amino-3- { 3-fluoro-1-hydroxy-1- [4- (methylsulfonyl) phenyl ] -2-propylamino } -1- [4- (methylsulfonyl) phenyl ] -1-propanol (compound V-b).
2g of the above concentrate of 2-amino-3- { 3-fluoro-1-hydroxy-1- [4- (methylsulfonyl) phenyl ] -2-propylamino } -1- [4- (methylsulfonyl) phenyl ] -1-propanol (compound V-b), 30g of dichloromethane and 0.85mL of triethylamine were added to a reaction flask, and a dichloromethane solution of dichloroacetyl chloride (0.66g of dichloroacetyl chloride added to 10g of dichloromethane) was added dropwise with stirring at 20 to 25 ℃. And (3) after the dropwise addition, stirring and reacting for 2 hours at 20-25 ℃, and monitoring by TLC (thin layer chromatography) to show that the raw materials are basically completely converted. The organic phase was washed with 2 × 20g of water, concentrated and purified by column chromatography to give 1.27g of 2, 2-dichloro-N- [3- (3-fluoro-1-hydroxy-1- [4- (methylsulfonyl) phenyl ] -propyl-2-amino) ] -1-hydroxy-1- [4- (methylsulfonyl) phenyl ] propylacetamide (compound VI-b) in 41.6% overall yield over four steps with HPLC purity > 98%.
2, 2-dichloro-N- [3- (3-fluoro-1-hydroxy-1- [4- (methylsulfonyl) phenyl)]-propyl-2-amino group)]-1-hydroxy-1- [4- (methylsulfonyl) phenyl]Propyl acetamide:1H NMR(CDCl3)δ：2.83-2.93(m,2H),3.03(s,3H),3.05(s,3H),3.20-3.23(m,1H),4.01-4.02(m,1H),4.22-4.58(m,2H),4.80(d,1H),5.09(s,1H),5.78(s,1H),7.06(d,1H),7.45(d,2H),7.62(d,2H),7.82(d,2H),7.93(d,2H).13C NMR(CDCl3)δ：47.14，51.74,57.64,66.75，66.87,68.90,74.43，74.46,75.28,83.36，84.49,129.32,130.11,130.20,130.37,142.38,142.84,149.81,150.24,167.00.MS：(M+H)+＝585。
Claims (10)
1. a method for synthesizing florfenicol dimer impurities is characterized by comprising the following steps:
(1) carrying out imidization reaction on the compound I and the compound II to obtain an intermediate III;
the structure of the compound I is shown as the formula (I):
the structure of the compound II is shown as the formula (II):
the structure of the intermediate III is shown as the formula (III):
(2) carrying out reduction reaction on the intermediate III obtained in the step (1) and a reducing agent to obtain an intermediate IV;
the structure of the intermediate IV is shown as a formula (IV):
(3) carrying out deprotection reaction on the intermediate IV obtained in the step (2) to obtain an intermediate V;
the structure of the intermediate V is shown as the formula (V):
(4) carrying out acylation reaction on the intermediate V obtained in the step (3) and dichloroacetyl chloride under the action of alkali to obtain the florfenicol dimer impurity;
the structure of the florfenicol dimer impurity is shown as a formula (VI):
2. the method for synthesizing florfenicol dimer impurity of claim 1, wherein in step (1), the solvent for imidization is at least one of methanol, ethanol, ethyl acetate, and tetrahydrofuran.
3. The method for synthesizing florfenicol dimer impurities as recited in claim 1, wherein in step (1), the reaction temperature is 0-80 ℃ and the reaction time is 6-10 hours.
4. The method for synthesizing florfenicol dimer impurity of claim 1, wherein in step (2), the reducing agent is at least one of hydrogen/palladium on carbon, hydrogen/raney nickel, lithium aluminum hydride, sodium borohydride, and potassium borohydride.
5. The method for synthesizing florfenicol dimer impurity of claim 1, wherein in step (2), the solvent for the reduction reaction is selected from at least one of methanol, ethanol, ethyl acetate, and tetrahydrofuran.
6. The method for synthesizing florfenicol dimer impurity according to any of claims 1, 2, or 5, wherein in step (1), the reaction solution obtained from the imidization reaction is directly subjected to step (2) for reaction without being subjected to post-treatment.
7. The method for synthesizing florfenicol dimer impurity according to claim 1, wherein in step (3), the reagent used for the deprotection reaction is selected from one of hydrochloric acid, HCl/methanol, HCl/ethanol, HCl/dioxane, HCl/ethyl acetate, HCl/tetrahydrofuran, or trifluoroacetic acid;
in the step (3), in the deprotection reaction, two protecting groups are removed simultaneously.
8. The method for synthesizing florfenicol dimer impurity according to claim 1, wherein in step (3), the solvent used for the deprotection reaction is selected from one of methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate and dichloromethane.
9. The method for synthesizing florfenicol dimer impurity of claim 1, wherein in step (4), the base is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, triethylamine, diisopropylamine, and diisopropylethylamine.
10. The method for synthesizing florfenicol dimer impurity of claim 1, wherein in step (4), the solvent for the acylation reaction is selected from one of methanol, ethanol, tetrahydrofuran, dichloromethane and ethyl acetate.
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