Preparation method and use of aromatic benzo[c]phenanthridine alkaloid intermediate compound

Abstract

The present invention relates to the field of pharmaceutical synthesis, and discloses a preparation method and use of an aromatic benzo[c]phenanthridine alkaloid intermediate compound. The method of the present invention uses 1,2-methylenedioxybenzene (piperonyl ring) as a starting material, and replaces the controlled compound piperonal to synthesize an aromatic benzo[c]phenanthridine alkaloid intermediate compound (6,7-methylenedioxy-1-naphthylamine and N-methyl-6,7-(methylenedioxy)-1-naphthylamine), which has the advantages of easy availability of raw materials, short steps, mild reaction conditions, low production cost, environmental protection, high yield, and high purity. In addition, the synthesis of N-methyl-6,7-(methylenedioxy)-1-naphthylamine no longer passes through the 6,7-methylenedioxy-1-naphthylamine intermediate, and does not require column chromatography purification, which is more convenient.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical synthesis, and in particular to a preparation method and application of an aromatic benzo[c]phenanthridine alkaloid intermediate compound. Background Art

[0002] Aromatic benzo[c]phenanthridine alkaloids are alkaloid components in many traditional Chinese medicines. They have antiviral, antimalarial, antifungal and antitumor effects and have been widely studied and researched, such as sanguinarine (SA), chelerythrine (CHE), and nitidine chloride (NC).

[0003]

[0004] The benzo[c]phenanthridine skeleton is mainly composed of phenanthridine rings (A, B, C rings) and a benzene ring (D ring). The synthesis method can be classified by the order of ring construction, that is, the synthesis method is classified according to which ring is formed in the last step of the structure. According to existing literature, the construction of B ring or C ring in the last step is the most commonly used method in the synthesis of this type of compound.

[0005]

[0006] Among them, 6,7-methylenedioxy-1-naphthylamine (Compound I) is a key intermediate for constructing the B ring of benzo[c]phenanthridine skeletons such as sanguinarine, chelerythrine, and nitidine chloride.

[0007]

[0008] Compound I

[0009] Compound I can be prepared from piperonal (compound A1) as a starting material, through three steps of Wittg olefination (3-bromopropionic acid triphenylphosphine salt in THF / DMSO solvent system, NaH initiation, 20h; hydrochloric acid quenching, ethyl acetate extraction), catalytic hydrogenation (0.2eqPd / C, methanol solvent, diatomaceous earth filtration and vacuum concentration), FC acylation (PPA, dichloromethane solvent, reflux 4h, saturated sodium bicarbonate solution quenching, vacuum concentration) and column chromatography to prepare an α-tetralone intermediate (intermediate compound II) with a yield of 66%; and then through three steps of ketoximylation, phenylmethylsulfonylation and Semmler-Wolff aromatization and column chromatography to prepare an α-tetralone intermediate (intermediate compound II) with a yield of 50%. The route is shown below.

[0010]

[0011] De, Subhadip, et al. "Expeditious approach to pyrrolophenanthridones, phenanthridines, and benzo[c]phenanthridines via organocatalytic directbiaryl-coupling promoted by potassium tert-butoxide." The Journal of organicchemistry 78.16 (2013): 7823-7844

[0012] On the other hand, N-methyl-6,7-(methylenedioxy)-1-naphthylamine is also a key intermediate for constructing the B ring of benzo[c]phenanthridine skeletons such as sanguinarine, chelerythrine, and nitidine chloride.

[0013]

[0014] Subhadip De et al. (JOC 2013) used piperonal as the starting material and prepared α-tetralone intermediate compound (compound 13d in the literature) through three steps of Wittg olefination, catalytic hydrogenation and FC acylation, and then column chromatography, with a yield of 66%; prepared naphthylamine intermediate (compound 14b in the literature) through three steps of ketoximylation, benzylsulfonylation and Semmler-Wolff aromatization, and then column chromatography, with a yield of 50%; then prepared N-methyl-6,7-(methylenedioxy)-1-naphthylamine (compound 15b in the literature) through two steps of methyl chloroformate N-acylation and lithium aluminum hydride reduction, and then column chromatography, with a yield of 65%; the route is shown below.

[0015]

[0016] Harayama et al. (Synthesis 2002) used naphthylamine (compound 15 in the literature) as the starting material, N-acylated it with trifluoroacetic anhydride, N-methylated it with iodomethane, and then alkaline hydrolyzed it to prepare N-methylnaphthylamine (compound 17 in the literature) with a yield of 76%.

[0017] The preparation of N-methylnaphthylamine from naphthylamine requires at least two more steps of reaction, which lengthens the overall reaction route. The yield of the N-acylation and N-methylation route is 76%, and genotoxic methylation reagents such as iodomethane are required. The yield of the N-acylation and reduction route is 65%, and irritating methyl chloroformate reagents, active lithium aluminum hydride and other strong alkaline reagents are required, which poses hidden dangers to operation and product safety, and is not suitable for industrial production.

[0018] In addition, piperonal belongs to the first category of non-pharmaceutical precursor chemicals, with limited supply and difficult to be applied to mass industrial production. Therefore, it is necessary to develop an alternative synthesis route with easy-to-obtain raw materials, short preparation process, mild reaction conditions, low production cost, environmental protection, high yield and high purity. Summary of the invention

[0019] In order to solve the above technical problems, the present invention provides a preparation method and use of an aromatic benzo[c]phenanthridine alkaloid intermediate compound. The method of the present invention uses 1,2-methylenedioxybenzene (piperonyl ring) as a starting material, and replaces the controlled compound piperonal to synthesize two aromatic benzo[c]phenanthridine alkaloid intermediate compounds (6,7-methylenedioxy-1-naphthylamine and N-methyl-6,7-(methylenedioxy)-1-naphthylamine), which has the advantages of easy availability of raw materials, short steps, mild reaction conditions, low production cost, environmental protection, high yield, and high purity, and can meet the high quality requirements of pharmaceutical products. Among them, the synthesis of N-methyl-6,7-(methylenedioxy)-1-naphthylamine no longer passes through the 6,7-methylenedioxy-1-naphthylamine intermediate, and does not require column chromatography purification, which is more convenient.

[0020] The specific technical scheme of the present invention is:

[0021] In a first aspect, the present invention provides a method for preparing an α-tetralone intermediate compound:

[0022] (1) 1,2-methylenedioxybenzene A2 (piperazine) is used as the starting material to obtain compound B through FC acylation, and then compound C is obtained through catalytic hydrogenation and hydrolysis. Finally, α-tetralone intermediate compound II is prepared through cyclization reaction. The synthetic route is as follows:

[0023]

[0024] Preferably, in step (1), the FC acylation is carried out by reacting 1,2-methylenedioxybenzene with an acylating agent and a catalyst A in a reaction solvent A at a reaction temperature of 0-40°C.

[0025] Further preferably, in step (1), the acylating agent is selected from butyric anhydride, ethyl succinate chloride or methyl succinate chloride; the catalyst A is selected from anhydrous aluminum chloride, anhydrous ferric chloride, trifluoroacetic acid, anhydrous zinc chloride, PPA, ferric chloride or silica gel supported methanesulfonic acid; the reaction solvent A is selected from one or more of dichloromethane, nitromethane, nitrobenzene and carbon disulfide; the reaction temperature of the FC acylation is 10-30°C; the equivalent ratio of the 1,2-methylenedioxybenzene, the acylating agent and the catalyst A is 1:1-1.5:1-1.5.

[0026] Preferably, in step (1), the catalytic hydrogenation is carried out with compound B and catalyst B in reaction solvent B at a reaction temperature of 50-80°C.

[0027] Further preferably, in step (1), the catalyst B is Pd / C; the reaction solvent B is selected from one or more of methanol, ethanol and isopropanol; and the reaction temperature of the catalytic hydrogenation is 60-80°C.

[0028] Preferably, in step (1), the cyclization reaction is carried out by reacting compound C with acidic catalyst C in reaction solvent C at a reaction temperature of 20-110°C.

[0029] Further preferably, in step (1), the acidic catalyst C is selected from one or more of polyphosphoric acid, sulfuric acid, methanesulfonic acid, ferric chloride, aluminum chloride, tin tetrachloride, acetic anhydride, boron trifluoride etherate, trifluoroacetic acid, trifluoroacetic anhydride and PPE; the reaction solvent C is selected from one or more of dichloromethane, toluene and chlorobenzene; the reaction temperature of the cyclization reaction is 20-40°C; and the equivalent ratio of the compound C to each acidic catalyst C is 1:0.5-1.5.

[0030] In a second aspect, the present invention provides a method for preparing an aromatic benzo[c]phenanthridine alkaloid intermediate compound (6,7-methylenedioxy-1-naphthylamine):

[0031] (1) Preparation of α-tetralone intermediate compound II.

[0032] (2) The α-tetralone intermediate compound II is subjected to an oximation reaction to obtain an intermediate compound III, and finally subjected to an aromatization reaction to obtain 6,7-methylenedioxy-1-naphthylamine I. The synthetic route is as follows:

[0033]

[0034] Preferably, in step (2), the oximation reaction is carried out by reacting compound II with oximation reagent II and buffer salt in reaction solvent II at a reaction temperature of 40-80°C.

[0035] Further preferably, in step (2), the oximation reagent II is selected from one or more of hydroxylamine hydrochloride, hydroxylamine sulfate, and hydroxylamine phosphate; the buffer salt is selected from one or more of sodium acetate, potassium acetate, and sodium hydroxide; the reaction solvent II is selected from one or more of methanol, ethanol, and isopropanol; the reaction temperature of the oximation reaction is 50-80°C; and the equivalent ratio of the compound II, the oximation reagent II, and the buffer salt is 1:1.0-2.0:0.5-2.5.

[0036] Preferably, in step (2), the aromatization reaction is carried out by reacting compound III with catalyst III in reaction solvent III at a reaction temperature of 110-280°C.

[0037] Further preferably, in step (2), the catalyst III is Pd / C; the reaction solvent III is selected from one or more of diethylene glycol monomethyl ether, triethylene glycol monomethyl ether, diethylene glycol dimethyl ether and triethylene glycol dimethyl ether; and the reaction temperature of the aromatization is 150-250°C.

[0038] In a third aspect, the present invention provides a method for preparing an aromatic benzo[c]phenanthridine alkaloid intermediate compound (N-methyl-6,7-(methylenedioxy)-1-naphthylamine):

[0039] (A) Preparation of α-tetralone intermediate compound II.

[0040] (B) α-tetralone intermediate compound II is subjected to condensation reaction to obtain intermediate compound E, and finally subjected to aromatization reaction to obtain N-methyl-6,7-(methylenedioxy)-1-naphthylamine F; the synthetic route is as follows:

[0041]

[0042] Preferably, in step (B), the condensation reaction is carried out between the α-tetralone intermediate compound II and methylamine in a reaction solvent D at a reaction temperature of 40-80°C.

[0043] Further preferably, in step (B), the reaction solvent D is selected from one or more of methanol, ethanol and isopropanol; the methylamine and the reaction solvent D are pre-formed into a methylamine methanol solution, a methylamine ethanol solution, or a methylamine isopropanol solution; the reaction temperature of the condensation reaction is 50-80°C; and the equivalent ratio of the α-tetralone intermediate compound II to methylamine is 1:2.0-10.0.

[0044] Preferably, in step (B), the aromatization reaction is carried out with the intermediate compound E, catalyst E, hydrogen acceptor E and pH adjusting agent E in the reaction solvent E at a reaction temperature of 110-280°C.

[0045] Further preferably, in step (B), the catalyst E is Pd / C; the hydrogen acceptor E is one or more of ethyl methacrylate, propyl methacrylate, cyclohexene, cyclohexanone, and naphthalene; the pH adjusting agent E is one or more of sodium acetate, sodium bicarbonate, sodium carbonate, and sodium phosphate; the reaction solvent E is one or more of mesitylene, xylene, o-dichlorobenzene, and m-dichlorobenzene; and the aromatization reaction temperature is 150-250° C. The equivalent ratio of the intermediate compound E, the hydrogen acceptor E, and the pH adjusting agent E is 1:0.5-2.0:0.5-2.0.

[0046] In a fourth aspect, the present invention provides the use of the above aromatic benzo[c]phenanthridine alkaloid intermediate compound in the synthesis of sanguinarine, sanguinarine, chelerythrine or nitidine chloride.

[0047] Compared with the prior art, the beneficial effects of the present invention are:

[0048] (1) The present invention uses 1,2-methylenedioxybenzene (piperonyl cyclopentane) instead of piperonal, a controlled precursor chemical raw material, as the starting material for the synthesis of two aromatic benzo[c]phenanthridine alkaloid intermediate compounds (6,7-methylenedioxy-1-naphthylamine and N-methyl-6,7-(methylenedioxy)-1-naphthylamine), which has the advantages of easy availability of raw materials and low cost.

[0049] (2) The present invention uses 1,2-methylenedioxybenzene (piperonyl ring) as a starting material, and successively undergoes FC acylation, catalytic hydrogenation, hydrolysis, and cyclization to synthesize an α-tetralone intermediate compound. The reaction temperature of the cyclization step is milder than that of the traditional route, and the acidic catalyst is used at an equivalent level, so that less three wastes are generated.

[0050] (3) After obtaining the α-tetralone intermediate compound, the present invention further performs oximation reaction and aromatization reaction to obtain 6,7-methylenedioxy-1-naphthylamine, which shortens the three steps (oximation, benzylsulfonylation, Semmler-Wolff aromatization) of the prior art (Comparative Example 1) to two steps (oximation, aromatization), and the steps are shorter. Compared with the traditional route, the protection and hydrolysis of the oxime group are omitted, and the use of dangerous reagents such as NaH is avoided. Post-treatment operations such as ethyl acetate extraction and saturated sodium chloride washing are reduced, and the reaction is safer and more environmentally friendly. In addition, the reaction conditions are milder, the yield is higher, and the purity is higher.

[0051] (4) After obtaining the α-tetralone intermediate compound, the present invention further performs a condensation reaction and an aromatization reaction to obtain N-methyl-6,7-(methylenedioxy)-1-naphthylamine. Compared with the prior art, the method no longer uses a 6,7-methylenedioxy-1-naphthylamine intermediate (comparative examples 2 and 3 require first synthesizing a 6,7-methylenedioxy-1-naphthylamine intermediate and then synthesizing N-methyl-6,7-(methylenedioxy)-1-naphthylamine through multiple steps), and the reaction steps are reduced by at least 2 steps, thereby improving the overall yield. In addition, in the aromatization reaction, heterogeneous noble metal catalytic dehydrogenation conditions are adopted, and under the joint action of a hydrogen acceptor reagent and a pH regulator, the aromatization of the tetralone imine substrate is successfully achieved, the product yield is further improved, and impurities are effectively controlled. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 is the GC spectrum of the product of Example 1;

[0053] Figure 2 is the GC spectrum of the product of Example 2;

[0054] Figure 3 is the GC spectrum of the product of Example 3;

[0055] Figure 4 is the GC spectrum of the product of Example 4;

[0056] Figure 5 This is the GC spectrum of the crude product of Example 5;

[0057] Figure 6 is the GC spectrum of the product of Example 5;

[0058] Figure 7 is the GC spectrum of the product of Example 6;

[0059] Figure 8 This is the GC spectrum of the product of Example 7. DETAILED DESCRIPTION

[0060] The present invention will be further described below in conjunction with the embodiments.

[0061] Overall embodiment

[0062] A method for preparing an α-tetralone intermediate compound specifically comprises the following steps:

[0063] (1) 1,2-methylenedioxybenzene A2 (piperazine) is used as the starting material to obtain compound B through FC acylation, and then compound C is obtained through catalytic hydrogenation and hydrolysis. Finally, α-tetralone intermediate compound II is prepared through cyclization reaction. The synthetic route is as follows:

[0064]

[0065] Specifically:

[0066] FC acylation is carried out by reacting 1,2-methylenedioxybenzene with an acylating agent (preferably butyric anhydride, succinic acid monoethyl chloride, succinic acid monomethyl chloride, etc.), and a catalyst A (anhydrous aluminum chloride, trifluoroacetic acid, anhydrous zinc chloride, PPA, ferric chloride, or silica gel-supported methanesulfonic acid) in a reaction solvent A (preferably dichloromethane, nitromethane, nitrobenzene, etc.) at a reaction temperature of 0-40° C. (preferably 10-30° C.), wherein the equivalent ratio of 1,2-methylenedioxybenzene, the acylating agent, and the catalyst A is 1:1-1.5:1-1.5.

[0067] The catalytic hydrogenation is carried out by reacting compound B and catalyst B (Pd / C) in a reaction solvent B (preferably methanol, ethanol, isopropanol, etc.) at a reaction temperature of 50 to 80° C. (preferably 60 to 80° C.).

[0068] The cyclization reaction is carried out by reacting compound C with an acidic catalyst C (preferably polyphosphoric acid, sulfuric acid, methanesulfonic acid, ferric chloride, aluminum chloride, tin tetrachloride, acetic anhydride, boron trifluoride etherate, trifluoroacetic acid, trifluoroacetic anhydride and PPE, etc.) in a reaction solvent C (preferably dichloromethane, toluene and chlorobenzene, etc.) at a reaction temperature of 20-110° C. (preferably 20-40° C.), wherein the equivalent ratio of compound C to each acidic catalyst C is 1:0.5-1.5.

[0069] A method for preparing 6,7-methylenedioxy-1-naphthylamine, comprising the following steps:

[0070] (1) Preparation of α-tetralone intermediate compound II.

[0071] (2) The α-tetralone intermediate compound II is subjected to an oximation reaction to obtain an intermediate compound III, and finally subjected to an aromatization reaction to obtain 6,7-methylenedioxy-1-naphthylamine I. The synthetic route of step (2) is as follows:

[0072]

[0073] Specifically:

[0074] The oximation reaction is carried out by reacting compound II and oximation reagent II (preferably hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxylamine phosphate, etc.), and buffer salt (preferably sodium acetate, potassium acetate, sodium hydroxide, etc.) in reaction solvent II (preferably methanol, ethanol, isopropanol, etc.) at a reaction temperature of 40-80° C. (preferably 50-80° C.), wherein the equivalent ratio of compound II, oximation reagent II, and buffer salt is 1:1.0-2.0:0.5-2.5.

[0075] The aromatization reaction is carried out by reacting compound III and catalyst III (Pd / C) in reaction solvent III (preferably diethylene glycol monomethyl ether, triethylene glycol monomethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, etc.) at a reaction temperature of 110-280° C. (preferably 150-250° C.).

[0076] A method for preparing N-methyl-6,7-(methylenedioxy)-1-naphthylamine:

[0077] (A) Preparation of α-tetralone intermediate compound II.

[0078] (B) α-tetralone intermediate compound II is subjected to condensation reaction to obtain intermediate compound E, and finally subjected to aromatization reaction to obtain N-methyl-6,7-(methylenedioxy)-1-naphthylamine F; the synthetic route of step (B) is as follows:

[0079]

[0080] Specifically:

[0081] The condensation reaction is carried out by reacting compound II and methylamine in a reaction solvent D (preferably methanol, ethanol, isopropanol, etc.) at a reaction temperature of 40-80° C. (preferably 50-80° C.), wherein the equivalent ratio of compound II to methylamine is 1:2.0-10.0.

[0082] The aromatization reaction is carried out by reacting compound E and catalyst E (Pd / C) in reaction solvent E (preferably mesitylene, xylene, o-dichlorobenzene, m-dichlorobenzene, etc.) at a reaction temperature of 110-280° C. (preferably 150-250° C.). The equivalent ratio of compound E, hydrogen acceptor E, and pH adjusting agent E is 1:0.5-2.0:0.5-2.0. Specific embodiments

[0084] Example 1-3: Synthesis of α-tetralone intermediate compound

[0085] Example 1: FC acylation to prepare intermediate compound B, R = Et

[0086]

[0087] In a 2L four-necked flask, 100g of piperine, 500mL of dichloromethane, and 148g of succinic acid monoethyl chloride were added, the temperature was lowered to 10°C, and 146g of anhydrous ferric chloride was added in batches. The reaction of the raw materials was followed by GC. 110g of aqueous hydrochloric acid solution was added to the reaction flask, and the mixture was stirred at low temperature for 1h. Then 1L of water was added, the temperature was raised to 25°C and stirred for 2h. The layers were separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, and 210.8g of a brown viscous liquid was obtained after vacuum distillation. The GC purity was 87.96% (as Figure 1The crude yield was 102.8%, which was directly used for the next step reaction.

[0088] Example 1a

[0089] In a 1L four-necked flask, 50g of piperine, 200mL of nitrotoluene, and 68g of succinic acid monomethyl chloride were added, and the temperature was lowered to 20°C. 61.5g of anhydrous zinc chloride was added in batches. The reaction was followed by GC until the reaction of the raw materials was completed. 60g of aqueous hydrochloric acid solution was added to the reaction flask, and the mixture was stirred at low temperature for 1h. Then 500mL of water was added, and the mixture was heated to 25°C and stirred for 2h. The layers were separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined and distilled under reduced pressure to obtain 103.2g of a brown viscous liquid with a GC purity of 89.91% and a crude yield of 100.7%, which was directly used in the next step.

[0090] Example 1b

[0091] In a 1L four-necked flask, 50g of piperine, 300mL of dichloromethane, and 56g of trifluoroacetic acid were added, and the temperature was lowered to 15°C. 87.5g of succinic acid monoethyl chloride was added dropwise. The reaction of the raw materials was followed by GC. Dichloromethane and trifluoroacetic acid were removed by rotary evaporation under reduced pressure. Then 200mL of water was added and stirred at room temperature for 2h. The aqueous phase was extracted with dichloromethane, and the organic phases were combined and distilled under reduced pressure to obtain 99.6g of a brown viscous liquid with a GC purity of 86.09% and a crude yield of 97.2%, which was directly used in the next step.

[0092] The differences in reagents and process parameters between Examples 1a and 1b are shown in the following table:

[0093]

[0094] Example 2: Catalytic hydrogenation and hydrolysis to prepare intermediate compound C

[0095]

[0096] 210.8 g of compound B (R = Et) prepared in the first step (Example 1), 1000 ml of ethanol, and 10.5 g of 5% Pd / C were added to a 2L autoclave. The autoclave was closed, and hydrogen was vented 5 times. Hydrogen was then introduced to 1.2 MPa, and the reaction was heated to 75°C for 24 h. The reaction was followed by GC until the reaction of the raw materials was completed. The catalyst was filtered, and a portion of the ethanol was removed by rotary evaporation of the filtrate. 500 mL of water was added to the reaction solution, and 300 g of a 20% aqueous sodium hydroxide solution was added dropwise. The reaction solution was heated to 50°C and stirred for 2 h. The reaction was followed by GC until the hydrolysis was completed (R was hydrolyzed from Et to H). Most of the ethanol was removed by vacuum distillation, and the remaining aqueous phase was extracted with dichloromethane. Hydrochloric acid was added dropwise to the aqueous phase under ice water to adjust the pH to about 1. A large amount of solid was precipitated, and 154 g of compound C was obtained by filtration. The GC purity was 99.39% (as Figure 2 The total yield of the first and second steps was 90.3%.

[0097] Example 2a

[0098] 100.4 g of compound B (R=Me) prepared in the first step (Example 1a), 600 ml of methanol, and 10.5 g of 5% Pd / C were added to a 2L autoclave. The autoclave was closed, and hydrogen was vented 5 times. Hydrogen was then introduced to 1 MPa, and the reaction was heated to 60°C for 24 h. The reaction was followed by GC until the reaction of the raw materials was completed. The catalyst was filtered, and a portion of methanol was removed by rotary evaporation of the filtrate. 250 mL of water was added to the reaction solution, and 150 g of a 20% aqueous sodium hydroxide solution was added dropwise. The reaction solution was heated to 50°C and stirred for 2 h. The reaction was followed by GC until the hydrolysis was completed (R was hydrolyzed from Me to H). Most of the methanol was removed by reduced pressure distillation, and the remaining aqueous phase was extracted with dichloromethane. Hydrochloric acid was added dropwise to the aqueous phase under ice water to adjust the pH to about 1. A large amount of solid was precipitated, and 76.2 g of compound C was obtained by filtration. The GC purity was 98.97%, and the total yield of the first and second steps was 89.4%.

[0099] Example 2b

[0100] 99.6 g of compound B prepared in the first step (Example 1b), 650 ml of isopropanol, and 5 g of 10% Pd / C were added to a 2L autoclave. The autoclave was closed, and hydrogen was vented 5 times. Hydrogen was then introduced to 1.1 MPa, and the reaction was heated to 80°C for 20 h. The reaction was followed by GC until the reaction of the raw materials was completed. The catalyst was filtered, and the filtrate was evaporated to remove a portion of isopropanol. 250 mL of water was added to the reaction solution, and 150 g of 20% sodium hydroxide aqueous solution was added dropwise. The reaction solution was heated to 50°C and stirred for 2 h. The hydrolysis was followed by GC until the hydrolysis was completed (R was hydrolyzed from Et to H). Most of the isopropanol was removed by vacuum distillation, and the remaining aqueous phase was extracted with dichloromethane. Hydrochloric acid was added dropwise to the aqueous phase under ice water to adjust the pH to about 1. A large amount of solid was precipitated, and 75.8 g of compound C was obtained by filtration. The GC purity was 98.59%, and the total yield of the first and second steps was 88.9%.

[0101] The differences in reagents, process parameters and test results in Examples 2a and 2b are shown in the following table:

[0102] Serial number Compound B Catalyst B Reaction solvent B temperature product GC purity, combined yield Example 2a 100.4g(1a) 5%Pd / C 10.5g Methanol 600ml 60℃ 76.2g 98.97％，89.4％ Example 2b 99.6g(1b) 10%Pd / C 5g Isopropyl alcohol 650ml 80℃ 75.8g 98.59％，88.9％

[0103] Example 3: Preparation of Intermediate Compound II (α-Tetralone Intermediate Compound) by Cyclization Reaction

[0104]

[0105] In a 5L four-necked flask, 500g of compound C (R = H) (Example 2) and 2500mL of dichloromethane were added dropwise, 356g of boron trifluoride ether solution was added dropwise, and then 343g of acetic anhydride was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 2h. GC was followed until the conversion of the raw materials was completed. 1000ml of water was added and the stirring was continued for 5h. The liquid was separated, the organic layer was washed with water and separated, and the organic layer concentrate was poured into 2.5L of water, stirred for 1h, filtered and dried to obtain 420g of compound II with a GC purity of 99.23% (as Figure 3 The yield of compound II was 91.95%. The combined yield of compound II was 83%.

[0106] Example 3a

[0107] To a 2L four-necked flask, 200g of compound C (R=H) and 1200mL of toluene were added dropwise, 142.5g of boron trifluoride ether solution was added dropwise, and then 282g of trifluoroacetic anhydride was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 2h and followed by GC until the conversion of the raw materials was completed. 500ml of water was added and stirring was continued for 5h. The liquids were separated, the organic layer was washed with water and separated, and the organic layer concentrate was poured into 1L of water, stirred for 1h, filtered and dried to obtain 165.4g of compound II with GC purity of 99.40% and a yield of 90.5%.

[0108] Example 3b

[0109] To a 1L four-necked flask, 100g of compound C (R=H) and 500mL of dichloromethane were added, and 65g of methanesulfonic acid was added dropwise. After the addition was completed, the temperature was raised to 40°C for insulation reaction. GC was used to track the conversion of the raw materials. 200ml of water was added and stirring was continued for 5h. The liquids were separated, the organic layer was washed with water and separated, and the organic layer concentrate was poured into 500mL of water. The mixture was stirred for 1h, filtered and dried to obtain 85.1g of compound II with a GC purity of 98.63% and a yield of 93.2%.

[0110] The differences in reagents, process parameters and test results in Examples 3a and 3b are shown in the following table:

[0111]

[0112] Example 4-5 (Synthesis of 6,7-methylenedioxy-1-naphthylamine)

[0113] Example 4: Preparation of Compound III by Oximation

[0114]

[0115] In a 2L four-necked bottle, 100g of compound II, 1000mL of methanol, 86g of sodium acetate, and 55g of hydroxylamine hydrochloride were added, stirred, and heated to 70°C for reaction. GC was followed until the conversion of the raw materials was complete. Ethanol was removed by rotary evaporation, and the rotary evaporation substrate was added to 500mL of water, heated to 60°C and stirred for 2h, cooled to room temperature, and filtered to obtain 102g of compound III with a GC purity of 94% (such as Figure 4 The yield was 94.5%.

[0116] Example 4a

[0117] To a 1L four-necked flask, 50g of compound II, 600mL of ethanol, 38.8g of potassium acetate, and 56.1g of hydroxylamine sulfate were added, and the mixture was stirred and heated to 80°C for reaction. The reaction was followed by GC until the conversion of the raw materials was completed. The ethanol was removed by rotary evaporation, and the rotary evaporation substrate was added to 250mL of water, heated to 60°C and stirred for 2h. The mixture was cooled to room temperature and filtered to obtain 52.4g of compound III with a GC purity of 90.55% and a yield of 97.1%.

[0118] Example 4b

[0119] To a 1L four-necked flask, 50g of compound II, 500mL of isopropanol, 11.6g of sodium hydroxide, and 38g of hydroxylamine phosphate were added, and the mixture was stirred and heated to 75°C for reaction. The reaction was followed by GC until the conversion of the raw materials was completed. The isopropanol was removed by rotary evaporation, and the rotary evaporation substrate was added to 250mL of water, heated to 60°C and stirred for 2h. The mixture was cooled to room temperature and filtered to obtain 51.6g of compound III with a GC purity of 87.01% and a yield of 95.6%.

[0120] The differences in reagents, process parameters and test results in Examples 4a and 4b are shown in the following table:

[0121] Serial number Compound C Oximation reagent II and buffer salt Reaction Solvent II temperature product GC purity, yield Example 4a 50g Hydroxylamine sulfate 56.1g, potassium acetate 38.8g Ethanol 600ml 80℃ 52.4g 90.55％，97.1％ Example 4b 50g Hydroxylamine phosphate 38g, sodium hydroxide 11.6g Isopropyl alcohol 500ml 75℃ 51.6g 87.01％，95.6％

[0122] Example 5: Preparation of Compound I (6,7-methylenedioxy-1-naphthylamine) by aromatization

[0123]

[0124] In a 250mL four-necked bottle, add 5g of compound III, 50mL of triethylene glycol dimethyl ether, 1g of 10% Pd / C, and 2g of sodium bicarbonate, stir and heat the reaction solution to 230°C for reaction, and track by GC until the conversion of the raw materials is complete. Cool to room temperature, filter, add the filtrate to 300mL of ice water, filter and dry to obtain 4.3g of crude product with a GC purity of 94.7% (as Figure 5 shown).

[0125] The crude product was added to 100 mL of methanol, and then 0.2 g of activated carbon was added. After heating and dissolving, the filtrate was filtered. The filtrate was cooled to room temperature and filtered to obtain 3.2 g of yellow crystals with a GC purity of 99.15% (such as Figure 5 The yield was 70.2%.

[0126] Example 5a

[0127] In a 250mL four-necked bottle, add 5g of compound III, 70mL of diethylene glycol monomethyl ether, 1g of 10% Pd / C, and 2g of sodium bicarbonate, stir and heat the reaction solution to 180°C for reaction, and track by GC until the conversion of the raw materials is complete. Cool to room temperature, filter, add the filtrate to 300mL of ice water, filter and dry to obtain 4.5g of crude product with a GC purity of 90.53%.

[0128] The crude product was added to 100 mL of methanol, and then 0.2 g of activated carbon was added. The mixture was heated to dissolve and then filtered. The filtrate was cooled to room temperature and filtered to obtain 3.4 g of yellow crystals with a GC purity of 98.93% and a yield of 74.5%.

[0129] Example 5b

[0130] 5 g of compound III, 60 mL of diethylene glycol dimethyl ether, 2 g of 5% Pd / C, and 2 g of sodium bicarbonate were added to a 250 mL four-necked bottle, and the reaction solution was stirred and heated to 160°C for reaction, and GC was used to track the conversion of the raw materials. The solution was cooled to room temperature, filtered, and the filtrate was added to 300 mL of ice water, filtered and dried to obtain 4.4 g of a crude product with a GC purity of 87.97%.

[0131] The crude product was added to 100 mL of methanol, and then 0.2 g of activated carbon was added. The mixture was heated to dissolve and then filtered. The filtrate was cooled to room temperature and filtered to obtain 3.3 g of yellow crystals with a GC purity of 99.42% and a yield of 72.3%.

[0132] The differences in reagents, process parameters and test results in Examples 5a and 5b are shown in the following table:

[0133]

[0134] Comparative Example 1: Synthesis of 6,7-methylenedioxy-1-naphthylamine

[0135] Comparative Example 1 Synthesis method and data recorded in reference (De, Subhadip, et al The Journal of organic chemistry 78.16 (2013): 7823-7844):

[0136] (1) Synthesis of α-tetralone intermediate compound II: Using piperonal as the starting material, α-tetralone intermediate compound II (reference compound 13d) was prepared by three steps of Wittg olefination, catalytic hydrogenation, and FC acylation, followed by column chromatography, with a combined yield of 66%. The details are as follows:

[0137] Wittg olefination: 1.0eq 3-bromopropionic acid triphenylphosphine salt was cooled to 0°C in a 1:1 THF / DMSO solvent system (2ml / 1mmol), 2.5eq NaH was added in batches, stirred for 10min, 1eq piperonal (149.5mmol) in a 1:1 THF / DMSO solution (10ml) was added dropwise at 0°C, and the reaction was allowed to proceed for 20h at room temperature; TLC monitored the complete reaction of the raw material, quenched with 4N hydrochloric acid, 100ml ethyl acetate was added, and 100ml water was extracted; the aqueous layer was extracted twice with 50ml ethyl acetate. The organic layers were combined, dried, and concentrated under reduced pressure.

[0138] Catalytic hydrogenation: olefination intermediate (according to 1.0 eq) 0.2 eq Pd / C, methanol solvent, celite filtration and vacuum concentration.

[0139] FC acylation: PPA, dichloromethane solvent, reflux for 4 h, quench with saturated sodium bicarbonate solution, and concentrate in vacuo.

[0140] (2) Synthesis of 6,7-methylenedioxy-1-naphthylamine: Compound II was subjected to three steps of ketoximylation, benzylsulfonylation, and Semmler-Wolff aromatization, followed by column chromatography to prepare compound I (6,7-methylenedioxy-1-naphthylamine). The details are as follows:

[0141] Ketoximination: 2 g of compound II (10.5 mmol), 2.5 eq of hydroxylamine hydrochloride, 1.5 eq of sodium acetate, add 3 ml of ethanol, 4 ml of water, stir at room temperature for 2 h, track by TLC until the starting material disappears, dilute with 20 ml of ethyl acetate, extract with 20 ml of water; separate the organic layer, dry over anhydrous sodium sulfate and concentrate in vacuo, the product is not separated.

[0142] Benzenesulfonylation: Add ethylene glycol dimethyl ether to the product of the previous step (10.5 mmol) under argon protection, cool to 0°C, add 5.0 eq NaH in batches, add 3.0 eq p-TsCl, warm to room temperature, and react in an oil bath at 70°C for 24 hours. Track by TLC until the starting material disappears, quench the reaction with ice water, add 30 ml ethyl acetate for extraction, and then add 15 ml water for separation. After the organic layer is dried, it is concentrated in vacuo, and the product is not separated.

[0143] Aromatization: The product of the previous step (according to 10.5 mmol) was added with KOH / methanol solution, methanol solvent; the dark red reaction solution was refluxed for 6 h, cooled to room temperature and poured into 20 ml of ice water, extracted twice with 10 ml of ethyl acetate. Washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain black solid compound I (elution solvent 30% ethyl acetate / n-hexane), no purity data, combined yield 50%.

[0144] The synthesis route of compound I (6,7-methylenedioxy-1-naphthylamine) prepared from compound II, in Examples 1-5 of the present invention, has the following advantages over Comparative Example 1:

[0145] (1) The reaction steps for synthesizing 6,7-methylenedioxy-1-naphthylamine from compound II are shortened from three steps (oximation, toluenesulfonylation, Semmler-Wolff aromatization) in comparative example 1 to two steps (oximation, aromatization), with a combined yield of 66%, which is much higher than the combined yield of 50% in comparative example 1;

[0146] (2) The aromatization reaction of the present invention adopts a noble metal catalyst to catalyze the reaction. Compared with Comparative Example 1, the p-toluenesulfonyl protection of the oxime group and the KOH / methanol hydrolysis are omitted, the use of dangerous reagents such as NaH is avoided, and post-treatment operations such as ethyl acetate extraction and saturated sodium chloride washing are reduced, making the reaction safer and more environmentally friendly.

[0147] (3) The compound I (6,7-methylenedioxy-1-naphthylamine) obtained in the present invention is of high purity, yellow crystals, and GC purity is 99.15%. Comparative Example 1 is a black solid with no purity data. The post-processing operation is simple, and high-purity compound I crystals can be obtained by only recrystallization from methanol without the need for column chromatography elution and separation.

[0148] Example 6-7 (N-methyl-6,7-(methylenedioxy)-1-naphthylamine)

[0149] Example 6: Preparation of Ketimine Compound E by Condensation Reaction

[0150]

[0151] Add 10g of crude compound II and 21.8g of 30% methylamine methanol solution to a thick-walled pressure bottle, seal it and place it in an oil bath, heat it to 50°C, keep it warm and stir it for 16h, cool it to -10°C, keep it warm and stir it for 3h, filter it, wash the filter cake twice with 15ml of methanol, recycle the reaction mother liquor and methanol concentrate (add new compound II and methylamine methanol solution to react again), dry the solid to 7.3g, and the GC purity is 94.20% (such as Figure 7 As shown), the yield was 68.3% (the mother liquor was recycled once, and the total yield was >88%).

[0152] Example 6a

[0153] To a thick-walled pressure bottle, 20 g of crude compound II and 32.6 g of 20% methylamine isopropanol solution were added. The bottle was sealed and placed in an oil bath. The temperature was raised to 70°C, and the reaction was stirred for 12 h. The temperature was lowered to -10°C, and the reaction was stirred for 3 h. The filter cake was washed twice with 30 ml of isopropanol. The reaction mother liquor and isopropanol concentrate were recovered and reused (new compound II and methylamine isopropanol solution were added for re-reaction). 13.9 g of the solid was dried with a GC purity of 91.03% and a yield of 65.0% (the mother liquor was recovered and reused once, and the total yield was >86%).

[0154] Example 6b

[0155] To a thick-walled pressure bottle, 100 g of crude compound II and 355 g of 30% methylamine ethanol solution were added. The bottle was sealed and placed in an oil bath. The temperature was raised to 60°C, and the reaction was stirred for 12 h. The temperature was lowered to -10°C, and the reaction was stirred for 3 h. The filter cake was washed twice with 150 ml of ethanol. The reaction mother liquor and ethanol concentrate were recovered and reused (new compound II and methylamine ethanol solution were added for re-reaction). The solid was dried to 72.8 g, with a GC purity of 93.74% and a yield of 68.1% (the mother liquor was recovered and reused once, and the total yield was >90%).

[0156] The reagents, process parameter differences and test data in Examples 6a and 6b are shown in the following table:

[0157] Serial number Compound II Methylamine reagent + reaction solvent temperature product GC purity, yield Example 6a 20g 20% Methylamine isopropyl alcohol 32.6g 70℃ 13.9g 91.03％，65.0％ Example 6b 100g 30% methylamine ethanol 355g 60℃ 72.8g 93.74％，68.1％

[0158] Example 7: Preparation of N-methyl-6,7-(methylenedioxy)-1-naphthylamine F by aromatization

[0159]

[0160] In a 500mL four-necked bottle, 1g 5% Pd / C, 4.7g naphthalene, 6g sodium carbonate, and 150ml mesitylene were added, the temperature was raised to 150°C with stirring, and a solution of 15g crude imine E in mesitylene was slowly added. The mixture was reacted at 150°C for 5h, the temperature was lowered, and the mixture was filtered. The filtrate was transferred to a 500mL four-necked bottle, 100ml 10% aqueous sulfuric acid solution was added dropwise, the temperature was raised to 50°C, and the mixture was kept warm and stirred for 1h. The liquids were separated, the aqueous phases were combined, the pH of the aqueous phase was adjusted to 11-12, a solid was precipitated, and the solid was extracted with dichloromethane. The organic phases were combined and rotary evaporated to obtain 10.4g of a brown solid with a purity of 96.88% (as Figure 8 The yield was 70%.

[0161] Example 7a

[0162] In a 1L four-necked bottle, 1g 5% Pd / C, 9.85g ethyl methacrylate, 9g sodium acetate, and 200ml xylene were added, the temperature was raised to 140°C with stirring, and a xylene solution of 20g crude imine E was slowly added, and the reaction was carried out at 140°C for 6h. The temperature was lowered and filtered, and the filtrate was transferred to a 1L four-necked bottle, and 300ml of 10% aqueous sulfuric acid solution was added dropwise. The temperature was raised to 50°C and stirred for 1h. The liquids were separated and the aqueous phases were combined. The pH of the aqueous phase was adjusted to 11-12, and a solid was precipitated. The solid was extracted with dichloromethane, and the organic phases were combined and rotary evaporated to obtain 14g of a brown solid with a purity of 96.19% and a yield of 70.7%.

[0163] Example 7b

[0164] In a 2L four-necked bottle, 1.2g 10% Pd / C, 48.3g cyclohexanone, 22.7g sodium bicarbonate, and 500ml o-dichlorobenzene were added, the temperature was raised to 170°C with stirring, 50g o-dichlorobenzene solution of crude imine E was slowly added, the reaction was carried out at 150°C for 4h, the temperature was lowered, the filtrate was filtered, the filtrate was transferred to a 2L four-necked bottle, 750ml of 10% sulfuric acid aqueous solution was added dropwise, the temperature was raised to 50°C with stirring for 1h, the liquids were separated, the aqueous phases were combined, the pH of the aqueous phase was adjusted to 11-12, the solid was precipitated, and the solid was extracted with dichloromethane, the organic phases were combined, and the reaction was performed by rotary evaporation to obtain 37.2g of brown solid with a purity of 93.3% and a yield of 75.2%.

[0165] The reagents, process parameter differences and test data in Examples 7a and 7b are shown in the following table:

[0166]

[0167] Comparative Example 2: Synthesis of N-methyl-6,7-(methylenedioxy)-1-naphthylamine (piperonal as starting material, via 6,7-methylenedioxy-1-naphthylamine intermediate)

[0168] Synthesis method and data described in reference (De, Subhadip, et al The Journal of organic chemistry 78.16 (2013): 7823-7844):

[0169] (1) Synthesis of α-tetralone intermediate compound II: same as Comparative Example 1.

[0170] (2) Synthesis of 6,7-methylenedioxy-1-naphthylamine: Same as Comparative Example 1.

[0171] (3) Synthesis of N-methyl-6,7-(methylenedioxy)-1-naphthylamine: 6,7-methylenedioxy-1-naphthylamine was N-acylated with methyl chloroformate, reduced with lithium aluminum hydride in two steps, and then subjected to column chromatography to prepare N-methyl-6,7-(methylenedioxy)-1-naphthylamine (compound 15b in the literature). No purity data was available, and the yield was 65%. The details are as follows:

[0172] N-acylation: 15 mmol 6,7-methylenedioxy-1-naphthylamine (1.0 eq) and 20 ml toluene / sodium bicarbonate were added to the reaction flask, and 2.0 eq methyl chloroformate was added dropwise. The mixture was stirred at room temperature for 4 h. The reaction was completed after TLC monitoring. 30 ml ethyl acetate / 25 ml water were added to extract and the organic layer was concentrated under reduced pressure. The product was not separated and was directly used in the next step.

[0173] Lithium aluminum hydride reduction: The product of the previous step (according to 1.0eq) was added to 30ml dry THF under argon protection and cooled to 0°C. 2.0eq LiAlH4 was added in batches within 10min, stirred at 0°C for 5min, the reaction system was heated to 23°C, and continued to stir for 10min; the reaction system was refluxed in an oil bath at 80°C for 6h, and the reaction was complete after TLC monitoring. The mixture was cooled to room temperature and continued to cool to 0°C, quenched with ethyl acetate, 4N NaOH was used to adjust the base, and extracted twice with 25ml ethyl acetate. The organic layers were combined, washed with 10ml NaCl solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain N-methyl-6,7-(methylenedioxy)-1-naphthylamine.

[0174] Comparative Example 3: Preparation of N-methyl-6,7-(methylenedioxy)-1-naphthylamine from 6,7-methylenedioxy-1-naphthylamine

[0175] Synthesis method and data described in reference (Harayama, Takashi; et al Synthesis (2002), (2), 237-241):

[0176] Using 6,7-methylenedioxy-1-naphthylamine as the starting material, N-methyl-6,7-(methylenedioxy)-1-naphthylamine was prepared by N-acylation with trifluoroacetic anhydride, N-methylation with methyl iodide, and alkaline hydrolysis, with a yield of 76%. The details are as follows:

[0177] N-acylation: 100 mg of 6,7-methylenedioxy-1-naphthylamine (0.53 mmol) was added to 3 ml of anhydrous pyridine solution, 0.11 ml of trifluoroacetic anhydride was added, and the mixture was stirred at 0°C for 30 min, poured into 10 ml of 10% HCl, extracted with ether, and the residue was recrystallized from ether-n-hexane to obtain 140 mg of N-trifluoroacetylnaphthylamine (compound 16 in Synthesis 2002), with a yield of 93%.

[0178] N-methylation: 105 mg N-trifluoroacetylnaphthylamine (0.37 mmol), 205 mg MeI, 10 ml anhydrous acetone solution, add solid 82.2 mg KOH, reflux the reactants for 20 min, and concentrate under reduced pressure. The residue is dissolved in 10 ml ethanol / 5 ml 5% NaOH, refluxed for 10 min, 40 ml water is added, and extracted with 100 ml ether. The concentrate is recrystallized from ethanol to obtain N-methyl-6,7-(methylenedioxy)-1-naphthylamine (Synthesis 2002 document compound 17).

[0179] The synthetic routes of Examples 1-3 and 6-7 of the present invention have the following advantages over Comparative Examples 2 and 3 in the literature: (1) The synthetic route of N-methyl-6,7-(methylenedioxy)-1-naphthylamine is short, and no longer involves the 6,7-methylenedioxy-1-naphthylamine intermediate, so the reaction steps are reduced by at least 2 steps, and the overall yield is improved;

[0180] (2) Using 1,2-methylenedioxybenzene (piperonyl aldehyde) as the starting material to replace the controlled compound piperonal, the availability of raw materials is improved and the supply chain security is ensured;

[0181] (3) Using heterogeneous noble metal catalytic dehydrogenation conditions, under the combined action of a hydrogen acceptor reagent and a pH regulator, the aromatization of the tetralone imine substrate was successfully achieved, with high product yield and effectively controlled impurities.

[0182] The raw materials and equipment used in the present invention, unless otherwise specified, are all commonly used raw materials and equipment in the art; the methods used in the present invention, unless otherwise specified, are all conventional methods in the art.

[0183] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any way. Any simple modification, change and equivalent transformation made to the above embodiment based on the technical essence of the present invention still falls within the protection scope of the technical solution of the present invention.

Claims

1. A method for preparing an α-tetralone intermediate compound, Features: (1) 1,2-methylenedioxybenzene A2 is used as the starting material to obtain compound B through FC acylation, and then compound C is obtained through catalytic hydrogenation and hydrolysis. Finally, α-tetralone intermediate compound II is prepared through cyclization reaction. The synthetic route is as follows: In the FC acylation reaction, succinic acid monoethyl chloride or succinic acid monomethyl chloride is used as the acylation reagent; ferric chloride, trifluoroacetic acid or anhydrous zinc chloride is used as the catalyst, and the reaction temperature is 10-30°C.

2. The preparation method according to claim 1, Features: In step (1), the FC acylation is carried out by reacting 1,2-methylenedioxybenzene with an acylating agent and a catalyst in a reaction solvent A.

3. The preparation method according to claim 2, Features: In step (1), the reaction solvent A is selected from one or more of dichloromethane, nitromethane, nitrobenzene and carbon disulfide; The equivalent ratio of the 1,2-methylenedioxybenzene, the acylating agent and the catalyst is 1:1-1.5:1-1.

5.

4. The preparation method according to claim 1, Features: In step (1), the catalytic hydrogenation is carried out with compound B and catalyst B in reaction solvent B at a reaction temperature of 50-80°C.

5. The preparation method according to claim 4, Features: In step (1), The catalyst B is Pd / C; The reaction solvent B is selected from one or more of methanol, ethanol and isopropanol; The reaction temperature of the catalytic hydrogenation is 60-80°C.

6. The preparation method according to claim 1, Features: In step (1), the cyclization reaction is carried out by reacting compound C with acidic catalyst C in reaction solvent C at a reaction temperature of 20-110°C.

7. The preparation method according to claim 6, Features: In step (1), The acidic catalyst C is selected from one or more of polyphosphoric acid, sulfuric acid, methanesulfonic acid, ferric chloride, aluminum chloride, tin tetrachloride, acetic anhydride, boron trifluoride etherate, trifluoroacetic acid, trifluoroacetic anhydride and PPE; The reaction solvent C is selected from one or more of dichloromethane, toluene and chlorobenzene; The reaction temperature of the cyclization reaction is 20-40°C; The equivalent ratio of the compound C to each acid catalyst C is 1:0.5-1.

5.

8. A method for preparing an aromatic benzo[c]phenanthridine alkaloid intermediate compound, Features: The aromatic benzo[c]phenanthridine alkaloid intermediate compound is 6,7-methylenedioxy-1-naphthylamine, and the preparation method comprises: (1) synthesizing the α-tetralone intermediate compound II by the preparation method according to any one of claims 1 to 7; (2) The α-tetralone intermediate compound II is subjected to an oximation reaction to obtain an intermediate compound III, and finally subjected to an aromatization reaction to obtain 6,7-methylenedioxy-1-naphthylamine I. The synthetic route is as follows:

9. The preparation method according to claim 8, Features: In step (2), the oximation reaction is carried out by reacting compound II, oximation reagent II and buffer salt in reaction solvent II at a reaction temperature of 40-80°C.

10. The preparation method according to claim 9, Features: In step (2), The oximation reagent II is selected from one or more of hydroxylamine hydrochloride, hydroxylamine sulfate, and hydroxylamine phosphate; The buffer salt is selected from one or more of sodium acetate, potassium acetate and sodium hydroxide; The reaction solvent II is selected from one or more of methanol, ethanol and isopropanol; The reaction temperature of the oximation reaction is 50-80°C; The equivalent ratio of the compound II, the oximation reagent II and the buffer salt is 1:1.0-2.0:0.5-2.

5.

11. The preparation method according to claim 8, Features: In step (2), the aromatization reaction is carried out by reacting compound III and catalyst III in reaction solvent III at a reaction temperature of 110-280°C.

12. The preparation method according to claim 11, Features: In step (2), The catalyst III is Pd / C; The reaction solvent III is selected from one or more of diethylene glycol monomethyl ether, triethylene glycol monomethyl ether, diethylene glycol dimethyl ether and triethylene glycol dimethyl ether; The aromatization reaction temperature is 150-250°C.

13. A method for preparing an aromatic benzo[c]phenanthridine alkaloid intermediate compound, Features: The aromatic benzo[c]phenanthridine alkaloid intermediate compound is N-methyl-6,7-(methylenedioxy)-1-naphthylamine, and the preparation method comprises: (A) synthesizing the α-tetralone intermediate compound II by the preparation method according to any one of claims 1 to 7; (B) α-tetralone intermediate compound II is subjected to condensation reaction to obtain intermediate compound E, and finally subjected to aromatization reaction to obtain N-methyl-6,7-(methylenedioxy)-1-naphthylamine F; the synthetic route is as follows:

14. The preparation method according to claim 13, Features: In step (B), The condensation reaction is carried out by reacting the α-tetralone intermediate compound II with methylamine in a reaction solvent D at a reaction temperature of 40-80°C.

15. The preparation method according to claim 14, Features: In step (B), The reaction solvent D is selected from one or more of methanol, ethanol and isopropanol; The methylamine and reaction solvent D are pre-formed into methylamine methanol solution, methylamine ethanol solution and methylamine isopropanol solution; The reaction temperature of the condensation reaction is 50-80°C; The equivalent ratio of the α-tetralone intermediate compound II to methylamine is 1:2.0-10.

0.

16. The preparation method according to claim 13, Features: In step (B), The aromatization reaction is carried out by using an intermediate compound E, a catalyst E, a hydrogen acceptor E and a pH adjusting agent E in a reaction solvent E at a reaction temperature of 110-280°C.

17. The preparation method according to claim 16, Features: In step (B), The catalyst E is Pd / C; The hydrogen acceptor E is one or more of ethyl methacrylate, propyl methacrylate, cyclohexene, cyclohexanone, and naphthalene; The pH adjusting agent E is one or more of sodium acetate, sodium bicarbonate, sodium carbonate, and sodium phosphate; The reaction solvent E is selected from one or more of mesitylene, xylene, o-dichlorobenzene, and m-dichlorobenzene; The aromatization reaction temperature is 150-250°C; The equivalent ratio of the intermediate compound E, the hydrogen acceptor E and the pH adjusting agent E is 1:0.5-2.0:0.5-2.

0.

18. Use of the aromatic benzo[c]phenanthridine alkaloid intermediate compound obtained by the preparation method according to any one of claims 8 to 17 in the synthesis of sanguinarine, chelerythrine or nitidine chloride.

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