A method for the synthesis of xanomeline

Abstract

The application discloses a synthetic method of xanomeline. The application provides a preparation method of compound iii, which comprises the following steps: step S1, addition reaction of compound i and compound ii in a solvent; the solvent is an organic solvent, or a mixed solvent of an organic solvent and water; the organic solvent is a cyclic ether solvent and / or a nitrile solvent; and step S2, mixing of an ammonium salt, water and ammonia with the reaction solution obtained in step S1 to generate compound iii through substitution reaction. The raw material used in the method is not related to a toxic product, is green and environment-friendly, has a short synthetic route, a simple process, controllable reaction and simple operation.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for synthesizing fenofibrate. Background Technology

[0002] Neurotransmitters are chemical messengers secreted by neurons to facilitate the flow of information and communicate with other cells in the central and peripheral nervous systems, such as muscle or nerve-like cells. Acetylcholine is one of the key neurotransmitters in the brain, and it has two different classes of receptors: muscarinic receptors (M receptors, G protein-coupled receptors) and nicotinic receptors (N receptors, ion channel receptors).

[0003] The M receptor family comprises five subtypes, M1 through M5, all expressed in the brain and surrounding tissues and playing crucial physiological roles in cognitive, behavioral, sensory, motor, and autonomic nervous processes. Disruption of M receptor signaling can lead to memory and cognitive impairments in patients with various diseases, including schizophrenia and Alzheimer's disease, and exacerbate psychosis. Conversely, third-party preclinical and clinical data suggest that enhanced M receptor signaling improves these symptoms. Furthermore, M receptors, particularly M1, M2, and M4 receptors, are also believed to be associated with analgesia.

[0004] Xanomeline is a partial agonist of muscarinic receptors, acting on all five subtypes of the receptor without selectivity. Developed and marketed jointly by Eli Lilly (USA) and Novo Nordisk (Denmark), it is primarily used clinically for the treatment of Alzheimer's disease. Xanomeline's chemical name is 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine, and its chemical structure is as follows:

[0005] The general synthetic route of cyclophosphamide is as follows: starting from 3-pyridinecarboxaldehyde, it is obtained through cyano addition reaction, substitution reaction, cyclization reaction, etherification reaction, methylation reaction and reduction reaction.

[0006] All reported synthetic methods currently available require the use of highly toxic or hazardous reagents. For example, the cyano addition step requires the use of highly toxic cyanides such as potassium cyanide, sodium cyanide, or trimethylcyanosilane, or the etherification reaction uses highly dangerous sodium hydride as a base. The high toxicity of these reagents and the operational risks pose a serious challenge to the safe production of xanomelide. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to overcome the defects in the prior art and provide a method for synthesizing fenofibrate.

[0008] The present invention solves the above-mentioned technical problems through the following technical solution: This invention provides a method for preparing compound iii, which includes the following steps: In step S1, compound i and compound ii undergo an addition reaction in a solvent; The solvent is an organic solvent, or a mixture of an organic solvent and water; the organic solvent is a cyclic ether solvent and / or a nitrile solvent. In step S2, the mixture of ammonium salt, water and ammonia is mixed with the reaction solution obtained in step S1 to carry out a substitution reaction and generate compound iii; .

[0009] In one embodiment, in step S1, the solvent is a mixture of an organic solvent and water.

[0010] In one embodiment, in step S1, the cyclic ether solvent may be tetrahydrofuran.

[0011] In one embodiment, the nitrile solvent in step S1 may be acetonitrile.

[0012] In one embodiment, in step S1, the volume ratio of the organic solvent to water can be (0.5-4):1, for example 0.5:1, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1 or 4:1, preferably 1:1.

[0013] In one embodiment, in step S1, the molar volume ratio of compound ii to water in step S1 can be 2.5-3.5 mol / L, for example 2.5 mol / L, 2.6 mol / L, 2.7 mol / L, 2.8 mol / L, 2.9 mol / L, 3.0 mol / L, 3.1 mol / L, 3.2 mol / L, 3.3 mol / L, 3.4 mol / L, or 3.5 mol / L, and for example 3.1 mol / L.

[0014] In one embodiment, in step S1, the molar ratio of compound i to compound ii can be 1:(1-1.5), for example 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5, or for example 1:1.2.

[0015] In one embodiment, the temperature of the addition reaction in step S1 can be 15-75°C, for example 15°C, 25°C, 35°C, 45°C, 55°C, 66°C or 75°C, or for example 25°C or 66°C.

[0016] In one embodiment, the addition reaction in step S1 can take 2-8 hours, for example 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours or 8 hours, or for example 5 hours.

[0017] In one embodiment, in step S1, the post-processing step of the addition reaction can be performed without purification, and the resulting reaction solution can be directly added to the next step.

[0018] In one embodiment, in step S2, the ammonium salt may be ammonium chloride, ammonium acetate, or ammonium carbonate, such as ammonium chloride.

[0019] In one embodiment, in step S2, the molar ratio of the ammonium salt to compound i can be (2-5):1, for example 2:1, 2.5:1, 3:1, 3.6:1, 4:1, 4.5:1 or 5:1, and for example 3.6:1.

[0020] In one embodiment, in step S2, the mass-to-volume ratio of the ammonium salt to the water in step S2 can be 0.2-1 g / mL, for example 0.2 g / mL, 0.5 g / mL, 0.8 g / mL or 1 g / mL, or for example 0.5 g / mL.

[0021] In one embodiment, in step S2, the molar ratio of ammonia to compound i can be (2-4):1, for example (2.8-3.2):1.

[0022] In one embodiment, in step S2, the ammonia is added to the substitution reaction in the form of ammonia water, wherein the ammonia water may be ammonia water with a mass fraction of 25-28%.

[0023] In one embodiment, in step S2, ammonia water can be added to the ammonium salt and water to obtain the mixture.

[0024] In one embodiment, the temperature of the substitution reaction in step S2 can be 15-35°C, for example 15°C, 20°C, 25°C, 30°C or 35°C, or for example 25°C.

[0025] In one embodiment, the substitution reaction in step S2 can take 2-8 hours, for example 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours or 8 hours, or for example 5 hours.

[0026] In one embodiment, the post-processing step of the substitution reaction in step S2 may be: extraction with an organic solvent (e.g., with dichloromethane or a mixture of dichloromethane and methanol (v / v=7:3)), combining the organic phases, drying, and concentrating to obtain the final product.

[0027] This invention provides a method for preparing compound v, comprising the following steps: in an organic solvent, in the presence of a C1-C6 alkane alcohol alkali metal salt, compound iv and n-hexanol undergo an etherification reaction to generate compound v. .

[0028] In one embodiment, the organic solvent may be a cyclic ether solvent, such as tetrahydrofuran.

[0029] In one embodiment, the mass-to-volume ratio of the hexanol to the organic solvent can be 0.05-0.30 g / mL, for example 0.05 g / mL, 0.08 g / mL, 0.1 g / mL, 0.12 g / mL, 0.14 g / mL or 0.16 g / mL, or for example 0.12 g / mL.

[0030] In one embodiment, the C1-C6 alkane alcohol alkali metal salt may be an alkali metal tert-butoxide salt, such as potassium tert-butoxide.

[0031] In one embodiment, the molar ratio of compound iv to the C1-C6 alkane alcohol alkali metal salt can be 1:(2-6), for example 1:2, 1:3, 1:4, 1:5 or 1:6, and for example 1:4.

[0032] In one embodiment, the molar ratio of compound iv to n-hexanol may be 1:(2-5), for example 1:2, 1:3, 1:4 or 1:5, or for example 1:3.

[0033] In one embodiment, the etherification reaction can be carried out at a temperature of 60-75°C (e.g., reflux).

[0034] In one embodiment, the etherification reaction can be carried out until the compound IV reaction is complete.

[0035] In one embodiment, the etherification reaction can be performed as follows: Step a, mixing the n-hexanol with volume A of the organic solvent; Step b: The C1-C6 alkane alcohol alkali metal salt is added to the solution from step a to react. Step c, dissolve the compound iv in the organic solvent of volume B, and then add it to the solution of step b to carry out the etherification reaction; the volume ratio of volume A to volume B can be (2-6):1, for example 2:1, 3:1, 4:1, 5:1 or 6:1, and for example 4:1; the organic solvent is as described above.

[0036] In one embodiment, in step a, the mixture can be cooled to 0-10°C using an ice bath.

[0037] In one embodiment, in step b, the temperature of the reaction can be 10-40°C, for example, room temperature (i.e., 15-30°C).

[0038] In one embodiment, the reaction time in step b can be 1-5 hours, for example, 2 hours.

[0039] In one embodiment, in step c, the addition can be done by dripping.

[0040] In one embodiment, the post-treatment steps of the etherification reaction may include cooling, quenching (e.g., quenching with a saturated aqueous sodium carbonate solution), extraction (e.g., extraction with ethyl acetate), washing, drying, and concentration.

[0041] This invention provides a method for synthesizing compound vii, which includes the following steps: reacting compound i with the following reaction to synthesize compound vii; ; The synthesis methods of compounds iii and v are as described above.

[0042] In one embodiment, in an organic solvent, compound iii undergoes a cyclization reaction with disulfide dichloride to generate compound iv.

[0043] In one embodiment, compound v undergoes a methylation reaction with iodomethane in an organic solvent to generate compound vi.

[0044] In one embodiment, compound vi undergoes a reduction reaction with sodium borohydride in an organic solvent to produce compound vii.

[0045] In one embodiment, the organic solvent used in the cyclization reaction can be a conventional organic solvent in the art, such as an amide solvent or DMF.

[0046] In one embodiment, the molar ratio of compound iii to disulfur dichloride in the cyclization reaction can be (1-3):1, for example, 2:1.

[0047] In one embodiment, the cyclization reaction can be carried out at a temperature that is conventional in the art, such as 0-10°C or 0-5°C.

[0048] In one embodiment, the cyclization reaction can take a reaction time that is conventional in the art, such as 3 hours.

[0049] In one embodiment, the organic solvent used in the methylation reaction may be a conventional organic solvent in the art, such as a ketone solvent, or acetone.

[0050] In one embodiment, the molar ratio of compound v to iodomethane in the methylation reaction can be (0.1-0.5):1, for example, 0.25:1.

[0051] In one embodiment, the reaction temperature in the methylation reaction can be a conventional reaction temperature in the art, such as 10-40°C, or room temperature (i.e., 15-30°C).

[0052] In one embodiment, the reaction time in the methylation reaction can be a reaction time conventional in the art.

[0053] In one embodiment, the organic solvent used in the reduction reaction can be a conventional organic solvent in the art, such as an alcohol solvent, or methanol.

[0054] In one embodiment, the molar ratio of compound vi to sodium borohydride in the reduction reaction can be (2-6):1, for example, 4:1.

[0055] In one embodiment, the reduction reaction temperature can be a conventional reaction temperature in the art, such as 10-40°C, or room temperature (i.e., 15-30°C).

[0056] In one embodiment, the reaction time in the reduction reaction can be a reaction time conventional in the art.

[0057] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0058] The positive and progressive effects of this invention are as follows: The synthetic route of this invention is a completely new route. The method for synthesizing the xuanomelene intermediate of this invention is as follows: using 3-pyridinecarboxaldehyde and benzoyl nitrile as raw materials, the addition and substitution reactions are completed in a one-pot process, followed by cyclization, etherification, methylation and reduction, for a total of five steps to prepare xuanomelene. The raw materials used in this method do not involve highly toxic substances, are green and environmentally friendly, and the synthetic route is short, the process is simple, the reaction is controllable and the operation is convenient. Detailed Implementation

[0059] The present invention will be further illustrated by way of embodiments below, but the present invention is not limited to the scope of the embodiments described herein.

[0060] Example 1

[0061] In this embodiment, a method for synthesizing xuanomeline involves first reacting 3-pyridinecarboxaldehyde with benzoyl nitrile, followed by a one-pot reaction with ammonia and ammonium chloride aqueous solution to obtain compound iii; compound iii undergoes cyclization with disulfide dichloride to obtain a cyclized product (compound iv); compound iv reacts with n-hexanol under potassium tert-butoxide as a base to obtain an etherified product (compound v); compound v is then reacted with iodomethane to obtain a methylated product (compound vi); finally, compound vi is reduced with sodium borohydride to obtain xuanomeline, i.e., compound vii.

[0062] The specific synthesis route is as follows:

[0063] The specific steps are as follows: (a) Take a 500 mL three-necked flask, insert a thermometer, set up a magnetic stirrer, and add 28 g of 3-pyridinecarboxaldehyde (compound i), 41 g of benzoyl nitrile (compound ii), and 200 mL of a mixture of tetrahydrofuran and water (v / v=1:1) in sequence. After the addition is complete, react at 25 °C for 5 h. When the raw materials are completely converted, stop the reaction. No purification is required. Proceed directly to the next step.

[0064] (b) Take a 250 mL three-necked flask, insert a thermometer, set up a magnetic stirrer, first add 50 g of ammonium chloride and 100 mL of water, stir at 25°C, then add 50 mL of ammonia water (mass concentration 25-28%), stir at 25°C. Add the resulting reaction solution to the reaction solution obtained after the first step, react at 25°C for 5 h until the reactants have completely reacted, then stop the reaction and extract with DCM (400 mL). 4) The aqueous phase was then extracted with a mixture of DCM and MeOH (v / v=7:3) (400 mL) 4) Combine the organic phases, dry the organic phases with anhydrous sodium sulfate, concentrate to give a yellow oily substance, and give 30.8 g of compound iii, with a yield of 88.5%.

[0065] (c) Take a 250 mL three-necked flask, insert a thermometer, set up a magnetic stirrer, add 64 g of disulfide dichloride and 150 mL of DMF, cool and stir in an ice bath, add 30.8 g of compound iii dissolved in DMF (50 mL) dropwise at 0-5℃, and react in an ice bath until the reactants have completely reacted. After the reaction is complete, carefully quench the reaction with ice water dropwise in an ice bath, filter, wash the filter cake with ethyl acetate, and collect the filtrate. Add 200 mL of 9M sodium hydroxide aqueous solution dropwise to the filtrate, stir for ten minutes, and extract with ethyl acetate (300 mL) 5) Combine the organic phases and wash with saturated saline solution (300 mL). 3) After drying with anhydrous sodium sulfate, the solution was concentrated to obtain 34.4 g of compound IV, with a yield of 75.3%.

[0066] (d) Take a 500 mL three-necked flask, insert a thermometer, set up a magnetic stirrer, add 31 g of n-hexanol and 200 mL of tetrahydrofuran, cool in an ice bath while stirring, then add 45 g of potassium tert-butoxide. After the addition is complete, stir the reaction at room temperature for 2 hours. Add 20 g of compound iv dissolved in tetrahydrofuran (50 mL) dropwise at room temperature. Heat the system under reflux until the reactants have reacted completely. Cool the reaction system in an ice bath, quench the reaction with a saturated sodium carbonate aqueous solution dropwise in an ice bath, and extract with ethyl acetate (200 mL). 3) Combine the organic phases and wash with saturated saline solution (200 mL). 2) After drying with anhydrous sodium sulfate, the compound v was concentrated to obtain a total of 25.1 g, with a yield of 94.2%.

[0067] (e) Take a 250 mL three-necked flask, insert a thermometer, set up a magnetic stirrer, add 16 g of compound v and 150 mL of acetone, add 35 g of iodomethane dropwise while stirring at room temperature, and react at room temperature until the reactants are completely reacted. The product compound vi precipitates from the system, and after filtration, a total of 24.0 g of compound vi is obtained, with a yield of 97.5%.

[0068] (f) Take a 250 mL three-necked flask, insert a thermometer, set up a magnetic stirrer, add 18 g of compound vi and 50 mL of methanol, cool in an ice bath, and add dropwise a 100 mL suspension of 6.6 g sodium borohydride in methanol under ice bath conditions. React at room temperature until the reactants have completely reacted, quench with water, and extract with 100 mL of ethyl acetate. 3) Combine the organic phases and wash with saturated saline (100 mL). 3) After drying with anhydrous sodium sulfate, the solution was concentrated to obtain 12.1 g of compound vii. Yield: 96.8%, purity: 99.5%.

[0069] The yield in this embodiment is a molar yield. Its NMR spectrum is: 1 H NMR (400 MHz, CDCl3) δ 7.07 (m,1H), 4.44 (t, J = 6.8 Hz, 2H), 3.45 (q, J = 2.4 Hz, 2H), 2.57 (t, J = 6.0 Hz,2H), 2.46 (s, 5H), 1.88 – 1.79 (m, 2H), 1.52 – 1.41 (m, 2H), 1.39 – 1.29 (m,4H), 0.95 – 0.86 (m, 3H).

[0070] 13C NMR (101 MHz, CDCl3) δ 162.58, 146.87, 129.36, 128.35, 70.97, 55.03, 51.25, 45.91, 31.40, 28.83, 26.61, 25.65, 22.52, 13.96.

[0071] ESI-MS: m / z calcd for C 14 H 24 N3OS [M+H] + = 282.16; found:282.10.

[0072] Example 2

[0073] Following the operating conditions and feed amounts of Example 1, only the mixture of tetrahydrofuran and water (v / v=1:1) in step (a) was replaced with a mixture of acetonitrile and water (v / v=1:1), resulting in a yield of 81.7% for compound iii. Finally, 11.1 g of compound vii was obtained, with a yield of 89.7% and a purity of 92.3% in the final step.

[0074] Example 3

[0075] Following the operating conditions and feed amounts of Example 1, only the mixture of tetrahydrofuran and water (v / v=1:1) in step (a) was replaced with tetrahydrofuran, resulting in a yield of 71.7% for compound iii. Finally, 9.2 g of compound vii was obtained, with a yield of 74.8% and a purity of 88.6% in the final step.

[0076] Example 4

[0077] Following the operating conditions and feed amounts of Example 1, only the reaction temperature in step (a) was replaced with 66°C, and the yield of compound iii was 74.5%. Finally, 10.1 g of compound vii was obtained, with a yield of 81.7% and a purity of 93.8% in the final step.

[0078] Comparative Example 1

[0079] Following the operating conditions and feed amounts of Example 1, only the mixture of tetrahydrofuran and water (v / v=1:1) in step (a) was replaced with a mixture of anhydrous ethanol and toluene (v / v=1:5), and the reaction time was changed to 24 h. TLC plate analysis at sampling points showed that the starting material did not react completely, but new spots were formed. The yield of compound iii was 14.1%. Finally, 1.0 g of compound vii was obtained, with the yield of the last step being less than 10.0%.

[0080] Comparative Example 2

[0081] Following the operating conditions and feed amounts of Example 1, only the mixture of tetrahydrofuran and water (v / v=1:1) in step (a) was replaced with dimethyl sulfoxide, and the reaction time was changed to 24 h. TLC plate analysis at sampling points showed that the starting materials did not react completely, but new spots were formed. The yield of compound iii was 67.2%. Finally, 7.8 g of compound vii was obtained, with a yield of 63.1% in the final step and a purity of less than 40%.

[0082] Comparative Example 3

[0083] Following the operating conditions and feed amounts of Example 1, the mixture of tetrahydrofuran and water (v / v=1:1) in step (a) was replaced with N,N-dimethylformamide, and the reaction time was changed to 24 h. TLC plate analysis at sampling points showed that the starting material did not react completely, but new spots were formed. The yield of compound iii was 13.4%. Finally, 0.8 g of compound vii was obtained, with the yield of the last step being less than 10.0%.

[0084] Comparative Example 4

[0085] Following the operating conditions and feed amounts of Example 1, only 45 g of potassium tert-butoxide in step (d) was replaced with 43 g of lithium diisopropylamino, resulting in a yield of 23.6% for compound iii. Finally, 1.1 g of compound vii was obtained, with a yield of less than 10.0% in the last step.

[0086] Comparative Example 5

[0087] Following the operating conditions and feed amounts of Example 1, but replacing 45 g of potassium tert-butoxide in step (d) with 36 g of sodium hydride, the yield of compound iii was 76.8%. Finally, 9.2 g of compound vii was obtained, with a final yield of 73.4% and a purity of 89.3%.

[0088] Comparative Example 6

[0089] Following the operating conditions and feed amounts of Example 1, the volume ratio (v / v) of the tetrahydrofuran and water mixture in step (a) was changed from 1:1 to 9:1. TLC plate analysis at the sampling points showed that the raw materials did not react completely, but new spots were formed. The yield of compound iii was 63.7%. Finally, 8.2 g of compound vii was obtained, with a yield of 65.6% and a purity of 88.7% in the final step.

[0090] Comparative Example 7

[0091] Following the operating conditions and feed amounts of Example 1, only the mixture of tetrahydrofuran and water (v / v=1:1) in step (a) was replaced with a mixture of dimethyl sulfoxide and water (v / v=5:1). TLC plate analysis at the sampling points showed that the starting material did not react completely, but new spots were formed. The yield of compound iii was 58.7%. Finally, 7.4 g of compound vii was obtained, with a yield of 59.2% and a purity of 84.9% in the final step.

[0092] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and the scope of protection of the present invention is defined by the appended claims. Those skilled in the art can make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but all such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A method for preparing compound iii, characterized in that, It includes the following steps: In step S1, compound i and compound ii undergo an addition reaction in a solvent; The solvent is an organic solvent, or a mixture of an organic solvent and water; the organic solvent is a cyclic ether solvent and / or a nitrile solvent. In step S2, the mixture of ammonium salt, water and ammonia is mixed with the reaction solution obtained in step S1 to carry out a substitution reaction and generate compound iii; 。 2. The method for preparing compound iii as described in claim 1, characterized in that, It satisfies one or more of the following conditions: (1) In step S1, the cyclic ether solvent is tetrahydrofuran; (2) In step S1, the nitrile solvent is acetonitrile; (3) In step S1, the volume ratio of the organic solvent to water is (0.5-4):1; (4) In step S1, the molar volume ratio of compound ii to water in step S1 is 2.5-3.5 mol / L; (5) In step S1, the molar ratio of compound i to compound ii is 1:(1-1.5). (6) In step S1, the temperature of the addition reaction is 15-75℃; (7) In step S1, the post-processing step of the addition reaction does not require purification, and the resulting reaction solution is directly added to the next step; (8) In step S2, the ammonium salt is ammonium chloride, ammonium acetate or ammonium carbonate; (9) In step S2, the molar ratio of ammonium chloride to compound i is (2-5):1; (10) In step S2, the mass-to-volume ratio of the ammonium chloride to the water in step S2 is 0.2-1 g / mL; (11) In step S2, the molar ratio of ammonia to compound i is (2-4):1; (12) In step S2, the ammonia is added to the substitution reaction in the form of ammonia water; (13) In step S2, the temperature of the substitution reaction is 15-35℃; (14) In step S2, the post-processing steps of the substitution reaction are: extraction with organic solvent, merging organic phases, drying, and concentration.

3. The method for preparing compound iii as described in claim 2, characterized in that, It satisfies one or more of the following conditions: (1) In step S1, the volume ratio of the organic solvent to water is 0.5:1, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1 or 4:1; (2) In step S1, the molar volume ratio of compound ii to water in step S1 is 2.5 mol / L, 2.6 mol / L, 2.7 mol / L, 2.8 mol / L, 2.9 mol / L, 3.0 mol / L, 3.1 mol / L, 3.2 mol / L, 3.3 mol / L, 3.4 mol / L or 3.5 mol / L; (3) In step S1, the molar ratio of compound i to compound ii is 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5; (4) In step S1, the temperature of the addition reaction is 15°C, 25°C, 35°C, 45°C, 55°C, 66°C or 75°C; (5) In step S2, the ammonium salt is ammonium chloride; (6) In step S2, the molar ratio of the ammonium salt to compound i is 2:1, 2.5:1, 3:1, 3.6:1, 4:1, 4.5:1 or 5:1; (7) In step S2, the mass-to-volume ratio of the ammonium salt to the water in step S2 is 0.2 g / mL, 0.5 g / mL, 0.8 g / mL or 1 g / mL; (8) In step S2, the molar ratio of ammonia to compound i is (2.8-3.2):1; (9) In step S2, the ammonia water is ammonia water with an ammonia mass fraction of 25-28%; (10) In step S2, ammonia water is added to the ammonium salt and water to obtain the mixture; (11) In step S2, the temperature of the substitution reaction is 15°C, 20°C, 25°C, 30°C or 35°C.

4. The method for preparing compound iii as described in claim 3, characterized in that, It satisfies one or more of the following conditions: (1) In step S1, the volume ratio of the organic solvent to water is 1:1; (2) In step S1, the molar volume ratio of compound ii to water in step S1 is 3.1 mol / L; (3) In step S1, the molar ratio of compound i to compound ii is 1:1.2; (4) In step S1, the temperature of the addition reaction is 25°C or 66°C; (5) In step S2, the molar ratio of the ammonium salt to compound i is 3.6:1; (6) In step S2, the mass-to-volume ratio of the ammonium salt to the water in step S2 is 0.5 g / mL; (7) In step S2, the temperature of the substitution reaction is 25°C.

5. A method for preparing compound v, characterized in that, It includes the following steps: In an organic solvent, in the presence of a C1-C6 alkane alcohol alkali metal salt, compound iv undergoes an etherification reaction with n-hexanol to generate compound v. 。 6. The method for preparing compound v according to claim 5, characterized in that, It satisfies one or more of the following conditions: (1) The organic solvent is a cyclic ether solvent; (2) The mass-to-volume ratio of the n-hexanol to the organic solvent is 0.05-0.30 g / mL; (3) The C1-C6 alkane alcohol alkali metal salt is an alkali metal tert-butoxide salt; (4) The molar ratio of the compound iv to the C1-C6 alkane alcohol alkali metal salt is 1:(2-6). (5) The temperature of the etherification reaction is 60-75℃; (6) The operation steps of the etherification reaction are as follows: Step a, mixing the n-hexanol with volume A of the organic solvent; Step b: The C1-C6 alkane alcohol alkali metal salt is added to the solution from step a to react. Step c, the compound iv is dissolved in the organic solvent of volume B, and then added to the solution of step b to carry out the etherification reaction; the volume ratio of volume A to volume B is (2-6):1; (7) The post-processing steps of the etherification reaction are cooling, quenching, extraction, washing, drying and concentration.

7. The method for preparing compound v according to claim 6, characterized in that, It satisfies one or more of the following conditions: (1) The organic solvent is tetrahydrofuran; (2) The mass-to-volume ratio of the n-hexanol to the organic solvent is 0.05 g / mL, 0.08 g / mL, 0.1 g / mL, 0.12 g / mL, 0.14 g / mL or 0.16 g / mL; (3) The C1-C6 alkane alcohol alkali metal salt is potassium tert-butoxide; (4) The molar ratio of the compound iv to the C1-C6 alkane alcohol alkali metal salt is 1:2, 1:3, 1:4, 1:5 or 1:6; (5) In step a), the mixture is cooled to 0-10°C using an ice bath; (6) In step b, the temperature of the reaction is 10-40℃; (7) In step c, the addition is done by dripping; (8) The volume ratio of volume A to volume B is 2:1, 3:1, 4:1, 5:1 or 6:

1.

8. The method for preparing compound v according to claim 7, characterized in that, It satisfies one or more of the following conditions: (1) The mass-to-volume ratio of the n-hexanol to the organic solvent is 0.12 g / mL; (2) The molar ratio of compound iv to the C1-C6 alkane alcohol alkali metal salt is 1:4; (3) In step b, the reaction temperature is room temperature; (4) The volume ratio of volume A to volume B is 4:

1.

9. A method for synthesizing compound vii, characterized in that, It includes the following steps: Compound i was subjected to the following reaction to synthesize compound vii; ； The method for synthesizing compound iii is as described in any one of claims 1-4, and the method for synthesizing compound v is as described in any one of claims 5-8.

10. The method for synthesizing compound vii as described in claim 9, characterized in that, It satisfies one or more of the following conditions: (1) In an organic solvent, compound iii undergoes a cyclization reaction with disulfur dichloride to generate compound iv; (2) In an organic solvent, compound v undergoes a methylation reaction with iodomethane to generate compound vi; (3) In an organic solvent, compound vi undergoes a reduction reaction with sodium borohydride to generate compound vii; Preferably, the method for synthesizing compound vii satisfies one or more of the following conditions: (1) In the cyclization reaction, the organic solvent is an amide solvent, such as DMF; (2) In the cyclization reaction, the molar ratio of compound iii to disulfur dichloride is (1-3):1, for example 2:1; (3) In the cyclization reaction, the reaction temperature is 0-10℃, for example 0-5℃; (4) In the methylation reaction, the organic solvent is a ketone solvent, such as acetone; (5) In the methylation reaction, the molar ratio of compound v to iodomethane is (0.1-0.5):1, for example 0.25:1; (6) In the methylation reaction, the reaction temperature is 10-40℃, for example, room temperature; (7) In the reduction reaction, the organic solvent is an alcohol solvent, such as methanol; (8) In the reduction reaction, the molar ratio of compound vi to sodium borohydride is (2-6):1, for example 4:1; (9) In the reduction reaction, the reaction temperature is 10-40℃, for example, room temperature.

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