Preparation method of 3-methoxy-4, 5-methylenedioxy phenylethylamine

Abstract

The invention relates to the technical field of organic synthesis, and provides a preparation method of 3-methoxy-4, 5-methylenedioxy phenylethylamine. According to the invention, myristic aldehyde and diethyl cyano phosphate are adopted as initial raw materials, and the 3-methoxy-4, 5-methylenedioxy phenylethylamine is prepared through wittig reaction, reduction reaction, hydrolysis reaction and Hofmann reaction. According to the preparation method provided by the invention, each step is simple and convenient to operate, the product yield is high (the total yield is 78.3%-84.2%), and the purity is high; furthermore, the preparation method provided by the invention is mild in reaction condition, does not need explosive and highly toxic chemicals, does not need column chromatography purification of products in each step, and is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing 3-methoxy-4,5-methylenedioxyphenethylamine. Background Art

[0002] Lekeping is a classic antitussive drug and can also be used to treat stroke and edema. Currently, the main chemical synthesis method of Lekeping is the Bischler-Napieralski method. In the process of synthesizing Lekeping using the Bischler-Napieralski chemical synthesis method, 3-methoxy-4,5-methylenedioxyphenylethylamine is the main key intermediate. The structure of Lekeping is as follows:

[0003]

[0004] The related art reports that 3,4,5-trihydroxybenzoic acid is used as the starting material and the target product is obtained through esterification, cyclization, methylation, reduction, chlorination, cyanation and reduction. The route is as follows: Figure 4 shown.

[0005] This route has many reaction steps, complicated operation, and low product yield, with an overall yield of only 19.5%. Summary of the invention

[0006] In view of this, the present invention provides a preparation method of 3-methoxy-4,5-methylenedioxyphenylethylamine. The preparation method provided by the present invention has a short synthesis route, simple operation and high product yield.

[0007] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0008] A method for preparing 3-methoxy-4,5-methylenedioxyphenethylamine comprises the following steps:

[0009] (1) mixing myristic aldehyde, diethyl cyanophosphate, an alkaline reagent and a solvent to perform a wittig reaction to obtain a first intermediate; the structure of the first intermediate is shown in formula ND-1;

[0010] (2) mixing the first intermediate, alcohol and a hydrogenation catalyst, and performing a reduction reaction under hydrogen conditions to obtain a second intermediate; the structural formula of the second intermediate is shown in Formula ND-2;

[0011] (3) hydrolyzing the second intermediate under alkaline conditions to obtain a third intermediate; the structural formula of the third intermediate is shown in Formula ND-3;

[0012] (4) mixing the third intermediate, an alkali reagent, sodium hypochlorite and a solvent to carry out a Hofmann reaction to obtain the 3-methoxy-4,5-methylenedioxyphenethylamine;

[0013]

[0014] Preferably, in step (1), the alkaline reagent comprises one or more of sodium hydride and alkali metal hydroxide; the molar ratio of myristic aldehyde, alkaline reagent and diethyl cyanophosphate is 1:0.8-2.0:0.8-2.5;

[0015] The solvent used in the wittig reaction includes one or more of tetrahydrofuran, N,N-dimethylformamide, dichloromethane and 1,4-dioxane.

[0016] Preferably, the temperature of the wittig reaction is 5 to 60° C., and the reaction time is 0.5 to 8 h.

[0017] Preferably, in step (2), the hydrogenation catalyst includes one or more of a palladium-based catalyst and a nickel-based catalyst; the alcohol used in the reduction reaction includes one or more of methanol, ethanol and isopropanol;

[0018] The mass ratio of the first intermediate to the hydrogenation catalyst is 1:0.01-1.

[0019] Preferably, the reduction reaction temperature is 10-80° C., the pressure is normal pressure to 3 MPa, and the reaction time is 0.5-24 h.

[0020] Preferably, in the step (3), the hydrolysis reaction comprises: mixing the second intermediate, an alkaline reagent, hydrogen peroxide and a solvent for a hydrolysis reaction to obtain the third intermediate; the alkaline reagent used in the hydrolysis reaction comprises one or more of an alkali metal carbonate and an alkali metal hydroxide; the solvent used in the hydrolysis reaction is dimethyl sulfoxide; the molar ratio of the second intermediate, the alkaline reagent and hydrogen peroxide is 1:0.8-2.5:0.8-3; the temperature of the hydrolysis reaction is 5-35°C, and the reaction time is 0.5-24h.

[0021] Preferably, in the step (3), the hydrolysis reaction comprises: mixing the second intermediate, alcohol, water and sodium hydroxide for hydrolysis reaction to obtain the third intermediate; the alcohol used in the hydrolysis reaction comprises one or more of methanol, ethanol, isopropanol, n-butanol, tert-butanol and ethylene glycol; the molar ratio of the second intermediate to sodium hydroxide is 1:0.8-3; the temperature of the hydrolysis reaction is 10-100°C, and the reaction time is 0.5-24h.

[0022] Preferably, after the hydrolysis reaction is completed, the obtained reaction solution is cooled and crystallized; the temperature of the cooling and crystallization is -5 to 30°C, and the time is 0.5 to 5 hours.

[0023] Preferably, in step (4), the alkaline reagent is an alkali metal hydroxide; the molar ratio of the third intermediate, the alkaline reagent and sodium hypochlorite is 1:2-50:1-3; and the solvent used in the Hofmann reaction is alcohol and / or water.

[0024] Preferably, the temperature of the Hofmann reaction is 0 to 90° C., and the reaction time is 0.5 to 24 h.

[0025] The present invention provides a preparation method of 3-methoxy-4,5-methylenedioxyphenethylamine. The present invention uses myristic aldehyde and diethyl cyanophosphate as starting materials, and prepares 3-methoxy-4,5-methylenedioxyphenethylamine through Wittig reaction, reduction reaction, hydrolysis reaction and Hofmann reaction. The preparation method provided by the present invention has a short synthesis route, simple operation of each step, high product yield (total yield is 78.3% to 84.2%), and high purity of the final product; further, the preparation method provided by the present invention has mild reaction conditions, does not need to use explosive and highly toxic chemicals, and does not need column chromatography purification of the products of each step, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The NMR spectrum of the third intermediate ND-3 prepared in Example 3;

[0027] Figure 2 HPLC chromatogram of 3-methoxy-4,5-methylenedioxyphenethylamine prepared in Example 5;

[0028] Figure 3 The NMR spectrum of 3-methoxy-4,5-methylenedioxyphenethylamine prepared in Example 5;

[0029] Figure 4 A roadmap for the synthesis of 3-methoxy-4,5-methylenedioxyphenethylamine for related technologies;

[0030] Figure 5 The invention provides a route for synthesizing 3-methoxy-4,5-methylenedioxyphenethylamine. DETAILED DESCRIPTION

[0031] The present invention provides a method for preparing 3-methoxy-4,5-methylenedioxyphenethylamine, comprising the following steps:

[0032] (1) mixing myristic aldehyde, diethyl cyanophosphate, an alkaline reagent and a solvent to perform a wittig reaction to obtain a first intermediate; the structure of the first intermediate is shown in formula ND-1;

[0033] (2) mixing the first intermediate, alcohol and a hydrogenation catalyst, and performing a reduction reaction under hydrogen conditions to obtain a second intermediate; the structural formula of the second intermediate is shown in Formula ND-2;

[0034] (3) hydrolyzing the second intermediate under alkaline conditions to obtain a third intermediate; the structural formula of the third intermediate is shown in Formula ND-3;

[0035] (4) mixing the third intermediate, an alkali reagent, sodium hypochlorite and a solvent to carry out a Hofmann reaction to obtain the 3-methoxy-4,5-methylenedioxyphenethylamine;

[0036]

[0037] In the present invention, the synthetic route of 3-methoxy-4,5-methylenedioxyphenethylamine is as follows Figure 5 shown.

[0038] The preparation method of the present invention is described in detail below.

[0039] The present invention mixes myristic aldehyde, diethyl cyanophosphate, an alkali agent and a solvent to perform a wittig reaction to obtain a first intermediate. In the present invention, the alkali agent preferably includes one or more of sodium hydride (NaH) and an alkali metal hydroxide, and the alkali metal hydroxide preferably includes sodium hydroxide and / or potassium hydroxide; the alkali agent is preferably used in the form of an alkali agent solution, the concentration of the alkali agent solution is preferably 60wt%, and the solvent is preferably water; the molar ratio of the myristic aldehyde, the alkali agent and diethyl cyanophosphate is preferably 1:0.8-2.0:0.8-2.5, more preferably 1:1-1.5:1-2; the solvent used in the wittig reaction preferably includes one or more of tetrahydrofuran, N,N-dimethylformamide, dichloromethane and 1,4-dioxane; the temperature of the wittig reaction is preferably 5-60°C, specifically 30°C, 40°C or 50°C, and the time of the wittig reaction is preferably 0.5-8h, specifically 2h, 3h, 5h or 6h. The present invention performs the Wittig reaction under the above conditions, which can promote the reaction and improve the yield of the product.

[0040] In a specific embodiment of the present invention, preferably, the solvent is first added to the reaction device, and then the alkaline reagent solution is added, and the temperature is controlled not to exceed 30°C, and diethyl cyanophosphate is added dropwise. After the addition is completed, the mixture is stirred at 30°C for 0.5 to 2 hours, preferably for 1 hour, and then cooled to 10 to 20°C, preferably to 15°C, and myristic aldehyde is added in batches. After the addition is completed, the mixture is kept warm at the temperature of the wittig reaction for reaction. After the wittig reaction is completed, the present invention preferably pours the obtained reaction system into ice water, and then extracts with ethyl acetate, and concentrates the obtained organic phase to dryness to obtain the first intermediate.

[0041] After obtaining the first intermediate, the present invention mixes the first intermediate, alcohol and a hydrogenation catalyst, and performs a reduction reaction under hydrogen conditions to obtain a second intermediate. In the present invention, the hydrogenation catalyst preferably includes one or more of a palladium catalyst and a nickel catalyst, the palladium catalyst preferably includes one or more of palladium carbon, palladium acetate and palladium hydroxide, and the palladium content in the palladium catalyst is preferably 1-15wt%, more preferably 10wt%; the nickel catalyst is preferably Raney nickel; the mass ratio of the first intermediate and the hydrogenation catalyst is preferably 1:0.01-1, specifically 1:0.03, 1:0.05, 1:0.1 or 1:0.5; the alcohol used in the reduction reaction includes one or more of methanol, ethanol and isopropanol; the temperature of the reduction reaction is preferably 10-80°C, specifically 20°C, 30°C, 50°C or 60°C, the pressure of the reduction reaction is preferably normal pressure-3MPa, specifically 0.1MPa, 0.5MPa, 1MPa or 2MPa, and the time of the reduction reaction is preferably 0.5-24h, specifically 3h, 4h, 6h or 12h. The present invention performs a reduction reaction under the above conditions, which can promote the reaction and improve the product yield.

[0042] In a specific embodiment of the present invention, it is preferred to first add the first intermediate, alcohol and hydrogenation catalyst into the hydrogenation reaction kettle, then replace the air with nitrogen, and then replace the nitrogen with hydrogen, and then react at the temperature and pressure of the reduction reaction. After the reduction reaction is completed, the present invention preferably filters the obtained reaction and concentrates the obtained filtrate to dryness to obtain the second intermediate.

[0043] After obtaining the second intermediate, the present invention hydrolyzes the second intermediate under alkaline conditions to obtain a third intermediate. In the present invention, there are two modes of the hydrolysis reaction, which are referred to as Mode 1 and Mode 2, and are described in detail below.

[0044] In the present invention, the first mode of the hydrolysis reaction preferably includes: mixing the second intermediate, the alkaline reagent, hydrogen peroxide and the solvent for hydrolysis reaction (referred to as the first hydrolysis reaction) to obtain the third intermediate. The alkaline reagent used in the first hydrolysis reaction preferably includes one or more of alkali metal carbonates and alkali metal hydroxides, the alkali metal carbonate preferably includes potassium carbonate and / or sodium carbonate, and the alkali metal hydroxide preferably includes potassium hydroxide and / or sodium hydroxide; the solvent used in the first hydrolysis reaction is preferably dimethyl sulfoxide (DMSO); the hydrogen peroxide is preferably used in the form of hydrogen peroxide, and the concentration of the hydrogen peroxide is preferably 20-40wt%, specifically 30wt%; the molar ratio of the second intermediate, the alkaline reagent and hydrogen peroxide is preferably 1:0.8-2.5:0.8-3, more preferably 1:1-1.5:1-2; the temperature of the first hydrolysis reaction is preferably 5-35°C, specifically 10°C, 20°C or 25°C, and the time of the first hydrolysis reaction is preferably 0.5-24h, specifically 3h, 4h, 6h or 12h. In the first hydrolysis reaction, the alkaline reagent makes the reaction system alkaline, and hydrogen peroxide will generate HOO under alkaline conditions. - (Its nucleophilicity is greater than HO - ), which undergoes nucleophilic addition to the nitrile to generate peroxyimidic acid, which reacts with the added DMSO to generate propionamide.

[0045] In a specific embodiment of the present invention, the second intermediate, the solvent and the alkaline reagent are preferably first added to the reaction device, and then hydrogen peroxide is added dropwise, and the reaction is carried out at the temperature of the first hydrolysis reaction. After the first hydrolysis reaction is completed, the present invention preferably pours the obtained reaction solution into ice water, stirs it, and then filters it, washes the obtained filter cake with water, and then dries it to obtain the third intermediate.

[0046] In the present invention, the second mode of the hydrolysis reaction preferably includes: mixing the second intermediate, alcohol, water and sodium hydroxide for hydrolysis reaction (recorded as the second hydrolysis reaction) to obtain the third intermediate; the alcohol used in the hydrolysis reaction preferably includes one or more of methanol, ethanol, isopropanol, n-butanol, tert-butanol and ethylene glycol; the present invention has no requirements for the mass ratio of the alcohol and water, and any mass ratio can be used. In a specific embodiment of the present invention, the mass ratio of the alcohol and water is 1:1; the molar ratio of the second intermediate and sodium hydroxide is preferably 1:0.8-3, specifically 1:1, 1:1.5 or 1:2; the temperature of the second hydrolysis reaction is preferably 10-100°C, specifically 30°C, 60°C or 70°C, and the time of the second hydrolysis reaction is preferably 0.5-24h, specifically 3h, 4h, 6h or 12h. The present invention performs the second hydrolysis reaction under the above conditions, which can promote the reaction and improve the product yield.

[0047] After the second hydrolysis reaction is completed, the present invention preferably cools the obtained reaction solution for crystallization; the temperature of the cooling and crystallization is preferably -5 to 30°C, specifically 5°C, 10°C or 15°C, and the cooling and crystallization time is preferably 0.5 to 5h, specifically 2h, 3h, 4h. After cooling and crystallization, the present invention preferably filters the obtained crystallization system, washes the obtained filter cake with water and then dries it to obtain the third intermediate. The present invention performs the above treatment after the second hydrolysis reaction, which can improve the purity of the product and reduce the water content in the product.

[0048] After obtaining the third intermediate, the present invention mixes the third intermediate, an alkali reagent, sodium hypochlorite and a solvent to perform a Hofmann reaction to obtain the 3-methoxy-4,5-methylenedioxyphenylethylamine. In the present invention, the alkali reagent used in the Hofmann reaction is preferably an alkali metal hydroxide, specifically preferably sodium hydroxide and / or potassium hydroxide; the molar ratio of the third intermediate, the alkali reagent and the sodium hypochlorite is preferably 1:2-50:1-3, more preferably 1:5-30:2.5-3; the alkali reagent is preferably used in the form of an alkali reagent aqueous solution, and the concentration of the alkali reagent aqueous solution is preferably 1-60wt%, specifically 10wt%, 20wt%, 30wt% or 50wt%; the sodium hypochlorite is preferably used in the form of a sodium hypochlorite aqueous solution, and the concentration of the sodium hypochlorite aqueous solution is preferably 2-12wt%, specifically 5wt%, 8wt% or 10wt%. The solvent used in the Hofmann reaction is preferably alcohol and / or water, and the alcohol is preferably methanol and / or ethanol; the temperature of the Hofmann reaction is preferably 0 to 90°C, specifically 10°C, 30°C, 60°C or 80°C. In a specific embodiment of the present invention, the reaction is preferably carried out under reflux conditions; the time of the Hofmann reaction is preferably 0.5 to 24h, specifically 5h, 10h, 16h or 18h. The present invention performs the Hofmann reaction under the above conditions, which can improve the yield of the product.

[0049] In the present invention, when the reaction solvent is water or a water / alcohol system, the Hofmann reaction preferably includes a first stage and a second stage, wherein the first stage includes: mixing a low-concentration alkaline reagent aqueous solution, a sodium hypochlorite aqueous solution and a third intermediate or an alcohol solution of the third intermediate, and reacting at 5 to 40° C. for 0.5 to 6 hours, preferably at 30° C. for 1 hour; the second stage includes: adding a high-concentration alkaline reagent aqueous solution to the reaction solution of the first stage, heating to reflux reaction for 1 to 12 hours, specifically 1 hour, 3 hours, 5 hours, 8 hours or 10 hours; the concentration of the low-concentration alkaline reagent aqueous solution is preferably 5 to 30wt%, specifically 10wt%, 15wt%, 20wt% or 25wt%; the concentration of the high-concentration alkaline reagent aqueous solution is preferably 40 to 70wt%, specifically 50wt%, 55wt%, 60wt% or 65wt%. Specifically, the process of mixing the low-concentration alkali reagent aqueous solution, the sodium hypochlorite aqueous solution and the third intermediate or the alcohol solution of the third intermediate in the first stage preferably includes: first adding the low-concentration alkali reagent aqueous solution to the reaction device, then dripping 10wt% sodium hypochlorite aqueous solution at 0-5°C, and then adding the third intermediate or the alcohol solution of the third intermediate in batches, controlling the system temperature not to exceed 10°C during the addition of the third intermediate or the alcohol solution of the third intermediate, and heating to 5-40°C after the addition, preferably heating to 30°C, and carrying out the first stage reaction under stirring. The present invention first adds a low-concentration alkali reagent aqueous solution to carry out the first stage reaction to generate an amide or isocyanate intermediate, and then adds a high-concentration alkali reagent aqueous solution to hydrolyze the intermediate product into the target product.

[0050] After the Hofmann reaction is completed, the present invention preferably further comprises: cooling the obtained reaction solution and extracting it with toluene, washing the obtained organic layer and concentrating it to dryness under reduced pressure to obtain the 3-methoxy-4,5-methylenedioxyphenethylamine.

[0051] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0052] Example 1 Synthesis of 3-(7-methoxybenzo[d][1,3]dioxolan-5-yl)acrylonitrile (ND-1)

[0053] Add 200g of tetrahydrofuran and 13.3g of 60wt% sodium hydride solution to the reaction bottle, control the temperature not to exceed 30°C, add 49.8g of diethyl cyanophosphate dropwise, keep stirring at 30°C for 1h after the addition, cool to 15°C, add 50g of myristic aldehyde in batches, control the temperature not to exceed 30°C, keep reacting at 30°C for 2h after the addition, pour the reaction system into 500mL of ice water, extract twice with ethyl acetate, 200g each time, combine the organic layers, and concentrate under reduced pressure to dryness to obtain 56.3g of off-white solid, which is the first intermediate ND-1, with a yield of 99.9%.

[0054] Example 2 Synthesis of 3-(7-methoxybenzo[d][1,3]dioxol-5-yl)propionitrile (ND-2)

[0055] Add 56.3g ND-1, 200g ethanol, 5.6g palladium carbon with a palladium content of 10wt% into the hydrogenation reactor, replace the air with nitrogen, replace the nitrogen with hydrogen, heat to 50°C, hydrogen pressure 0.5MPa, react for 4h, cool to room temperature, filter, and concentrate the filtrate to dryness under reduced pressure to obtain 56.8g of an off-white solid, which is the second intermediate ND-2, with a yield of 99.9%.

[0056] Example 3 Synthesis of 3-(7-methoxybenzo[d][1,3]dioxolan-5-yl)propionamide (ND-3)

[0057] Add 50g DN-2, 500g DMSO, and 40.4g potassium carbonate to a reaction bottle, and add 35.9g of 30wt% hydrogen peroxide at 20°C. After the addition is complete, stir and react at 25°C for 4h. Add the reaction solution into 1500g ice water, stir for 30min after the addition, filter with suction, wash the filter cake with water, and dry at 60°C to obtain 49.8g of an off-white solid, which is the third intermediate ND-3, with a yield of 91.5%.

[0058] The NMR spectrum of the product is Figure 1 As shown, the NMR data are as follows: 1 H-NMR(400MHz,DMSO-d6)δ:7.281(1H,s),6.781(1H,s),6.488(2H,d),3.799(3H,s),2.729(2H,t),2.334(2H,t).

[0059] Example 4 Synthesis of 3-(7-methoxybenzo[d][1,3]dioxolan-5-yl)propionamide (ND-3)

[0060] Add 100 g ethanol, 50 g ND-2, 100 g water, and 13.7 g sodium hydroxide to a reaction bottle, heat to 60°C, keep warm for 6 hours, cool to 5°C, keep warm for 2 hours to crystallize, filter with suction, wash the filter cake with water, and dry at 60°C to obtain 46.3 g of an off-white solid, which is the third intermediate ND-3, with a yield of 85.1%.

[0061] Example 5 Synthesis of 3-methoxy-4,5-methylenedioxyphenethylamine

[0062] Add 190 g of 10 wt % sodium hydroxide aqueous solution to the reaction bottle, cool to 0 ° C, add 100 g of 10 wt % sodium hypochlorite aqueous solution dropwise, control the temperature not to exceed 5 ° C, add 19 g ND-3, control the temperature not to exceed 10 ° C, raise the temperature to 30 ° C, stir and react for 1 h, add 130 g of 50 wt % sodium hydroxide aqueous solution, heat to reflux and react for 3 h, cool to room temperature, extract twice with toluene, 100 g each time, combine the organic layers, wash once with 50 g of water, and reduce the pressure on the organic layer to dryness to obtain 15.3 g of an oily substance, i.e. 3-methoxy-4,5-methylenedioxyphenethylamine, with a yield of 92.2%.

[0063] The purity test spectrum of the product is as follows Figure 2 As shown, the test results show that the liquid phase purity of 3-methoxy-4,5-methylenedioxyphenethylamine prepared in this example is 98.880%.

[0064] The NMR spectrum of the product is Figure 3 As shown, the NMR data are as follows: 1 H-NMR(400MHz,DMSO-d6)δ:6.461(2H,d),5.930(2H,s),3.810(3H,s),2.743(2H,t),2.544(2H,m),1.354(2H,s).

[0065] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing 3-methoxy-4,5-methylenedioxyphenethylamine, characterized in that: The following steps are involved: (1) mixing myristic aldehyde, diethyl cyanophosphate, an alkaline reagent and a solvent to perform a wittig reaction to obtain a first intermediate; the structure of the first intermediate is shown in formula ND-1; (2) mixing the first intermediate, alcohol and a hydrogenation catalyst, and performing a reduction reaction under hydrogen conditions to obtain a second intermediate; the structural formula of the second intermediate is shown in Formula ND-2; (3) hydrolyzing the second intermediate under alkaline conditions to obtain a third intermediate; the structural formula of the third intermediate is shown in Formula ND-3; (4) mixing the third intermediate, an alkali reagent, sodium hypochlorite and a solvent to carry out a Hofmann reaction to obtain the 3-methoxy-4,5-methylenedioxyphenethylamine; 2. The preparation method according to claim 1, characterized in that: In the step (1), the alkaline reagent comprises one or more of sodium hydride and alkali metal hydroxide; the molar ratio of myristic aldehyde, alkaline reagent and diethyl cyanophosphate is 1:0.8-2.0:0.8-2.5; The solvent used in the wittig reaction includes one or more of tetrahydrofuran, N,N-dimethylformamide, dichloromethane and 1,4-dioxane.

3. The preparation method according to claim 1 or 2, characterized in that: The temperature of the wittig reaction is 5 to 60° C., and the reaction time is 0.5 to 8 hours.

4. The preparation method according to claim 1, characterized in that: In the step (2), the hydrogenation catalyst includes one or more of a palladium-based catalyst and a nickel-based catalyst; the alcohol used in the reduction reaction includes one or more of methanol, ethanol and isopropanol; The mass ratio of the first intermediate to the hydrogenation catalyst is 1:0.01-1.

5. The preparation method according to claim 1 or 4, characterized in that: The temperature of the reduction reaction is 10-80° C., the pressure is normal pressure to 3 MPa, and the reaction time is 0.5-24 h.

6. The preparation method according to claim 1, characterized in that: In the step (3), the hydrolysis reaction comprises: mixing the second intermediate, an alkali reagent, hydrogen peroxide and a solvent for a hydrolysis reaction to obtain the third intermediate; the alkali reagent used in the hydrolysis reaction comprises one or more of an alkali metal carbonate and an alkali metal hydroxide; the solvent used in the hydrolysis reaction is dimethyl sulfoxide; the molar ratio of the second intermediate, the alkali reagent and hydrogen peroxide is 1:0.8-2.5:0.8-3; the temperature of the hydrolysis reaction is 5-35°C, and the reaction time is 0.5-24h.

7. The preparation method according to claim 1, characterized in that: In the step (3), the hydrolysis reaction comprises: mixing the second intermediate, alcohol, water and sodium hydroxide for hydrolysis reaction to obtain the third intermediate; the alcohol used in the hydrolysis reaction comprises one or more of methanol, ethanol, isopropanol, n-butanol, tert-butanol and ethylene glycol; the molar ratio of the second intermediate to sodium hydroxide is 1:0.8-3; the temperature of the hydrolysis reaction is 10-100°C, and the reaction time is 0.5-24h.

8. The preparation method according to claim 7, characterized in that: After the hydrolysis reaction is completed, the obtained reaction solution is cooled and crystallized; the temperature of the cooling and crystallization is -5 to 30°C and the time is 0.5 to 5 hours.

9. The preparation method according to claim 1, characterized in that: In the step (4), the alkaline reagent is an alkali metal hydroxide; the molar ratio of the third intermediate, the alkaline reagent and sodium hypochlorite is 1:2-50:1-3; and the solvent used in the Hofmann reaction is alcohol and / or water.

10. The preparation method according to claim 1 or 9, characterized in that: The temperature of the Hofmann reaction is 0 to 90° C., and the reaction time is 0.5 to 24 hours.

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