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. The preparation method comprises the following steps: by taking myristic aldehyde as an initial raw material, carrying out a Knoevenagel condensation reaction, a hydrogenation reaction, a decarboxylation reaction, an amidation reaction and a Hofmann reaction, so as to obtain the 3-methoxy-4, 5-methylenedioxy phenylethylamine. The preparation method provided by the invention is simple to operate, short in synthetic route and high in product yield; furthermore, conventional reagents are adopted in all the steps, the reaction conditions are mild, column chromatography purification of products in all the steps is not needed, operation is easy and convenient, and the method 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 bronchial spasmolytic antitussive drug that can relieve bronchial smooth muscle spasms and inhibit cough caused by pulmonary stretch reflex. It can also be used to treat stroke and edema.

[0003] At present, the main chemical synthesis method of Lecoping is the Bischler-Napieralski method. In the process of synthesizing Lecoping by the Bischler-Napieralski method, 3-methoxy-4,5-methylenedioxyphenethylamine is the main key intermediate. The structures of Lecoping and 3-methoxy-4,5-methylenedioxyphenethylamine are as follows:

[0004]

[0005] The relevant technology 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:

[0006]

[0007] The synthetic route of the product is relatively long, and the total yield of the product is only 19.5%. Summary of the invention

[0008] 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 simple steps and high product yield.

[0009] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0010] A method for preparing 3-methoxy-4,5-methylenedioxyphenethylamine comprises the following steps:

[0011] (1) mixing myristic aldehyde, a compound having a structure shown in Formula I, a basic catalyst and a solvent to carry out a Knoevenagel condensation reaction to obtain a first intermediate; the structure of the first intermediate is shown in Formula LK-1;

[0012] (2) mixing the first intermediate, a hydrogenation catalyst and a solvent, and performing a hydrogenation reaction under hydrogen conditions to obtain a second intermediate; the structure of the second intermediate is shown in Formula LK-2;

[0013] (3) mixing the second intermediate, an alkali reagent and a solvent to carry out a decarboxylation reaction to obtain a third intermediate; the structural formula of the third intermediate is shown in Formula LK-3;

[0014] (4) subjecting the third intermediate to an amidation reaction under the action of an amidating agent to obtain a fourth intermediate; the structural formula of the fourth intermediate is shown in Formula LK-4;

[0015] (5) mixing the fourth intermediate, an alkali reagent, sodium hypochlorite and a solvent to carry out a Hofmann reaction to obtain the 3-methoxy-4,5-methylenedioxyphenethylamine;

[0016]

[0017] In Formula I, Formula LK-1 and Formula LK-2: R is H or a C1-C2 alkyl group.

[0018] Preferably, in step (1), the alkaline catalyst comprises one or more of 1,1,3,3-tetramethylguanidine, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, piperidine, pyridine, sodium alkoxide, potassium alkoxide and alkali metal carbonate; the molar ratio of myristic aldehyde, alkaline catalyst and compound of the structure shown in formula I is 1:0.01-2:0.8-2.5;

[0019] The solvent for the Knoevenagel condensation reaction includes one or more of an alcohol solvent, an ester solvent and a benzene solvent.

[0020] Preferably, the Knoevenagel condensation reaction is carried out at a temperature of 5 to 110° C. and for a time of 2 to 24 hours.

[0021] Preferably, in step (2), the hydrogenation catalyst comprises one or more of a palladium-based catalyst, a nickel-based catalyst and a cobalt-based catalyst; the mass ratio of the first intermediate to the hydrogenation catalyst is 1:0.01-1;

[0022] The solvent used in the hydrogenation reaction includes one or more of an alcohol solvent, an ester solvent and an ether solvent;

[0023] The temperature of the hydrogenation reaction is 5 to 80° C. and the time is 1 to 24 hours.

[0024] Preferably, in step (3), the alkaline reagent comprises one or more of alkali metal carbonate, alkali metal hydroxide and barium hydroxide; the molar ratio of the second intermediate to the alkaline reagent is 1:0.5-10;

[0025] The solvent used in the decarboxylation reaction is alcohol and / or water;

[0026] The temperature of the decarboxylation reaction is 5 to 110° C., and the time is 1 to 24 hours.

[0027] 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 third intermediate; the acidifying agent for the acidification comprises one or more of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid and formic acid.

[0028] Preferably, the amidation reagent is a first amidation reagent or a second amidation reagent; the first amidation reagent includes formamide and / or urea; the second amidation reagent includes an acyl chloride reagent and an ammonia-containing reagent, and the acyl chloride reagent includes one or more of thionyl chloride, oxalyl chloride, phosphorus trichloride and phosphorus pentachloride.

[0029] Preferably, when the amidation reagent is a first amidation reagent, the amidation reaction is recorded as a first amidation reaction; the first amidation reaction comprises: mixing the third intermediate and the first amidation reagent to perform a first amidation reaction to obtain the fourth intermediate; the molar ratio of the third intermediate to the first amidation reagent is 1:1 to 50;

[0030] The first amidation reaction is carried out in the presence of a solvent or without 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.

[0031] Preferably, when the amidation reagent is a second amidation reagent, the amidation reaction is recorded as a second amidation reaction; the second amidation reaction includes: mixing the third intermediate and an acyl chlorination reagent to perform an acyl chlorination reaction to obtain an acyl chloride product, and mixing the acyl chloride product and an ammonia-containing reagent to perform an amination reaction to obtain the fourth intermediate.

[0032] Preferably, in step (5), the alkaline reagent is an alkali metal hydroxide; the molar ratio of the fourth intermediate, the alkaline reagent and sodium hypochlorite is 1:2-50:1-3; the solvent used in the Hofmann reaction is alcohol and / or water;

[0033] The temperature of the Hofmann reaction is 0 to 90° C., and the reaction time is 0.5 to 24 hours.

[0034] The present invention provides a preparation method of 3-methoxy-4,5-methylenedioxyphenethylamine. The present invention uses myristic aldehyde as a starting material, and obtains the 3-methoxy-4,5-methylenedioxyphenethylamine through Knoevenagel condensation reaction, hydrogenation reaction, decarboxylation reaction, amidation reaction and Hofmann reaction. The preparation method provided by the present invention is simple to operate, short in synthesis route, high in product yield, and the comprehensive yield can reach more than 88%, and the purity of the final product is high; further, conventional reagents are used in each step of the present invention, and the reaction conditions are mild, and the products of each step do not need to be purified by column chromatography, and the operation is simple and suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 The NMR spectrum of the third intermediate LK-3 prepared in Example 7;

[0036] Figure 2 The NMR spectrum of the fourth intermediate LK-4 prepared in Example 10;

[0037] Figure 3 HPLC chromatogram of 3-methoxy-4,5-methylenedioxyphenethylamine prepared in Example 12;

[0038] Figure 4 This is the NMR spectrum of 3-methoxy-4,5-methylenedioxyphenethylamine prepared in Example 12. DETAILED DESCRIPTION

[0039] The present invention provides a method for preparing 3-methoxy-4,5-methylenedioxyphenethylamine, comprising the following steps:

[0040] (1) mixing myristic aldehyde, a compound having a structure shown in Formula I, a basic catalyst and a solvent to carry out a Knoevenagel condensation reaction to obtain a first intermediate; the structure of the first intermediate is shown in Formula LK-1;

[0041] (2) mixing the first intermediate, a hydrogenation catalyst and a solvent, and performing a hydrogenation reaction under hydrogen conditions to obtain a second intermediate; the structure of the second intermediate is shown in Formula LK-2;

[0042] (3) mixing the second intermediate, an alkali reagent and a solvent to carry out a decarboxylation reaction to obtain a third intermediate; the structural formula of the third intermediate is shown in Formula LK-3;

[0043] (4) subjecting the third intermediate to an amidation reaction under the action of an amidating agent to obtain a fourth intermediate; the structural formula of the fourth intermediate is shown in Formula LK-4;

[0044] (5) mixing the fourth intermediate, an alkali reagent, sodium hypochlorite and a solvent to carry out a Hofmann reaction to obtain the 3-methoxy-4,5-methylenedioxyphenethylamine;

[0045]

[0046] In Formula I, Formula LK-1 and Formula LK-2: R is H or a C1-C2 alkyl group.

[0047] In the present invention, the synthesis route of the 3-methoxy-4,5-methylenedioxyphenethylamine is as follows:

[0048]

[0049] The preparation method of the present invention is described in detail below in conjunction with the above-mentioned synthetic route.

[0050] The present invention mixes myristic aldehyde, a compound of the structure shown in Formula I, an alkaline catalyst and a solvent to perform a Knoevenagel condensation reaction to obtain a first intermediate. In the present invention, the compound of the structure shown in Formula I is preferably malonic acid or a malonic ester, and the malonic ester is preferably dimethyl malonate or diethyl malonate; the alkaline catalyst preferably includes one or more of 1,1,3,3-tetramethylguanidine, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), piperidine, pyridine, sodium 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 is preferably potassium tert-butoxide, and the alkali metal carbonate preferably includes potassium carbonate and / or sodium carbonate; in the present invention, In a specific embodiment of the invention, the alkaline catalyst is preferably one or more of 1,1,3,3-tetramethylguanidine, a pyridine-piperidine composite catalyst and triethylamine, and the mass ratio of the pyridine-piperidine composite catalyst is preferably 8-12:1, specifically 10:1; the molar ratio of the myristic aldehyde, the alkaline catalyst and the compound of the structure shown in Formula I is preferably 1:0.01-2:0.8-2.5, more preferably 1:0.05-1.5:1-2, specifically 1:0.01:1, 1:0.02:2, 1:0.1:1.5 or 1:1:2.

[0051] In the present invention, the solvent for the Knoevenagel condensation reaction preferably includes one or more of an alcohol solvent, an ester solvent and a benzene solvent; the alcohol solvent preferably includes one or more of methanol, ethanol, isopropanol, n-butanol and sec-butanol; the ester solvent preferably includes ethyl acetate and / or isopropyl acetate; the benzene solvent preferably includes one or more of toluene, benzene, chlorobenzene and nitrobenzene; the mass ratio of the myristic aldehyde to the solvent is preferably 1:3-5, specifically 1:4.

[0052] In the present invention, the temperature of the Knoevenagel condensation reaction is preferably 5 to 110°C, specifically 30°C, 50°C, 55°C, 75°C, 80°C or 100°C. In a specific embodiment of the present invention, the Knoevenagel condensation reaction can also be carried out under reflux conditions; the time of the Knoevenagel condensation reaction is preferably 2 to 24h, specifically 5h, 8h, 12h, 15h or 20h. The present invention carries out the Knoevenagel condensation reaction under the above conditions, which can promote the reaction and improve the product yield.

[0053] In a specific embodiment of the present invention, when the compound of the structure shown in Formula I is a malonate, the alkaline catalyst is preferably 1,1,3,3-tetramethylguanidine or a pyridine-piperidine composite catalyst. When conducting the reaction, it is preferred to first add the solvent, myristic aldehyde, and malonate to the reaction device, and then dropwise add the alkaline catalyst under stirring conditions, and then react at the temperature of the above-mentioned Knoevenagel condensation reaction. After the reaction is completed, the present invention preferably mixes the obtained reaction solution and water and then separates the liquids, and the obtained organic layer is concentrated to dryness under reduced pressure to obtain the first intermediate.

[0054] In a specific embodiment of the present invention, when the compound of the structure shown in Formula I is malonic acid, the alkaline catalyst is preferably triethylamine. When the reaction is carried out, the solvent, myristic aldehyde, alkaline catalyst and malonic acid are preferably added to the reaction device first, and then the reaction is carried out at the temperature of the above-mentioned Knoevenagel condensation reaction. After the reaction is completed, the obtained reaction solution is preferably decompressed to remove the solvent, and then mixed with water, and a first cooling, pH adjustment, second cooling, stirring and solid-liquid separation are carried out in sequence, and the obtained filter cake is washed with water to obtain the first intermediate; the temperature of the first cooling is preferably 0 to 20°C, more preferably 10°C, the acid used to adjust the pH is preferably hydrochloric acid, the pH adjustment is preferably to adjust the pH of the mixed solution after the first cooling to 1 to 5, more preferably to 2, the temperature of the second cooling is preferably -5 to 10°C, more preferably 5°C, and the stirring time is preferably 0.5 to 5h, more preferably 2h.

[0055] After obtaining the first intermediate, the present invention mixes the first intermediate, a hydrogenation catalyst and a solvent, and performs a hydrogenation reaction under hydrogen conditions to obtain a second intermediate. In the present invention, the hydrogenation catalyst preferably includes one or more of a palladium-based catalyst, a nickel-based catalyst and a cobalt-based catalyst, and the palladium-based catalyst preferably includes one or more of palladium carbon, palladium acetate, palladium chloride and palladium hydroxide. The palladium content in the palladium-based catalyst is preferably 1 to 15 wt%, more preferably 10 wt%; the nickel-based catalyst is preferably Raney nickel; the cobalt-based catalyst is preferably Raney cobalt; the mass ratio of the first intermediate and the hydrogenation catalyst is preferably 1:0.01 to 1, specifically 1:0.03, 1:0.05, 1:0.1 or 1:0.5; the solvent used in the reduction reaction preferably includes one or more of an alcohol solvent, an ester solvent and an ether solvent; the alcohol solvent preferably includes methanol , ethanol, isopropanol, n-butanol and sec-butanol; the ester solvent preferably includes ethyl acetate and / or isopropyl acetate; the ether solvent preferably includes isopropyl ether, ethyl ether and methyl tert-butyl ether; the mass ratio of the first intermediate and the solvent is preferably 6 to 9:15; the temperature of the hydrogenation reaction is preferably 5 to 80°C, specifically 10°C, 20°C, 30°C, 50°C or 60°C, the pressure of the reduction reaction is preferably normal pressure to 5MPa, specifically 0.1MPa, 0.5MPa, 1MPa, 2MPa, 3MPa or 4MPa, and the time of the hydrogenation reaction is preferably 1 to 24h, specifically 3h, 4h, 6h, 12h, 15h or 18h. The present invention carries out the hydrogenation reaction under the above conditions, which can promote the reaction and improve the product yield.

[0056] In a specific embodiment of the present invention, it is preferred to first add the first intermediate, the solvent and the hydrogenation catalyst into the autoclave, then replace the air with nitrogen, and then replace the nitrogen with hydrogen, and then react at the temperature and pressure of the above hydrogenation reaction. After the hydrogenation reaction is completed, the present invention preferably filters the obtained reaction and concentrates the obtained filtrate to dryness to obtain the second intermediate.

[0057] After obtaining the second intermediate, the present invention mixes the second intermediate, an alkali reagent and a solvent to carry out a decarboxylation reaction to obtain a third intermediate. In the present invention, the alkaline reagent used in the decarboxylation reaction preferably includes one or more of alkali metal carbonates, alkali metal hydroxides and barium hydroxide, the alkali metal carbonates preferably include potassium carbonate and / or sodium carbonate, and the alkali metal hydroxides preferably include one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide; the molar ratio of the second intermediate to the alkaline reagent is preferably 1:0.5-10, specifically 1:2, 1:3, 1:5, 1:6 or 1:8; 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-butanol and n-butanol; the mass ratio of the second intermediate to the solvent is preferably 6-10:40-50; 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, 15h, 18h, 20h or 24h. The present invention carries out the decarboxylation reaction under the above conditions, which can promote the reaction and improve the yield of the product.

[0058] After the decarboxylation reaction is completed, the present invention preferably further comprises: post-processing the reaction liquid obtained by the decarboxylation reaction, and the post-processing preferably comprises: acidifying, crystallizing, solid-liquid separation, washing and drying the reaction liquid obtained by the decarboxylation reaction in sequence to obtain the third intermediate; the acidifying agent for acidification comprises one or more of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid and formic acid; the pH value of the acidification is preferably 2, and the acidification temperature is preferably 5°C; the crystallization temperature is preferably 5°C, and the crystallization time is preferably 1h; the washing is preferably water washing; the drying temperature is preferably 50-60°C, more preferably 55°C.

[0059] After obtaining the third intermediate, the present invention mixes the third intermediate and the amidating agent under the action of an amidating agent to carry out an amidation reaction to obtain a fourth intermediate. In the present invention, the amidating agent is preferably the first amidating agent or the second amidating agent; the first amidating agent includes formamide and / or urea; the second amidating agent includes an acyl chloride agent and an ammonia-containing agent; the acyl chloride agent preferably includes one or more of thionyl chloride, oxalyl chloride, phosphorus trichloride and phosphorus pentachloride; the ammonia-containing agent is preferably an organic solvent solution of ammonia water and / or ammonia gas, the organic solvent used in the organic solvent solution of ammonia gas preferably includes one or more of alcohol, tetrahydrofuran, acetonitrile and acetone, and the alcohol preferably includes one or more of methanol, ethanol, isopropanol, tert-butanol and n-butanol.

[0060] In the present invention, when the amidation reagent is the first amidation reagent, the amidation reaction is recorded as the first amidation reaction; the first amidation reaction preferably includes: mixing the third intermediate and the first amidation reagent for a first amidation reaction to obtain the fourth intermediate; the molar ratio of the third intermediate to the first amidation reagent is preferably 1:1 to 50, specifically 1:1, 1:2, 1:5, 1:20 or 1:30; the first amidation reaction is preferably 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 preferably includes N-methylpyrrolidone (NMP), N,N-dimethylformamide One or more of amine (DMF) and dimethyl sulfoxide (DMSO); specifically, when the first amidation reagent is urea, the first amidation reaction is preferably carried out under solvent conditions, and when the amidation reagent is formamide, the first 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 first 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 present invention carries out the first amidation reaction under the above conditions, which can promote the reaction and improve the yield of the product.

[0061] After the first amidation reaction is completed, the present invention preferably further comprises: removing the solvent or excess formamide in the reaction liquid obtained from the first 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 fourth intermediate; the cooling temperature is preferably 40 to 60° C., more preferably 50° C.; the washing is preferably carried out using a saturated sodium bicarbonate aqueous solution and water in sequence.

[0062] In the present invention, when the amidation reagent is the second amidation reagent, the amidation reaction is recorded as the second amidation reaction; the second amidation reaction comprises: mixing the third intermediate and the acyl chloride reagent for acyl chloride reaction to obtain an acyl chloride product, mixing the acyl chloride product and the ammonia-containing reagent for amination reaction to obtain the fourth intermediate; the molar ratio of ammonia in the third intermediate, the acyl chloride reagent and the ammonia-containing reagent is preferably 1:1-10:0.5-50, more preferably 1:2-6:1-40, specifically 1:1:2, 1:2:5, 1:10:20, 1:5:10 or 1:5:30; the temperature of the chlorination reaction is preferably 0-100°C, specifically 20°C, 30°C, 50°C, 60°C, 70°C or 80°C; the time of the chlorination reaction is preferably 0.5-24h, specifically 2h, 3h, 4h, 8h, 10h, 12h or 20h; the chlorination reaction is preferably carried out with or without a solvent. When carried out with a solvent, the solvent used is preferably a chlorinated alkane or a benzene solvent. The chlorinated alkane is preferably dichloromethane and / or 1,2-dichloroethane, and the benzene solvent is preferably toluene and / or benzene.

[0063] After the acyl chlorination reaction is completed, the present invention preferably further comprises: removing the solvent from the reaction solution obtained by the acyl chlorination reaction under reduced pressure, and subjecting the obtained concentrated product to an amination reaction with an ammonia-containing reagent.

[0064] In the present invention, the temperature of the amination reaction is preferably 0-20°C, specifically 3°C, 5°C, 10°C or 15°C, and the time of the amination reaction is preferably 2min-3h, specifically 10min, 30min, 1h, 1.5h or 2h; after the amination reaction, the present invention preferably extracts the obtained reaction solution with dichloromethane, and concentrates the obtained organic layer to dryness under reduced pressure to obtain the fourth intermediate.

[0065] After obtaining the fourth intermediate, the present invention mixes the fourth intermediate, an alkali reagent, sodium hypochlorite and a solvent to carry out a Hofmann reaction to obtain the 3-methoxy-4,5-methylenedioxyphenethylamine. In the present invention, the alkaline 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 fourth intermediate, the alkaline reagent and the sodium hypochlorite is preferably 1:2-50:1-3, more preferably 1:3-40:1.5-2.5, specifically 1:5:1.5, 1:2:2, 1:10:1, 1:50:1 or 1:25:2; the alkaline reagent is preferably used in the form of an alkaline reagent aqueous solution, and the concentration of the alkaline 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 promote the reaction and improve the yield of the product.

[0066] 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 0.5-6h, preferably at 30°C for 1h; the second stage includes: adding a high-concentration sodium hydroxide solution to the reaction solution of the first stage, heating to reflux reaction for 1-12h, specifically 1h, 3h, 5h, 8h or 10h; the concentration of the low-concentration alkaline 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 alkaline 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 alkaline reagent aqueous solution to the reaction device, then dripping the 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 the temperature to 5-40°C after the addition, preferably heating the temperature to 30°C, and carrying out the first stage reaction under stirring. The present invention first adds a low-concentration alkaline reagent aqueous solution to carry out the first stage reaction to generate an amide or isocyanate intermediate, and then adds a high-concentration sodium hydroxide solution to hydrolyze the intermediate product into the target product.

[0067] After the Hofmann reaction is completed, the present invention preferably cools the obtained reaction solution and extracts it with toluene, washes the obtained organic layer and concentrates it to dryness under reduced pressure to obtain the 3-methoxy-4,5-methylenedioxyphenethylamine.

[0068] 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.

[0069] Example 1 Synthesis of dimethyl 2-((7-methoxybenzo[d][1,3]dioxolan-5-yl)methylene)malonate (LK-1)

[0070] Add 200 g of toluene, 50 g of myristic aldehyde, and 45 g of dimethyl malonate to a reaction flask, add 6.4 g of 1,1,3,3-tetramethylguanidine dropwise while stirring, raise the temperature to 55°C, keep the reaction for 12 hours, cool to 25°C, add 50 g of water, stir for 30 minutes, separate the liquids, and concentrate the organic layer to dryness under reduced pressure to obtain 80.9 g of an oily substance, which is the first intermediate LK-1, with a yield of 99.0%.

[0071] Example 2 Synthesis of diethyl 2-((7-methoxybenzo[d][1,3]dioxolan-5-yl)methylene)malonate (LK-1)

[0072] Add 200g toluene, 50g myristic aldehyde, 54g diethyl malonate to the reaction bottle, heat to 50°C with stirring, and dropwise add a pre-prepared 20g toluene solution of 6.6g pyridine and 0.66g piperidine. After the addition is complete, heat to 75°C and keep the reaction for 5h. Cool to 25°C, add 50g water, stir for 30min, separate the liquids, and concentrate the organic layer to dryness under reduced pressure to obtain 89.45g of an oily substance, which is the first intermediate LK-1, with a yield of 100%.

[0073] Example 3 Synthesis of 2-((7-methoxybenzo[d][1,3]dioxol-5-yl)methylene)malonic acid (LK-1)

[0074] Add 200 g methanol, 50 g myristic aldehyde, 84.3 g triethylamine, and 37.6 g malonic acid to a reaction flask, heat to reflux reaction for 24 h, remove the solvent under reduced pressure, add 200 g water, cool to 10 ° C, adjust the pH to 2 with hydrochloric acid, cool to 5 ° C and stir for 2 h, filter with suction, wash the filter cake with appropriate amount of water to obtain 63.5 g of off-white solid, which is the first intermediate LK-1, with a yield of 85.9%.

[0075] Example 4 Synthesis of dimethyl 2-((7-methoxybenzo[d][1,3]dioxolan-5-yl)methyl)malonate (LK-2)

[0076] In a high-pressure reactor, 80.9 g of LK-1 obtained in Example 1, 150 g of ethanol, and 8 g of palladium carbon with a palladium content of 5 wt% were added. The air was replaced by nitrogen, and the nitrogen was replaced by hydrogen. The pressure was controlled at 0.5 MPa, and the reaction was carried out at 50° C. for 10 h. The temperature was lowered to 20° C., filtered, and the filtrate was decompressed to dryness to obtain 81.5 g of an oily substance, which was the second intermediate LK-2, with a yield of 100%.

[0077] Example 5 Synthesis of diethyl 2-((7-methoxybenzo[d][1,3]dioxolan-5-yl)methyl)malonate (LK-2)

[0078] In a high-pressure reactor, 89.5 g of LK-1 obtained in Example 2, 150 g of ethanol, and 9 g of palladium carbon having a palladium content of 5 wt% were added. The air was replaced by nitrogen, and the nitrogen was replaced by hydrogen. The pressure was controlled at 0.5 MPa, and the reaction was carried out at 50° C. for 10 h. The temperature was lowered to 20° C., filtered, and the filtrate was decompressed to dryness to obtain 90.1 g of an oily substance, which was the second intermediate LK-2, with a yield of 100%.

[0079] Example 6 Synthesis of 2-((7-methoxybenzo[d][1,3]dioxolan-5-yl)methyl)malonic acid (LK-2)

[0080] In a high-pressure reactor, 60 g of LK-1 obtained in Example 3, 150 g of methanol, and 6 g of palladium carbon with a palladium content of 5 wt% were added. The air was replaced by nitrogen, and the nitrogen was replaced by hydrogen. The pressure was controlled at 0.5 MPa, and the reaction was carried out at 50° C. for 10 h. The temperature was lowered to 20° C., filtered, and the filtrate was decompressed to dryness to obtain 60.5 g of solid, which was the second intermediate LK-2, with a yield of 100%.

[0081] Example 7 Synthesis of 3-(7-methoxybenzo[d][1,3]dioxolan-5-yl)propanoic acid (LK-3)

[0082] Add 81.5 g of LK-2 (prepared in Example 4), 50 g of sodium hydroxide, and 500 g of water into 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 57.9 g of an off-white solid, which is the third intermediate LK-3, with a yield of 93.8%.

[0083] The NMR spectrum of the product is Figure 1 As shown, the NMR data are as follows: 1 H-NMR(400MHz,DMSO-d6)δ:12.137(1H,s),6.513(2H,d),5.933(2H,s),3.803(3H,s),2.751(2H,t),2.516(2H,t).

[0084] Example 8 Synthesis of 3-(7-methoxybenzo[d][1,3]dioxolan-5-yl)propanoic acid (LK-3)

[0085] Add 90.1 g LK-2 (prepared in Example 5), 50 g sodium hydroxide, and 500 g water into 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 60 g of an off-white solid, which is the third intermediate LK-3, with a yield of 96.3%.

[0086] Example 9 Synthesis of 3-(7-methoxybenzo[d][1,3]dioxolan-5-yl)propanoic acid (LK-3)

[0087] Add 60 g of LK-2 (prepared in Example 6), 41 g of sodium hydroxide, and 450 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 47.6 g of an off-white solid, which is the third intermediate LK-3, with a yield of 94.8%.

[0088] Example 10 Synthesis of 3-(7-methoxybenzo[d][1,3]dioxolan-5-yl)propionamide (LK-4)

[0089] 50 g of LK-3 (prepared in Example 7) and 150 g of formamide were added to a 500 ml reaction bottle, heated to 180° C., kept warm for 6 h, the solvent was removed under reduced pressure, the temperature was lowered to 50° C., 150 g of toluene was added, and the mixture was washed once with 50 g of saturated sodium bicarbonate aqueous solution and once with 50 g of water. The organic layer was concentrated under reduced pressure to dryness to obtain 45.6 g of an off-white solid, which was the fourth intermediate LK-4, with a yield of 91.6%.

[0090] The NMR spectrum of the product is Figure 2 As shown, the NMR data are as follows: 1 H-NMR(400MHz,DMSO-d6)δ:7.270(1H,s),6.765(1H,s),6.488(2H,d),3.804(3H,s),2.736(2H,t),2.342(2H,t).

[0091] Example 11 Synthesis of 3-(7-methoxybenzo[d][1,3]dioxolan-5-yl)propionamide (LK-4)

[0092] Add 50g LK-3 (prepared in Example 8) and 53.1g thionyl chloride to a reaction flask, heat to 70°C, keep warm for 4h, remove the solvent under reduced pressure, slowly add the concentrated product to 100g ammonia water pre-cooled to 0°C, react at 5°C for 1h after the addition, extract twice with dichloromethane, 100g each time, and concentrate the organic layer to dryness under reduced pressure to obtain 49.5g of an off-white solid, which is the fourth intermediate LK-4, with a yield of 99.4%.

[0093] Example 12 Synthesis of 3-methoxy-4,5-methylenedioxyphenethylamine

[0094] 450 g of 10 wt % sodium hydroxide aqueous solution was added to the reaction flask, the temperature was lowered to 0°C, 237 g of 10 wt % sodium hypochlorite aqueous solution was added dropwise, the temperature was controlled not to exceed 5°C, 45 g of LK-4 (prepared in Example 10) was added, the temperature was controlled not to exceed 10°C, the temperature was raised to 30°C after the addition, the reaction was stirred for 1 h, 308 g of 50 wt % sodium hydroxide aqueous solution was added, the temperature was raised to reflux for 3 h, the temperature was lowered to room temperature, and toluene was extracted twice, 230 g each time, the organic layers were combined and washed once with 115 g of water, and the organic layer was decompressed to dryness to obtain 36.5 g of an oily substance, i.e. 3-methoxy-4,5-methylenedioxyphenethylamine, with a yield of 92.8%.

[0095] The purity test spectrum of the product is as follows Figure 3 As shown, the test results show that the liquid phase purity of 3-methoxy-4,5-methylenedioxyphenethylamine prepared in this example is 99.540%.

[0096] The NMR spectrum of the product is Figure 4 As shown, the NMR data are as follows: 1 H-NMR(400MHz,DMSO-d6)δ:6.460(2H,d),5.931(2H,s),3.809(3H,s),2.742(2H,t),2.543(2H,m),1.353(2H,s).

[0097] 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, a compound having a structure shown in Formula I, a basic catalyst and a solvent to carry out a Knoevenagel condensation reaction to obtain a first intermediate; the structure of the first intermediate is shown in Formula LK-1; (2) mixing the first intermediate, a hydrogenation catalyst and a solvent, and performing a hydrogenation reaction under hydrogen conditions to obtain a second intermediate; the structure of the second intermediate is shown in Formula LK-2; (3) mixing the second intermediate, an alkali reagent and a solvent to carry out a decarboxylation reaction to obtain a third intermediate; the structural formula of the third intermediate is shown in Formula LK-3; (4) subjecting the third intermediate to an amidation reaction under the action of an amidating agent to obtain a fourth intermediate; the structural formula of the fourth intermediate is shown in Formula LK-4; (5) mixing the fourth 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, Formula LK-1 and Formula LK-2: R is H or a C1-C2 alkyl group.

2. The preparation method according to claim 1, characterized in that: In the step (1), the alkaline catalyst comprises one or more of 1,1,3,3-tetramethylguanidine, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, piperidine, pyridine, sodium alkoxide, potassium alkoxide and alkali metal carbonate; the molar ratio of the myristic aldehyde, the alkaline catalyst and the compound of the structure shown in formula I is 1:0.01-2:0.8-2.5; The solvent for the Knoevenagel condensation reaction includes one or more of an alcohol solvent, an ester solvent and a benzene solvent.

3. The preparation method according to claim 1 or 2, characterized in that: The Knoevenagel condensation reaction is carried out at a temperature of 5 to 110° C. and for a time of 2 to 24 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, a nickel-based catalyst and a cobalt-based catalyst; the mass ratio of the first intermediate to the hydrogenation catalyst is 1:0.01-1; The solvent used in the hydrogenation reaction includes one or more of an alcohol solvent, an ester solvent and an ether solvent; The temperature of the hydrogenation reaction is 5 to 80° C. and the time is 1 to 24 hours.

5. The preparation method according to claim 1, characterized in that: In the step (3), the alkaline reagent includes one or more of alkali metal carbonate, alkali metal hydroxide and barium hydroxide; the molar ratio of the second intermediate to the alkaline reagent is 1:0.5-10; The solvent used in the decarboxylation reaction is alcohol and / or water; The temperature of the decarboxylation reaction is 5 to 110° C., and the time is 1 to 24 hours.

6. The preparation method according to claim 1 or 5, 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 third intermediate; the acidifying agent for acidification includes one or more of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid and formic acid.

7. The preparation method according to claim 1, characterized in that: The amidation reagent is a first amidation reagent or a second amidation reagent; the first amidation reagent includes formamide and / or urea; the second amidation reagent includes an acyl chloride reagent and an ammonia-containing reagent, and the acyl chloride reagent includes one or more of thionyl chloride, oxalyl chloride, phosphorus trichloride and phosphorus pentachloride.

8. The preparation method according to claim 7, characterized in that: When the amidation reagent is the first amidation reagent, the amidation reaction is recorded as the first amidation reaction; the first amidation reaction comprises: mixing the third intermediate and the first amidation reagent to perform a first amidation reaction to obtain the fourth intermediate; the molar ratio of the third intermediate to the first amidation reagent is 1:1 to 50; The first amidation reaction is carried out in the presence of a solvent or without 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.

9. The preparation method according to claim 7, characterized in that: When the amidation reagent is the second amidation reagent, the amidation reaction is recorded as the second amidation reaction; the second amidation reaction includes: mixing the third intermediate and the acyl chlorination reagent to perform an acyl chlorination reaction to obtain an acyl chloride product, and mixing the acyl chloride product and an ammonia-containing reagent to perform an amination reaction to obtain the fourth intermediate.

10. The preparation method according to claim 1, characterized in that: In the step (5), the alkaline reagent is an alkali metal hydroxide; the molar ratio of the fourth intermediate, the alkaline reagent and sodium hypochlorite is 1:2-50:1-3; the solvent used in the Hofmann reaction is alcohol and / or water; 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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