Preparation method of piperidine methyl cyclopropane derivative and intermediate thereof

Abstract

The invention relates to a preparation method of piperidine methyl cyclopropane derivatives and intermediates thereof, and belongs to the field of organic chemistry. The invention provides a preparation method of a piperidine methyl cyclopropane derivative compound 5, and the reaction is as follows: # imgabs0 #, in which R1 is Ms, Ts, Ns or Tf; r2 is methyl or ethyl; the method comprises the following steps: 1, reacting a compound 1 with piperidine under the action of alkali and a catalytic amount of NaI to obtain a compound 2; 2, hydrolyzing the compound 2 under the action of alkali to obtain a compound 3; 3, reacting the compound 3 with a chlorination reagent in an inert solvent to obtain a compound 4; and 4, reacting the compound 4 with N, O-dimethyl hydroxylamine or a salt thereof in alkali and an organic solvent to obtain a compound 5. The method has the advantages of being high in conversion rate, easy and convenient to operate, economical, rapid, short in consumed time, good in reproducibility and high in atom utilization rate, is suitable for industrial production, and therefore has good market value and profound practical significance.

Description

Technical Field

[0001] The invention relates to a preparation method of a piperidine methyl cyclopropane derivative and an intermediate thereof, and belongs to the field of organic chemistry. Background Art

[0002] Piperidinylmethylcyclopropane is an important molecular building block, which is often used to introduce piperidine groups into molecules. It is an important intermediate in drug synthesis, for example, it is used to synthesize Lasmiditan (CN 110981854 B), Donepezil (CN109415359), etc.

[0003] N-methoxy-N-methyl-1-(piperidin-1-methyl)cyclopropanecarboxamide is a new type of molecular building block, and its structure is shown in Formula 5:

[0004]

[0005] The key intermediate formula 2 of the compound of formula 5 is as follows:

[0006]

[0007] Wherein, R2 is methyl or ethyl;

[0008] The prior art does not disclose a method for preparing a compound of formula 2. WO2010 / 136778 discloses a method for preparing a similar compound of formula 2, and the reaction formula is as follows:

[0009]

[0010] In this patent, the compound of formula 1A, morpholine, potassium carbonate and acetonitrile are reacted at 80° C. to obtain an analogue of compound 2, and the reaction yield is only 50.9%, which is low and not suitable for commercial production.

[0011] Currently, there is no report on the preparation of N-methoxy-N-methyl-1-(piperidin-1-methyl)cyclopropanecarboxamide in the prior art, so a real, feasible, economical, fast, simple to operate, simple to post-process, high yield and high purity synthesis method is needed.

[0012] The invention provides a method for preparing N-methoxy-N-methyl-1-(piperidin-1-methyl)cyclopropanecarboxamide, a piperidinemethylcyclopropane molecular building block. The method does not require the use of dangerous reagents such as oxidants, explosives, and flammables, and has the advantages of being economical, quick, easy to operate, simple to post-process, and having a high conversion rate. The method is suitable for industrial production, and therefore has good market value and far-reaching practical significance. Summary of the invention

[0013] In view of the above technical background, the present invention provides a method for preparing piperidine methyl cyclopropane derivatives and intermediates thereof. The method has simple process, high yield, high reproducibility, low cost, is green and environmentally friendly, and is conducive to industrial production.

[0014] The first aspect of the present invention provides a method for preparing compound 2, the reaction is as follows:

[0015]

[0016] Wherein, R1 is methanesulfonyl (Ms), phenylmethylsulfonyl (Ts), nitrobenzenemethylsulfonyl (Ns), trifluoromethanesulfonyl (Tf); R2 is methyl or ethyl;

[0017] The following steps are involved:

[0018] Step 1: Compound 1 and piperidine react under the action of a base and NaI to obtain compound 2;

[0019] As a further improvement of the present invention, including but not limited to, the base in step 1 is selected from one or more of DIPEA, triethylamine, pyridine, DMAP, diethylamine, potassium carbonate, sodium carbonate, and cesium carbonate, preferably one or more of DIPEA, triethylamine, and pyridine.

[0020] As a further improvement of the present invention, including but not limited to, the reaction solvent of step 1 is selected from one or more of DMF, DMA, DMSO, acetonitrile, toluene, dioxane, THF, preferably one or more of DMF, DMA, DMSO.

[0021] As a further improvement of the present invention, including but not limited to, in step 1, the molar ratio of compound 1, piperidine and base is 1:(1-10):(1-10), preferably 1:(1-8):(1.5-8).

[0022] As a further improvement of the present invention, including but not limited to, the molar ratio of compound 1 to NaI in step 1 is 1:(0.05-0.3), preferably 1:(0.05-0.2).

[0023] As a further improvement of the present invention, including but not limited to, the reaction temperature in step 1 is 50-100°C, preferably 60-90°C.

[0024] As a further improvement of the present invention, including but not limited to, the reaction time in step 1 is 6 to 42 hours, preferably 8 to 24 hours.

[0025] As a further improvement of the present invention, including but not limited to, in certain embodiments, the base in step 1 is pyridine.

[0026] As a further improvement of the present invention, including but not limited to, in certain embodiments, the reaction solvent in step 1 is DMF.

[0027] As a further improvement of the present invention, including but not limited to, in certain embodiments, the molar ratio of compound 1, piperidine and base in step 1 is 1:5:5.

[0028] As a further improvement of the present invention, including but not limited to, in certain embodiments, the molar ratio of compound 1 to NaI in step 1 is 1:0.1.

[0029] As a further improvement of the present invention, including but not limited to, in certain embodiments, the reaction temperature in step 1 is 80°C.

[0030] As a further improvement of the present invention, including but not limited to, as a further improvement of the present invention, including but not limited to, in certain embodiments, R1 of compound 1 and compound 2 in step 1 is methylsulfonyl, and R2 in compound 2 is ethyl.

[0031] As a further improvement of the present invention, including but not limited to, as a further improvement of the present invention, in certain embodiments, compound 1 reacts in the presence of piperidine, diisopropylethylamine and sodium iodide to obtain compound 2.

[0032] As a further improvement of the present invention, including but not limited to, as a further improvement of the present invention, in certain embodiments, compound 1 is dissolved in DMF, piperidine (5 eq), diisopropylethylamine (5 eq) and sodium iodide (0.1 eq) are added and reacted at 80°C to obtain compound 2.

[0033] As a further improvement of the present invention, including but not limited to, in certain embodiments, after the reaction of step 1 is completed, it is quenched with water, extracted with an organic solvent, washed, and dried to obtain compound 2.

[0034] As a further improvement of the present invention, including but not limited to, in certain embodiments, the organic solvent is ethyl acetate.

[0035] As a further improvement of the present invention, including but not limited to, in certain embodiments, water and saturated brine are used for washing in the above post-treatment.

[0036] As a further improvement of the present invention, including but not limited to, when the catalytic amount of NaI is not used in step 1 of the present invention, the reaction is incomplete and the reaction is very slow. After adding the catalytic amount of NaI, the yield of step 1 is significantly improved, which is more than 35% higher than the yield of the prior art without adding the catalytic amount of NaI.

[0037] The second aspect of the present invention provides a method for preparing compound 5, the reaction is as follows:

[0038]

[0039] Wherein, R1 is methanesulfonyl (Ms), phenylmethylsulfonyl (Ts), nitrobenzenemethylsulfonyl (Ns), trifluoromethanesulfonyl (Tf); R2 is methyl or ethyl;

[0040] The following steps are included:

[0041] Step 1: Compound 1 and piperidine react under the action of a base and NaI to obtain compound 2;

[0042] Step 2: Compound 2 is hydrolyzed under the action of a base to obtain compound 3;

[0043] Step 3: Compound 3 reacts with a chlorinating agent in an inert solvent to obtain compound 4;

[0044] Step 4: Compound 4 is reacted with N,O-dimethylhydroxylamine or a salt thereof in a base and an organic solvent to obtain compound 5.

[0045] The preferred technical solution of the present invention, step 1 can refer to the entire technical solution of step 1 of the method for preparing compound 2 in the first aspect of the present invention;

[0046] As a further improvement of the present invention, including but not limited to, the base in step 2 is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide aqueous solution, sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, preferably one of lithium hydroxide or lithium hydroxide aqueous solution.

[0047] As a further improvement of the present invention, including but not limited to, the molar ratio of compound 2 to base in step 2 is 1:(1-10), preferably 1:(2-6).

[0048] As a further improvement of the present invention, including but not limited to, the reaction solvent in step 2 is selected from any one or more of water, ethanol, methanol, isopropanol, and tetrahydrofuran, preferably one or more of water, ethanol, and methanol.

[0049] As a further improvement of the present invention, including but not limited to, the reaction temperature in step 2 is 10-50°C, preferably 20-40°C.

[0050] As a further improvement of the present invention, including but not limited to, in step 2, the reaction time is 0.5 to 18 hours, preferably 1 to 12 hours.

[0051] As a further improvement of the present invention, including but not limited to, in certain embodiments, the base in step 2 is lithium hydroxide.

[0052] As a further improvement of the present invention, including but not limited to, in certain embodiments, the molar ratio of compound 2 to base in step 2 is 1:4.

[0053] As a further improvement of the present invention, including but not limited to, in certain embodiments, the reaction solvent in step 2 is a mixed solution of ethanol and water.

[0054] As a further improvement of the present invention, including but not limited to, in certain embodiments, the reaction solvent in step 2 is a mixed solution of ethanol and water, and the volume ratio of ethanol to water in the mixed solution is 4.5:1.

[0055] As a further improvement of the present invention, including but not limited to, in certain embodiments, the reaction temperature in step 2 is room temperature.

[0056] As a further improvement of the present invention, including but not limited to, in certain embodiments, after the reaction of step 2 is completed, hydrochloric acid solution is added to adjust the pH to 1-5, and organic solvent extraction, washing, drying and concentration are performed to obtain compound 3.

[0057] As a further improvement of the present invention, including but not limited to, in certain embodiments, the hydrochloric acid solution is selected from one or more of hydrochloric acid aqueous solution, hydrochloric acid ethyl acetate solution, and hydrochloric acid dioxane solution, such as 1M hydrochloric acid aqueous solution.

[0058] As a further improvement of the present invention, including but not limited to, in certain embodiments, the organic solvent is ethyl acetate.

[0059] As a further improvement of the present invention, including but not limited to, in step 3, the chlorination agent is selected from one of oxalyl chloride, thionyl chloride, sulfuryl chloride, and phosphorus oxychloride, preferably oxalyl chloride.

[0060] As a further improvement of the present invention, including but not limited to, in step 3, a catalytic amount of DMF is optionally added;

[0061] As a further improvement of the present invention, including but not limited to, step 3 comprises reacting compound 3, oxalyl chloride and a catalytic amount of DMF in an inert solvent to obtain compound 4.

[0062] As a further improvement of the present invention, including but not limited to, the inert solvent in step 3 is selected from one or more of dichloromethane, dichloroethane, chloroform, tetrahydrofuran, and diethyl ether, preferably dichloromethane.

[0063] As a further improvement of the present invention, including but not limited to, the molar ratio of compound 3 to oxalyl chloride in step 3 is 1:(2-15), preferably 1:(3-13).

[0064] As a further improvement of the present invention, including but not limited to, in step 3, the reaction temperature is 0 to 40°C, preferably 10 to 40°C.

[0065] As a further improvement of the present invention, including but not limited to, in step 3, the reaction time is 1 to 12 hours, preferably 1 to 6 hours.

[0066] As a further improvement of the present invention, including but not limited to, in certain embodiments, after the reaction of step 3 is completed, the compound 4 is obtained by concentration under reduced pressure and directly used in the next step.

[0067] As a further improvement of the present invention, including but not limited to, the salt of N,O-dimethylhydroxylamine in step 4 is preferably N,O-dimethylhydroxylamine hydrochloride.

[0068] As a further improvement of the present invention, including but not limited to, the base in step 4 is selected from one or more of triethylamine, DIEPA, pyridine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, preferably triethylamine.

[0069] As a further improvement of the present invention, including but not limited to, the organic solvent in step 4 is selected from at least one of dichloromethane, dichloroethane, chloroform, ether, THF, ethyl acetate, and DMF, preferably at least one of dichloromethane, dichloroethane, and chloroform.

[0070] As a further improvement of the present invention, including but not limited to, in step 4, the molar ratio of compound 4, N,O-dimethylhydroxylamine or its salt and base is 1:(1-5):(1-10), preferably 1:(1-3):(1-5).

[0071] As a further improvement of the present invention, including but not limited to, the reaction temperature in step 4 is 0 to 40° C., preferably 0 to 35° C.;

[0072] As a further improvement of the present invention, including but not limited to, the reaction temperature in step 4 is 1 to 8 hours, preferably 1 to 5 hours;

[0073] As a further improvement of the present invention, including but not limited to, in certain embodiments, after the reaction of step 4 is completed, filtration and vacuum concentration are performed to obtain a crude product of compound 5.

[0074] As a further improvement of the present invention, in certain embodiments, the crude product can be further subjected to column chromatography to obtain a pure product of compound 5, wherein the column chromatography eluent is, for example, petroleum ether:ethyl acetate = 1:5.

[0075] The third aspect of the present invention provides a compound having the following structural formula:

[0076]

[0077] The fourth aspect of the present invention provides a method for synthesizing compound 5, which comprises the preparation method of compound 2 provided in the first aspect of the present invention or the preparation method of compound 5 provided in the second aspect of the present invention and compound 4 described in the third aspect.

[0078] Beneficial technical effects of the present invention:

[0079] 1. Through creative labor, the present invention synthesized a new intermediate of compound 5 and proposed a feasible preparation method of compounds 2, 3, and 5, which is the first route for these three compounds and fills the gap in the preparation of compounds 2, 3, and 5.

[0080] 2. The route proposed by the present invention is simple to operate, has no harsh reaction conditions, and adopts a mild reaction to obtain the final product. The risk factor of the synthetic route is low, which is conducive to industrial scale-up production. Therefore, it has good market value and far-reaching practical significance.

[0081] 3. More importantly, the present invention, through creative labor, finally determined important process parameters such as suitable solvents, reaction conditions, such as the selection of base and catalyst in step 1, thereby efficiently preparing compound 5 and its new intermediate compound 4.

[0082] 4. The yield of step 1 of the present invention is increased by more than 35% compared with the prior art. When the inventors repeatedly did not use a catalytic amount of NaI, the reaction was incomplete and the reaction was very slow. After adding a catalytic amount of NaI, the yield of step 1 was significantly improved, which is conducive to amplifying the reaction; and the method of the present invention has good reproducibility and high purity, and is suitable for industrial production.

[0083] 5. The route provided by the invention has low time cost and simple post-processing, which makes it possible to mass-produce the product. DETAILED DESCRIPTION

[0084] The present invention will be further described below in conjunction with specific examples. It should be understood that the following detailed description of the technical solution of the present invention with examples will help to further understand the advantages and effects of the technical solution of the present invention, and the examples do not limit the protection scope of the present invention, which is determined by the claims.

[0085] The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or conditions recommended by the manufacturers.

[0086] Unless otherwise specified, the raw materials and reagents used in the examples are commercially available.

[0087] Unless otherwise specified, the reagents were used directly without purification. All solvents were purchased from commercial suppliers and used without further treatment.

[0088] Embodiment 1:

[0089]

[0090] Compound 1A (11 g, 49.5 mmol) was dissolved in DMF (110 mL), and piperidine (21 g, 246.6 mmol, 5 eq), diisopropylethylamine (31.9 g, 246.8 mmol, 5 eq) and sodium iodide (742 mg, 4.95 mmol, 0.1 eq) were added. The resulting mixture was stirred overnight in an 80 ° C oil bath. Then it was cooled to room temperature and quenched with water, extracted with ethyl acetate, and the organic layer was washed with water and brine and dried to obtain a yellow oil compound 2A (9 g, yield 86.1%).

[0091] Embodiment 2:

[0092]

[0093] Compound 1A (1 g, 4.5 mmol) was dissolved in DMF (10 mL), and piperidine (1.91 g, 22.4 mmol, 5 eq), diisopropylethylamine (2.9 g, 22.4 mmol, 5 eq) and sodium iodide (67 mg, 0.45 mmol, 0.1 eq) were added. The resulting mixture was stirred overnight in an 80 ° C oil bath. Then it was cooled to room temperature and quenched with water, extracted with ethyl acetate, and the organic layer was washed with water and brine and dried to obtain a yellow oil compound 2A (0.73 g, yield 76.8%).

[0094] Embodiment 3:

[0095]

[0096] Compound 1A (8 g, 36 mmol) was dissolved in DMF (80 mL), and piperidine (15.3 g, 180 mmol, 5 eq), diisopropylethylamine (23.26 g, 180 mmol, 5 eq) and sodium iodide (540 mg, 3.6 mmol, 0.1 eq) were added. The resulting mixture was stirred overnight in an 80 ° C oil bath. Then it was cooled to room temperature and quenched with water, extracted with ethyl acetate, and the organic layer was washed with water and brine and dried to obtain a yellow oil compound 2A (6.5 g, yield 85.5%).

[0097] Embodiment 4:

[0098]

[0099] Compound 2 (9.0 g, 42.59 mmol) and lithium hydroxide (4.08 g, 170.37 mmol, 4 eq) were dissolved in ethanol (90 mL) and water (20 ml) and stirred at room temperature for 2 hours. The mixture was poured into ice water, the pH value was adjusted to 4 with 1M HCl solution, and then extracted with ethyl acetate, washed with brine, separated, dried with Na2SO4, and then concentrated to obtain compound 3 (7 g, yield 89.7%) as a white solid.

[0100] Embodiment 5:

[0101]

[0102] Compound 3 (7.0 g, 38.20 mmol) was dissolved in dichloromethane (35 mL) under ice bath conditions, and oxalyl chloride (35 ml, 10.7 eq) and a catalytic amount of DMF (0.02 mL) were added. The ice bath was removed, and the mixture was stirred at room temperature for 4 hours, and concentrated under reduced pressure to obtain compound 4 (7.0 g, yield: 90.85%) as a light yellow oil, which was used directly in the next step.

[0103] Embodiment 6:

[0104]

[0105] N, O-dimethylhydroxylamine hydrochloride (5.08 g, 52.1 mmol, 1.5 eq) was added to a solution of compound 4 (7.0 g, 34.71 mmol) in dichloromethane (70 mL), and triethylamine (7.02 g, 69.4 mmol, 2 eq) was slowly added at 0 ° C. The resulting mixture was stirred at room temperature for 4 hours. Then, the solid was filtered out. The solvent was concentrated in vacuo and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0 / 1) to obtain compound 5 as a yellow oil (2.72 g, yield 34.6%, purity 96.4%).

[0106] Comparative Example 1:

[0107]

[0108] Compound 1 (1 g, 4.5 mmol) was dissolved in DMF (10 mL), and piperidine (1.92 g, 22.5 mmol, 5 eq) and diisopropylethylamine (2.91 g, 22.5 mmol, 5 eq) were added. The resulting mixture was stirred in an oil bath at 80°C overnight. The reaction was controlled by TLC, which showed that about two-thirds of the raw materials remained, and the reaction was still incomplete after a longer period of time.

[0109] Comparative Example 2:

[0110]

[0111] Compound 1 (1 g, 4.5 mmol) was dissolved in DMF (10 mL), and piperidine (1.92 g, 22.5 mmol, 5 eq), diisopropylethylamine (2.91 g, 22.5 mmol, 5 eq) and sodium iodide (67 mg, 446.98 umol) were added. The resulting mixture was stirred at room temperature overnight. TLC showed that a large amount of raw materials remained, with only a small amount of product, and the reaction was still incomplete after a longer time.

[0112] The above description of the embodiments is to facilitate the understanding and use of the invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.

Claims

1. A method for preparing compound 5, characterized in that: The reaction is as follows: Wherein, R1 is methanesulfonyl, phenylmethylsulfonyl, nitrobenzenemethylsulfonyl, trifluoromethanesulfonyl; R2 is methyl or ethyl; The following steps are included: Step 1: Compound 1 and piperidine react under the action of a base and NaI to obtain compound 2; Step 2: Compound 2 is hydrolyzed under the action of a base to obtain compound 3; Step 3: Compound 3 reacts with a chlorinating agent in an inert solvent to obtain compound 4; Step 4: Compound 4 is reacted with N,O-dimethylhydroxylamine or a salt thereof in a base and an organic solvent to obtain compound 5.

2. A method for preparing compound 2, characterized in that: The reaction is as follows: Wherein, R1 is methanesulfonyl, phenylmethylsulfonyl, nitrobenzenemethylsulfonyl, trifluoromethanesulfonyl; R2 is methyl or ethyl; The following steps are involved: Step 1: Compound 1 and piperidine react in the presence of a base and NaI to obtain compound 2.

3. The preparation method according to claim 1 or 2, characterized in that: The preparation method satisfies one or more of the following conditions: (1) The base in step 1 is selected from one or more of DIPEA, triethylamine, pyridine, DMAP, diethylamine, potassium carbonate, sodium carbonate, and cesium carbonate, preferably one or more of DIPEA, triethylamine, and pyridine; (2) the reaction solvent of step 1 is selected from one or more of DMF, DMA, DMSO, acetonitrile, toluene, dioxane, THF, preferably one or more of DMF, DMA, DMSO; (3) In step 1, the molar ratio of compound 1, piperidine and base is 1:(1-10):(1-10), preferably 1:(1-8): (1.5～8)； (4) In step 1, the molar ratio of compound 1 to NaI is 1:(0.05-0.3), preferably 1:(0.05-0.2); (5) The reaction temperature in step 1 is 50 to 100° C., preferably 60 to 90° C.; (6) The reaction time in step 1 is 6 to 42 hours, preferably 8 to 24 hours.

4. The preparation method according to claim 1, characterized in that: The preparation method satisfies one or more of the following conditions: (1) The base in step 2 is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide aqueous solution, sodium hydroxide aqueous solution, and potassium hydroxide aqueous solution, preferably one of lithium hydroxide or lithium hydroxide aqueous solution; (2) In step 2, the molar ratio of compound 2 to the base is 1:(1-10), preferably 1:(2-6); (3) The reaction solvent in step 2 is selected from any one or more of water, ethanol, methanol, isopropanol, and tetrahydrofuran, preferably one or more of water, ethanol, and methanol; (4) The reaction temperature in step 2 is 10 to 50° C., preferably 20 to 40° C.; (5) In step 2, the reaction time is 0.5 to 18 hours, preferably 1 to 12 hours.

5. The preparation method according to claim 1, characterized in that: The preparation method satisfies one or more of the following conditions: (1) In step 3, the chlorination agent is selected from one of oxalyl chloride, thionyl chloride, sulfuryl chloride, and phosphorus oxychloride, preferably oxalyl chloride; (2) optionally adding a catalytic amount of DMF in step 3; (3) Step 3 comprises reacting compound 3, oxalyl chloride and a catalytic amount of DMF in an inert solvent to obtain compound 4; (4) The inert solvent in step 3 is selected from one or more of dichloromethane, dichloroethane, chloroform, tetrahydrofuran, and diethyl ether, preferably dichloromethane; (5) In step 3, the molar ratio of compound 3 to oxalyl chloride is 1:(2-15), preferably 1:(3-13); (6) In step 3, the reaction temperature is 0 to 40°C, preferably 10 to 40°C; (7) In step 3, the reaction time is 1 to 12 hours, preferably 1 to 6 hours.

6. The preparation method according to claim 1, characterized in that: The preparation method satisfies one or more of the following conditions: (1) The salt of N,O-dimethylhydroxylamine in step 4 is preferably N,O-dimethylhydroxylamine hydrochloride; (2) in step 4, the base is selected from one or more of triethylamine, DIEPA, pyridine, potassium carbonate, potassium bicarbonate, sodium carbonate, and sodium bicarbonate, preferably triethylamine; (3) the organic solvent in step 4 is selected from at least one of dichloromethane, dichloroethane, chloroform, ether, THF, ethyl acetate, and DMF, preferably at least one of dichloromethane, dichloroethane, and chloroform; (4) In step 4, the molar ratio of compound 4, N,O-dimethylhydroxylamine or its salt and base is 1:(1-5):(1-10), preferably 1:(1-3):(1-5); (5) The reaction temperature in step 4 is 0 to 40° C., preferably 0 to 35° C.; (6) The reaction temperature in step 4 is 1 to 8 hours, preferably 1 to 5 hours.

7. The preparation method according to claim 1 or 2, characterized in that: The preparation method satisfies one or more of the following conditions: (1) The base in step 1 is pyridine; (2) The reaction solvent in step 1 is DMF; (3) The molar ratio of compound 1, piperidine and base in step 1 is 1:5:5; (4) In step 1, the molar ratio of compound 1 to NaI is 1:0.1; (5) The reaction temperature in step 1 is 80° C. (6) In step 1, R1 of compound 1 and compound 2 is methylsulfonyl, and R2 of compound 2 is ethyl; (7) After the reaction of step 1 is completed, the reaction is quenched with water, extracted with an organic solvent, washed, and dried to obtain compound 2.

8. The preparation method according to claim 1, characterized in that: The preparation method satisfies one or more of the following conditions: (1) The alkali in step 2 is lithium hydroxide; (2) In step 2, the molar ratio of compound 2 to the base is 1:4; (3) The reaction solvent in step 2 is a mixed solution of ethanol and water; (4) The reaction solvent in step 2 is a mixed solution of ethanol and water, and the volume ratio of ethanol to water in the mixed solution is 4.5:1; (5) The reaction temperature in step 2 is room temperature.

9. The preparation method according to claim 1, characterized in that: The preparation method satisfies one or more of the following conditions: (1) After the reaction of step 2 is completed, a hydrochloric acid solution is added to adjust the pH to 1-5, and organic solvent extraction, washing, drying and concentration are performed to obtain compound 3; (2) After the reaction of step 4 is completed, the mixture is filtered and concentrated in vacuo to obtain a crude compound 5. The crude compound 5 can be further purified by column chromatography to obtain a pure compound 5.

10. A compound having the following structural formula:

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