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

Abstract

The invention relates to the technical field of organic synthesis, and provides a synthesis method of 3-methoxy-4, 5-methylenedioxy phenylethylamine. According to the invention, 6-(chloromethyl)-4-methoxybenzo [d] [1, 3] dioxane is used as an initial raw material, and the 3-methoxy-4, 5-methylenedioxy phenylethylamine is obtained through a nucleophilic reaction, a decarboxylation reaction, an amidation reaction and a Hofmann reaction. The synthesis method provided by the invention is simple to operate, the product yield is high, the total yield reaches 78.9-81.8%, flammable and explosive chemicals are not needed, and the safety is good; furthermore, the synthesis method provided by the invention is mild in reaction conditions, does not need column chromatography purification of the product 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 synthesizing 3-methoxy-4,5-methylenedioxyphenethylamine. Background Art

[0002] Lekeping is a classic antitussive drug that can inhibit lung stretch reflex, relieve bronchial smooth muscle spasm, and has a good antitussive effect; Lekeping can also be used to treat stroke and edema. At present, the chemical synthesis method of Lekeping is mainly the Bischler-Napieralski method. In the process of synthesizing Lekeping by the Bischler-Napieralski method, 3-methoxy-4,5-methylenedioxyphenethylamine is the main key intermediate. The structures of Lekeping and 3-methoxy-4,5-methylenedioxyphenethylamine are as follows:

[0003]

[0004] The related art reports that vanillin is used as the starting material, and the target compound is obtained through bromination, hydroxylation, cyclization, Henry reaction and reduction. The route is as follows:

[0005]

[0006] This route uses vanillin as the starting material and obtains the target product through a five-step reaction, but the total yield is only 13.4%. The process also requires the use of explosive nitromethane and flammable lithium aluminum hydride, which is very dangerous. Summary of the invention

[0007] In view of this, the present invention provides a method for synthesizing 3-methoxy-4,5-methylenedioxyphenylethylamine. The synthetic method provided by the present invention has simple steps, high product yield and good safety.

[0008] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0009] A method for synthesizing 3-methoxy-4,5-methylenedioxyphenethylamine comprises the following steps:

[0010] (1) mixing 6-(chloromethyl)-4-methoxybenzo[d][1,3]dioxane, a compound of the structure shown in Formula I, an alkaline reagent and a solvent for a nucleophilic reaction to obtain a first intermediate; the structural formula of the first intermediate is shown in Formula XA-1;

[0011] (2) mixing the first intermediate, an alkali reagent and a solvent to carry out a decarboxylation reaction to obtain a second intermediate; the structural formula of the second intermediate is shown in Formula XA-2;

[0012] (3) mixing the second intermediate and an amidation agent to carry out an amidation reaction to obtain a third intermediate; the third intermediate has a structural formula as shown in Formula XA-3;

[0013] (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;

[0014]

[0015] In Formula I and Formula XA-1, R is H or a C1-C5 alkyl group.

[0016] Preferably, in step (1), the alkaline reagent comprises one or more of sodium alcoholate, potassium alcoholate and alkali metal carbonate; the molar ratio of 6-(chloromethyl)-4-methoxybenzo[d][1,3]dioxane, the alkaline reagent and the compound of the structure shown in formula I is 1:0.8-2.0:0.8-2.5;

[0017] The solvent used in the nucleophilic reaction includes one or more of alcohol, toluene, N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran and N-methylpyrrolidone.

[0018] Preferably, the temperature of the nucleophilic reaction is 5 to 80° C., and the time is 0.5 to 12 h.

[0019] Preferably, in step (2), the alkaline reagent comprises one or more of alkali metal carbonate, alkali metal hydroxide and barium hydroxide; the molar ratio of the first intermediate to the alkaline reagent is 1:0.5-10;

[0020] The solvent used in the decarboxylation reaction is alcohol and / or water.

[0021] Preferably, the decarboxylation reaction is carried out at a temperature of 5 to 110° C. and for a time of 1 to 24 hours.

[0022] Preferably, after the decarboxylation reaction is completed, the method further comprises post-processing the obtained reaction liquid, wherein the post-processing comprises: sequentially acidifying, crystallizing, solid-liquid separation, washing and drying the reaction liquid obtained by the decarboxylation reaction to obtain the second intermediate; the acidifying agent for the acidification comprises one or more of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid and formic acid.

[0023] Preferably, in step (3), the amidation reagent comprises formamide and / or urea; the molar ratio of the second intermediate to the amidation reagent is 1:1 to 50;

[0024] The amidation reaction is carried out in the presence of a solvent or in the absence of a solvent. When carried out in the presence of a solvent, the solvent used includes one or more of N-methylpyrrolidone, N,N-dimethylformamide and dimethyl sulfoxide.

[0025] Preferably, the amidation reaction is carried out at a temperature of 90 to 210° C. and for a time of 1 to 12 hours.

[0026] 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.

[0027] Preferably, the temperature of the Hofmann reaction is 0 to 90° C., and the reaction time is 0.5 to 24 h.

[0028] The present invention provides a method for synthesizing 3-methoxy-4,5-methylenedioxyphenylethylamine. The present invention uses 6-(chloromethyl)-4-methoxybenzo[d][1,3]dioxane as a starting material, and obtains the 3-methoxy-4,5-methylenedioxyphenylethylamine through nucleophilic reaction, decarboxylation reaction, amidation reaction and Hofmann reaction. The synthesis method provided by the present invention is simple to operate, has a high product yield, and the total yield reaches 78.9-81.8%. The purity of the final product is high, and no flammable and explosive chemicals are required, so the product has good safety and is suitable for industrial production. Furthermore, the synthesis method provided by the present invention has mild reaction conditions, and the products of each step do not need to be purified by column chromatography, so the product is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 The NMR spectrum of the second intermediate XA-2 prepared in Example 3;

[0030] Figure 2 HPLC chromatogram of 3-methoxy-4,5-methylenedioxyphenethylamine prepared in Example 6;

[0031] Figure 3 This is the NMR spectrum of 3-methoxy-4,5-methylenedioxyphenethylamine prepared in Example 6. DETAILED DESCRIPTION

[0032] The present invention provides a method for synthesizing 3-methoxy-4,5-methylenedioxyphenethylamine, comprising the following steps:

[0033] (1) mixing 6-(chloromethyl)-4-methoxybenzo[d][1,3]dioxane, a compound of the structure shown in Formula I, an alkaline reagent and a solvent for a nucleophilic reaction to obtain a first intermediate; the structural formula of the first intermediate is shown in Formula XA-1;

[0034] (2) mixing the first intermediate, an alkali reagent and a solvent to carry out a decarboxylation reaction to obtain a second intermediate; the structural formula of the second intermediate is shown in Formula XA-2;

[0035] (3) mixing the second intermediate and an amidation agent to carry out an amidation reaction to obtain a third intermediate; the third intermediate has a structural formula as shown in Formula XA-3;

[0036] (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;

[0037]

[0038] In Formula I and Formula XA-1, R is H or a C1-C5 alkyl group.

[0039] In the present invention, the synthesis route of the 3-methoxy-4,5-methylenedioxyphenethylamine is as follows:

[0040]

[0041] The synthesis method of the present invention is described in detail below.

[0042] The present invention mixes 6-(chloromethyl)-4-methoxybenzo[d][1,3]dioxane, a compound of the structure shown in Formula I, an alkali agent and a solvent for a nucleophilic reaction to obtain a first intermediate. In the present invention, the compound of the structure shown in Formula I preferably includes one or more of malonic acid, dimethyl malonate, diethyl malonate, dipropyl malonate, dibutyl malonate and dipentyl malonate; the alkali agent used in the nucleophilic reaction preferably includes one or more of sodium alcoholate, potassium alcoholate and alkali metal carbonate, the sodium alcoholate preferably includes one or more of sodium methoxide, sodium ethoxide and sodium tert-butoxide, the potassium alcoholate preferably includes one or more of potassium methoxide, potassium ethoxide and potassium tert-butoxide, and the alkali metal carbonate preferably includes potassium carbonate and / or sodium carbonate; the 6-(chloromethyl)-4-methoxybenzo[d][ The molar ratio of 1,3]dioxane, the base reagent and the compound of the structure shown in Formula I is preferably 1:0.8-2.0:0.8-2.5, more preferably 1:1-1.5:1-2; the solvent used in the nucleophilic reaction preferably includes one or more of alcohol, toluene, DMF, 1,4-dioxane, tetrahydrofuran and NMP, and the alcohol preferably includes one or more of methanol, ethanol, isopropanol, tert-butanol and n-butanol; the mass ratio of 6-(chloromethyl)-4-methoxybenzo[d][1,3]dioxane and the solvent is preferably 1:30-50, more preferably 1:40. In the present invention, the temperature of the nucleophilic reaction is preferably 5-80°C, specifically 30°C, 40°C, 50°C, 60°C, 70°C or 75°C, and the time of the nucleophilic reaction is preferably 0.5-12h, specifically 1h, 3h, 5h or 10h. The present invention performs nucleophilic reaction under the above conditions, which can promote the reaction and improve the yield of the product.

[0043] In a specific embodiment of the present invention, preferably, a solvent, an alkali reagent, and a compound of the structure shown in Formula I are first added to a reaction device, the temperature is raised to 30 to 100° C. and stirred for 0.5 to 3 hours, preferably the temperature is raised to 60° C. and kept for 1 hour, and then 6-(chloromethyl)-4-methoxybenzo[d][1,3]dioxane is added in batches, and then the reaction is carried out at the above-mentioned nucleophilic reaction temperature.

[0044] After the nucleophilic reaction is completed, the present invention preferably further comprises: pouring the reaction solution obtained from the nucleophilic reaction into ice water, extracting with ethyl acetate, and concentrating the obtained organic phase under reduced pressure to dryness to obtain the first intermediate.

[0045] After obtaining the first intermediate, the present invention mixes the first intermediate, the alkali reagent and the solvent for decarboxylation reaction to obtain the second intermediate. In the present invention, the alkali reagent used in the decarboxylation reaction preferably includes one or more of alkali metal carbonates, alkali metal hydroxides and barium hydroxide, the alkali metal carbonate preferably includes potassium carbonate and / or sodium carbonate, and the alkali metal hydroxide preferably includes one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide; the molar ratio of the first intermediate and the alkali reagent is preferably 1:0.5-10, specifically 1:2, 1:3, 1:5 or 1:6; the solvent used in the decarboxylation reaction is preferably alcohol and / or water, and the alcohol preferably includes one or more of methanol, ethanol, isopropanol, tert-butyl alcohol and n-butyl alcohol; the mass ratio of the first intermediate and the solvent is preferably 7-8:50; the temperature of the decarboxylation reaction is preferably 5-110°C, specifically 20°C, 40°C, 50°C, 60°C, 70°C or 100°C, and the time of the decarboxylation reaction is preferably 1-24h, specifically 3h, 5h, 12h or 15h. The present invention carries out the decarboxylation reaction under the above conditions, which can promote the reaction and improve the yield of the product.

[0046] After the decarboxylation reaction is completed, the present invention preferably further comprises: acidifying, crystallizing, solid-liquid separation, washing and drying the reaction solution obtained by the decarboxylation reaction in sequence to obtain the second intermediate; the acidifying agent for the acidification preferably comprises one or more of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid and formic acid; the pH value of the acidification is preferably 1 to 5, more preferably 2, the acidification temperature is preferably -5 to 10°C, more preferably 5°C; the crystallization temperature is preferably 0.5 to 5°C, more preferably 5°C, the crystallization time is preferably 0.5 to 3h, more preferably 1h; the washing is preferably water washing; the drying temperature is preferably 50 to 60°C, more preferably 55°C.

[0047] After obtaining the second intermediate, the present invention mixes the second intermediate and an amidation agent to perform an amidation reaction to obtain a third intermediate. In the present invention, the amidation agent preferably includes formamide and / or urea; the molar ratio of the second intermediate to the amidation agent is preferably 1:1 to 50, specifically 1:1, 1:2, 1:5, 1:20 or 1:30; the amidation reaction can be carried out in the presence of a solvent or in the absence of a solvent. When carried out in the presence of a solvent, the solvent used preferably includes one or more of N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO); specifically, when When the amidation reagent is urea, the amidation reaction is preferably carried out under solvent conditions; when the amidation reagent is formamide, the amidation reaction is preferably carried out under solvent-free conditions, in which case the formamide acts as a solvent in addition to being a reactant; the temperature of the amidation reaction is preferably 90 to 210°C, specifically 100°C, 120°C, 150°C, 180°C or 200°C, and the time of the amidation reaction is preferably 1 to 12h, specifically 1h, 2h, 5h, 6h or 10h. The amidation reaction of the present invention under the above conditions can promote the reaction and improve the yield of the product.

[0048] After the amidation reaction is completed, the present invention preferably further comprises: removing the solvent or excess formamide in the reaction solution obtained by the amidation reaction, then cooling, mixing the cooled liquid with toluene, then washing and stratifying, and concentrating the obtained organic layer under reduced pressure to dryness to obtain the third intermediate; the cooling temperature is preferably 40 to 60° C., more preferably 50° C.; the washing is preferably carried out by washing with a saturated sodium bicarbonate aqueous solution and water in sequence.

[0049] 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 1:3-40:1.5-2.5, and further preferably 1:5-35:1.5-2; 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 Hofmann 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 promote the reaction and improve the yield of the product.

[0050] In the present invention, the reaction solvent is water or a water / alcohol system, and the Hofmann reaction preferably includes a first stage and a second stage. 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 5-40° C. for 0.5-6 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 1-12 hours, specifically 1 hour, 3 hours, 5 hours, 8 hours or 10 hours; the concentration of the low-concentration hydrogen alkali reagent aqueous solution is preferably 5-30wt%, specifically 10wt%, 15wt%, 20wt% or 25wt%; the concentration of the high-concentration alkaline reagent aqueous solution is preferably 40-70wt%, 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 to not 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.

[0051] After the Hofmann reaction is completed, the present invention preferably further comprises: cooling the reaction solution obtained by the Hofmann reaction 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.

[0052] 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.

[0053] Example 1 Synthesis of dimethyl 2-((7-methoxybenzo[d][1,3]dioxolan-5-yl)methyl)malonate (XA-1)

[0054] Add 200 g of ethanol, 20.4 g of sodium ethoxide, and 39.5 g of dimethyl malonate to a reaction flask. After the addition is complete, heat the mixture to 60°C and stir for 1 h. Add 50 g of 6-(chloromethyl)-4-methoxybenzo[d][1,3]dioxane in batches. After the addition is complete, heat the mixture to 75°C and react for 10 h. Then cool the mixture to 25°C and pour the reaction solution into 600 g of ice water. Extract the mixture with ethyl acetate three times, 200 g each time. Concentrate the organic layer under reduced pressure to dryness to obtain 73.86 g of an oily substance, which is the first intermediate XA-1 with a yield of 99.8%.

[0055] Example 2 Synthesis of diethyl 2-((7-methoxybenzo[d][1,3]dioxolan-5-yl)methyl)malonate (XA-1)

[0056] Add 200 g of ethanol, 20.4 g of sodium ethoxide, and 48.1 g of diethyl malonate to a reaction flask. After the addition is complete, heat the mixture to 60°C and stir for 1 h. Add 50 g of 6-(chloromethyl)-4-methoxybenzo[d][1,3]dioxane in batches. After the addition is complete, heat the mixture to 75°C and react for 10 h. Then cool the mixture to 25°C and pour the reaction solution into 600 g of ice water. Extract the mixture with ethyl acetate three times, 200 g each time. Concentrate the organic layer under reduced pressure to dryness to obtain 81.0 g of an oily substance, which is the first intermediate XA-1, with a yield of 100%.

[0057] Example 3 Synthesis of 3-(7-methoxybenzo[d][1,3]dioxolan-5-yl)propanoic acid (XA-2)

[0058] Add 73.9 g of XA-1 (prepared in Example 1), 45 g of sodium hydroxide, and 500 g of water to a reaction bottle, heat to 100° C., keep warm for 12 h, cool to 5° C., adjust the pH to 2 with hydrochloric acid, keep warm at 5° C. for 1 h to crystallize, filter, wash with water, and dry at 55° C. to obtain 52.3 g of an off-white solid, which is the second intermediate XA-2, with a yield of 93.6%.

[0059] The NMR spectrum of the product is Figure 1 As shown, the NMR data are as follows: 1 H-NMR(400MHz,DMSO-d6)δ:12.140(1H,s),6.515(2H,d),5.935(2H,s),3.805(3H,s),2.753(2H,t),2.517(2H,t).

[0060] Example 4 Synthesis of 3-(7-methoxybenzo[d][1,3]dioxolan-5-yl)propanoic acid (XA-2)

[0061] Add 81.0 g of XA-1 (prepared in Example 2), 45 g of sodium hydroxide, and 500 g of water to a reaction bottle, heat to 100° C., keep warm for 12 h, cool to 5° C., adjust the pH to 2 with hydrochloric acid, keep warm at 5° C. for 1 h to crystallize, filter, wash with water, and dry at 55° C. to obtain 54.1 g of an off-white solid, which is the second intermediate XA-2, with a yield of 96.8%.

[0062] Example 5 Synthesis of 3-(7-methoxybenzo[d][1,3]dioxolan-5-yl)propionamide (XA-3)

[0063] Add 50g XA-2 and 150g formamide to the reaction bottle, heat to 180°C, keep the reaction warm for 6h, remove excess formamide under reduced pressure, cool to 50°C, add 150g toluene, wash once with 50g saturated sodium bicarbonate aqueous solution and once with 50g water, and concentrate the organic layer under reduced pressure to dryness to obtain 45.6g of off-white solid, which is the third intermediate XA-3, with a yield of 91.6%.

[0064] Example 6 Synthesis of 3-methoxy-4,5-methylenedioxyphenethylamine

[0065] Add 200 g of 10% sodium hydroxide aqueous solution to the reaction bottle, cool to 0°C, add 105.3 g of 10% sodium hypochlorite aqueous solution dropwise, control the temperature not to exceed 5°C, add 20 g of 3-(7-methoxybenzo[d][1,3]dioxolane-5-yl)propionamide, control the temperature not to exceed 10°C, raise the temperature to 30°C after the addition, stir and react for 1 h, add 137 g of 50% sodium hydroxide aqueous solution, raise the temperature 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 16.3 g of an oily substance, i.e. 3-methoxy-4,5-methylenedioxyphenethylamine, with a yield of 93.2%.

[0066] 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 99.279%.

[0067] The NMR spectrum of the product is Figure 3 As shown, the NMR data are as follows: 1 H-NMR(400MHz,DMSO-d6)δ:6.465(2H,d),5.933(2H,s),3.814(3H,s),2.745(2H,t),2.547(2H,m),1.357(2H,s).

[0068] 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 synthesizing 3-methoxy-4,5-methylenedioxyphenethylamine, characterized in that: The following steps are involved: (1) mixing 6-(chloromethyl)-4-methoxybenzo[d][1,3]dioxane, a compound of the structure shown in Formula I, an alkaline reagent and a solvent for a nucleophilic reaction to obtain a first intermediate; the structural formula of the first intermediate is shown in Formula XA-1; (2) mixing the first intermediate, an alkali reagent and a solvent to carry out a decarboxylation reaction to obtain a second intermediate; the structural formula of the second intermediate is shown in Formula XA-2; (3) mixing the second intermediate and an amidation agent to carry out an amidation reaction to obtain a third intermediate; the third intermediate has a structural formula as shown in Formula XA-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; In Formula I and Formula XA-1, R is H or a C1-C5 alkyl group.

2. The synthesis method according to claim 1, characterized in that In the step (1), the alkaline reagent comprises one or more of sodium alcoholate, potassium alcoholate and alkali metal carbonate; the molar ratio of the 6-(chloromethyl)-4-methoxybenzo[d][1,3]dioxane, the alkaline reagent and the compound of the structure shown in formula I is 1:0.8-2.0:0.8-2.5; The solvent used in the nucleophilic reaction includes one or more of alcohol, toluene, N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran and N-methylpyrrolidone.

3. The synthesis method according to claim 1 or 2, characterized in that The temperature of the nucleophilic reaction is 5 to 80° C., and the time is 0.5 to 12 hours.

4. The synthesis method according to claim 1, characterized in that In the step (2), the alkaline reagent includes one or more of alkali metal carbonate, alkali metal hydroxide and barium hydroxide; the molar ratio of the first intermediate to the alkaline reagent is 1:0.5-10; The solvent used in the decarboxylation reaction is alcohol and / or water.

5. The synthesis method according to claim 1 or 4, characterized in that: The temperature of the decarboxylation reaction is 5 to 110° C., and the time is 1 to 24 hours.

6. The synthesis method according to claim 1 or 4, characterized in that: After the decarboxylation reaction is completed, the obtained reaction liquid is subjected to post-treatment, and the post-treatment includes: acidifying, crystallizing, solid-liquid separation, washing and drying the reaction liquid obtained by the decarboxylation reaction in sequence to obtain the second intermediate; the acidifying agent for acidification includes one or more of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid and formic acid.

7. The synthesis method according to claim 1, characterized in that In the step (3), the amidation reagent includes formamide and / or urea; the molar ratio of the second intermediate to the amidation reagent is 1:1 to 50; The amidation reaction is carried out in the presence of a solvent or in the absence of a solvent. When carried out in the presence of a solvent, the solvent used includes one or more of N-methylpyrrolidone, N,N-dimethylformamide and dimethyl sulfoxide.

8. The synthesis method according to claim 1 or 7, characterized in that: The temperature of the amidation reaction is 90-210° C. and the time is 1-12 hours.

9. The synthesis 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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