Synthesis method of baricitinib key intermediate

Abstract

The invention provides a synthesis method of a key intermediate of baricitinib, namely a method for synthesizing 2-[1-(ethylsulfonyl)-3-azacyclobutyl subunit] acetonitrile. By optimizing the preparation process, the reaction time is shortened, the yield and the purity are improved, and batch modular industrial production is facilitated.

Description

Technical Field

[0001] The present invention belongs to a drug synthesis method, and specifically relates to a method for synthesizing 2-[1-(ethylsulfonyl)-3-azetidinylidene]acetonitrile, a key intermediate of baricitinib. Background Art

[0002] Baricitinib, trade name Olumiant, is a Janus kinase (JAK) inhibitor developed jointly by Eli Lilly and Company and its partner, Incyte. The JAK kinase family includes four members: JAK1, JAK2, JAK3, and TYK2. The JAK-STAT pathway, mediated by the JAK family, is one of the most important inflammatory pathways in the human body and is associated with the pathogenesis of multiple autoimmune diseases. Baricitinib inhibits the activated inflammatory pathway by blocking two members, JAK1 and JAK2. The drug was approved by the European Union in 2017 for the treatment of moderate to severe rheumatoid arthritis in adults who are unresponsive to or intolerant of current rheumatoid arthritis medications. It can be used as a single agent or in combination with the widely used methotrexate. In recent years, baricitinib has been found to be used to treat alopecia areata. On March 27, 2023, Eli Lilly announced that its drug baricitinib (trade name Alemin) for the treatment of severe alopecia areata in adults has been approved by the China National Medical Products Administration (NMPA).

[0003] The chemical English name of baricitinib is: 1-(Ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidineacetonitrile, Chinese name: 1-(Ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidineacetonitrile, CAS: 1187594-09-7.

[0004] The synthetic route for baricitinib is relatively complex, involving the Witting-Horner reaction, Suzuki coupling, Michael addition, and protection and deprotection reactions. 2-[1-(ethylsulfonyl)-3-azetidinylidene]acetonitrile is a key intermediate in baricitinib, and its preparation is particularly crucial for its production. The existing synthesis of this intermediate often follows the route disclosed in PCT patent WO2009114512. The specific steps are as follows: The process has a long synthesis route and requires the use of palladium-carbon hydrogenation catalyst, which makes this step too costly. In addition, the catalytic components required for the addition of protective groups are relatively dangerous and the steps are cumbersome. The preparation methods in the existing technology have relatively harsh conditions for the synthesis process of key intermediates and do not have the characteristics of mildness and controllability. The product purity is low. Therefore, it is necessary to find a synthesis method with a short route, low cost and simple operation. Summary of the Invention

[0005] The present invention unexpectedly obtains a more convenient and controllable method for preparing the intermediate 2-[1-(ethylsulfonyl)-3-azetidinylidene]acetonitrile through a one-pot process during preparation. This method not only greatly reduces costs and optimizes the early preparation steps of baricitinib, but also has mild reaction conditions and is easy to operate under numerical control. Under specific conditions, the method is highly reproducible, can simplify steps and reduce costs, and improves purity and yield.

[0006] The process flow is as follows: Step 1: triphenylmethane and 1,1-dichloro-2,2-dimethoxycyclopropane undergo a substitution ring closure reaction in a solvent to generate intermediate 1, i.e., compound 1-(trityl)-3,3-di(methoxy)azetidine; Step 2: Intermediate 1 reacts with ethylsulfonyl chloride under acidic conditions to produce intermediate 2; Step 3: Intermediate 2 and diethyl cyanomethylphosphonate are reacted in a solvent to prepare a compound of formula I, 2-[1-(ethylsulfonyl)-3-azetidinylidene]acetonitrile; Furthermore, intermediate 1 is deprotected by acetalization and then reacted with ethylsulfonyl chloride; in another optional technical solution, step 2 and / or step 3 is a one-pot reaction.

[0007] Preferably, the reaction conditions in step 1 are alkaline, and the solvent is selected from one or more of isopropanol, ethanol, propanol, ethyl acetate, methyl tert-butyl ether, isopropyl ether, dichloromethane, tetrahydrofuran, and water. Preferably, the one-pot reaction in step 2 is acidic, and the solvent is selected from one or more of dichloromethane, ether, tetrahydrofuran, hexane, pentane, heptane, methyl tert-butyl ether, and ethyl acetate. Preferably, the reaction conditions in step 3 are alkaline, and the solvent is selected from one or more of isopropanol, ethanol, propanol, ethyl acetate, methyl tert-butyl ether, isopropyl ether, dichloromethane, tetrahydrofuran, and water.

[0008] In a preferred technical solution, the base comprises one or more of potassium phosphate, potassium carbonate, sodium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, and sodium hydroxide; preferably one or more of sodium bicarbonate, potassium bicarbonate, potassium carbonate, and potassium phosphate; the acid comprises one or more of trifluoroacetic acid, trichloroacetic acid, p-TsOH, nitroacetic acid, pentafluoropropionic acid, difluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, and phosphoric acid, preferably one or more of trifluoroacetic acid, trichloroacetic acid, p-TsOH, nitroacetic acid, and trifluoromethanesulfonic acid, more preferably trifluoroacetic acid.

[0009] Preferably, in step 1, the molar ratio of triphenylmethane, 1,1-dichloro-2,2-dimethoxycyclopropane and base is 1-5:1-5:5-20; in step 2, the molar ratio of compound II, ethylsulfonyl chloride and acid is 50-200:50-200:0.5-2; and in step 3, the molar ratio of compound III, diethyl cyanomethylphosphonate and base is 1-5:1-5:5-20.

[0010] Another technical solution of the present invention is a method for synthesizing 2-[1-(ethylsulfonyl)-3-azetidinylidene]acetonitrile, Wherein TFA represents trifluoroacetic acid.

[0011] Preferably, the deprotection of the tritylamine group, the deprotection of the acetal group and the introduction of the ethylsulfonyl group are one-pot reactions.

[0012] Another preferred synthesis method of the present invention is: Step 1: triphenylmethylamine and an alkaline reagent are added to a solvent, stirred at room temperature, and then heated to reflux. 1,1-dichloro-2,2-dimethoxycyclopropane is added dropwise under reflux, and the mixture is kept under reflux for overnight reaction. After cooling to room temperature, the mixture is filtered and concentrated, extracted with a solvent, washed with water, and dried and concentrated to obtain Compound II. Step 2: Compound II is added to a solvent, stirred and cooled to below zero, an acidic substance and ethylsulfonyl chloride are added dropwise, and the reaction is continued for 1-5 hours, and the temperature is slowly raised to room temperature. Water is added to quench the reaction, and the mixture is stirred at room temperature, separated and extracted, dried, concentrated, and filtered to obtain Compound III. Step 3: Add compound III and diethyl cyanomethylphosphonate to a solvent, add an alkaline substance, stir and reflux, add an organic solvent and water after the reaction is complete, extract by layers, concentrate and dry, add an organic solvent and continue to filter and wash, and dry to obtain compound I.

[0013] Preferably, the solvent in the above steps is one or more of isopropanol, ethyl acetate, dichloromethane, tetrahydrofuran, ethanol, propanol, and water. The alkaline substance includes one or more of potassium phosphate, potassium carbonate, sodium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, and sodium hydroxide; preferably one or more of sodium bicarbonate, potassium bicarbonate, potassium carbonate, and potassium phosphate. The acid includes one or more of trifluoroacetic acid, trichloroacetic acid, p-TsOH, nitroacetic acid, pentafluoropropionic acid, difluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, and phosphoric acid; preferably one or more of trifluoroacetic acid, trichloroacetic acid, p-TsOH, nitroacetic acid, and trifluoromethanesulfonic acid, and more preferably trifluoroacetic acid.

[0014] In step 1, the molar ratio of triphenylmethane, 1,1-dichloro-2,2-dimethoxycyclopropane and base is 1-5:1-5:5-20; in step 2, the molar ratio of compound II, ethylsulfonyl chloride and acid is 50-200:50-200:0.5-2; in step 3, the molar ratio of compound III, diethyl cyanomethylphosphonate and base is 1-5:1-5:5-20.

[0015] All raw materials and reagents in the present invention were purchased commercially, among which 1,1-dichloro-2,2-dimethoxycyclopropane (C5H8CL2O2, PSA 18.46, LogP 1.55310) was purchased from MOLBASE; triphenylmethane was purchased from Clamar Reagent Company (chemically pure); and the remaining reagents and equipment were purchased from Sigma.

[0016] Beneficial effects of the present invention: 1) The intermediates 1 and 2 obtained in the present invention are relatively stable, which is conducive to separation and purification. Under specific conditions, the purity of the product can be increased, some organic impurities can be degraded, and the generation of by-products can be reduced.

[0017] 2) Through direct acetal deprotection and ethanesulfonyl addition, the process steps are optimized and the reaction route is shortened. Furthermore, the raw materials used, such as triphenylmethylamine and 1,1-dichloro-2,2-dimethoxycyclopropane, are low-cost. The reaction is carried out using common acid, base, and solvent reflux, significantly reducing costs and avoiding the use of byproducts and hazardous reagents. 3) High yield and high purity, mild preparation conditions, easy to repeat, suitable for large-scale CNC production. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 LC-MS detection spectrum of the final product of Examples 1 and 2 Figure 2 The HNMR detection spectrum of the final product of Examples 1 and 2 (compound of formula I) DETAILED DESCRIPTION Example 1: Prepared as follows: 1. Synthesis of 1-(trityl)-3,3-di(methoxy)azetidine (Compound II) Under nitrogen protection, 260 ml of isopropyl alcohol, 25.9 g (0.1 mol) of triphenylmethane, and 25.2 g (0.3 mol, 3 eq) of sodium bicarbonate were added to a 1000 ml three-necked flask. After stirring at room temperature for 30 min, the temperature was raised to reflux with stirring. A solution of 17.1 g (0.1 mol, 1 eq) of 1,1-dichloro-2,2-dimethoxycyclopropane in isopropyl alcohol (170 ml) was added dropwise under reflux. After the addition was completed, the temperature was kept under reflux for 24 h. h, sampling HPLC to control the raw material triphenylamine to less than 0.5%, cooling to room temperature and filtering, the filtrate was concentrated to recover isopropanol, and then extracted and washed with 200 ml of ethyl acetate and 100 ml of water. The aqueous phase was extracted twice with 100 ml of ethyl acetate*2, and the combined organic phases were washed once with 100 ml of saturated brine. After separation, the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 33.39 g of a light yellow oil, namely compound II. The H NMR spectrum data was tested as follows: 1 H-NMR (400 MHz, DMSO-d6) δ: 3.36 (s, 6H), 3.68 (s, 2H), 3.75 (s, 2H), 7.38-7.27 (m, 15H), MS mass spectrometry value: C 24 H 25 NO2MS: [M+1]=360, yield 93%, HPLC purity 99.2%.

[0019] After changing the solvent from isopropanol / ethyl acetate to propanol / tetrahydrofuran, the compound detection data were the same as above, with a yield of 89% and an HPLC purity of 98.3%; After replacing the alkaline substance with potassium carbonate from sodium bicarbonate, the compound detection data was the same as above, with a yield of 91% and a HPLC purity of 98.1%; After being sealed and stored at room temperature for 120 hours, the above three samples were tested again and the purities were 99.2%, 98.2% and 97.7% respectively.

[0020] Synthesis of 2,3,3-bis(methoxy)azetidine trifluoroacetate Under nitrogen protection, 360 ml of dichloromethane, 35.9 g (0.1 mol) of compound II, and 45.61 g (0.4 mol, 4 eq) of trifluoroacetic acid were added to a 500 ml three-necked flask and stirred at room temperature for 6-8 h. After sampling, TLC showed that the reaction of the raw material was complete, and 21.95 g of an off-white solid was obtained by filtration. The H NMR spectrum data was as follows: 1H-NMR (400 MHz, DMSO-d6) δ: 3.30 (s, 6H), 3.82 (s, 2H), 3.78 (s, 2H), 2.11 (s, 1H), yield 95%.

[0021] 3. Synthesis of Compound III Under nitrogen protection, 230 ml of dichloromethane and 23.11 g (0.1 mol) of 3,3-bis(methoxy)azetidine trifluoroacetate were added to a 1000 ml three-necked flask, and the temperature was cooled to -5 to -10 °C with stirring. 41.36 g (0.32 mol, 3.2 eq) of N,N-diisopropylethylamine was added dropwise, and the temperature was kept stirring for 5 min. 15.4 g (0.12 mol, 1.2 eq) of ethylsulfonyl chloride was added dropwise. After the addition was completed, the temperature was kept at -5 to -10 °C for 3 h, and then the temperature was slowly raised to room temperature for 6 min. -8h, sampling TLC raw material reaction is complete, stop the reaction, add 100ml of water to quench the reaction, add concentrated hydrochloric acid dropwise to adjust the pH to 1-2, stir at room temperature for 2h, separate the liquid, add 100ml of dichloromethane to the aqueous phase and extract once, combine the organic phases, add anhydrous sodium sulfate, dry and concentrate, add 150ml of n-hexane to the concentrated oil, beat at room temperature for 1h and then filter, dry the filter cake to obtain 14.26g of the product, and the mass spectrum data is C5H9NO3S, MS: [M+1] = 164 (measured value), and the nuclear magnetic resonance hydrogen spectrum data is 1 H-NMR (400 MHz, DMSO-d6) δ: 1.12-1.21 (m, 3H), 3.25-3.30 (m, 2H), 4.84 (s, 4H), yield 88%, HPLC purity 99.6%.

[0022] After changing the solvent from dichloromethane to tetrahydrofuran, the compound detection data was the same as above, with a yield of 87% and an HPLC purity of 98.8%; After the alkaline substance was replaced by triethylamine from N,N-diisopropylethylamine, the compound detection data was the same as above, with a yield of 85% and a HPLC purity of 98.5%; After being sealed and stored at room temperature for 120 hours, the above three samples were tested again and the purities were 99.5%, 98.8% and 97.7% respectively.

[0023] 4. Synthesis of 2-[1-(ethylsulfonyl)-3-azetidinylidene]acetonitrile (Compound I) Add 163ml of tetrahydrofuran and intermediate 2 into a 500ml three-necked flask. 16.32g (0.1mol), 19.5g (0.11mol, 1.1eq) of diethyl cyanomethylphosphonate, and 14.5g (0.105mol, 1.05eq) of potassium carbonate were stirred and heated to reflux. The reaction was refluxed for 8-10h. The raw material was sampled and the reaction was complete by TLC. The reaction was cooled to room temperature. 100ml of ethyl acetate and 100ml of water were added, the layers were washed with water, and the aqueous phase was extracted twice with 100ml*2 of ethyl acetate. The organic phases were combined and washed with 100ml of saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrated oil was added with 80ml of isopropanol and 2g of activated carbon, stirred and heated to dissolve. The mixture was kept warm and stirred at reflux for 1h, then filtered and washed. The filtrate was slowly stirred and cooled to room temperature, then filtered. The filter cake was dried to obtain the product, which was detected to be 16.92g of 2-[1-(ethylsulfonyl)-3-azetidinylidene]acetonitrile (see the detection data spectrum). Figure 1 , Figure 2 ), yield 90.83%, HPLC purity 99.8%, single impurity less than 0.1%.

[0024] After the solvent was changed from tetrahydrofuran to dichloromethane, the compound detection data was the same as above, with a yield of 87% and an HPLC purity of 98.4%; After replacing the alkaline substance with potassium phosphate from potassium carbonate, the compound detection data was the same as above, with a yield of 79% and an HPLC purity of 99.7%; After being stored in a sealed container at room temperature for 120 hours, the above products were tested again and the purities were 99.7%, 98.2% and 96.7% respectively.

[0025] Example 2: Prepared as follows: Intermediate 2 was prepared by a one-pot reaction of intermediate 1 through deprotection of the tritylamine group, deprotection of the acetal group, and introduction of the ethylsulfonyl group.

[0026] 1. Synthesis of 1-(trityl)-3,3-di(methoxy)azetidine (Compound II) Under nitrogen protection, 260 ml of isopropyl alcohol, 25.9 g (0.1 mol) of triphenylmethane, and 25.2 g (0.3 mol, 3 eq) of sodium bicarbonate were added to a 1000 ml three-necked flask. After stirring at room temperature for 30 min, the temperature was raised to reflux with stirring. A solution of 17.1 g (0.1 mol, 1 eq) of 1,1-dichloro-2,2-dimethoxycyclopropane in isopropyl alcohol (170 ml) was added dropwise under reflux. After the addition was completed, the temperature was kept under reflux for 24 h. h, sampling HPLC to control the raw material triphenylamine to less than 0.5%, cooling to room temperature and filtering, the filtrate was concentrated to recover isopropanol, and then extracted and washed with 200 ml of ethyl acetate and 100 ml of water. The aqueous phase was extracted twice with 100 ml of ethyl acetate*2, and the combined organic phases were washed once with 100 ml of saturated brine. After separation, the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 33.39 g of a light yellow oil, namely compound II. The H NMR spectrum data was tested as follows: 1 H-NMR (400 MHz, DMSO-d6) δ: 3.36 (s, 6H), 3.68 (s, 2H), 3.75 (s, 2H), 7.38-7.27 (m, 15H), MS mass spectrometry value: C 24 H 25 NO2MS: [M+1]=360, yield 93%, HPLC purity 99.2%.

[0027] After changing the solvent from isopropanol / ethyl acetate to propanol / tetrahydrofuran, the compound detection data were the same as above, with a yield of 89% and an HPLC purity of 98.3%; After replacing the alkaline substance with potassium carbonate from sodium bicarbonate, the compound detection data was the same as above, with a yield of 91% and a HPLC purity of 98.1%; After being sealed and stored at room temperature for 120 hours, the above three samples were tested again and the purities were 99.2%, 98.2% and 97.7% respectively.

[0028] 2. Synthesis of Compound III Under nitrogen protection, 360 ml of dichloromethane and compound II were added to a 1000 ml three-necked flask. 35.9g (0.1mol), stirred and cooled to -5 to -10℃, 0.11g (0.001mol, 0.01eq) of trifluoroacetic acid was added dropwise, and the mixture was stirred for 5min. 15.4g (0.12mol, 1.2eq) of ethylsulfonyl chloride was added dropwise. After the addition was completed, the mixture was kept at -5 to -10℃ for 3h, and then slowly heated to room temperature for 6-8h. The raw material intermediate 1 was controlled to be less than 0.5% by HPLC. The reaction was stopped and 100ml of water was added to quench the reaction. After stirring at room temperature for 2h, the liquid was separated, and the aqueous phase was extracted once with 100ml of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The concentrated oil was slurried with 150ml of n-hexane at room temperature for 1h, and then filtered. The filter cake was dried to obtain 14.84g of the product. After testing, the mass spectrum data was C5H9NO3S, MS: [M+1] = 164 (measured value), and the nuclear magnetic resonance hydrogen spectrum data was 1 H-NMR (400 MHz, DMSO-d6) δ: 1.12-1.21 (m, 3H), 3.25-3.30 (m, 2H), 4.84 (s, 4H), yield 91%, HPLC purity 99.6%.

[0029] After the solvent was changed from dichloromethane to tetrahydrofuran, the compound detection data was the same as above, with a yield of 92% and an HPLC purity of 98.9%; After replacing the above acidic substance with pentafluoropropionic acid from trifluoroacetic acid, the compound detection data was the same as above, with a yield of 89% and an HPLC purity of 98.7%; After being sealed and stored at room temperature for 120 hours, the above three samples were tested again and the purities were 99.5%, 98.9% and 97.7% respectively.

[0030] 3. Synthesis of 2-[1-(ethylsulfonyl)-3-azetidinylidene]acetonitrile (Compound I) Add 163ml of tetrahydrofuran and intermediate 2 into a 500ml three-necked flask. 16.32g (0.1mol), 19.5g (0.11mol, 1.1eq) of diethyl cyanomethylphosphonate, and 14.5g (0.105mol, 1.05eq) of potassium carbonate were stirred and heated to reflux. The reaction was refluxed for 8-10h. The raw material was sampled and the reaction was complete by TLC. The reaction was cooled to room temperature. 100ml of ethyl acetate and 100ml of water were added, the layers were washed with water, and the aqueous phase was extracted twice with 100ml*2 of ethyl acetate. The organic phases were combined and washed with 100ml of saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrated oil was added with 80ml of isopropanol and 2g of activated carbon, stirred and heated to dissolve. The mixture was kept warm and stirred at reflux for 1h, then filtered and washed. The filtrate was slowly stirred and cooled to room temperature, then filtered. The filter cake was dried to obtain the product, which was detected to be 16.92g of 2-[1-(ethylsulfonyl)-3-azetidinylidene]acetonitrile (see the detection data spectrum). Figure 1 , Figure 2 ), yield 90.83%, HPLC purity 99.8%, single impurity less than 0.1%.

[0031] After the solvent was changed from tetrahydrofuran to dichloromethane, the compound detection data was the same as above, with a yield of 87% and an HPLC purity of 98.4%; After replacing the alkaline substance with potassium phosphate from potassium carbonate, the compound detection data was the same as above, with a yield of 79% and an HPLC purity of 99.7%; After being stored in a sealed container at room temperature for 120 hours, the above products were tested again and the purities were 99.7%, 98.2% and 96.7% respectively.

[0032] The above test results show that by optimizing the preparation process, a high-purity product was obtained. At the same time, intermediates 1 and 2 and the final product are relatively stable, allowing for easy storage and separation, which is particularly beneficial for batch-based modular CNC production. The optimized steps shorten the reaction route and significantly reduce material costs.

[0033] The above specific embodiments do not limit the protection scope of the present invention. Those skilled in the art can make various changes and applications to the present invention based on the above description.

Claims

1. A method for synthesizing a key intermediate of baricitinib, wherein the intermediate is 2-[1-(ethylsulfonyl)-3-azetidinylidene]acetonitrile represented by formula (I), Formula (I) It is characterized by comprising the following steps: Step 1: Triphenylmethane and 1,1-dichloro-2,2-dimethoxycyclopropane undergo a substitution ring-closure reaction in a basic substance and one or more solvents selected from isopropyl alcohol, ethanol, propanol, ethyl acetate, methyl tert-butyl ether, isopropyl ether, dichloromethane, tetrahydrofuran, and water to produce the compound 1-(trityl)-3,3-di(methoxy)azetidine represented by formula (II); Formula (II) Step 2: The compound of formula (II) is deprotected by acetalization in an acidic substance and one or more solvents selected from dichloromethane, ether, tetrahydrofuran, hexane, pentane, heptane, methyl tert-butyl ether, and ethyl acetate, and reacted with ethylsulfonyl chloride to produce a compound of formula (III); Formula (III) Step 3: The compound of formula (III) and diethyl cyanomethylphosphonate are reacted in an alkaline substance and one or more solvents selected from isopropanol, ethanol, propanol, ethyl acetate, methyl tert-butyl ether, isopropyl ether, dichloromethane, tetrahydrofuran, and water to prepare the compound of formula I, 2-[1-(ethylsulfonyl)-3-azetidinylidene]acetonitrile.

2. The method according to claim 1, wherein: The base includes one or more of potassium phosphate, potassium carbonate, sodium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, and sodium hydroxide. In step 1, the molar ratio of triphenylmethylamine, 1,1-dichloro-2,2-dimethoxycyclopropane, and the base is 1-5:1-5:5-20.

3. The method according to claim 1, characterized in that The acid comprises one or more of trifluoroacetic acid, trichloroacetic acid, p-TsOH, nitroacetic acid, pentafluoropropionic acid, difluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, and phosphoric acid. The molar ratio of the compound of formula II, ethylsulfonyl chloride, and acid in step 2 is 50-200:50-200:0.5-2.

4. The method according to claim 1, wherein The base includes one or more of potassium phosphate, potassium carbonate, sodium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, and sodium hydroxide. In step 3, the molar ratio of compound III, diethyl cyanomethyl phosphate, and the base is 1-5:1-5:5-20.

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