A method for synthesizing a key intermediate of baricitinib

Abstract

This invention provides a method for synthesizing a key intermediate of baricitinib, namely, a method for synthesizing 2-[1-(ethylsulfonyl)-3-azacyclobutylene]acetonitrile; this invention optimizes the preparation process, shortens the reaction time, improves the yield and purity, and is conducive to batch-by-batch modular industrial production.

Description

Technical Field

[0001] This invention pertains to drug synthesis methods, specifically relating to a method for synthesizing 2-[1-(ethylsulfonyl)-3-azacyclobutanediol]acetonitrile, a key intermediate of baricitinib. Background Technology

[0002] Baricitinib (brand name Olumiant) is a Janus kinase (JAK) inhibitor co-developed 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 JAK1, is one of the most important inflammatory pathways in the human body and is associated with the pathogenesis of many autoimmune diseases. Baricitinib inhibits the activated inflammatory pathway by blocking two members, JAK1 and JAK2. It was approved in 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 monotherapy or in combination with the widely used methotrexate. In recent years, baricitinib has been found to be effective in treating alopecia areata. On March 27, 2023, Eli Lilly announced that its drug baricitinib (trade name Alermin), developed for the treatment of severe alopecia areata in adults, has been approved by the National Medical Products Administration (NMPA) of China.

[0003] The chemical name of baricitinib is 1-(Ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidineacetonitrile, and its Chinese name is 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azacyclobutaneacetonitrile. Its CAS number is 1187594-09-7.

[0004] The synthetic route of baricitinib is relatively complex, involving the Witting-Horner reaction, Suzuki coupling, Michael addition, and protection and deprotection processes. 2-[1-(ethylsulfonyl)-3-azacyclobutylene]acetonitrile, as one of the key intermediates in baricitinib, is crucial to the formation of baricitinib. Existing technologies often employ the route disclosed in PCT patent WO2009114512 for the synthesis of this intermediate. The specific steps are as follows:

[0005]

[0006] The current synthesis route is long and requires the use of palladium carbon hydrogenation catalysis, which makes this step too costly. Furthermore, the catalytic components used in the protecting group addition are quite dangerous and the steps are cumbersome. The existing preparation methods require harsh conditions for the synthesis of key intermediates and lack mild and controllable characteristics, resulting in low product purity. Therefore, it is necessary to find a synthesis method that is short, low-cost, and simple to operate. Summary of the Invention

[0007] This invention unexpectedly yields a more convenient and controllable method for preparing the intermediate 2-[1-(ethylsulfonyl)-3-azacyclobutanediol]acetonitrile through a one-pot process. This not only significantly reduces costs and optimizes the initial preparation steps of baricitinib, but also provides mild reaction conditions and is easily controlled by numerical control. The method exhibits high reproducibility under specific conditions, simplifies steps, reduces costs, and improves both purity and yield.

[0008] The process flow is shown below.

[0009]

[0010] Step 1: Triphenylmethylamine and 1,1-dichloro-2,2-dimethoxycyclopropane undergo a substitution cyclization reaction in a solvent to generate intermediate 1, namely compound 1-(triphenylmethyl)-3,3-di(methoxy)azacyclobutane;

[0011] Step 2: Intermediate 1 reacts with ethylsulfonyl chloride under acidic conditions to generate intermediate 2;

[0012] Step 3: Intermediate 2 and diethyl cyanomethyl phosphate were reacted in a solvent to prepare compound I, 2-[1-(ethylsulfonyl)-3-azacyclobutanediyl]acetonitrile;

[0013] Furthermore, intermediate 1 is deprotected by acetal and then reacted with ethylsulfonyl chloride; in another alternative technical solution, step 2 and / or step 3 is a one-pot reaction.

[0014] 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, step 2 is a one-pot reaction, and the reaction conditions are acidic, with the solvent selected from one or more of dichloromethane, diethyl 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.

[0015] In a preferred embodiment, the alkali 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, and more preferably trifluoroacetic acid.

[0016] Preferably, in step 1, the molar ratio of triphenylmethylamine, 1,1-dichloro-2,2-dimethoxycyclopropane, and the base is 1-5:1-5:5-20; in step 2, the molar ratio of compound II, ethylsulfonyl chloride, and the acid is 50-200:50-200:0.5-2; and in step 3, the molar ratio of compound III, diethyl cyanomethyl phosphate, and the base is 1-5:1-5:5-20.

[0017] Another technical solution of the present invention is a method for synthesizing 2-[1-(ethylsulfonyl)-3-azacyclobutene]acetonitrile.

[0018]

[0019] TFA stands for trifluoroacetic acid.

[0020] Preferably, the deprotection of the triphenylmethylamine group, the deprotection of the acetal group, and the introduction of the ethanesulfonyl group are carried out in a one-pot reaction.

[0021] Another preferred synthesis method of the present invention is as follows:

[0022] Step 1: Add triphenylmethane and a basic reagent to a solvent, stir at room temperature, then heat to reflux. Add 1,1-dichloro-2,2-dimethoxycyclopropane dropwise under reflux, keep the mixture under reflux overnight, cool to room temperature, filter and concentrate, extract with solvent, wash with water, dry and concentrate to obtain compound II.

[0023] Step 2: Add compound II to the solvent, stir and cool to below zero degrees Celsius, add acidic substance and ethyl sulfonyl chloride dropwise, react for 1-5 hours, slowly raise to room temperature and continue the reaction, add water to quench the reaction, stir at room temperature, extract by liquid-liquid extraction, dry and concentrate, filter and dry to obtain compound III;

[0024] Step 3: Add compound III and diethyl cyanomethylphosphonate to the solvent, add an alkaline substance, stir and reflux, and after the reaction is complete, add organic solvent and water, extract in layers, concentrate and dry, add organic solvent and continue to filter and wash, and dry to obtain compound I.

[0025] 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; more preferably, trifluoroacetic acid.

[0026] In step 1, the molar ratio of triphenylmethylamine, 1,1-dichloro-2,2-dimethoxycyclopropane, and the base is 1-5:1-5:5-20; in step 2, the molar ratio of compound II, ethylsulfonyl chloride, and the acid is 50-200:50-200:0.5-2; in step 3, the molar ratio of compound III, diethyl cyanomethylphosphonate, and the base is 1-5:1-5:5-20.

[0027] All raw materials and reagents used in this invention were commercially available. 1,1-Dichloro-2,2-dimethoxycyclopropane (C5H8CL2O2, PSA 18.46, LogP 1.55310) was purchased from MOLBASE; triphenylmethane was purchased from Kramar Reagent Company (chemically pure); and the remaining reagents and equipment were purchased from Sigma.

[0028] The beneficial effects of this invention are:

[0029] 1) The intermediates 1 and 2 obtained by this invention are relatively stable and are conducive to separation and purification. Under specific conditions, they can increase product purity, degrade some organic impurities, and reduce the generation of by-products.

[0030] 2) The steps were optimized and the reaction route was shortened by direct acetal deprotection and ethanesulfonyl addition. The raw materials used, such as triphenylmethane and 1,1-dichloro-2,2-dimethoxycyclopropane, are low in cost. The reaction was carried out by reflux reaction with common acid, base and solvent, which greatly reduced the cost and avoided the use of by-products and harmful reagents.

[0031] 3) High yield and high purity, mild preparation conditions, easy to repeat, suitable for large-scale CNC production. Attached Figure Description

[0032] Figure 1 LC-MS spectra of the final products in Examples 1 and 2

[0033] Figure 2 The HNMR spectra of the final products (compounds of formula I) in Examples 1 and 2. Detailed Implementation

[0034] Example 1:

[0035] Prepared using the following process:

[0036]

[0037] 1. Synthesis of 1-(triphenylmethyl)-3,3-di(methoxy)azacyclobutane (compound II)

[0038] Under nitrogen protection, 260 ml of isopropanol, 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 mixture was heated to reflux. Under reflux, a solution of 17.1 g (0.1 mol, 1 eq) of 1,1-dichloro-2,2-dimethoxycyclopropane in 170 ml of isopropanol was added dropwise. After the addition was completed, the mixture was kept at reflux for 24 hours. h, the starting material triphenylmethane was sampled and controlled to be less than 0.5% in HPLC. After cooling to room temperature, it was filtered. The filtrate was concentrated to recover isopropanol, and then extracted with 200 ml of ethyl acetate and 100 ml of water. After washing with water, the aqueous phase was extracted twice with 100 ml of ethyl acetate. The combined organic phases were washed once with 100 ml of saturated brine. After separation, the organic phase was dried with anhydrous sodium sulfate and concentrated to obtain 33.39 g of a pale yellow oil, namely compound II. The 1H NMR spectrum data was as follows: 1 ¹H NMR (400MHz, DMSO-d6) δ: 3.36 (s, 6H), 3.68 (s, 2H), 3.75 (s, 2H), 7.38–7.27 (m, 15H); MS mass spectrometry values: C 24 H 25 NO2MS: [M+1]=360, yield 93%, HPLC purity 99.2%.

[0039] 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%.

[0040] After replacing sodium bicarbonate with potassium carbonate, the compound detection data remained the same, with a yield of 91% and an HPLC purity of 98.1%.

[0041] After being stored at room temperature in a sealed container for 120 hours, the three samples were tested again, and their purities were 99.2%, 98.2%, and 97.7%, respectively.

[0042] Synthesis of 2,3,3-bis(methoxy)azacyclobutane trifluoroacetate

[0043] 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. The mixture was stirred at room temperature for 6-8 hours. A TLC sample was taken after the reaction was complete, and 21.95 g of an off-white solid was obtained by filtration. The 1H NMR spectrum data were as follows: 1 ¹H-NMR (400MHz, DMSO-d6) δ: 3.30 (s, 6H), 3.82 (s, 2H), 3.78 (s, 2H), 2.11 (s, 1H), yield 95%.

[0044] 3. Synthesis of Compound III

[0045] Under nitrogen protection, 230 ml of dichloromethane and 23.11 g (0.1 mol) of 3,3-di(methoxy)azacyclobutane trifluoroacetate were added to a 1000 ml three-necked flask. The mixture was stirred and cooled to -5 to -10 °C. 41.36 g (0.32 mol, 3.2 eq) of N,N-diisopropylethylamine was added dropwise. The mixture was kept at this temperature and stirred for 5 min. Then, 15.4 g (0.12 mol, 1.2 eq) of ethylsulfonyl chloride was added dropwise. After the addition was complete, the mixture was kept at -5 to -10 °C for 3 h, and then slowly raised to room temperature for 6 h. -8h, the TLC sample was taken and the reaction was complete. The reaction was stopped, 100ml of water was added to quench the reaction, concentrated hydrochloric acid was added dropwise to adjust the pH to 1-2, and the mixture was stirred at room temperature for 2h. After separation, the aqueous phase was extracted once with 100ml of dichloromethane, the organic phases were combined, dried with anhydrous sodium sulfate, and concentrated. The concentrated oily substance was added with 150ml of n-hexane, stirred at room temperature for 1h, and then filtered. The filter cake was dried to obtain 14.26g of product. The mass spectrometry data was C5H9NO3S, MS: [M+1]=164 (measured value), and the 1H NMR data was... 1 ¹H-NMR (400MHz, 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%.

[0046] After changing the solvent from dichloromethane to tetrahydrofuran, the compound detection data were the same as above, with a yield of 87% and an HPLC purity of 98.8%.

[0047] After replacing the above-mentioned alkaline substance with triethylamine, the compound detection data were the same as above, with a yield of 85% and an HPLC purity of 98.5%.

[0048] After being stored at room temperature in a sealed container for 120 hours, the three samples were tested again, and their purities were 99.5%, 98.8%, and 97.7%, respectively.

[0049] 4. Synthesis of 2-[1-(ethylsulfonyl)-3-azacyclobutanediyl]acetonitrile (Compound I)

[0050] Add 163 ml of tetrahydrofuran and intermediate 2 ml to a 500 ml three-necked flask. 16.32 g (0.1 mol), 19.5 g (0.11 mol, 1.1 eq) of diethyl cyanomethylphosphonate, and 14.5 g (0.105 mol, 1.05 eq) of potassium carbonate were stirred and heated to reflux for 8-10 h. The reaction was carried out by TLC until the raw materials were completely reacted. The mixture was cooled to room temperature, and 100 ml of ethyl acetate and 100 ml of water were added. The mixture was washed with water to separate the layers. The aqueous phase was extracted twice with 100 ml of ethyl acetate. The organic phases were combined, washed with 100 ml of saturated brine, and separated into layers. The organic phase was dried with anhydrous sodium sulfate and concentrated. The resulting oily substance was dissolved in 80 ml of isopropanol and 2 g of activated carbon by stirring and heating. The mixture was kept at reflux and stirred for 1 h, then filtered and washed. The filtrate was slowly stirred and cooled to room temperature before being filtered again. The filter cake was dried to obtain the product, which was identified as 16.92 g of 2-[1-(ethylsulfonyl)-3-azacyclobutanediol]acetonitrile (see chromatogram for detection data). Figure 1 , Figure 2 The yield was 90.83%, the HPLC purity was 99.8%, and the single impurity was less than 0.1%.

[0051] After changing the solvent from tetrahydrofuran to dichloromethane, the compound detection data were the same as above, with a yield of 87% and an HPLC purity of 98.4%.

[0052] After replacing the above-mentioned alkaline substance with potassium phosphate instead of potassium carbonate, the compound detection data were the same as above, with a yield of 79% and an HPLC purity of 99.7%.

[0053] After being stored at room temperature in a sealed container for 120 hours, the above products were tested again, and the purities were 99.7%, 98.2%, and 96.7%, respectively.

[0054] Example 2:

[0055] Prepared using the following process:

[0056]

[0057] Intermediate 2 was prepared by a one-pot reaction of intermediate 1, involving the deprotection of the triphenylmethylamine group, the deprotection of the acetal group, and the introduction of the ethanesulfonyl group.

[0058] 1. Synthesis of 1-(triphenylmethyl)-3,3-di(methoxy)azacyclobutane (compound II)

[0059] Under nitrogen protection, 260 ml of isopropanol, 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 mixture was heated to reflux. Under reflux, a solution of 17.1 g (0.1 mol, 1 eq) of 1,1-dichloro-2,2-dimethoxycyclopropane in 170 ml of isopropanol was added dropwise. After the addition was completed, the mixture was kept at reflux for 24 hours. h, the starting material triphenylmethane was sampled and controlled to be less than 0.5% in HPLC. After cooling to room temperature, it was filtered. The filtrate was concentrated to recover isopropanol, and then extracted with 200 ml of ethyl acetate and 100 ml of water. After washing with water, the aqueous phase was extracted twice with 100 ml of ethyl acetate. The combined organic phases were washed once with 100 ml of saturated brine. After separation, the organic phase was dried with anhydrous sodium sulfate and concentrated to obtain 33.39 g of a pale yellow oil, namely compound II. The 1H NMR spectrum data was as follows: 1 ¹H NMR (400MHz, DMSO-d6) δ: 3.36 (s, 6H), 3.68 (s, 2H), 3.75 (s, 2H), 7.38–7.27 (m, 15H); MS mass spectrometry values: C 24 H 25 NO2MS: [M+1]=360, yield 93%, HPLC purity 99.2%.

[0060] 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%.

[0061] After replacing sodium bicarbonate with potassium carbonate, the compound detection data remained the same, with a yield of 91% and an HPLC purity of 98.1%.

[0062] After being stored at room temperature in a sealed container for 120 hours, the three samples were tested again, and their purities were 99.2%, 98.2%, and 97.7%, respectively.

[0063] 2. Synthesis of Compound III

[0064] Under nitrogen protection, 360 ml of dichloromethane and compound II were added to a 1000 ml three-necked flask. 35.9 g (0.1 mol) was stirred and cooled to -5 to -10 °C. 0.11 g (0.001 mol, 0.01 eq) of trifluoroacetic acid was added dropwise, and the mixture was kept at this temperature and stirred for 5 min. Then, 15.4 g (0.12 mol, 1.2 eq) of ethylsulfonyl chloride was added dropwise. After the addition was complete, the mixture was kept at -5 to -10 °C for 3 h, then slowly raised to room temperature and reacted for 6-8 h. The HPLC control showed that the concentration of intermediate 1 was less than 0.5%, at which point the reaction was stopped. 100 ml of water was added to quench the reaction, and the mixture was stirred at room temperature for 2 h. The mixture was then separated into liquid and liquid phases. The aqueous phase was extracted once with 100 ml of dichloromethane. The combined organic phases were dried with anhydrous sodium sulfate and concentrated. The resulting oily substance was slurried with 150 ml of n-hexane at room temperature for 1 h, then filtered. The filter cake was dried to obtain 14.84 g of the product. Mass spectrometry data showed C5H9NO3S, MS: [M+1]=164 (measured value), and nuclear magnetic resonance (NMR) data showed... 1 ¹H-NMR (400MHz, 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%.

[0065] After changing the solvent from dichloromethane to tetrahydrofuran, the compound detection data were the same as above, with a yield of 92% and an HPLC purity of 98.9%.

[0066] After replacing the above acidic substance with pentafluoropropionic acid, the compound detection data were the same as above, with a yield of 89% and an HPLC purity of 98.7%.

[0067] After being stored at room temperature in a sealed container for 120 hours, the three samples were tested again, and their purities were 99.5%, 98.9%, and 97.7%, respectively.

[0068] 3. Synthesis of 2-[1-(ethylsulfonyl)-3-azacyclobutanediyl]acetonitrile (Compound I)

[0069] Add 163 ml of tetrahydrofuran and intermediate 2 ml to a 500 ml three-necked flask. 16.32 g (0.1 mol), 19.5 g (0.11 mol, 1.1 eq) of diethyl cyanomethylphosphonate, and 14.5 g (0.105 mol, 1.05 eq) of potassium carbonate were stirred and heated to reflux for 8-10 h. The reaction was carried out by TLC until the raw materials were completely reacted. The mixture was cooled to room temperature, and 100 ml of ethyl acetate and 100 ml of water were added. The mixture was washed with water to separate the layers. The aqueous phase was extracted twice with 100 ml of ethyl acetate. The organic phases were combined, washed with 100 ml of saturated brine, and separated into layers. The organic phase was dried with anhydrous sodium sulfate and concentrated. The resulting oily substance was dissolved in 80 ml of isopropanol and 2 g of activated carbon by stirring and heating. The mixture was kept at reflux and stirred for 1 h, then filtered and washed. The filtrate was slowly stirred and cooled to room temperature before being filtered again. The filter cake was dried to obtain the product, which was identified as 16.92 g of 2-[1-(ethylsulfonyl)-3-azacyclobutanediol]acetonitrile (see chromatogram for detection data). Figure 1 , Figure 2 The yield was 90.83%, the HPLC purity was 99.8%, and the single impurity was less than 0.1%.

[0070] After changing the solvent from tetrahydrofuran to dichloromethane, the compound detection data were the same as above, with a yield of 87% and an HPLC purity of 98.4%.

[0071] After replacing the above-mentioned alkaline substance with potassium phosphate instead of potassium carbonate, the compound detection data were the same as above, with a yield of 79% and an HPLC purity of 99.7%.

[0072] After being stored at room temperature in a sealed container for 120 hours, the above products were tested again, and the purities were 99.7%, 98.2%, and 96.7%, respectively.

[0073] The above experimental results show that by optimizing the preparation process, a product with high purity was obtained. Meanwhile, intermediates 1 and 2, along with the product, are relatively stable, facilitating storage and separation, which is particularly beneficial for batch-based modular CNC production. The optimized steps shortened the reaction route and significantly reduced material costs.

[0074] The specific embodiments described above do not constitute a limitation on the scope of protection 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, said intermediate as shown in compound I, Compound I Its features are, Includes the following steps: The preparation process is shown below: Step 1: Triphenylmethane and 1,1-dichloro-2,2-dimethoxycyclopropane undergo a substitution cyclization reaction in one or more solvents selected from isopropanol, ethanol, propanol, ethyl acetate, methyl tert-butyl ether, isopropyl ether, dichloromethane, tetrahydrofuran, and water to generate compound II; Step 2: Compound II reacts with ethylsulfonyl chloride under trifluoroacetic acid conditions to generate compound III; Step 3: Compound I was prepared by reacting compound III and diethyl cyanomethyl phosphate in an alkaline substance and solvent.

2. The method according to claim 1, characterized in that: The reaction conditions in step 1 are alkaline. The base includes one or more of potassium phosphate, potassium carbonate, sodium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, and sodium hydroxide. The molar ratio of triphenylmethane, 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, In step 2, the molar ratio of compound II, ethylsulfonyl chloride, and trifluoroacetic acid is 50-200:50-200:0.5-2.

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

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