A method for the synthesis of non-sulazane

Abstract

This invention provides a method for synthesizing non-surazine, relating to the field of organic chemical intermediate synthesis technology. The non-surazine is prepared by using m-difluorobenzene as a starting material and oxaloyl chloride monoester under Lewis acid catalysis via Friedel-Crafts acylation, followed by cyclization with aminopropionitrile under alkaline conditions, methylation with a methylating agent under alkaline conditions, catalytic reduction, and nucleophilic addition with m-fluorobenzenesulfonyl chloride under alkaline conditions. Finally, it is prepared by condensation with methylamine, reduction, and salt formation with hydrogen chloride solution. This invention overcomes the shortcomings of existing technologies, providing a method for synthesizing non-surazine with readily available raw materials, high yield, good quality, simple operation, and suitability for industrial production.

Description

Technical Field

[0001] This invention relates to the field of organic chemical intermediate synthesis technology, specifically to a method for synthesizing non-Surazanol. Background Technology

[0002] Fisorazan is a potassium-competitive acid blocker (P-CAB). Compared to traditional proton pump inhibitors (PPIs), P-CABs exhibit stronger acid-suppressing capabilities, higher pKa values, and do not require proton pump activation, resulting in a faster onset of action and significantly reducing the occurrence of nocturnal acid breakthrough (NAB). It has also become an ideal partner for core antibiotics in Helicobacter pylori treatment regimens. In summary, fisorazan currently has wide applications in pharmaceutical synthesis, and its synthetic process has significant development potential.

[0003] Korean patent WO,2016 / 175555[P] reports the synthetic route of non-surazine intermediate compound VIII as follows:

[0004]

[0005] The overall yield of this synthetic route is only 9%, making it unsuitable for large-scale industrial production.

[0006] Patent WO,2018 / 236153A1[P] reports the following synthetic route:

[0007]

[0008] This route uses m-difluorobenzene as a raw material and involves Strecker, Boc protection, condensation, cyclization, methylation, and deBoc protection reactions, achieving a yield of 28.8%. However, this route involves the use of highly toxic sodium cyanide, has a long process, low atom economy, and is not suitable for industrial production.

[0009] Chinese patent CN, 10867617A [P] reports the following synthetic route:

[0010]

[0011] Using m-difluorobenzaldehyde as a raw material, TosMIC reagent was prepared through condensation addition and dehydration reactions, followed by VanLeusen reaction. This route is shorter and simpler to operate, but the overall yield is only 25.3%, indicating significant room for improvement.

[0012] Chinese patent CN, 107001263A1[P] reports a non-surazine synthetic route, as shown below:

[0013]

[0014] Using intermediate VIII as a raw material, sulfonation is carried out with 3-fluorobenzenesulfonyl chloride under the action of strong base sodium hydrogen. Then, diisobutylaluminum hydride (DIBAL) is used as a reducing agent to reduce the ester group to a hydroxyl group. The hydroxyl group is then oxidized to an aldehyde group using pyridinium chlorochromate (PCC). Finally, the product is obtained by reductive amination and salt formation with hydrochloric acid. The overall yield is 51.4%. This route uses hazardous reagents such as sodium hydrogen and diisobutylaluminum hydride. Pyridinium chlorochromate is extremely harmful to the environment and is not suitable for large-scale industrial production.

[0015] In summary, the existing synthetic routes have drawbacks such as long steps, low atom economy, use of highly toxic sodium cyanide, and low overall synthetic yield. Summary of the Invention

[0016] To address the shortcomings of existing technologies, this invention provides a non-Surazan synthesis method that uses readily available raw materials, has a high yield, good quality, is easy to operate, and is suitable for industrial production.

[0017] To achieve the above objectives, the present invention provides the following technical solution:

[0018] A method for synthesizing a non-Surazan, the method comprising the following steps:

[0019] S1. Compound II was prepared by Friedel-Crafts acylation of m-difluorobenzene (compound I) with oxaloyl chloride monoester under Lewis acid catalysis.

[0020] S2. Compound II was prepared by cyclizing it with aminopropionitrile under the action of alkaline reagent I to obtain compound III;

[0021] S3. Compound III was prepared by reacting it with a methylating agent under the action of a basic reagent II via a methylation reaction.

[0022] S4. Compound IV was placed in a solvent and catalytically reduced in a hydrogen-pressurized environment to prepare compound V.

[0023] S5. Compound V was prepared by nucleophilic addition reaction with m-fluorobenzenesulfonyl chloride under the action of alkaline reagent II;

[0024] S6. Compound VI is first condensed with methylamine to obtain an imine, which is then reduced and amination with a reducing agent to obtain a free base. The free base is then salted with hydrogen chloride solution to prepare compound VII, which is non-surazine.

[0025] The specific synthesis route is as follows:

[0026]

[0027] Preferably, the structural formula of the oxaloyl chloride monoester is:

[0028]

[0029] R is an ester formed from carbon chains with a length of 1 to 20.

[0030] Preferably, in step S1, the Lewis acid is selected from one or more of ferric chloride, aluminum chloride, and boron trifluoride complex.

[0031] Preferably, the molar ratio of compound II, aminopropionitrile, and alkaline reagent II in step S2 is 1:1.0-5.0:1.0-10.0.

[0032] Preferably, in step S3, the molar ratio of compound III, methylating agent, and basic agent is 1:1.0-5.0:1.0-10.0.

[0033] Preferably, the methylating agent is selected from at least one of iodomethane, dimethyl sulfate, and (trimethylsilyl)diazomethane; the catalyst is selected from at least one of Raney nickel, tetraphenylphosphine nickel, and supported tetraphenylphosphine nickel; and the solvent is a mixture of ethanol, water, and acetic acid.

[0034] Preferably, the hydrogen pressure controlled during catalytic reduction in step S4 is 0.1–0.5 MPa, and the reaction temperature is 20–55 °C.

[0035] Preferably, the molar ratio of compound V, m-fluorobenzenesulfonyl chloride and alkaline reagent in step S5 is 1:0.8-5.0:0.8-10.0.

[0036] Preferably, the reducing agent in step S6 is one or more of lithium borohydride, sodium borohydride, potassium borohydride, sodium triacetoxyborohydride, and sodium cyanoborohydride.

[0037] Preferably, the first alkaline reagent is one or more of the following: lithium n-butyllithium, potassium tert-butoxide, sodium tert-butoxide, lithium di(trimethylsilyl)amino, sodium di(trimethylsilyl)amino, potassium di(trimethylsilyl)amino, lithium diisopropylamino, and sodium diisopropylamino; the second alkaline reagent is one or more of the following: lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, N-methylmorpholine, tetramethylethylenediamine, and pyridine.

[0038] This invention provides a method for synthesizing non-surazine, which has the following advantages compared with the prior art:

[0039] The synthesis method of this invention synthesizes non-Surazine by designing the construction of pyrrole rings and selectively reducing cyano groups, which meets the current demand for green, safe and inexpensive production in commercial production. The entire synthesis process reduces the use of polluting and toxic components and ensures the yield of non-Surazine, making it suitable for large-scale production. Detailed Implementation

[0040] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0041] Example 1:

[0042] Non-Surazan synthesis route:

[0043]

[0044] The specific synthesis method is as follows:

[0045] (1) Under nitrogen protection, 50.0 g (0.44 mol, 1.0 equiv.) of compound I, 70.7 g (0.53 mol, 1.2 equiv.) of aluminum trichloride, and 100.0 g (2.0 w / w) of dichloromethane were added to the reaction flask. The temperature was controlled at 0 °C. 75.6 g (0.62 mol, 1.4 equiv.) of monomethyl oxalate was slowly added dropwise to the reaction flask. After the addition was complete, the mixture was kept at this temperature for 3 h. After the temperature was complete, the reaction solution was slowly added dropwise to 200.0 g of ice water to quench the reaction and separate the layers. The aqueous layer was extracted with 100.0 g of dichloromethane, and the organic phases were combined and washed with 200.0 g of water. The organic phase was taken and distilled to obtain compound II-1 with a yield of 68.3%. The NMR data of the compound are as follows: 1 H NMR (600MHz, DMSO-d6) δ7.99-7.93(m,1H),7.44-7.39(m,1H),7.28-7.23(m,1H),3.88(s,3H); 13C NMR(600MHz,DMSO-d6)δ182.6,168.4,168.3,165.8,165.7,164.6,164.5,164.0,162.0,161.9,133.74,133.72,1 33.63,133.61,118.39,118.35,118.29,118.25,113.71,113.68,113.49,113.46,106.1,105.8,105.5,53.5ppm.

[0046] (2) 17.5 g (0.25 mol, 1.0 equiv.) of 3-aminopropionitrile and 150.0 g (3.0 w / w) of tetrahydrofuran were purged with nitrogen three times. The reaction flask was placed in a cold trap and cooled to -80 °C. 45.8 g (0.25 mol, 1.0 equiv.) of sodium di(trimethylsilyl)aminoacetate was slowly added dropwise, and the mixture was kept at this temperature and stirred for 1 h. The internal temperature was controlled below -70 °C, and 50.0 g (1.0 w / w) of a tetrahydrofuran solution containing 50.0 g (0.25 mol, 1.0 equiv.) of compound II-1 was added dropwise, and the reaction mixture was kept at this temperature for 2 h. At -80 °C, the reaction mixture was added dropwise in three batches to an AcOH-MeOH solution, and the internal temperature was controlled at -30 °C, and the mixture was stirred overnight. The solid was filtered through a Buchner funnel under vacuum, washed with toluene (200 mL × 2), and dried under vacuum at 50 °C for 16 h to obtain compound III.

[0047] (3) Under nitrogen protection, add compound III and methanol (3.0 w / w) from the previous step into the reaction flask, control the temperature at 15°C, and slowly add N,N-diisopropylethylamine (0.45 mol, 1.8 equiv.) dropwise into the reaction flask. After the addition is complete, keep the reaction at the temperature for 10 min. The reaction mixture was prepared by adding 0.50 mol (2.0 equiv.) of iodomethane dropwise to the reaction system at a controlled temperature of 15–20 °C. After the addition was complete, the mixture was kept at this temperature for 5 hours. Then, 200 g of water was slowly added dropwise to quench the reaction mixture, resulting in solid formation. The mixture was then kept at 15–20 °C and stirred for 3 hours. After stirring, the filter cake was washed with 50 g of a 20% methanol aqueous solution. The mixture was then heated to 50 ± 5 °C under a vacuum of -0.08 to -0.1 MPa to concentrate the reaction solution to 150 g. After concentration, the temperature was lowered to 15 °C and stirred for 3 hours. The mixture was then filtered, and the filter cake was washed with 60 g of tap water to obtain compound IV. The two-step yield was 64.2%. The NMR data of the compound are as follows: 1 HNMR(600MHz,DMSO-d6)δ11.75(s,1H),7.58-7.55(m,1H),7.54-7.51(m,1H),7.35-7.29(m,1H),7.17-7.11(m,1H),3.78(s,3H);13 C NMR(600MHz,DMSO-d6)δ163.2,160.6,160.3,160.2,157.8,157.7,145.6,131.6,131.55,131.50,131.45,125 .4,119.0,116.0,115.1,115.0,112.43,112.39,112.33,112.22,112.18,105.2,104.9,104.6,84.9,61.5ppm.

[0048] (4) At room temperature (20℃), 100.0 g (0.43 mol, 1.0 equiv.) of compound IV, 200.0 g (5.0 w / w) of ethanol, 200.0 g (5 w / w) of water, 200.0 g (2.0 w / w) of acetic acid, and 30.0 g (0.3 w / w) of Raney-Ni were added to a hydrogenation reactor. H2 was replaced three times, with 0.30 MPa of H2 added each time. The H2 pressure was 0.50 MPa, and the reaction was maintained at 50℃ for 24 h. The hydrogenation reactor was then cooled to 20℃, and the reaction solution was vacuum filtered through a Buchner funnel. The solid was washed with 80.0 g of methyl tert-butyl ether to obtain compound V, with a yield of 70.2%. The NMR data of the compounds are as follows: 1 H NMR (600MHz, DMSO-d6) δ11.70(s,1H),9.65(s,1H),7.65-7.55(m,2H),7.33-7.28(m,1H),7.16-7.10(m,1H),3.76(s,3H); 13 C NMR (600MHz, DMSO-d6) δ184.2,163.0,162.9,160.4,160.2,160.1,157.8,157.7,143.3,131.51,131. 46,131.41,131.37,128.6,118.6,115.6,115.4,114.7,112.3,112.1,105.1,104.8,104.6,61.8ppm.

[0049] (5) Under nitrogen protection, add 300.0 g (3.0 w / w) of tetrahydrofuran and 100.0 g (0.42 mol, 1.0 equiv.) of compound V to the reaction flask, control the temperature at 0-5℃, and slowly add 64.6 g (0.50 mol, 1.2 equiv.) of N,N-diisopropylethylamine to the reaction flask. After the addition is complete, keep the reaction at the temperature for 30 min. Controlling the temperature at 0–5 °C, 89.2 g (0.46 mol, 1.1 equiv.) of m-fluorobenzenesulfonyl chloride was added dropwise. The reaction was maintained at this temperature for 2 h. After the temperature was maintained, 400.0 g of water was slowly added dropwise to quench the reaction mixture, controlling the temperature at 0–5 °C. After the addition was complete, the mixture was stirred at 25 °C for 1 h. The mixture was then heated to 50 ± 5 °C under a vacuum of -0.08 to -0.1 MPa to concentrate the reaction solution to 500.0 g. After concentration, ethyl acetate (500 mL × 3) was added, and the mixture was allowed to separate into layers. The organic phases were combined and heated to 50 ± 5 °C under a vacuum of -0.08 to -0.1 MPa to remove the ethyl acetate, yielding crude compound VI. The crude compound VI was washed with a solution of HE:EA = 10:1 (300.0 g). The temperature was lowered to 25 °C, and the mixture was stirred for 3 h. After filtration, the filter cake was washed with 100.0 g of tap water and dried to obtain compound VI, with a yield of 93.1%. The NMR data of the compound are as follows: 1 H NMR (600MHz, DMSO-d6) δ9.90(s,1H),8.53(s,1H),7.71(s,2H),7.42-7.41(m,2H),7.32-7.24(m,2H),7.18-7.15(m,1H),3.61(s,3H); 13 CNMR(600MHz,DMSO-d6)δ185.4,164.9,164.8,163.2,163.1,162.9,162.4,162. 3,161.2,160.8,160.7,146.6,138.53,138.48,136.1,136.0,132.9,124.10,12 4.08,123.2,123.1,122.13,122.11,121.2,115.0,114.9,114.8,112.9,112.25 ,112.22,112.14,112.12,111.8,111.68,111.66,104.5,104.4,104.2,61.7ppm.

[0050] (6) Under nitrogen protection, 500.0 g of methanol (5.0 w / w) and 100.0 g of compound VI (0.25 mol, 1.0 equiv.) were added to the reaction flask. The temperature was controlled at 20-25 °C. 17.1 g of methylamine methanol solution (0.50 mol, 2.0 equiv., 30% in methanol) was slowly added dropwise to the reaction flask. After the addition was completed, the reaction was kept at the temperature for 1 h. The temperature was controlled at 0–5 °C. 11.3 g (0.30 mol, 1.2 equiv.) of sodium borohydride was added in portions to the reaction flask, keeping the internal temperature below 10 °C. After the addition was complete, the reaction was maintained at this temperature for 2 hours. Then, 100 g of water was added dropwise to the reaction system, and the temperature was controlled at 25 °C. The reaction solution was concentrated to 350 g. After concentration, ethyl acetate (500 mL × 3) was added, the layers were separated, and the organic phases were combined. Part of the ethyl acetate was removed by distillation, and the reaction solution was reduced to 300 g. The temperature was controlled at 0–5 °C. Hydrogen chloride (1 M in EA) was added dropwise to the reaction solution until pH ≈ 1 and a solid was formed. The temperature was controlled at 0–5 °C, and the reaction was maintained at this temperature for 2 hours to obtain crude compound VII. The crude compound VII was washed with EA (100 mL) and dried at 50 °C under normal pressure to obtain compound VII, with a yield of 92.7%. The NMR data of the compound are as follows: 1 H NMR(600MHz,D2O)δ7.50(s,1H),7.23-7.19(m,1H),7.07-7.06(m,1H),7.02-6.99(m,1H),6.80-6.76( m,1H),6.72-6.71(m,1H),6.53-6.50(m,1H),6.44-6.41(m,1H),3.91(s,2H),3.11(s3H),2.52(s,3H); 13 C NMR(600MHz,D2O)δ164.5,162.9,162.3,160.7,160.5,148.0,138.6,138.5,135.7,131.8,123.1,1 22.9,121.6,114.1,113.9,112.8,112.7,111.0,110.8,110.5,103.3,103.2,60.0,41.2,31.7ppm.

[0051] Example 2:

[0052] Non-Surazan synthesis route:

[0053]

[0054] The specific synthesis method is as follows:

[0055] (1) Under nitrogen protection, 50.0 g of compound I (0.44 mol, 1.0 equiv.), 70.7 g of aluminum trichloride (0.53 mol, 1.2 equiv.), and 100 mL of dichloromethane (2 w / w) were added to the reaction flask. The temperature was controlled at 20 °C. 64.6 g of monomethyl oxalate (0.53 mol, 1.2 equiv.) was slowly added dropwise to the reaction flask. After the addition was complete, the mixture was kept at this temperature for 3 h. After the temperature was complete, the reaction solution was slowly added dropwise to 200.0 g of ice water to quench the reaction and separate the layers. The aqueous layer was extracted with 100.0 g of dichloromethane. The organic phases were combined and then washed with 200.0 g of water to obtain a mixed solution of compound II-1 and dichloromethane. After distillation, the solution was added to the next reaction step.

[0056] (2) 3-Aminopropionitrile (0.66 mol, 1.5 equiv.) and tetrahydrofuran (3.0 w / w) were purged with nitrogen three times. The reaction flask was placed in a cold trap and cooled to -80 °C. Sodium di(trimethylsilyl)aminoacetate (0.53 mol, 1.2 equiv.) was slowly added dropwise, and the mixture was stirred for 1 h. The internal temperature was controlled below -70 °C, and a tetrahydrofuran solution (1.0 w / w) of compound II-1 from step one was added dropwise, and the reaction was maintained for 2 h. At -80 °C, the reaction mixture was added dropwise in three batches to an AcOH-MeOH solution, and the internal temperature was controlled at -30 °C, with stirring overnight. The solid was filtered through a Buchner funnel under vacuum, washed with toluene (200 mL × 2), and dried under vacuum at 50 °C for 16 h to obtain compound III. The two-step yield was 51.3%. The NMR data of the compound are as follows: 1 H NMR (600MHz, DMSO-d6) δ11.42(s,1H),9.19(s,1H),7.72-7.65(m,1H),7.37(d,J=5.40,1H),7.27-7.21(m,1H),7.12-7.07(m,1H); 13 C NMR(600MHz,DMSO-d6)δ162.5,162.4,160.05,159.95,159.92,159.8,157.5,157.4,142.9,130.95,130.90,130.86, 130.80,124.1,116.4,116.0,115.90,115.87,112.11,112.08,111.90,111.87,109.9,104.9,104.7,104.4,85.5ppm.

[0057] (3) Under nitrogen protection, 200.0 g (5.0 w / w) of methanol and 40.0 g (0.18 mol, 1.0 equiv.) of compound III were added to the reaction flask. The temperature was controlled at 15-20℃. 34.9 g (0.27 mol, 1.5 equiv.) of N,N-diisopropylethylamine was slowly added dropwise to the reaction flask. After the addition was completed, the reaction was kept at the temperature for 10 min. Controlling the temperature at 15–20°C, 38.3 g of iodomethane (0.27 mol, 1.5 equiv.) was added dropwise. The reaction was maintained at this temperature for 3 hours. After the reaction was completed, 400.0 g of water was slowly added dropwise to quench the reaction mixture, resulting in solid formation. The temperature was then controlled at 15–20°C, and the mixture was stirred for 2 hours. After stirring, the filter cake was washed with 80.0 g of 20% methanol aqueous solution. The mixture was heated to 50±5°C under a vacuum of -0.08 to -0.1 MPa to concentrate the reaction solution to 350.0 g. After concentration, the temperature was lowered to 15–20°C, and the mixture was stirred for 3 hours. The mixture was then filtered, and the filter cake was washed with 100.0 g of tap water to obtain crude compound IV, with a yield of 85.9%.

[0058] The NMR data of the compound are as follows: 1 H NMR (600MHz, DMSO-d6) δ11.75(s,1H),7.58-7.55(m,1H),7.54-7.51(m,1H),7.35-7.29(m,1H),7.17-7.11(m,1H),3.78(s,3H); 13 C NMR(600MHz,DMSO-d6)δ163.2,160.6,160.3,160.2,157.8,157.7,145.6,131.6,131.55,131.50,131.45,125 .4,119.0,116.0,115.1,115.0,112.43,112.39,112.33,112.22,112.18,105.2,104.9,104.6,84.9,61.5ppm.

[0059] (4) At room temperature (20℃), 100.0 g (0.43 mol, 1.0 equiv.) of compound IV, 200.0 g (5.0 w / w) of ethanol, 200.0 g (5 w / w) of water, 180.0 g (1.8 w / w) of acetic acid, and 20.0 g (0.2 w / w) of Raney-Ni were added to a hydrogenation reactor. H2 was replaced three times, with 0.30 MPa of H2 added each time. The H2 pressure was 0.20 MPa, and the reaction was maintained at 50℃ for 48 h. The hydrogenation reactor was then cooled to 20℃, and the reaction solution was vacuum filtered through a Buchner funnel. The solid was washed with 100.0 g of methyl tert-butyl ether to obtain compound V, with a yield of 67.3%. The NMR data of the compounds are as follows:1 H NMR (600MHz, DMSO-d6) δ11.70(s,1H),9.65(s,1H),7.65-7.55(m,2H),7.33-7.28(m,1H),7.16-7.10(m,1H),3.76(s,3H); 13 CNMR(600MHz,DMSO-d6)δ184.2,163.0,162.9,160.4,160.2,160.1,157.8,157.7,143.3,131.51,131 .46,131.41,131.37,128.6,118.6,115.6,115.4,114.7,112.3,112.1,105.1,104.8,104.6,61.8ppm.

[0060] (5) Under nitrogen protection, compound V100.0g (0.42mol, 1.0equiv.) and tetrahydrofuran300.0g (3.0w / w) were added to the reaction flask, and the temperature was controlled at 0-5℃. Potassium tert-butoxide56.1g (0.50mol, 1.2equiv.) was added to the reaction flask, and the reaction was kept at this temperature for 30min. Controlling the temperature at 0–5 °C, 81.5 g (0.42 mol, 1.0 equiv.) of m-fluorobenzenesulfonyl chloride was added dropwise. The reaction was maintained at this temperature for 2 h. After the temperature was maintained, 400.0 g of water was slowly added dropwise to quench the reaction mixture, controlling the temperature at 0–5 °C. After the addition was complete, the mixture was stirred at 25 °C for 1 h. The mixture was then heated to 50 ± 5 °C under a vacuum of -0.08 to -0.1 MPa to concentrate the reaction solution to 500.0 g. After concentration, ethyl acetate (500 mL × 3) was added, causing the layers to separate. The organic phases were combined and heated to 50 ± 5 °C under a vacuum of -0.08 to -0.1 MPa to remove the ethyl acetate, yielding crude compound VI. The crude compound VI was washed with a solution of HE:EA = 10:1 (300.0 g). The temperature was lowered to 25 °C, and the mixture was stirred for 3 h. After filtration, the filter cake was washed with 100.0 g of tap water and dried to obtain compound VI, with a yield of 90.9%. The NMR data of the compound are as follows: 1 H NMR (600MHz, DMSO-d6) δ9.90(s,1H),8.53(s,1H),7.71(s,2H),7.42-7.41(m,2H),7.32-7.24(m,2H),7.18-7.15(m,1H),3.61(s,3H); 13C NMR(600MHz,DMSO-d6)δ185.4,164.9,164.8,163.2,163.1,162.9,162.4,162.3 ,161.2,160.8,160.7,146.6,138.53,138.48,136.1,136.0,132.9,124.10,124 .08,123.2,123.1,122.13,122.11,121.2,115.0,114.9,114.8,112.9,112.25, 112.22,112.14,112.12,111.8,111.68,111.66,104.5,104.4,104.2,61.7ppm.

[0061] (6) Under nitrogen protection, 300.0 g of methanol (3.0 w / w) and 100.0 g of compound VI (0.25 mol, 1.0 equiv.) were added to the reaction flask. The temperature was controlled at 20-25℃. 17.1 g of methanol solution of methylamine (0.50 mol, 2.0 equiv., 30% inmethanol) was slowly added dropwise to the reaction flask. After the addition was completed, the reaction was kept at the temperature for 1 h. Under controlled temperature of 0–5 °C, 18.9 g (0.30 mol, 1.2 equiv.) of sodium cyanoborohydride was added in portions to the reaction flask, keeping the internal temperature below 10 °C. After the addition was complete, the reaction was maintained at this temperature for 2 h. Subsequently, 100.0 g of water was added dropwise to the reaction system, and the temperature was controlled at 25 °C to concentrate the reaction solution to 350.0 g. After concentration, ethyl acetate (500 mL × 3) was added, the layers were separated, the organic phases were combined, and some ethyl acetate was removed by distillation, keeping the reaction solution to 300.0 g. Under controlled temperature of 0–5 °C, hydrogen chloride (1 M in EA) was added dropwise to the reaction solution until pH≈1 and solids were formed. The temperature was controlled at 0–10 °C, and the reaction was maintained at this temperature for 2 h to obtain crude compound VII. The crude compound VII was washed with EA (100 mL) and dried at 50 °C under normal pressure to obtain compound VII, with a yield of 91.8%. The NMR data of the compound are as follows: 1 H NMR(600MHz,D2O)δ7.50(s,1H),7.23-7.19(m,1H),7.07-7.06(m,1H),7.02-6.99(m,1H),6.8 0-6.76(m,1H),6.72-6.71(m,1H),6.53-6.50(m,1H),6.44-6.41(m,1H),3.91(s,2H),3.11(s 3H),2.52(s,3H); 13C NMR(600MHz,D2O)δ164.5,162.9,162.3,160.7,160.5,148.0,138.6,138.5,135.7,131.8,123.1,1 22.9,121.6,114.1,113.9,112.8,112.7,111.0,110.8,110.5,103.3,103.2,60.0,41.2,31.7ppm.

[0062] Example 3:

[0063] Non-Surazan synthesis route:

[0064]

[0065] The specific synthesis method is as follows:

[0066] (1) Under nitrogen protection, 50.0 g (0.44 mol, 1.0 equiv.) of compound I, 70.7 g (0.53 mol, 1.2 equiv.) of aluminum trichloride, and 100.0 g (2 w / w) of dichloromethane were added to the reaction flask. The temperature was controlled at 20 °C. 95.2 g (0.69 mol, 1.6 equiv.) of monoethyl oxalate was slowly added dropwise to the reaction flask. After the addition was complete, the mixture was kept at this temperature for 3 h. After the temperature was complete, the reaction solution was slowly added dropwise to 200.0 g of ice water to quench the reaction and separate the layers. The aqueous layer was extracted with 100.0 g of dichloromethane, and the organic phases were combined and washed with 200.0 g of water. The organic phase was collected, distilled, and compound II-2 was added to the next reaction step.

[0067] (2) 3-Aminopropionitrile (0.66 mol, 1.5 equiv.) and tetrahydrofuran (3.0 w / w) were purged with nitrogen three times. The reaction flask was placed in a cold trap and cooled to -80 °C. Sodium di(trimethylsilyl)aminoacetate (0.66 mol, 1.5 equiv.) was slowly added dropwise, and the mixture was stirred at this temperature for 1 h. The internal temperature was controlled below -70 °C, and a tetrahydrofuran solution (1.0 w / w) of compound II-2 (0.44 mol, 1.0 equiv.) was added dropwise, and the reaction was maintained at this temperature for 2 h. At -80 °C, the reaction mixture was added dropwise in three batches to an AcOH-MeOH solution, and the internal temperature was controlled at -30 °C, with stirring overnight. The solid was filtered through a Buchner funnel under vacuum and washed with toluene (200 mL × 2) to obtain compound III, which was then added to the next reaction step.

[0068] (3) Under nitrogen protection, methanol (3.0 w / w) and compound III from the previous step were added to the reaction flask. The temperature was controlled at 15-20℃. MeONa (0.79 mol, 1.8 equiv.) was added to the reaction flask in batches. After the addition was completed, the reaction was kept at the temperature for 10 min. Controlling the temperature at 15–20°C, 0.79 mol (1.8 equiv.) of trimethylsilyl)diazomethane was added dropwise. The reaction was maintained at this temperature for 3 hours. After the reaction was complete, 300.0 g of water was slowly added dropwise to quench the reaction mixture, resulting in solid formation. The temperature was then controlled at 15–20°C, and the mixture was stirred for 2 hours. After stirring, the filter cake was washed with 80.0 g of a 20% methanol aqueous solution. The mixture was heated to 50±5°C under a vacuum of -0.08 to -0.1 MPa to concentrate the reaction solution to 350.0 g. After concentration, the temperature was lowered to 15–20°C, and the mixture was stirred for 3 hours. After filtration, the filter cake was washed with 100.0 g of tap water to obtain crude compound IV. The three-step yield was 36.3%. The NMR data of the compound are as follows: 1 HNMR(600MHz,DMSO-d6)δ11.75(s,1H),7.58-7.55(m,1H),7.54-7.51(m,1H),7.35-7.29(m,1H),7.17-7.11(m,1H),3.78(s,3H); 13 C NMR(600MHz,DMSO-d6)δ163.2,160.6,160.3,160.2,157.8,157.7,145.6,131.6,131.55,131.50,131.45,125 .4,119.0,116.0,115.1,115.0,112.43,112.39,112.33,112.22,112.18,105.2,104.9,104.6,84.9,61.5ppm.

[0069] (4) At room temperature (20°C), 100.0 g (0.43 mol, 1.0 equiv.) of compound IV, 200.0 g (5.0 w / w) of ethanol, 200.0 g (5 w / w) of water, 200.0 g (2.0 w / w) of acetic acid, and 30.0 g (3.0 w / w) of Raney-Ni were added to a hydrogenation reactor. H2 was replaced three times, with 0.30 MPa of H2 added each time. The H2 pressure was 0.20 MPa, the temperature was 50°C, and the reaction was maintained for 24 h. The hydrogenation reactor was then cooled to 20°C, and the reaction solution was vacuum filtered through a Buchner funnel. The solid was washed with 80.0 g of methyl tert-butyl ether to obtain compound V, which was then added to the next step of the reaction.

[0070] (5) Under nitrogen protection, add tetrahydrofuran (3.0 w / w) and compound V (0.43 mol, 1.0 equiv.) from the previous step to the reaction flask, control the temperature at 0-5℃, add cesium carbonate (0.43 mol, 1.0 equiv.) to the reaction flask, and after the addition is complete, keep the reaction at the temperature for 30 min. Controlling the temperature at 0–5 °C, m-fluorobenzenesulfonyl chloride (0.52 mol, 1.2 equiv.) was added dropwise. The reaction was maintained at this temperature for 2 h. After the temperature was maintained, 400.0 g of water was slowly added dropwise to quench the reaction mixture at 0–5 °C. After the addition was complete, the mixture was stirred at 25 °C for 1 h. The mixture was then heated to 50 ± 5 °C under a vacuum of -0.08 to -0.1 MPa to concentrate the reaction mixture to 500.0 g. After concentration, ethyl acetate (500 mL × 3) was added, and the mixture was allowed to separate into layers. The organic phases were combined and heated to 50 ± 5 °C under a vacuum of -0.08 to -0.1 MPa to remove the ethyl acetate, yielding crude compound VI. The crude compound VI was washed with HE:EA = 10:1 (300.0 g). The temperature was lowered to 25 °C, and the mixture was stirred for 3 h. The mixture was filtered, and the filter cake was washed with 100.0 g of tap water. After drying, compound VI was obtained. The yield of the two steps was 60.1%. The NMR data of the compound are as follows: 1 H NMR (600MHz, DMSO-d6) δ9.90(s,1H),8.53(s,1H),7.71(s,2H),7.42-7.41(m,2H),7.32-7.24(m,2H),7.18-7.15(m,1H),3.61(s,3H); 13 C NMR(600MHz,DMSO-d6)δ185.4,164.9,164.8,163.2,163.1,162.9,162.4,162.3 ,161.2,160.8,160.7,146.6,138.53,138.48,136.1,136.0,132.9,124.10,124 .08,123.2,123.1,122.13,122.11,121.2,115.0,114.9,114.8,112.9,112.25, 112.22,112.14,112.12,111.8,111.68,111.66,104.5,104.4,104.2,61.7ppm.

[0071] (6) Under nitrogen protection, add 500.0g of methanol and 100.0g of compound VI (0.25mol, 1.0equiv.) to the reaction flask, control the temperature at 20-25℃, and slowly add 17.1g of methylamine methanol solution (0.50mol, 2.0equiv., 30% inmethanol) dropwise to the reaction flask. After the addition is complete, keep the reaction at the temperature for 1h. Under controlled temperature of 0–5°C, 11.3 g (0.30 mol, 1.2 equiv.) of sodium borohydride was added in portions to the reaction flask, keeping the internal temperature below 10°C. After the addition was complete, the reaction was maintained at this temperature for 2 hours. Then, 100 g of water was added dropwise to the reaction system, and the temperature was controlled at 25°C to concentrate the reaction solution to 350 g. After concentration, ethyl acetate (500 mL × 3) was added, the layers were separated, the organic phases were combined, and some ethyl acetate was removed by distillation, keeping the reaction solution to 300 g. Under controlled temperature of 0–5°C, hydrogen chloride (1 M in EA) was added dropwise to the reaction solution until pH≈1 and solids were formed. The temperature was controlled at 0–5°C, and the reaction was maintained at this temperature for 2 hours to obtain crude compound VII. The crude compound VII was washed with EA (100 mL) and dried at 50°C under normal pressure to obtain compound VII, with a yield of 93.5%. The NMR data of the compound are as follows: 1 H NMR(600MHz,D2O)δ7.50(s,1H),7.23-7.19(m,1H),7.07-7.06(m,1H),7.02-6.99(m,1H),6.8 0-6.76(m,1H),6.72-6.71(m,1H),6.53-6.50(m,1H),6.44-6.41(m,1H),3.91(s,2H),3.11(s 3H),2.52(s,3H); 13 CNMR(600MHz,D2O)δ164.5,162.9,162.3,160.7,160.5,148.0,138.6,138.5,135.7,131.8,123.1, 122.9,121.6,114.1,113.9,112.8,112.7,111.0,110.8,110.5,103.3,103.2,60.0,41.2,31.7ppm.

[0072] Example 4:

[0073] Non-Surazan synthesis route:

[0074]

[0075] The specific synthesis method is as follows:

[0076] (1) Under nitrogen protection, 50.0 g of compound I (0.44 mol, 1.0 equivalent) of aluminum trichloride (0.44 mol, 1.0 equivalent) and 100.0 g of dichloromethane (2 w / w) were added to the reaction flask. The temperature was controlled at 20 °C. 91.5 g of monomethyl oxalate (0.88 mol, 2.0 equivalent) was slowly added dropwise to the reaction flask. After the addition was complete, the mixture was kept at this temperature for 4 h. After the temperature was complete, the reaction solution was slowly added dropwise to 200.0 g of ice water to quench the reaction and separate the layers. The aqueous layer was extracted with 100.0 g of dichloromethane. The organic phases were combined and then washed with 200 mL of water. The organic phase was taken, evaporated to dryness, and compound II-1 was obtained with a yield of 72.2%. The NMR data of the compound are as follows: 1 H NMR (600MHz, DMSO-d6) δ7.99-7.93(m,1H),7.44-7.39(m,1H),7.28-7.23(m,1H),3.88(s,3H); 13 C NMR(600MHz,DMSO-d6)δ182.6,168.4,168.3,1658,165.7,164.6,164.5,164.0,162.0,161.9,133.74,133.72,1 33.63,133.61,118.39,118.35,118.29,118.25,113.71,113.68,113.49,113.46,106.1,105.8,105.5,53.5ppm.

[0077] (2) 26.6 g (0.38 mol, 1.5 equiv.) of 3-aminopropionitrile and 150.0 g (3.0 w / w) of tetrahydrofuran were purged with nitrogen three times. The reaction flask was placed in a cold trap and cooled to -80 °C. 68.7 g (0.38 mol, 1.5 equiv.) of sodium di(trimethylsilyl)aminoacetate was slowly added dropwise, and the mixture was stirred at this temperature for 1 h. The internal temperature was controlled below -70 °C, and 50.0 g (1.0 w / w) of a tetrahydrofuran solution containing 50.0 g (0.25 mol, 1.0 equiv.) of compound II-1 was added dropwise, and the reaction mixture was stirred at this temperature for 2 h. At -80 °C, the reaction mixture was added dropwise in three batches to an AcOH-MeOH solution, and the internal temperature was controlled at -30 °C, and the mixture was stirred overnight. The solid was filtered through a Buchner funnel under vacuum, washed with toluene (200 mL × 2), and dried under vacuum at 50 °C for 16 h to obtain compound III.

[0078] (3) Under nitrogen protection, methanol (3.0 w / w) and compound III from the previous step were added to the reaction flask. The temperature was controlled at 15-20℃. DBU (0.50 mol, 2.0 equiv.) was slowly added dropwise to the reaction flask. After the addition was complete, the reaction was kept at the temperature for 10 min. Controlling the temperature at 15–20°C, 0.38 mol (1.5 equiv.) of trimethylsilyl)diazomethane was added dropwise. The reaction was maintained at this temperature for 3 hours. After the reaction was complete, 300 g of water was slowly added dropwise to quench the reaction mixture, resulting in solid formation. The temperature was then controlled at 15–20°C, and the mixture was stirred for 2 hours. After stirring, the filter cake was washed with 50 g of a 20% methanol aqueous solution. The mixture was then heated to 50 ± 5°C under a vacuum of -0.08 to -0.1 MPa to concentrate the reaction solution to 350 g. After concentration, the temperature was lowered to 15–20°C, and the mixture was stirred for 3 hours. After filtration, the filter cake was washed with 100 g of tap water to obtain crude compound IV. The two-step yield was 55.2%. The NMR data of the compound are as follows: 1 HNMR(600MHz,DMSO-d6)δ11.75(s,1H),7.58-7.55(m,1H),7.54-7.51(m,1H),7.35-7.29(m,1H),7.17-7.11(m,1H),3.78(s,3H); 13 C NMR(600MHz,DMSO-d6)δ163.2,160.6,160.3,160.2,157.8,157.7,145.6,131.6,131.55,131.50,131.45,125 .4,119.0,116.0,115.1,115.0,112.43,112.39,112.33,112.22,112.18,105.2,104.9,104.6,84.9,61.5ppm.

[0079] (4) At room temperature (20°C), 100.0 g (0.43 mol, 1.0 equiv.) of compound IV, 200.0 g (5.0 w / w) of ethanol, 200.0 g (5 w / w) of water, 200.0 g (2.0 w / w) of acetic acid, and 50.0 g (0.5 w / w) of Raney-Ni were added to a hydrogenation reactor. H2 was replaced three times, with 0.3 MPa of H2 added each time. The H2 pressure was 0.10 MPa, the temperature was 50°C, and the reaction was maintained at this temperature for 24 h. The hydrogenation reactor was then cooled to 20°C, and the reaction solution was vacuum filtered through a Buchner funnel. The solid was washed with 100.0 g of methyl tert-butyl ether to obtain compound V, which was then added to the next step of the reaction.

[0080] (5) Under nitrogen protection, add tetrahydrofuran (3.0 w / w) and compound V to the reaction flask, control the temperature to -20 to -15℃, add sodium hydrogen (0.52 mol, 1.2 equiv.) in batches to the reaction flask, and after the addition is complete, keep the reaction at the temperature for 30 min. Controlling the temperature at 0–5 °C, m-fluorobenzenesulfonyl chloride (0.47 mol, 1.1 equiv.) was added dropwise. The reaction was maintained at this temperature for 2 h. After the temperature maintenance was completed, the temperature was controlled at -20–-15 °C, and 400.0 g of water was slowly added dropwise to quench the reaction mixture. After the addition was completed, the mixture was stirred at 25 °C for 1 h. The temperature was then raised to 50 ± 5 °C, and the vacuum was maintained at -0.08–-0.1 MPa. The reaction mixture was concentrated to 500.0 g. After the concentration was completed, ethyl acetate (500 mL × 3) was added. The mixture was separated into layers, and the organic phases were combined. The mixture was heated to 50 ± 5 °C, and the vacuum was maintained at -0.08–-0.1 MPa to remove the ethyl acetate, yielding crude compound VI. The crude compound VI was washed with HE:EA = 10:1 (300.0 g). The temperature was lowered to 25 °C, and the mixture was stirred for 3 h. The mixture was filtered, and the filter cake was washed with 100.0 g of tap water. After drying, compound VI was obtained. The yield of the two steps was 71.7%. The NMR data of the compound are as follows: 1 H NMR (600MHz, DMSO-d6) δ9.90(s,1H),8.53(s,1H),7.71(s,2H),7.42-7.41(m,2H),7.32-7.24(m,2H),7.18-7.15(m,1H),3.61(s,3H); 13 C NMR(600MHz,DMSO-d6)δ185.4,164.9,164.8,163.2,163.1,162.9,162.4,162.3 ,161.2,160.8,160.7,146.6,138.53,138.48,136.1,136.0,132.9,124.10,124 .08,123.2,123.1,122.13,122.11,121.2,115.0,114.9,114.8,112.9,112.25, 112.22,112.14,112.12,111.8,111.68,111.66,104.5,104.4,104.2,61.7ppm.

[0081] (6) Under nitrogen protection, 500.0 g of methanol and compound (VI) were added to the reaction flask.

[0082] 100.0 g (0.25 mol, 1.0 equiv.) of methylamine in methanol was slowly added dropwise to the reaction flask at a controlled temperature of 20–25 °C. After the addition was complete, the reaction was kept at this temperature for 1 hour. The temperature was controlled at 0–5 °C. 11.3 g (0.30 mol, 1.2 equiv.) of sodium borohydride was added in portions to the reaction flask, keeping the internal temperature below 10 °C. After the addition was complete, the reaction was maintained at this temperature for 2 hours. Then, 100 g of water was added dropwise to the reaction system, and the temperature was controlled at 25 °C. The reaction solution was concentrated to 350 g. After concentration, ethyl acetate (500 mL × 3) was added, the layers were separated, and the organic phases were combined. Part of the ethyl acetate was removed by distillation, and the reaction solution was reduced to 300 g. The temperature was controlled at 0–5 °C. Hydrogen chloride (1 M in EA) was added dropwise to the reaction solution until pH ≈ 1 and a solid was formed. The temperature was controlled at 0–5 °C, and the reaction was maintained at this temperature for 2 hours to obtain crude compound VII. The crude compound VII was washed with EA (100 mL) and dried at 50 °C under normal pressure to obtain compound VII, with a yield of 91.3%. The NMR data of the compound are as follows: 1 H NMR(600MHz,D2O)δ7.50(s,1H),7.23-7.19(m,1H),7.07-7.06(m,1H),7.02-6.99(m,1H),6.8 0-6.76(m,1H),6.72-6.71(m,1H),6.53-6.50(m,1H),6.44-6.41(m,1H),3.91(s,2H),3.11(s 3H),2.52(s,3H); 13 C NMR(600MHz,D2O)δ164.5,162.9,162.3,160.7,160.5,148.0,138.6,138.5,135.7,131.8,123.1,1 22.9,121.6,114.1,113.9,112.8,112.7,111.0,110.8,110.5,103.3,103.2,60.0,41.2,31.7ppm.

[0083] Example 5:

[0084] Non-Surazan synthesis route:

[0085]

[0086] The specific synthesis method is as follows:

[0087] (1) Under nitrogen protection, 100.0 g of compound I (0.88 mol, 1.0 equiv.), 164.0 g of aluminum trichloride (1.23 mol, 1.4 equiv.), and 200.0 g of dichloromethane (2 w / w) were added to a reaction flask. The temperature was controlled at 20 °C. 107.3 g of monomethyl oxalate (0.88 mol, 1.0 equiv.) was slowly added dropwise to the reaction flask. After the addition was complete, the mixture was kept at this temperature for 4 h. After the temperature was complete, the reaction solution was slowly added dropwise to 400.0 g of ice water to quench the reaction and separate the layers. The aqueous layer was extracted with 200.0 g of dichloromethane, and the organic phases were combined and washed with 300.0 g of water. The organic phase was taken and distilled to obtain compound II-1, which was then added to the next reaction step.

[0088] (2) 3-Aminopropionitrile (1.76 mol, 2.0 equiv.) and tetrahydrofuran (3.0 w / w) were purged with nitrogen three times. The reaction flask was placed in a cold trap and cooled to -80 °C. Sodium di(trimethylsilyl)aminoacetate (1.76 mol, 2.0 equiv.) was slowly added dropwise, and the mixture was stirred for 1 h. The internal temperature was controlled below -70 °C, and a tetrahydrofuran solution (1.5 w / w) of compound II-1 from step one was added dropwise, and the reaction was maintained for 2 h. At -80 °C, the reaction mixture was added dropwise in three batches to an AcOH-MeOH solution, and the internal temperature was controlled at -30 °C, and the mixture was stirred overnight. The solid was filtered through a Buchner funnel under vacuum and washed with toluene (300 mL × 2) to obtain compound III, which was then added to the next reaction step.

[0089] (3) Under nitrogen protection, methanol (5.0 w / w) and compound III (0.88 mol, 1.0 equiv.) were added to the reaction flask. The temperature was controlled at 15-20℃. N,N-diisopropylethylamine (1.32 mol, 1.5 equiv.) was slowly added dropwise to the reaction flask. After the addition was completed, the reaction was kept at the temperature for 10 min. Controlling the temperature at 15–20°C, dimethyl sulfate (1.32 mol, 1.5 equiv.) was added dropwise until the reaction was complete. The reaction was maintained at this temperature for 3 hours. After the reaction was complete, 400.0 g of water was slowly added dropwise to quench the reaction mixture, resulting in solid formation. The temperature was then controlled at 15–20°C, and the mixture was stirred for 2 hours. After stirring, the filter cake was washed with 80.0 g of 20% methanol aqueous solution. The mixture was then heated to 50±5°C under a vacuum of -0.08 to -0.1 MPa to concentrate the reaction solution to 350.0 g. After concentration, the temperature was lowered to 15–20°C, and the mixture was stirred for 3 hours. The mixture was then filtered, and the filter cake was washed with 150.0 g of tap water to obtain compound IV. The three-step yield was 42.5%. The NMR data of the compound are as follows: 1H NMR (600MHz, DMSO-d6) δ11.75(s,1H),7.58-7.55(m,1H),7.54-7.51(m,1H),7.35-7.29(m,1H),7.17-7.11(m,1H),3.78(s,3H); 13 C NMR(600MHz,DMSO-d6)δ163.2,160.6,160.3,160.2,157.8,157.7,145.6,131.6,131.55,131.50,131.45,125 .4,119.0,116.0,115.1,115.0,112.43,112.39,112.33,112.22,112.18,105.2,104.9,104.6,84.9,61.5ppm.

[0090] (4) At room temperature (20℃), 100.0 g (0.43 mol, 1.0 equiv.) of compound IV, 200.0 g (5.0 w / w) of ethanol, 200.0 g (5 w / w) of water, 180.0 g (1.8 w / w) of acetic acid, and 50.0 g (0.5 w / w) of supported Ni(PPh3)4 were added to a hydrogenation reactor. H2 was replaced three times, with 0.3 MPa of H2 added each time. The H2 pressure was 0.50 MPa, and the reaction was maintained at 25℃ for 24 h. The hydrogenation reactor was then cooled to 20℃, and the reaction solution was vacuum filtered through a Buchner funnel. The solid was washed with 80.0 g of methyl tert-butyl ether to obtain compound V, with a yield of 61.8%. The NMR data of the compounds are as follows: 1 H NMR (600MHz, DMSO-d6) δ11.70(s,1H),9.65(s,1H),7.65-7.55(m,2H),7.33-7.28(m,1H),7.16-7.10(m,1H),3.76(s,3H); 13 CNMR(600MHz,DMSO-d6)δ184.2,163.0,162.9,160.4,160.2,160.1,157.8,157.7,143.3,131.51,131 .46,131.41,131.37,128.6,118.6,115.6,115.4,114.7,112.3,112.1,105.1,104.8,104.6,61.8ppm.

[0091] (5) Under nitrogen protection, add 300.0 g (3.0 w / w) of tetrahydrofuran and 100.0 g (0.42 mol, 1.0 equiv.) of compound V to the reaction flask. Control the temperature at -20 to -15℃. Add 12.0 g (0.50 mol, 1.2 equiv.) of sodium hydrogen in portions to the reaction flask. After the addition is complete, maintain the temperature for 30 min. Control the temperature at 0 to 5℃. Add 89.2 g (0.46 mol, 1.1 equiv.) of m-fluorobenzenesulfonyl chloride. After the addition is complete, maintain the temperature for 2 h. After the temperature is complete, control the temperature at -20 to -15℃ and slowly add 400.0 g of water to quench the reaction mixture. After the addition is complete, stir at 25℃ for 1 h. Heat to 50±5℃ and maintain a vacuum of -0.08 to -0.1 MPa to concentrate the reaction mixture to 500.0 g. After concentration, Ethyl acetate (500 mL × 3) was added, the layers separated, the organic phases were combined, and the mixture was heated to 50 ± 5 °C under a vacuum of -0.08 to -0.1 MPa to remove ethyl acetate, yielding crude compound VI. The crude compound VI was washed with HE:EA = 10:1 (300.0 g), the temperature was lowered to 25 °C, and the mixture was stirred for 3 h. The mixture was filtered, and the filter cake was washed with 100.0 g of tap water. After drying, compound VI was obtained, with a yield of 83.7%. The NMR data of the compound are as follows: 1 HNMR(600MHz,DMSO-d6)δ9.90(s,1H),8.53(s,1H),7.71(s,2H),7.42-7.41(m,2H),7.32-7.24(m,2H),7.18-7.15(m,1H),3.61(s,3H); 13 C NMR(600MHz,DMSO-d6)δ185.4,164.9,164.8,163.2,163.1,162.9,162.4,162.3 ,161.2,160.8,160.7,146.6,138.53,138.48,136.1,136.0,132.9,124.10,124 .08,123.2,123.1,122.13,122.11,121.2,115.0,114.9,114.8,112.9,112.25, 112.22,112.14,112.12,111.8,111.68,111.66,104.5,104.4,104.2,61.7ppm.

[0092] (6) Under nitrogen protection, 500.0 g of methanol and 100.0 g of compound VI (0.25 mol, 1.0 equiv.) were added to the reaction flask. The temperature was controlled at 20-25℃. 17.1 g of methanol solution of methylamine (0.50 mol, 2.0 equiv., 30% in methanol) was slowly added dropwise to the reaction flask. After the addition was completed, the reaction was kept at the temperature for 1 h. The temperature was controlled at 0–5 °C. 11.3 g (0.30 mol, 1.2 equiv.) of sodium borohydride was added in portions to the reaction flask, keeping the internal temperature below 10 °C. After the addition was complete, the reaction was maintained at this temperature for 2 hours. Then, 100 g of water was added dropwise to the reaction system, and the temperature was controlled at 25 °C. The reaction solution was concentrated to 350 g. After concentration, ethyl acetate (500 mL × 3) was added, the layers were separated, and the organic phases were combined. Part of the ethyl acetate was removed by distillation, and the reaction solution was reduced to 300 g. The temperature was controlled at 0–5 °C. Hydrogen chloride (1 M in EA) was added dropwise to the reaction solution until pH ≈ 1 and a solid was formed. The temperature was controlled at 0–5 °C, and the reaction was maintained at this temperature for 2 hours to obtain crude compound VII. The crude compound VII was washed with EA (100 mL) and dried at 50 °C under normal pressure to obtain compound VII, with a yield of 93.2%. The NMR data of the compound are as follows: 1 H NMR(600MHz,D2O)δ7.50(s,1H),7.23-7.19(m,1H),7.07-7.06(m,1H),7.02-6.99(m,1H),6.8 0-6.76(m,1H),6.72-6.71(m,1H),6.53-6.50(m,1H),6.44-6.41(m,1H),3.91(s,2H),3.11(s 3H),2.52(s,3H); 13 C NMR(600MHz,D2O)δ164.5,162.9,162.3,160.7,160.5,148.0,138.6,138.5,135.7,131.8,123.1,1 22.9,121.6,114.1,113.9,112.8,112.7,111.0,110.8,110.5,103.3,103.2,60.0,41.2,31.7ppm.

[0093] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for synthesizing non-Surazanol, characterized in that, The synthesis method includes the following steps: S1. Compound II was prepared by Friedel-Crafts acylation of m-difluorobenzene with oxaloyl chloride monoester under Lewis acid catalysis. S2. Compound III was prepared by cyclizing compound II with aminopropionitrile under the action of alkaline reagent I: S3. Compound III was prepared by reacting it with a methylating agent under the action of a basic reagent II via a methylation reaction. S4. Compound IV was placed in a solvent and catalytically reduced using a catalyst in a hydrogen-pressurized environment to prepare compound V: S5. Compound V was prepared by nucleophilic addition reaction with m-fluorobenzenesulfonyl chloride under the action of alkaline reagent II; S6. Compound VI is first condensed with methylamine to obtain an imine, which is then reduced and aminationd with a reducing agent to obtain a free base. The free base is then reacted with hydrogen chloride solution to form a salt to prepare compound VII, which is non-surazine.

2. The synthesis method according to claim 1, characterized in that: The structural formula of the oxaloyl chloride monoester is: R is an ester formed from carbon chains with a length of 1 to 20.

3. The synthesis method according to claim 1, characterized in that: In step S1, the Lewis acid is selected from one or more of ferric chloride, aluminum chloride, and boron trifluoride complexes.

4. The synthesis method according to claim 1, characterized in that: In step S2, the molar ratio of compound II, aminopropionitrile, and basic reagent II is 1:1.0-5.0:1.0-10.

0.

5. The synthesis method according to claim 1, characterized in that: In step S3, the molar ratio of compound III, methylating agent, and basic agent is 1:1.0-5.0:1.0-10.

0.

6. The synthesis method according to claim 1, characterized in that: The methylating agent is selected from at least one of iodomethane, dimethyl sulfate, and (trimethylsilyl)diazomethane; the catalyst is selected from at least one of Raney nickel, tetra-triphenylphosphine nickel, and supported tetra-triphenylphosphine nickel; and the solvent is a mixture of ethanol, water, and acetic acid.

7. The synthesis method according to claim 1, characterized in that: In step S4, the hydrogen pressure during catalytic reduction is controlled at 0.1–0.5 MPa, and the reaction temperature is 20–55 °C.

8. The synthesis method according to claim 1, characterized in that: In step S5, the molar ratio of compound V, m-fluorobenzenesulfonyl chloride, and alkaline reagent is 1:0.8-5.0:0.8-10.

0.

9. The synthesis method according to claim 1, characterized in that: The reducing agent in step S6 is one or more of lithium borohydride, sodium borohydride, potassium borohydride, sodium triacetoxyborohydride, and sodium cyanoborohydride.

10. The synthesis method according to claim 1, characterized in that: The first alkaline reagent is one or more of the following: n-butyllithium, potassium tert-butoxide, sodium tert-butoxide, lithium di(trimethylsilyl)amino, sodium di(trimethylsilyl)amino, potassium di(trimethylsilyl)amino, lithium diisopropylamino, and sodium diisopropylamino; the second alkaline reagent is one or more of the following: lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, N-methylmorpholine, tetramethylethylenediamine, and pyridine.

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