CN109574961B - Method for preparing sofosbuvir intermediate - Google Patents
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Abstract
The invention provides a method for preparing a sofosbuvir intermediate. The method comprises the following steps: 2-C-methyl-4, S-O- (1-methylethylidene) -D-arabinonic acid ethyl ester cyclic sulfate and 4-phenyl-2-oxazolidone are subjected to condensation reaction to obtain a first compound; carrying out fluorination reaction on the first compound and a fluorinating agent, and then adding acid for deprotection reaction to obtain a second compound; reacting the second compound with sodium ethoxide to obtain a third compound; and after the third compound is subjected to rearrangement reaction, reacting a rearrangement product with benzoyl chloride to obtain the sofosbuvir intermediate. The method for preparing the sofosbuvir intermediate provides a new idea for synthesizing the sofosbuvir intermediate.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a method for preparing a sofosbuvir intermediate.
Background
Sofosbuvir (trade name Sofosbuvir, Sovaldi) is a drug developed by gillidae for the treatment of chronic hepatitis c and is a Hepatitis C Virus (HCV) nucleotide analogue NS5B polymerase inhibitor. Is suitable for use as a combination in a combined antiviral treatment regimen for the treatment of Chronic Hepatitis C (CHC) infection. The Food and Drug Administration (FDA) approved for marketing in the united states at 12 months in 2013, and the european drug administration (EMEA) approved for marketing in countries of the european union at 1 month in 2014. Was marketed in china in 2017. In 2017, the total global sales of the medicine reaches 90 hundred million dollars, and the medicine has great social value and commercial value.
In the process of synthesizing the sofosbuvir, 2R-2-deoxy-2-fluoro-2-methyl-D-erythropentonic acid-gamma-lactone-3, 5-dibenzoate is a key intermediate of the sofosbuvir. Wang et al use R-glyceraldehyde acetonide as raw material, take Wittig reaction with carbethoxymethylene triphenylphosphine, then oxidize with potassium permanganate to obtain cis-vicinal diol compound, react with thionyl chloride to form ring, oxidize with sodium hypochlorite under the action of tetramethylpiperidine nitroxide (TEMPO), then take fluoro reaction, then take cyclization reaction under the action of hydrochloric acid, finally take hydroxyl protection reaction with benzoyl chloride (BzCl) to obtain the key intermediate. Mayers et al use a six-membered lactone ring as a raw material, firstly carry out esterification reaction, then introduce fluorine atoms, then carry out cyclization condensation reaction under acidic conditions to obtain a five-membered ring compound, and then carry out hydroxyl protection reaction with benzoyl chloride to obtain the key intermediate. The existing synthesis methods have the problems of high cost and more side reactions.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The invention aims to provide a method for preparing a sofosbuvir intermediate, which has the advantages of low cost, less side reaction and high yield.
In order to achieve the above purpose of the present invention, the following technical solutions are adopted:
a process for the preparation of a sofosbuvir intermediate, said process comprising the steps of:
a, carrying out condensation reaction on 2-C-methyl-4, 5-O- (1-methylvinyl) -D-arabinonic acid ethyl ester cyclic sulfate and 4-phenyl-2-oxazolidone to obtain a first compound;
B. carrying out fluorination reaction on the first compound and a fluorinating agent, and then adding acid for deprotection reaction to obtain a second compound;
C. reacting the second compound with sodium ethoxide to obtain a third compound;
D. after the third compound is subjected to rearrangement reaction, a rearrangement product is reacted with benzoyl chloride to obtain the sofosbuvir intermediate; the structural formula of the sofosbuvir intermediate is as follows:
by adopting the reaction method, through ester-amine exchange, selective fluorination, deprotection, ester exchange, rearrangement and esterification reactions, the method has the advantages of less reaction impurities, good stereoselectivity, no side reactions such as elimination reaction and the like, and high yield.
Preferably, in the step A, the molar ratio of the 2-C-methyl-4, 5-O- (1-methylvinyl) -D-arabinonic acid ethyl ester cyclic sulfate to the 4-phenyl-2-oxazolidinone is 1:1.5-2.0, the reaction solvent is toluene, and the catalyst is 4-dimethylaminopyridine; preferably, the reaction temperature is 60-80 ℃ and the reaction time is 8-12 hours.
Toluene is selected as a solvent, and 4-dimethylaminopyridine is added as a catalyst, so that the reaction efficiency is improved, and the yield is improved. Further, the yield can be further improved by further optimizing the temperature and the reaction time.
Further preferably, the step a further includes a first post-processing step:
and after the reaction is finished, cooling the system to 20-30 ℃, washing with saturated saline solution, combining organic phases, and concentrating to obtain the first compound.
After post-treatment, the system is separated and purified, and the yield of the first compound can reach 90-95%.
Preferably, in the fluorination reaction, the molar ratio of the first compound to the fluorinating agent is 1: 1.8-2.0; preferably, the solvent is anhydrous 1, 4-dioxane, the fluorinating agent is tetraethylammonium fluoride, the reaction temperature is 105-115 ℃, and the reaction time is 16-18 hours.
More preferably, a mixed solution is obtained after the fluorination reaction is finished, and the mixed solution is cooled to room temperature and then added with 2, 2-dimethoxypropane and the acid for reaction; preferably, the addition amount of the 2, 2-dimethoxypropane is 10-15 times of the volume of the mixed solution, the acid is concentrated hydrochloric acid, and the addition amount is 1.0-1.5eq of the first compound.
The chiral auxiliary is used to participate in the reaction, so that the problems of poor selectivity and low yield of the fluorination reaction are efficiently solved.
Preferably, the step B further includes a second post-processing step:
after the deprotection reaction is finished, extracting, washing the organic phase obtained by extraction with a first washing solution and a second washing solution in sequence, adding a drying agent for drying, and performing vacuum distillation on the filtrate to obtain a second compound; preferably, the solvent used for extraction is ethyl acetate, the first washing solution is a cold saturated sodium bicarbonate solution, the second washing solution is saturated saline, and the drying agent is anhydrous sodium sulfate.
Through post-treatment, the yield of the second compound can reach 80-85%.
Preferably, in the step C, the reaction conditions are as follows: heating, refluxing and reacting for 1-2 hours, and extracting with ethyl acetate to obtain the third compound after the reaction is completed; preferably, the molar ratio of the second compound to the sodium ethoxide is 1:1.2-1.5, and the solvent of the reaction system is absolute ethyl alcohol.
Through the selection of reaction conditions and reagents, the yield of the third compound can reach 90-95%.
Preferably, the rearrangement reaction is: adding acid into the mixture of the third compound and absolute ethyl alcohol, adding an organic solvent into the mixed system after stirring and reacting completely to remove moisture by azeotropy, and then carrying out reduced pressure distillation to obtain the rearrangement product; preferably, the molar ratio of the third compound to the acid to the benzoyl chloride is 1:0.5:6.5-7, the acid is hydrochloric acid, the addition mode is dropwise addition, the reaction temperature is room temperature, the reaction time is 22-26 hours, the organic solvent is toluene, and the addition amount of the toluene is 2-4 times of the volume of the mixed system.
Preferably, the reaction of the rearrangement product with the benzoyl chloride is:
adding the rearrangement product into a first solvent and a second solvent to obtain a reaction mixed solution, adding the benzoyl chloride into the reaction mixed solution under the condition of a first temperature, carrying out a first-stage reaction, raising the temperature to a second temperature, continuing a second-stage reaction, and carrying out third post-treatment to obtain the sofosbuvir intermediate; preferably, the first solvent is acetonitrile, the second solvent is pyridine, the first temperature is-2 to 0 ℃, the second temperature is 10 to 30 ℃, the time of the first-stage reaction is 10 to 20min, and the time of the second-stage reaction is 40 to 60 min.
More preferably, the third post-processing is: adjusting the pH value of the system after the second-stage reaction is finished, extracting to obtain an organic phase, washing, and performing suction filtration to obtain the sofosbuvir intermediate; preferably, the pH is 6 to 7, the extraction solvent is ethyl acetate, and the washing solution is a saturated sodium bicarbonate solution and a saturated brine used in this order.
Obtaining the sofosbuvir intermediate through rearrangement and esterification reaction. The yield of the sofosbuvir intermediate reaches 75-80% by selecting reaction conditions and reagents and carrying out post-treatment.
Compared with the prior art, the invention has the beneficial effects that:
(1) provides a new idea for synthesizing the sofosbuvir intermediate;
(2) less side reaction, low cost and simple treatment.
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.
FIG. 1 is a chart of the third compound obtained in the example under the condition of H;
FIG. 2 is a chart of the intermediate H of Sofosbuvir obtained in the comparative example;
FIG. 3 is a high performance liquid chromatogram of the sofosbuvir intermediate obtained in the example.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Example 1
Taking 2-C-methyl-4, 5-O- (1-methylvinyl) -D-arabinonic acid ethyl ester cyclic sulfate and 4-phenyl-2-oxazolidinone according to the molar ratio of 1:1.5, adding toluene for reaction at the temperature of 60 ℃ for 12 hours. After the reaction, the temperature was reduced to 20 ℃, the reaction mixture was washed with saturated brine for 2 times, the organic phases were combined and concentrated to give a yellow oil (first compound) in a yield of 90% which was used directly in the next reaction. The reaction formula is shown as follows:
adding a first compound, tetraethylammonium fluoride and anhydrous 1, 4-dioxane into a reaction bottle, wherein the molar ratio of the first compound to the tetraethylammonium fluoride is 1:2.0, heating the obtained reaction mixture to 105 ℃, refluxing the solvent, and stirring for reacting for 16 hours. After the completion of the reaction of the starting material was monitored by TLC (thin layer chromatography), the reaction mixture was cooled to room temperature, 2-dimethoxypropane (10 times the volume of the reaction mixture) and concentrated hydrochloric acid (1.0 eq of the first compound) were added thereto, and the mixture was stirred at room temperature for 3 hours, and the completion of the reaction of the starting material was monitored by Thin Layer Chromatography (TLC). Adding ethyl acetate for extraction for 3 times (10 times of volume), collecting an organic phase, washing the organic phase for 2 times by using cold saturated sodium bicarbonate solution and saturated saline water respectively, adding anhydrous sodium sulfate for drying, performing suction filtration, and evaporating the filtrate under reduced pressure to remove the solvent to obtain a light yellow oily substance (a second compound) with the yield of 85 percent, wherein the product is used for the next reaction without separation and purification. The reaction formula is shown as follows:
adding a second compound, absolute ethyl alcohol and sodium ethoxide into a reaction bottle, wherein the molar ratio of the second compound to the sodium ethoxide is 1:1.5, heating and refluxing for 1 hour, monitoring the complete reaction of the raw materials by TLC (thin layer chromatography), extracting for 3 times by using ethyl acetate, combining ethyl acetate phases, and concentrating to obtain a yellow oily substance (a third compound), wherein the yield is 90%, and the melting point is 142-. The reaction formula is shown as follows:
a round bottom flask was charged with the third compound, absolute ethanol, hydrochloric acid was added dropwise to the reaction mixture, stirred at room temperature for 22 hours, and Thin Layer Chromatography (TLC) monitored complete reaction of starting materials. Toluene (2 volumes) was added thereto to azeotropically remove water, and the solvent was distilled off under reduced pressure to give a yellowish brown solid. Dissolving the yellow-brown solid in acetonitrile (5 times volume), adding pyridine (1 time volume), stirring, cooling to 0 ℃, dropwise adding benzoyl chloride into the reaction mixed solution, wherein the molar ratio of the third compound to the hydrochloric acid to the benzoyl chloride is 1:0.5:6.5, stirring for 10 minutes at 0 ℃, gradually increasing to 30 ℃, and continuing to stir for 60 minutes. Adding dilute hydrochloric acid to adjust the pH value to 6, extracting with ethyl acetate, collecting an organic phase, washing with a saturated sodium bicarbonate solution and a saturated saline solution respectively, performing suction filtration, evaporating the solvent from the filtrate through a rotary evaporator to obtain a white crystalline compound (sofosbuvir intermediate) with the yield of 95% and the melting point of 136-. The reaction formula is shown as follows:
example 2
Taking 2-C-methyl-4, 5-O- (1-methylvinyl) -D-arabinonic acid ethyl ester cyclic sulfate and 4-phenyl-2-oxazolidinone according to the molar ratio of 1:2.0, adding toluene for reaction at the temperature of 80 ℃ for 8 hours. After the reaction was completed, the temperature was reduced to 30 ℃, the reaction mixture was washed with saturated brine for 2 times, and the organic phases were combined and concentrated to obtain a yellow oily substance (first compound) with a yield of 95%, which was used directly in the next reaction.
Adding a first compound, tetraethylammonium fluoride and anhydrous 1, 4-dioxane into a reaction bottle, wherein the molar ratio of the first compound to the tetraethylammonium fluoride is 1:2.0, heating the obtained reaction mixture to 115 ℃, refluxing the solvent, and stirring for reacting for 18 hours. After the completion of the reaction of the starting materials was monitored by TLC (thin layer chromatography), the reaction mixture was cooled to room temperature, 2-dimethoxypropane (15 times the volume of the reaction mixture) and concentrated hydrochloric acid (1.5 eq of the first compound) were added thereto, and the mixture was stirred at room temperature for 3 hours, and the completion of the reaction of the starting materials was monitored by Thin Layer Chromatography (TLC). Adding ethyl acetate for extraction for 3 times (10 times of volume), collecting an organic phase, washing the organic phase for 2 times by using cold saturated sodium bicarbonate solution and saturated saline water respectively, adding anhydrous sodium sulfate for drying, performing suction filtration, and evaporating the filtrate under reduced pressure to remove the solvent to obtain a light yellow oily substance (a second compound) with the yield of 80 percent, wherein the product is used for the next reaction without separation and purification.
Adding a second compound, absolute ethyl alcohol and sodium ethoxide into a reaction bottle, wherein the molar ratio of the second compound to the sodium ethoxide is 1:1.2, heating and refluxing for 2 hours, monitoring the complete reaction of the raw materials by TLC (thin layer chromatography), extracting for 3 times by using ethyl acetate, combining ethyl acetate phases, and concentrating to obtain a yellow oily substance (a third compound), wherein the yield is 95%, and the melting point is 142-.
A round bottom flask was charged with the third compound, absolute ethanol, hydrochloric acid was added dropwise to the reaction mixture, stirred at room temperature for 26 hours, and Thin Layer Chromatography (TLC) monitored complete reaction of starting materials. Toluene (4 volumes) was added thereto to azeotropically remove water, and the solvent was distilled off under reduced pressure to give a yellowish brown solid. Dissolving the yellow-brown solid in acetonitrile (5 times volume), adding pyridine (1.5 times volume), stirring, cooling to-2 ℃, dropwise adding benzoyl chloride into the reaction mixed solution, stirring the third compound, hydrochloric acid and benzoyl chloride at a molar ratio of 1:0.5:7 at-2 ℃ for 20 minutes, gradually increasing to 10 ℃, and continuing to stir for 40 minutes. Adding dilute hydrochloric acid to adjust the pH value to 7, extracting with ethyl acetate, collecting an organic phase, washing with a saturated sodium bicarbonate solution and a saturated saline solution respectively, performing suction filtration, evaporating the solvent from the filtrate through a rotary evaporator to obtain a white crystalline compound (sofosbuvir intermediate), wherein the yield is 90%, and the melting point is 136-.
Example 3
Taking 2-C-methyl-4, 5-O- (1-methylvinyl) -D-arabinonic acid ethyl ester cyclic sulfate and 4-phenyl-2-oxazolidinone according to the molar ratio of 1:1.8, adding toluene for reaction at the temperature of 70 ℃ for 10 hours. After the reaction was completed, the temperature was reduced to 25 ℃, the reaction mixture was washed with saturated brine for 2 times, and the organic phases were combined and concentrated to obtain a yellow oily substance (first compound) in a yield of 92% and used directly in the next reaction.
Adding a first compound, tetraethylammonium fluoride and anhydrous 1, 4-dioxane into a reaction bottle, wherein the molar ratio of the first compound to the tetraethylammonium fluoride is 1:1.9, heating the obtained reaction mixture to 110 ℃, refluxing the solvent, and stirring for reacting for 17 hours. After the completion of the reaction of the starting material was monitored by TLC (thin layer chromatography), the reaction mixture was cooled to room temperature, 2-dimethoxypropane (12 times the volume of the reaction mixture) and concentrated hydrochloric acid (1.2 eq of the first compound) were added thereto, and the mixture was stirred at room temperature for 3 hours, and the completion of the reaction of the starting material was monitored by Thin Layer Chromatography (TLC). Adding ethyl acetate for extraction for 3 times (10 times of volume), collecting an organic phase, washing the organic phase for 2 times by using cold saturated sodium bicarbonate solution and saturated saline water respectively, adding anhydrous sodium sulfate for drying, performing suction filtration, and evaporating the filtrate under reduced pressure to remove the solvent to obtain a light yellow oily substance (a second compound) with the yield of 81 percent, wherein the product is used for the next reaction without separation and purification.
Adding a second compound, absolute ethyl alcohol and sodium ethoxide into a reaction bottle, wherein the molar ratio of the second compound to the sodium ethoxide is 1:1.4, heating and refluxing for 1.5 hours, monitoring the complete reaction of the raw materials by TLC (thin layer chromatography), extracting for 3 times by using ethyl acetate, combining ethyl acetate phases, and concentrating to obtain a yellow oily substance (a third compound) with the yield of 92%.
A round bottom flask was charged with the third compound, absolute ethanol, hydrochloric acid was added dropwise to the reaction mixture, stirred at room temperature for 24 hours, and Thin Layer Chromatography (TLC) monitored complete reaction of starting materials. Toluene (3 volumes) was added to azeotropically remove water, and the solvent was distilled off under reduced pressure to give a yellowish brown solid. Dissolving the yellow-brown solid in acetonitrile (5 times volume), adding pyridine (2 times volume), stirring, cooling to 0 ℃, dropwise adding benzoyl chloride into the reaction mixed solution, stirring for 15 minutes at 0 ℃, gradually increasing to 20 ℃, and continuing to stir for 45 minutes, wherein the molar ratio of the third compound to the hydrochloric acid to the benzoyl chloride is 1:0.5: 6.5-7. Adding dilute hydrochloric acid to adjust the pH value to 6.5, extracting with ethyl acetate, collecting an organic phase, washing with a saturated sodium bicarbonate solution and a saturated saline solution respectively, performing suction filtration, evaporating the solvent from the filtrate through a rotary evaporator to obtain a white crystalline compound (sofosbuvir intermediate) with the yield of 93 percent and the melting point of 136-.
The third compound (D-erythropentanoic acid-2-deoxy-2-fluoro-2-methyl-4, 5- (1-methylethylidene) -ethyl ester) and the purified sofosbuvir intermediate obtained in the examples were subjected to structural identification, respectively, as shown in fig. 1 and 2.
The data in FIG. 1 is parsed as:1H NMR(500MHz,CDCl3)：1.55(d,3H,J＝22.4Hz),2.24(1H,br),3.15(1H,br),3.70(dd,1H,J1＝13.3Hz,J2＝3.3Hz),3.95(dd,1H,J1＝13.3Hz,J2＝1.5Hz),4.56(1H,m),4.12(dd,1H,J1＝7.2Hz,J2＝21.5Hz)。
the data in FIG. 2 is parsed as: 1H NMR (500MHz, DMSO-d6):1.68(d,3H, J ═ 24.2Hz),4.62-4.74(m,2H),5.11-5.15(m,1H),5.76(dd,1H, J1 ═ 7.0, J2 ═ 18.4Hz),7.46(m,2H),7.55(m,2H),7.62(m,1H),7.70(m,1H),7.93(m,2H),8.06(m,2H),8.08(m, 2H). 13C NMR (125MHz, DMSO-d6) 18.7,63.9,72.5,78.3,92.3,128.9,129.4,129.5,129.6,130.0,133.3,134.3,134.8,165.4,165.9,170.2.
The high performance liquid chromatogram of the pure sofosbuvir intermediate 2R-2-deoxy-2-fluoro-2-methyl-D-erythropentonic acid-gamma-lactone-3, 5-dibenzoate is shown in figure 3.
Comparative example 1
The sofosbuvir intermediate is obtained by the following reaction, and the highest total yield is 24.9%.
Comparative example 2
The sofosbuvir intermediate is obtained by the following reaction, and the highest total yield is 16.4%.
The method for preparing the sofosbuvir intermediate has the advantages that the fluorination reaction selectivity is good, and the post-treatment does not need means such as chiral chromatographic column separation; the chiral auxiliary is cheap and easy to obtain and easy to remove, so that the process cost is reduced; the high-purity 2R-2-deoxy-2-fluoro-2-methyl-D-erythropentonic acid-gamma-lactone-3, 5-dibenzoate can be effectively obtained, and the optical purity is more than 98; is suitable for commercial production; the average total yield of the method provided by the invention is 59-70%.
While particular embodiments of the present invention have been illustrated and described, it would be obvious that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
Claims (8)
1. A process for the preparation of a sofosbuvir intermediate, characterized in that the process comprises the steps of:
a, carrying out condensation reaction on 2-C-methyl-4, 5-O- (1-methylvinyl) -D-arabinonic acid ethyl ester cyclic sulfate and 4-phenyl-2-oxazolidone to obtain a first compound; the reaction temperature is 60-80 ℃, and the reaction time is 8-12 hours; after the reaction is finished, cooling the system to 20-30 ℃, washing with saturated saline solution, combining organic phases, and concentrating to obtain the first compound; the structural formula of the first compound is as follows:
B. carrying out fluorination reaction on the first compound and a fluorinating agent, and then adding acid for deprotection reaction to obtain a second compound; in the fluorination reaction, the solvent is anhydrous 1, 4-dioxane, the fluorinating agent is tetraethylammonium fluoride, the reaction temperature is 105-115 ℃, and the reaction time is 16-18 hours; after the fluorination reaction is finished, obtaining a mixed solution, cooling the mixed solution to room temperature, and adding 2, 2-dimethoxypropane and the acid for reaction; after the deprotection reaction is finished, extracting, washing the organic phase obtained by extraction with a first washing solution and a second washing solution in sequence, adding a drying agent for drying, and performing vacuum distillation on the filtrate to obtain a second compound; the structural formula of the second compound is as follows:
C. heating, refluxing and reacting the second compound and sodium ethoxide for 1-2 hours, and extracting ethyl acetate to obtain a third compound after complete reaction; the structural formula of the third compound is shown as follows:
D. adding acid into a mixture of the third compound and absolute ethyl alcohol, adding an organic solvent into a mixed system after stirring and completely reacting to remove moisture through azeotropy, then carrying out reduced pressure distillation to obtain a rearrangement product, adding a first solvent and a second solvent into the rearrangement product to obtain a reaction mixed solution, adding benzoyl chloride into the reaction mixed solution under the condition of a first temperature, carrying out a first-stage reaction, raising the temperature to a second temperature, continuing a second-stage reaction, and carrying out third post-treatment to obtain the Sofosbuvir intermediate; the first solvent is acetonitrile, the second solvent is pyridine, the first temperature is-2 to 0 ℃, the second temperature is 10 to 30 ℃, the time of the first stage of reaction is 10 to 20min, and the time of the second stage of reaction is 40 to 60 min; the third treatment is as follows: adjusting the pH value of the system after the second-stage reaction is finished, extracting to obtain an organic phase, washing, and performing suction filtration to obtain the sofosbuvir intermediate; the structural formula of the sofosbuvir intermediate is as follows:
2. the method of claim 1, wherein in step A, the molar ratio of the ethyl 2-C-methyl-4, 5-O- (1-methylvinyl) -D-arabinonate cyclic sulfate to the 4-phenyl-2-oxazolidinone is 1:1.5-2.0, the reaction solvent is toluene, and the catalyst is 4-dimethylaminopyridine.
3. The method according to claim 1, wherein the molar ratio of the first compound to the fluorinating agent in the fluorination reaction is 1:1.8 to 2.0.
4. The method according to claim 1, wherein the 2, 2-dimethoxypropane is added in an amount of 10 to 15 times the volume of the mixed solution, the acid is concentrated hydrochloric acid, and the amount of the added acid is 1.0 to 1.5eq based on the first compound.
5. The method of claim 1, wherein the solvent used for the extraction is ethyl acetate, the first washing solution is a cold saturated sodium bicarbonate solution, the second washing solution is a saturated brine, and the drying agent is anhydrous sodium sulfate.
6. The method according to claim 1, wherein the molar ratio of the second compound to the sodium ethoxide is 1:1.2-1.5, and the solvent of the reaction system is absolute ethyl alcohol.
7. The method according to claim 1, wherein the molar ratio of the third compound to the acid to the benzoyl chloride is 1:0.5:6.5-7, the acid is hydrochloric acid, the addition mode is dropwise addition, the reaction temperature is room temperature, the reaction time is 22-26 hours, the organic solvent is toluene, and the addition amount of the toluene is 2-4 times of the volume of the mixed system.
8. The method according to claim 1, wherein the pH is 6 to 7, the extraction solvent is ethyl acetate, and the washing solution is a saturated sodium bicarbonate solution and a saturated brine, which are used in this order.
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