CN116444478A - Preparation method and application of aromatic benzo [ c ] phenanthridine alkaloid intermediate compound - Google Patents

Preparation method and application of aromatic benzo [ c ] phenanthridine alkaloid intermediate compound Download PDF

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CN116444478A
CN116444478A CN202310220698.7A CN202310220698A CN116444478A CN 116444478 A CN116444478 A CN 116444478A CN 202310220698 A CN202310220698 A CN 202310220698A CN 116444478 A CN116444478 A CN 116444478A
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reaction
compound
intermediate compound
naphthylamine
methylenedioxy
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叶力
陈旭栋
林玲
楼科侠
张达
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Ningbo Chemgoo Pharmaceutical Technology Innovation Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/70—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with ring systems containing two or more relevant rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/153—Ortho-condensed systems the condensed system containing two rings with oxygen as ring hetero atom and one ring with nitrogen as ring hetero atom
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract

The invention relates to the field of medicine synthesis, and discloses a preparation method and application of an aromatic benzo [ c ] phenanthridine alkaloid intermediate compound. The method takes 1, 2-methylenedioxybenzene (piperonyl) as a starting material to replace pipe compound piperonal to synthesize aromatic benzo [ c ] phenanthridine alkaloid intermediate compounds (6, 7-methylenedioxy-1-naphthylamine and N-methyl-6, 7- (methylenedioxy) -1-naphthylamine), and has the advantages of easily available raw materials, short steps, mild reaction conditions, low production cost, environmental protection, high yield and high purity. In addition, the synthesis of the N-methyl-6, 7- (methylenedioxy) -1-naphthylamine is more convenient and faster without the need of column chromatography purification through a 6, 7-methylenedioxy-1-naphthylamine intermediate.

Description

Preparation method and application of aromatic benzo [ c ] phenanthridine alkaloid intermediate compound
Technical Field
The invention relates to the field of medicine synthesis, in particular to a preparation method and application of an aromatic benzo [ c ] phenanthridine alkaloid intermediate compound.
Background
Aromatic benzo [ c ] phenanthridine alkaloids are alkaloid components in many traditional Chinese medicines, have antiviral, antimalarial, antifungal, antitumor and other effects, and are widely focused and studied. Such as Sanguinarine (SA), chelerythrine (CHE), nitidine chloride (Nitidine Chloride, NC), and the like.
The benzo [ c ] phenanthridine skeleton mainly consists of a phenanthridine ring (A, B, C ring) and 1 benzene ring (D ring), and the synthetic methods can be classified by the order in which the rings are constructed, i.e., the synthetic methods are classified according to which ring formation is the last step in constructing the structure. According to the prior art, the construction of the B-or C-ring in the last step is the most common method for the synthesis of such compounds.
Wherein, 6, 7-methylenedioxy-1-naphthylamine (compound I) is a key intermediate for constructing benzo [ c ] phenanthridine skeleton B ring such as sanguinarine, chelerythrine, chloridized nitine and the like.
Compound I
The compound I can be prepared into an alpha-tetralone intermediate (intermediate compound II) by taking piperonal (compound A1) as a starting material, performing 3-step reaction of Wittg olefination (3-bromopropionic acid triphenylphosphine salt is initiated by NaH in a THF/DMSO solvent system for 20h; hydrochloric acid quenching and ethyl acetate extraction), catalytic hydrogenation (0.2 eq Pd/C, methanol solvent and diatomite filtration and vacuum concentration), F-C acylation (PPA, dichloromethane solvent and reflux for 4h, saturated sodium bicarbonate solution quenching and vacuum concentration) and then performing column chromatography, wherein the yield is 66%; then the product is prepared by 3 steps of ketoximation, benzene methanesulfonylation, semmler-Wolff aromatization and column chromatography, the yield is 50 percent, and the route is shown as follows.
De，Subhadip，et al.″Expeditious approach to pyrrolophenanthridones，phenanthridines，and benzo[c]phenanthridines via organocatalytic direct biaryl-coupling promoted by potassium tert-butoxide.″The Journal of organic chemistry 78.16(2013)：7823-7844
On the other hand, N-methyl-6, 7- (methylenedioxy) -1-naphthylamine is also a key intermediate for constructing a B ring of a benzo [ c ] phenanthridine skeleton, such as sanguinarine, chelerythrine and nitidine chloride.
N-methyl-6, 7- (methylenedioxy) -1-naphthylamine Subhadip De et al (JOC 2013), piperonal is used as a starting material, a Wittg olefination, catalytic hydrogenation and F-C acylation are carried out for 3 steps, and then column chromatography is carried out to prepare an alpha-tetralone intermediate compound (a literature compound 13 d), wherein the yield is 66%; 3 steps of ketoximation, benzene methanesulfonylation, semmler-Wolff aromatization reaction and column chromatography to prepare naphthylamine intermediate (literature compound 14 b) with the yield of 50%; then N-acylating methyl chloroformate, reducing lithium aluminum hydride for 2 steps of reaction, and preparing N-methyl-6, 7- (methylenedioxy) -1-naphthylamine (literature compound 15 b) by column chromatography, wherein the yield is 65%; the route is shown below.
Harayama et al (Synthesis 2002) prepared N-methyl naphthylamine compound (literature compound 17) in 76% yield by N-acylation with trifluoroacetic anhydride, N-methylation with methyl iodide, and basic hydrolysis starting from naphthylamine (literature compound 15).
The preparation of N-methyl naphthylamine from naphthylamine requires at least 2 steps of reaction, and the overall reaction route is prolonged; the yield of the N-acylation and N-methylation routes is 76%, and a genotoxic methylation reagent such as methyl iodide and the like is required to be used; the yield of the N-acylation and reduction routes is 65%, and strong alkaline reagents such as a pungent methyl chloroformate reagent, living wave lithium aluminum hydride and the like are required to be used, so that hidden hazards such as operation and product use safety exist, and the method is not suitable for industrial production.
In addition, piperonal belongs to a non-drug type easy-to-poison chemical in the first class, is limited in supply and is difficult to be practically applied to mass industrial production. Therefore, it is necessary to develop an alternative synthetic route which has the advantages of easily available raw materials, short preparation process, mild reaction conditions, low production cost, environmental protection, high yield and high purity.
Disclosure of Invention
In order to solve the technical problems, the invention provides a preparation method and application of an aromatic benzo [ c ] phenanthridine alkaloid intermediate compound. The method takes 1, 2-methylenedioxybenzene (piperonyl) as a starting material to replace pipe 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), and has the advantages of easily available 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 medicinal products. Wherein, the synthesis of N-methyl-6, 7- (methylenedioxy) -1-naphthylamine is not carried out by a 6, 7-methylenedioxy-1-naphthylamine intermediate, and column chromatography purification is not needed, thus being more convenient.
The specific technical scheme of the invention is as follows:
in a first aspect, the present invention provides a process for the preparation of an alpha-tetralone intermediate compound:
(1) 1, 2-methylenedioxybenzene A2 (piperonyl) is taken as a starting material, F-C is acylated to obtain a compound B, then catalytic hydrogenation and hydrolysis are carried out to obtain a compound C, and finally cyclization reaction is carried out to obtain an alpha-tetralone intermediate compound II, wherein the synthetic route is shown as follows:
preferably, in the step (1), the F-C acylation to 1, 2-methylenedioxybenzene is carried out with an acylating agent and a catalyst A in a reaction solvent A at a reaction temperature of 0-40 ℃.
Further preferably, in the step (1), the acylating agent is selected from butyric anhydride, monoethyl succinate acid chloride or monomethyl succinate acid chloride, etc.; the catalyst A is selected from anhydrous aluminum trichloride, anhydrous ferric trichloride, trifluoroacetic acid, anhydrous zinc chloride, PPA, ferric trichloride 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 F-C acylation is 10-30 ℃; the equivalent ratio of the 1, 2-methylenedioxybenzene, the acylating agent and the catalyst A is 1:1-1.5:1-1.5.
Preferably, in step (1), the catalytic hydrogenation to compound B and catalyst B is carried out in reaction solvent B at a reaction temperature of 50-80 ℃.
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; the reaction temperature of the catalytic hydrogenation is 60-80 ℃.
Preferably, in the step (1), the cyclization reaction is carried out by reacting the compound C with the acid catalyst C in the reaction solvent C at a reaction temperature of 20-110 ℃.
Further preferably, in step (1), the acidic catalyst C is selected from one or more of polyphosphoric acid, sulfuric acid, methanesulfonic acid, ferric trichloride, aluminum trichloride, tin tetrachloride, acetic anhydride, boron trifluoride diethyl ether, 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 ℃; the equivalent ratio of the compound C to each of the acidic catalysts C is 1:0.5-1.5.
In a second aspect, the invention provides a method for preparing an aromatic benzo [ c ] phenanthridine alkaloid intermediate compound (6, 7-methylenedioxy-1-naphthylamine):
(1) Preparation of alpha-tetralone intermediate compound II.
(2) The intermediate compound III is obtained by oximation reaction of the alpha-tetralone intermediate compound II, and finally the 6, 7-methylenedioxy-1-naphthylamine I is obtained by aromatization reaction, and the synthetic route is shown as follows:
preferably, in the step (2), the oximation reaction is carried out in a reaction solvent II at a reaction temperature of 40-80 ℃ for the compound II, the oximation reagent II and the buffer salt.
Further preferably, in the step (2), the oximating 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 ℃; 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.
Preferably, in the step (2), the aromatization reaction is carried out with the compound III and the catalyst III in a reaction solvent III at a reaction temperature of 110 to 280 ℃.
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; the aromatization reaction temperature is 150-250 ℃.
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):
(A) Preparation of alpha-tetralone intermediate compound II.
(B) The alpha-tetralone intermediate compound II is subjected to condensation reaction to obtain an intermediate compound E, and finally, N-methyl-6, 7- (methylenedioxy) -1-naphthylamine F is prepared through aromatization reaction; the synthetic route is as follows:
preferably, in step (B), the condensation reaction is carried out in a reaction solvent D at a reaction temperature of 40-80 ℃ for the α -tetralone intermediate compound II and methylamine.
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 preformed into a methylamine methanol solution, a methylamine ethanol solution and a methylamine isopropanol solution; the reaction temperature of the condensation reaction is 50-80 ℃; the equivalent ratio of the alpha-tetralone intermediate compound II to the methylamine is 1:2.0-10.0.
Preferably, in the step (B), the aromatization reaction is carried out with the intermediate compound E, the catalyst E and the hydrogen acceptor E, pH adjusting agent E in the reaction solvent E at a reaction temperature of 110 to 280 ℃.
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 regulating reagent E is one or more of sodium acetate, sodium bicarbonate, sodium carbonate and sodium phosphate; the reaction solvent E is one or more selected from mesitylene, dimethylbenzene, o-dichlorobenzene and m-dichlorobenzene; the aromatization reaction temperature is 150-250 ℃. The equivalent ratio of the intermediate compound E to the hydrogen acceptor E, pH regulating reagent E is 1:0.5-2.0:0.5-2.0.
In a fourth aspect, the invention provides application of the aromatic benzo [ c ] phenanthridine alkaloid intermediate compound in synthesis of sanguinarine, chelerythrine or nitidine chloride.
Compared with the prior art, the invention has the beneficial effects that:
(1) According to the invention, 1, 2-methylenedioxybenzene (piperonyl) is used as a starting material for synthesizing two aromatic benzo [ c ] phenanthridine alkaloid intermediate compounds (6, 7-methylenedioxy-1-naphthylamine and N-methyl-6, 7- (methylenedioxy) -1-naphthylamine) instead of piperonal which is a chemical raw material for easily preparing the pipe, and the piperonal is easy to obtain in raw material and low in cost.
(2) The invention takes 1, 2-methylenedioxybenzene (piperonyl) as a starting material, and synthesizes the alpha-tetralone intermediate compound through F-C acylation, catalytic hydrogenation, hydrolysis and cyclization reaction in sequence, wherein the reaction temperature in the cyclization reaction step is milder than that in the traditional route, the acid catalyst uses equivalent grade, and the three wastes are less generated.
(3) According to the invention, after the alpha-tetralone intermediate compound is obtained, the oximation reaction and the aromatization reaction are further carried out to prepare the 6, 7-methylenedioxy-1-naphthylamine, 3 steps (ketoximation, benzenesulfonylation, semmller-Wolff aromatization) of the prior art (comparative example 1) are shortened to 2 steps (oximation and aromatization), the steps are shorter, the protection and hydrolysis of oxime groups are omitted compared with the traditional route, the use of hazardous reagents such as NaH and the like are avoided, the post-treatment operations such as ethyl acetate extraction, saturated sodium chloride washing and the like are reduced, and the reaction is safer and more environment-friendly. In addition, the reaction condition is milder, the yield is higher, and the purity is higher.
(4) The invention further prepares N-methyl-6, 7- (methylenedioxy) -1-naphthylamine through condensation reaction and aromatization reaction after obtaining alpha-tetralone intermediate compound, compared with the prior art, the invention does not need to synthesize 6, 7-methylenedioxy-1-naphthylamine intermediate (comparative examples 2 and 3 need to synthesize 6, 7-methylenedioxy-1-naphthylamine intermediate first, and then synthesize N-methyl-6, 7- (methylenedioxy) -1-naphthylamine through multiple steps), the reaction steps are reduced by at least 2 steps, and the overall yield is improved; in addition, heterogeneous noble metal catalytic dehydrogenation conditions are adopted in the aromatization reaction, under the combined action of a hydrogen acceptor reagent and a pH regulator, aromatization of the tetralone imine substrate is successfully realized, the product yield is further improved, and impurities are effectively controlled.
Drawings
FIG. 1 is a GC spectrum of the product of example 1;
FIG. 2 is a GC spectrum of the product of example 2;
FIG. 3 is a GC spectrum of the product of example 3;
FIG. 4 is a GC spectrum of the product of example 4;
FIG. 5 is a GC diagram of the crude product of example 5;
FIG. 6 is a GC diagram of the product of example 5;
FIG. 7 is a GC diagram of the product of example 6;
FIG. 8 is a GC spectrum of the product of example 7.
Detailed Description
The invention is further described below with reference to examples.
General examples
The preparation method of the alpha-tetralone intermediate compound specifically comprises the following steps:
(1) 1, 2-methylenedioxybenzene A2 (piperonyl) is taken as a starting material, F-C is acylated to obtain a compound B, then catalytic hydrogenation and hydrolysis are carried out to obtain a compound C, and finally cyclization reaction is carried out to obtain an alpha-tetralone intermediate compound II, wherein the synthetic route is shown as follows:
specifically:
F-C acylation to 1, 2-methylenedioxybenzene with an acylating agent (preferably butyric anhydride, succinic acid monoethyl ester acyl chloride, succinic acid monomethyl ester acyl chloride, etc.), catalyst A (anhydrous aluminum trichloride, trifluoroacetic acid, anhydrous zinc chloride, PPA, ferric trichloride or silica gel supported methanesulfonic acid) in a reaction solvent A (preferably dichloromethane, nitromethane, nitrobenzene, etc.) at a reaction temperature of 0-40deg.C (preferably 10-30deg.C). Wherein the equivalent ratio of the 1, 2-methylenedioxybenzene, the acylating agent and the catalyst A is 1:1-1.5:1-1.5.
The catalytic hydrogenation to compound B and catalyst B (Pd/C) is carried out in a reaction solvent B (preferably methanol, ethanol, isopropanol, etc.) at a reaction temperature of 50 to 80 ℃ (preferably 60 to 80 ℃).
The cyclization reaction is carried out by reacting the compound C with an acidic catalyst C (preferably polyphosphoric acid, sulfuric acid, methanesulfonic acid, ferric trichloride, aluminum trichloride, stannic tetrachloride, acetic anhydride, boron trifluoride diethyl ether, trifluoroacetic acid, trifluoroacetic anhydride, PPE, etc.) in a reaction solvent C (preferably dichloromethane, toluene, chlorobenzene, etc.) at a reaction temperature of 20-110 ℃ (preferably 20-40 ℃). Wherein the equivalent ratio of the compound C to each acid catalyst C is 1:0.5-1.5.
The preparation method of the 6, 7-methylenedioxy-1-naphthylamine specifically comprises the following steps:
(1) Preparation of alpha-tetralone intermediate compound II.
(2) The intermediate compound III is obtained by oximation reaction of the alpha-tetralone intermediate compound II, and finally the 6, 7-methylenedioxy-1-naphthylamine I is obtained by aromatization reaction, and the synthetic route of the step (2) is shown as follows:
specifically:
the oximation reaction is carried out in a reaction solvent II (preferably methanol, ethanol, isopropanol, etc.) at a reaction temperature of 40-80 ℃ (preferably 50-80 ℃) in a buffer salt (preferably sodium acetate, potassium acetate, sodium hydroxide, etc.) and a oximation reagent II (preferably hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxylamine phosphate, etc.), wherein 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.
The aromatization reaction is carried out in the presence of a compound III and a catalyst III (Pd/C) at a reaction temperature of 110-280 ℃ (preferably 150-250 ℃) in a reaction solvent III (preferably diethylene glycol monomethyl ether, triethylene glycol monomethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, etc.).
A preparation method of N-methyl-6, 7- (methylenedioxy) -1-naphthylamine:
(A) Preparation of alpha-tetralone intermediate compound II.
(B) The alpha-tetralone intermediate compound II is subjected to condensation reaction to obtain an intermediate compound E, and finally, N-methyl-6, 7- (methylenedioxy) -1-naphthylamine F is prepared through aromatization reaction; the synthetic route of the step (B) is as follows:
specifically:
the condensation reaction is carried out in a reaction solvent D (preferably methanol, ethanol, isopropanol, etc.) at a reaction temperature of 40-80 ℃ (preferably 50-80 ℃), wherein the equivalent ratio of compound II to methylamine is 1:2.0-10.0.
The aromatization reaction is carried out with the compound E and the catalyst E (Pd/C) in a reaction solvent E (preferably mesitylene, xylene, o-dichlorobenzene, m-dichlorobenzene, etc.) at a reaction temperature of 110-280 ℃ (preferably 150-250 ℃). The equivalent ratio of the compound E to the hydrogen acceptor E, pH regulating reagent E is 1:0.5-2.0:0.5-2.0.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Examples 1-3: synthesis of alpha-tetralone intermediate compound
Example 1: F-C acylation to prepare intermediate compound B, r=et
100g of piperonyl loop, 500mL of dichloromethane and 148g of succinic acid monoethyl ester acyl chloride are added into a 2L four-port bottle, the temperature is reduced to 10 ℃, 146g of anhydrous ferric trichloride is added in batches, GC is tracked until the raw material reaction is finished, 110g of hydrochloric acid aqueous solution is added into a reaction bottle, stirring is carried out for 1h at a low temperature, 1L of water is added, the temperature is increased to 25 ℃ and stirring is carried out for 2h, layering is carried out, the aqueous phase is extracted by dichloromethane, the organic phases are combined, the brown viscous liquid 210.8g is obtained after reduced pressure distillation, the GC purity 87.96% (shown in figure 1), and the crude yield is 102.8% and is directly used for the next reaction.
Example 1a
50g of piperonyl loop, 200mL of nitrotoluene, 68g of monomethyl succinate acyl chloride are added into a 1L four-port bottle, the temperature is reduced to 20 ℃, 61.5g of anhydrous zinc chloride is added in batches, GC is tracked until the raw material reaction is finished, 60g of hydrochloric acid aqueous solution is added into a reaction bottle, stirring is carried out for 1h at a low temperature, 500mL of water is added, the temperature is increased to 25 ℃ and stirring is carried out for 2h, layering is carried out, the aqueous phase is extracted by methylene dichloride, the organic phases are combined, and 103.2g of brown viscous liquid is obtained after reduced pressure distillation, the GC purity is 89.91%, and the crude yield is 100.7%, and is directly used for the next reaction.
Example 1b
50g of piperonyl ring, 300mL of dichloromethane and 56g of trifluoroacetic acid are added into a 1L four-port bottle, the temperature is reduced to 15 ℃, 87.5g of succinic acid monoethyl ester acyl chloride is dropwise added, GC is tracked until the raw material reaction is finished, dichloromethane and trifluoroacetic acid are removed by reduced pressure rotary evaporation, 200mL of water is added, stirring is carried out for 2 hours at room temperature, the aqueous phase is extracted by dichloromethane, the organic phases are combined, and the brown viscous liquid 99.6g with 86.09% GC purity and 97.2% crude yield is obtained after reduced pressure distillation and is directly used for the next reaction.
The reagents and process parameter differences in examples 1a and 1b are shown in the following table:
example 2: catalytic hydrogenation and hydrolysis to prepare intermediate compound C
210.8g of compound B (R=Et) prepared in the first step (example 1) and 1000mL of ethanol, 10.5g of 5% Pd/C are added into a 2L autoclave, the autoclave is closed, hydrogen is discharged for 5 times, hydrogen is further introduced into the autoclave to 1.2MPa, the reaction is heated to 75 ℃ for 24 hours, the GC is tracked until the raw materials are reacted, the catalyst is filtered, a part of ethanol is removed by rotary evaporation, 500mL of water is added into the reaction liquid, 300g of 20% aqueous sodium hydroxide solution is dropwise added, the mixture is heated to 50 ℃ and stirred for 2 hours, the GC is tracked until the hydrolysis is completed (R is hydrolyzed into H from Et), most of ethanol is removed by reduced pressure distillation, the residual aqueous phase is extracted by methylene dichloride, the pH of the aqueous phase is regulated to about 1 by dropwise adding hydrochloric acid under ice, a large amount of solids are separated out, the GC purity is 99.39% (as shown in figure 2), and the total yield of the first step and the second step is 90.3%).
Example 2a
100.4g of the compound B (R=Me) prepared in the first step (example 1 a) and 600mL of methanol, 10.5g of 5% Pd/C are added into a 2L autoclave, the autoclave is closed, hydrogen is discharged for 5 times, hydrogen is further introduced into the autoclave to 1MPa, the autoclave is heated to 60 ℃ for reaction for 24 hours, the GC is tracked until the raw materials are reacted, the catalyst is filtered, a part of the methanol is removed by rotary evaporation, 250mL of water is added into the reaction liquid, 150g of 20% sodium hydroxide aqueous solution is dropwise added, the mixture is heated to 50 ℃ and stirred for 2 hours, the GC is tracked until the hydrolysis is completed (R is hydrolyzed into H from Me), most of the methanol is removed by reduced pressure distillation, the dichloromethane is extracted to obtain a residual aqueous phase, hydrochloric acid is dropwise added into the aqueous phase to adjust the pH to about 1, a large amount of solids are separated out, the product is filtered to obtain the compound C76.2 g, the GC purity is 98.97%, and the total yield of the first step and the second step is 89.4%.
Example 2b
99.6g of the compound B prepared in the first step (example 1B), 650mL of isopropanol, 5g of 10% Pd/C, closing the autoclave, introducing hydrogen for 5 times, introducing hydrogen to 1.1MPa, heating to 80 ℃ for reaction for 20 hours, keeping the temperature of the reaction product until the raw materials are reacted, filtering the catalyst, removing part of isopropanol by rotary evaporation of the filtrate, adding 250mL of water into the reaction solution, dropwise adding 150g of 20% sodium hydroxide aqueous solution, heating to 50 ℃ for 2 hours, carrying out GC tracking until the hydrolysis is completed (R is hydrolyzed into H from Et), distilling the most isopropanol alcohol under reduced pressure, extracting the residual aqueous phase with methylene dichloride, dropwise adding hydrochloric acid into the aqueous phase under ice water to adjust the pH to about 1, precipitating a large amount of solids, filtering to obtain the compound C75.8 g, and the GC purity of 98.59%, wherein the total yield of the first step and the second step is 88.9%.
The reagents, process parameter differences and test results in examples 2a and 2b are shown in the following table:
sequence number Compound B Catalyst B Reaction solvent B Temperature (temperature) Product(s) 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％
Example 3: preparation of intermediate compound II (alpha-tetralone intermediate compound) by cyclization reaction
500g of compound C (R=H) (example 2), 2500mL of dichloromethane, 356g of boron trifluoride diethyl etherate solution and 343g of acetic anhydride are added dropwise, stirring is carried out for 2H at room temperature after the completion of the addition, GC is tracked until the conversion of the raw materials is finished, 1000mL of water is added for continuous stirring for 5H, liquid separation is carried out, the organic layer is washed with water and separated, the organic layer concentrate is poured into 2.5L of water, stirring is carried out for 1H, 420g of compound II is obtained by filtering and drying, the GC purity is 99.23% (shown in figure 3), and the yield is 91.95%. Compound II was prepared from piperonyl via a combination yield of 83%.
Example 3a
200g of compound C (R=H), 1200mL of toluene, 142.5g of boron trifluoride diethyl etherate solution are added dropwise, 282g of trifluoroacetic anhydride are added dropwise, stirring is carried out for 2 hours at room temperature after the completion of the addition, GC is tracked until the conversion of the raw materials is finished, 500mL of water is added for continuous stirring for 5 hours, liquid separation is carried out, the organic layer is washed with water and separated, the organic layer concentrate is poured into 1L of water, stirring is carried out for 1 hour, 165.4g of compound II is obtained after filtration and drying, the GC purity is 99.40%, and the yield is 90.5%.
Example 3b
100g of compound C (R=H), 500mL of dichloromethane and 65g of methanesulfonic acid are added into a 1L four-mouth bottle, the temperature is raised to 40 ℃ after the addition of the compound C and the dichloromethane, the reaction is kept at a temperature of 40 ℃, GC is tracked until the conversion of raw materials is finished, 200mL of water is added, stirring is continued for 5H, liquid separation is carried out, an organic layer is washed with water and separated, an organic layer concentrate is poured into 500mL of water, stirring is carried out for 1H, filtering and drying are carried out, and 85.1g of compound II with the GC purity of 98.63% and the yield of 93.2% are obtained.
The reagents, process parameter differences and test results in examples 3a and 3b are shown in the following table:
examples 4 to 5 (Synthesis of 6, 7-methylenedioxy-1-naphthylamine)
Example 4: oximation preparation of Compound III
100g of compound II, 1000mL of methanol, 86g of sodium acetate and 55g of hydroxylamine hydrochloride are added into a 2L four-necked flask, stirring is carried out, the mixture is heated to 70 ℃ for reaction, GC is tracked until the conversion of the raw materials is finished, ethanol is removed by rotary evaporation, a rotary evaporation substrate is added into 500mL of water and is heated to 60 ℃ for stirring for 2 hours, cooling to room temperature is carried out, the mixture is filtered to obtain 102g of compound III, the purity of GC is 94% (shown in figure 4), and the yield is 94.5%.
Example 4a
50g of compound II, 600mL of ethanol, 38.8g of potassium acetate and 56.1g of hydroxylamine sulfate are added into a 1L four-necked flask, stirring is carried out, the mixture is heated to 80 ℃ for reaction, GC is tracked until the raw material conversion is finished, ethanol is removed by rotary evaporation, a rotary evaporation substrate is added into 250mL of water and heated to 60 ℃ for stirring for 2 hours, cooling to room temperature, and filtering is carried out to obtain 52.4g of compound III with GC purity of 90.55% and yield of 97.1%.
Example 4b
50g of compound II, 500mL of isopropanol, 11.6g of sodium hydroxide and 38g of hydroxylamine phosphate are added into a 1L four-necked flask, stirring is carried out, the mixture is heated to 75 ℃ for reaction, GC is tracked until the raw material conversion is finished, the isopropanol is removed by rotary evaporation, the rotary evaporation substrate is added into 250mL of water and heated to 60 ℃ for stirring for 2 hours, the mixture is cooled to room temperature, and the mixture is filtered to obtain 51.6g of compound III with the GC purity of 87.01 percent and the yield of 95.6 percent.
The reagents, process parameter differences and test results for examples 4a and 4b are shown in the following table:
sequence number Compound C Oximation reagent II and buffer salt Reaction solvent II Temperature (temperature) Product(s) 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 Isopropanol 500ml 75℃ 51.6g 87.01％，95.6％
Example 5: aromatization to prepare compound I (6, 7-methylenedioxy-1-naphthylamine)
In a 250mL four-necked flask, 5g of Compound III,50mL of triethylene glycol dimethyl ether, 1g of 10% Pd/C and 2g of sodium bicarbonate were added, and the reaction mixture was heated to 230℃with stirring to react, followed by GC until the conversion of the raw materials was completed. Cooled to room temperature, filtered, and the filtrate was added to 300mL of ice water, filtered and dried to give crude 4.3g, 94.7% GC purity (as shown in FIG. 5).
The crude product was added to 100mL of methanol, followed by addition of 0.2g of activated carbon, filtration after heating to dissolve, cooling of the filtrate to room temperature, and filtration gave 3.2g of yellow crystals with a GC purity of 99.15% (as shown in FIG. 5) and a yield of 70.2%.
Example 5a
5g of compound III,70mL of diethylene glycol monomethyl ether, 1g of 10% Pd/C and 2g of sodium bicarbonate are placed in a 250mL four-necked flask, the reaction mixture is stirred and heated to 180 ℃ for reaction, and the GC is tracked until the conversion of the raw materials is completed. Cooled to room temperature, filtered, and the filtrate was added to 300mL of ice water, filtered and dried to give crude 4.5g, GC purity 90.53%.
The crude product is added into 100mL of methanol, then 0.2g of active carbon is added, the solution is heated and filtered, the filtrate is cooled to room temperature, and the yellow crystal 3.4g is obtained after filtration, the GC purity is 98.93%, and the yield is 74.5%.
Example 5b
In a 250mL four-necked flask, 5g of compound III,60mL of diethylene glycol dimethyl ether, 2g of 5% Pd/C and 2g of sodium bicarbonate were added, and the reaction mixture was heated to 160℃with stirring to react, followed by GC until the conversion of the raw materials was completed. Cooled to room temperature, filtered, and the filtrate was added to 300mL of ice water, filtered and dried to give crude 4.4g, GC purity 87.97%.
The crude product is added into 100mL of methanol, then 0.2g of active carbon is added, the solution is heated and filtered, the filtrate is cooled to room temperature, and the yellow crystal 3.3g with the GC purity of 99.42% and the yield of 72.3% is obtained by filtration.
The reagents, process parameter differences and test results in examples 5a and 5b are shown in the following table:
comparative example 1: synthesis of 6, 7-methylenedioxy-1-naphthylamine
Synthetic methods and data described in reference of comparative example 1 (De, subhalip, et al The Journal of organic chemistry 78.16 (2013): 7823-7844):
(1) Synthesis of alpha-tetralone intermediate Compound II: piperonal is used as a starting material, and is subjected to Wittg olefination, catalytic hydrogenation and F-C acylation for 3 steps, and then column chromatography is carried out to prepare an alpha-tetralone intermediate compound II (a literature compound 13 d), wherein the combined yield is 66%. The method comprises the following steps:
wittg olefination: 1.0eq of triphenylphosphine 3-bromopropionate was cooled to 0℃in a 1:1 THF/DMSO solvent system (2 ml/1 mmol), 2.5eq of NaH was added in portions, stirred for 10min, 1eq of piperonal (149.5 mmol) in 1:1 THF/DMSO solution (10 ml) was added dropwise at 0℃and reacted at room temperature for 20h; TLC monitoring the complete reaction of the raw materials, quenching with 4N hydrochloric acid, adding 100ml of ethyl acetate, and extracting with 100ml of water solution; the aqueous layer was extracted 2 times with 50ml ethyl acetate. The organic layers were combined, dried and concentrated under reduced pressure.
Catalytic hydrogenation: the alkylene intermediate (1.0 eq) was filtered over 0.2eq Pd/C, methanol solvent, celite and concentrated in vacuo.
F-C acylation: PPA, dichloromethane solvent, reflux for 4h, quench with saturated sodium bicarbonate solution, concentrate in vacuo.
(2) Synthesis of 6, 7-methylenedioxy-1-naphthylamine: the compound II is subjected to 3 steps of ketoxime reaction, benzenesulfonylation and Semmler-Wolff aromatization, and then is subjected to column chromatography to prepare the compound I (6, 7-methylenedioxy-1-naphthylamine). The method comprises the following steps:
ketoximation: 2g of Compound II (10.5 mmol), 2.5eq hydroxylamine hydrochloride, 1.5eq sodium acetate, 3ml ethanol, 4ml water are added and stirred at room temperature for 2h, TLC is followed until the starting material disappears, diluted with 20ml ethyl acetate, and extracted with 20ml water layer; the organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo, and the product was not isolated.
Benzenesulfonylation: the product of the last step (10.5 mmol) was added with ethylene glycol dimethyl ether under argon, cooled to 0 ℃, 5.0eq of NaH was added in portions, 3.0eq of p-TsCl was added, the mixture was warmed to room temperature and reacted for 24h at 70℃in an oil bath. TLC was followed until the starting material disappeared, the reaction was quenched with ice, extracted with 30ml of ethyl acetate and 15ml of aqueous solution was added. The organic layer was dried and concentrated in vacuo and the product was not isolated.
Aromatization: the product of the previous step (10.5 mmol) was added with KOH/methanol solution and methanol solvent; the dark red reaction was refluxed for 6h, cooled to room temperature, poured into 20ml ice water and extracted 2 times with 10ml ethyl acetate. Washing with saturated sodium chloride, drying with anhydrous sodium sulfate, concentrating under reduced pressure, separating by column chromatography to obtain black solid compound I (eluting solvent 30% ethyl acetate/n-hexane), and combining the yield of 50% without purity data.
Preparation of compound I (6, 7-methylenedioxy-1-naphthylamine) from compound II the synthetic route constituted by examples 1 to 5 of the present invention has the following advantages over comparative example 1:
(1) The reaction step of synthesizing 6, 7-methylenedioxy-1-naphthylamine from the compound II is shortened from 3 steps (ketoximation, benzenesulfonylation, semmler-Wolff aromatization) of comparative example 1 to 2 steps (oximation, aromatization), the combined yield is 66%, which is far higher than that of comparative example 1;
(2) Compared with comparative example 1, the method omits the protection of the p-toluenesulfonyl of the oxime group and the KOH/methanol hydrolysis, avoids using hazardous reagents such as NaH and the like, reduces the post-treatment operations such as extraction of ethyl acetate, washing with saturated sodium chloride and the like, and is safer and more environment-friendly.
(3) The compound I (6, 7-methylenedioxy-1-naphthylamine) obtained by the invention has high purity, yellow crystals and GC purity of 99.15%, and comparative example 1 is a black solid without purity data; the post-treatment operation is simple, and the high-purity compound I crystals can be obtained only by recrystallisation from methanol without column chromatography elution and separation.
Examples 6 to 7 (N-methyl-6, 7- (methylenedioxy) -1-naphthylamine)
Example 6: preparation of ketimine Compound E by condensation reaction
10g of crude product of the compound II, 21.8g of 30% methylamine methanol solution are added into a thick-wall pressure-resistant bottle, the bottle is sealed and placed into an oil bath, the temperature is raised to 50 ℃, the temperature is kept for stirring and reacting for 16 hours, the temperature is reduced to-10 ℃, the temperature is kept for stirring for 3 hours, the mixture is filtered, a filter cake is washed 2 times by 15ml of methanol, reaction mother liquor and methanol concentrated solution are recycled (new compound II and methylamine methanol solution are added for re-reaction), the solid is dried to 7.3g, the GC purity is 94.20% (as shown in figure 7), the yield is 68.3% (mother liquor is recycled 1 time and the total yield is more than 88%).
Example 6a
Adding 20g of crude product of the compound II into a thick-wall pressure-resistant bottle, sealing, placing in an oil bath after sealing, heating to 70 ℃, preserving heat, stirring for reaction for 12h, cooling to-10 ℃, preserving heat, stirring for 3h, filtering, washing a filter cake with 30ml of isopropanol for 2 times, recycling reaction mother liquor and isopropanol concentrated solution (new compound II and methylamine isopropanol solution can be added for re-reaction), drying the solid for 13.9g, ensuring that the GC purity is 91.03%, and the yield is 65.0% (mother liquor recycling and application for 1 time, and the total yield is more than 86%).
Example 6b
100g of crude product of the compound II is added into a thick-wall pressure-resistant bottle, 355g of 30% methylamine ethanol solution is sealed and placed into an oil bath, the temperature is raised to 60 ℃, the temperature is kept for stirring and reacting for 12 hours, the temperature is reduced to-10 ℃, the temperature is kept for stirring for 3 hours, the filtration is carried out, a filter cake is washed with 150ml of ethanol for 2 times, reaction mother liquor and ethanol concentrate are recycled (new compound II and methylamine ethanol solution can be added for re-reaction), solid is dried for 72.8g, the GC purity is 93.74%, the yield is 68.1% (mother liquor is recycled for 1 time, and the total yield is more than 90%).
The reagents, process parameter differences and test data for examples 6a and 6b are shown in the following table:
sequence number Compound II Methylamine reagent + reaction solvent Temperature (temperature) Product(s) GC purity, yield
Example 6a 20g 20% methylamine isopropyl alcohol 32.6g 70℃ 13.9g 91.03％，65.0％
Example 6b 100g 355g of 30% methylamine ethanol 60℃ 72.8g 93.74％，68.1％
Example 7: aromatization for preparing N-methyl-6, 7- (methylenedioxy) -1-naphthylamine F
1g of 5% Pd/C, 4.7g of naphthalene, 6g of sodium carbonate and 150mL of mesitylene are added into a 500mL four-port bottle, the temperature is raised to 150 ℃ and the mixture is stirred, 15g of mesitylene solution of an imine crude product E is slowly added, the mixture is reacted for 5 hours at 150 ℃, the temperature is reduced and filtered, the filtrate is transferred into a 500mL four-port bottle, 100mL of 10% sulfuric acid aqueous solution is dripped, the mixture is heated to 50 ℃ and is stirred for 1 hour at a temperature, the liquid is separated and the aqueous phase is combined, the pH of the aqueous phase is adjusted to 11-12, the solid is separated, the mixture is extracted by methylene dichloride, the organic phase is combined and the mixture is distilled in a rotary way, 10.4g of brown solid is obtained, the purity is 96.88% (shown in figure 8), and the yield is 70%.
Example 7a
1g of 5% Pd/C, 9.85g of ethyl methacrylate, 9g of sodium acetate and 200ml of xylene are added into a 1L four-port bottle, the temperature is raised to 140 ℃ and the mixture is stirred, 20g of xylene solution of an imine crude product E is slowly added, the mixture is reacted for 6 hours at 140 ℃, the temperature is reduced and filtered, the filtrate is transferred into the 1L four-port bottle, 300ml of 10% sulfuric acid aqueous solution is dropwise added, the temperature is raised to 50 ℃ and the mixture is kept for 1 hour, the liquid separation and the aqueous phase are combined, the pH of the aqueous phase is adjusted to 11-12, the solid is separated, the mixture is extracted by methylene dichloride, the organic phase is combined and the mixture is distilled in a rotary way, 14g of brown solid is obtained, the purity is 96.19%, and the yield is 70.7%.
Example 7b
1.2g of 10% Pd/C, 48.3g of cyclohexanone, 22.7g of sodium bicarbonate and 500ml of o-dichlorobenzene are added into a 2L four-port bottle, the temperature is raised to 170 ℃ and the mixture is stirred, 50g of o-dichlorobenzene solution of an imine crude product E is slowly added, the mixture is reacted for 4 hours at 150 ℃, the temperature is reduced and filtered, the filtrate is transferred into a 2L four-port bottle, 750ml of 10% sulfuric acid aqueous solution is dropwise added, the mixture is heated to 50 ℃ and stirred for 1 hour under heat preservation, the liquid is separated and the aqueous phase is combined, the pH of the aqueous phase is regulated to 11-12, the solid is separated, the mixture is extracted by methylene dichloride, and the organic phase is combined and distilled in a rotary way, thus obtaining 37.2g of brown solid with the purity of 93.3% and the yield of 75.2%.
The reagents, process parameter differences and test data for examples 7a and 7b are shown in the following table:
comparative example 2: synthesis of N-methyl-6, 7- (methylenedioxy) -1-naphthylamine (piperonal as starting material, via 6, 7-methylenedioxy-1-naphthylamine intermediate)
Synthetic methods and data described in the references (De, subhadip, et al The Journal of organic chemistry 78.16.16 (2013): 7823-7844):
(1) Synthesis of alpha-tetralone intermediate Compound II: as in comparative example 1.
(2) Synthesis of 6, 7-methylenedioxy-1-naphthylamine: as in comparative example 1.
(3) Synthesis of N-methyl-6, 7- (methylenedioxy) -1-naphthylamine: the 6, 7-methylenedioxy-1-naphthylamine is N-acylated by methyl chloroformate, the lithium aluminum hydride is reduced for 2 steps, and then the N-methyl-6, 7- (methylenedioxy) -1-naphthylamine (literature compound 15 b) is prepared by column chromatography, and the purity data is absent, and the yield is 65%. The method comprises the following steps:
n-acylation: 15mmol of 6, 7-methylenedioxy-1-naphthylamine (1.0 eq), 20ml of toluene/sodium bicarbonate, 2.0eq of methyl chloroformate were added dropwise to the flask, stirred at room temperature for 4h, TLC monitored complete reaction, 30ml of ethyl acetate/25 ml of water were added to extract the separated liquid, the organic layer was concentrated under reduced pressure, and the product was not isolated and used directly in the next reaction.
Lithium aluminum hydride reduction: the product of the last step (1.0 eq) was added to 30ml of dry THF under argon and cooled to 0 ℃. 2.0eq LiAlH was added in portions over 10min 4 Stirring at 0deg.C for 5min, heating the reaction system to 23deg.C, and stirring for 10min; the reaction system was refluxed at 80℃in an oil bath for 6h, and the reaction was complete by TLC. The mixture was cooled to room temperature, continued to cool to 0deg.C, quenched with ethyl acetate, made basic with 4N NaOH, and extracted 2 times with 25ml ethyl acetate. The organic layers were combined, washed with 10ml of NaCl solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purifying the crude product by column chromatography to obtain N-methyl-6, 7- (methylenedioxy) -1-naphthylamine.
Comparative example 3: preparation of N-methyl-6, 7- (methylenedioxy) -1-naphthylamine from 6, 7-methylenedioxy-1-naphthylamine
Methods and data for Synthesis described in the references (Harayama, takashi; et al Synthesis (2002), (2), 237-241):
6, 7-methylenedioxy-1-naphthylamine is used as a starting material, N-acylation and methyl iodide N-methylation are carried out by trifluoroacetic anhydride, and the N-methyl-6, 7- (methylenedioxy) -1-naphthylamine is prepared by alkaline hydrolysis, and the yield is 76%. The method comprises the following steps:
n-acylation: 100mg of 6, 7-methylenedioxy-1-naphthylamine (0.53 mmol), 3ml of anhydrous pyridine solution, 0.11ml of trifluoroacetic anhydride was added thereto, stirred at 0℃for 30min, poured into 10ml of 10% HCl, extracted with diethyl ether, and the residue diethyl ether-N-hexane was recrystallized to obtain 140mg of N-trifluoroacetyl naphthylamine (Synthesis 2002 document compound 16) in 93% yield.
N-methylation: 105mg of N-trifluoroacetyl naphthylamine (0.37 mmol), 205mg of MeI,10ml of anhydrous acetone solution, 82.2mg of KOH as a solid were added, and the reaction was refluxed for 20min and concentrated under reduced pressure. The residue was dissolved in 10ml of ethanol/5 ml of 5% NaOH, refluxed for 10min, added with 40ml of water and extracted with 100ml of diethyl ether. Ethanol recrystallization of the concentrate gave N-methyl-6, 7- (methylenedioxy) -1-naphthylamine (Synthesis 2002, compound 17).
The synthetic routes constituted by examples 1-3 and 6-7 of the present invention have the following advantages over comparative examples 2 and 3 of the literature: (1) The synthetic route of the N-methyl-6, 7- (methylenedioxy) -1-naphthylamine is short, the intermediate of the 6, 7-methylenedioxy-1-naphthylamine is not needed, the reaction steps are reduced by at least 2 steps, and the overall yield is improved;
(2) 1, 2-methylenedioxybenzene (piperonyl) is used as a starting material to replace pipe compound piperonal, so that the accessibility of the raw material is improved, and the safety of a supply chain is ensured;
(3) Under the combined action of a hydrogen acceptor reagent and a pH regulator, the heterogeneous noble metal catalytic dehydrogenation condition is adopted to successfully realize aromatization of the tetralone imine substrate, so that the product yield is high and the impurities are effectively controlled.
The raw materials and equipment used in the invention are common raw materials and equipment in the field unless specified otherwise; the methods used in the present invention are conventional in the art unless otherwise specified.
The foregoing description is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and any simple modification, variation and equivalent transformation of the above embodiment according to the technical substance of the present invention still fall within the scope of the technical solution of the present invention.

Claims (18)

1. A process for the preparation of an alpha-tetralone intermediate compound, characterized by:
(1) 1, 2-methylenedioxybenzene A2 is taken as a starting material, F-C is acylated to obtain a compound B, then catalytic hydrogenation and hydrolysis are carried out to obtain a compound C, and finally cyclization reaction is carried out to obtain an alpha-tetralone intermediate compound II, wherein the synthetic route is shown as follows:
2. the method of manufacturing according to claim 1, wherein: in the step (1), the F-C acylation of 1, 2-methylenedioxybenzene, an acylating agent and a catalyst A are carried out in a reaction solvent A at a reaction temperature of 0-40 ℃.
3. The method of manufacturing as claimed in claim 2, wherein: in the step (1), the step of (a),
the acylating reagent is selected from butyric anhydride, succinic acid monoethyl ester acyl chloride or succinic acid monomethyl ester acyl chloride;
the catalyst A is selected from anhydrous aluminum trichloride, anhydrous ferric trichloride, trifluoroacetic acid, anhydrous zinc chloride, PPA, ferric trichloride 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 F-C acylation is 10-30 ℃;
the equivalent ratio of the 1, 2-methylenedioxybenzene, the acylating agent and the catalyst A is 1:1-1.5:1-1.5.
4. The method of manufacturing according to claim 1, wherein: in step (1), the catalytic hydrogenation to compound B and catalyst B is carried out in reaction solvent B at a reaction temperature of 50-80 ℃.
5. The method of manufacturing according to claim 4, wherein: in the step (1), the step of (a),
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 ℃.
6. The method of manufacturing according to claim 1, wherein: in the step (1), the cyclization reaction is carried out by the compound C and the acid catalyst C in a reaction solvent C at a reaction temperature of 20-110 ℃.
7. The method of manufacturing according to claim 6, wherein: in the step (1), the step of (a),
the acid catalyst C is selected from one or more of polyphosphoric acid, sulfuric acid, methanesulfonic acid, ferric trichloride, aluminum trichloride, stannic chloride, acetic anhydride, boron trifluoride diethyl ether, 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 ℃;
the equivalent ratio of the compound C to each of the acidic catalysts C is 1:0.5-1.5.
8. A preparation method of an aromatic benzo [ c ] phenanthridine alkaloid intermediate compound is characterized by comprising the following steps of: the aromatic benzo [ c ] phenanthridine alkaloid intermediate compound is 6, 7-methylenedioxy-1-naphthylamine, and the preparation method comprises the following steps:
(1) Synthesizing an alpha-tetralone intermediate compound II from the preparation method of any one of claims 1 to 7;
(2) The alpha-tetralone intermediate compound II is subjected to oximation reaction to obtain an intermediate compound III, and finally, the intermediate compound III is subjected to aromatization reaction to obtain 6, 7-methylenedioxy-1-naphthylamine I, wherein the synthetic route is shown as follows:
9. the method of preparing as claimed in claim 8, wherein: in the step (2), the oximation reaction is that the compound II, the oximation reagent II and the buffer salt are carried out in a reaction solvent II at a reaction temperature of 40-80 ℃.
10. The method of preparing as claimed in claim 8, wherein: in the step (2), the step of (C),
the oximation reagent II is one or more selected from 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 ℃;
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 method of preparing as claimed in claim 8, wherein: in the step (2), the aromatization reaction is carried out by using a compound III and a catalyst III at a reaction temperature of 110-280 ℃ in a reaction solvent III.
12. The method of manufacturing as claimed in claim 11, wherein: in the step (2), the step of (C),
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 ℃.
13. A preparation method of an aromatic benzo [ c ] phenanthridine alkaloid intermediate compound is characterized by comprising the following steps of:
the aromatic benzo [ c ] phenanthridine alkaloid intermediate compound is N-methyl-6, 7- (methylenedioxy) -1-naphthylamine, and the preparation method comprises the following steps:
(A) Synthesizing an alpha-tetralone intermediate compound II from the preparation method of any one of claims 1 to 7;
(B) The alpha-tetralone intermediate compound II is subjected to condensation reaction to obtain an intermediate compound E, and finally, N-methyl-6, 7- (methylenedioxy) -1-naphthylamine F is prepared through aromatization reaction; the synthetic route is as follows:
14. the method of manufacturing as claimed in claim 13, wherein: in the step (B), the step of (B),
the condensation reaction is carried out by using an alpha-tetralone intermediate compound II and methylamine in a reaction solvent D at a reaction temperature of 40-80 ℃.
15. The method of preparing as claimed in claim 14, wherein: in the step (B), the step of (B),
the reaction solvent D is selected from one or more of methanol, ethanol and isopropanol;
the methylamine and the reaction solvent D are preformed into a methylamine methanol solution, a methylamine ethanol solution and a methylamine isopropanol solution;
the reaction temperature of the condensation reaction is 50-80 ℃;
the equivalent ratio of the alpha-tetralone intermediate compound II to the methylamine is 1:2.0-10.0.
16. The method of manufacturing as claimed in claim 13, wherein: in the step (B), the step of (B),
the aromatization reaction is carried out by using an intermediate compound E, a catalyst E and a hydrogen acceptor E, pH regulating reagent E at a reaction temperature of 110-280 ℃ in a reaction solvent E.
17. The method of manufacturing as claimed in claim 16, wherein: in the step (B), the step of (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 regulating reagent E is one or more of sodium acetate, sodium bicarbonate, sodium carbonate and sodium phosphate;
the reaction solvent E is one or more selected from mesitylene, dimethylbenzene, o-dichlorobenzene and m-dichlorobenzene;
the aromatization reaction temperature is 150-250 ℃;
the equivalent ratio of the intermediate compound E to the hydrogen acceptor E, pH regulating reagent E is 1:0.5-2.0:0.5-2.0.
18. Use of an aromatic benzo [ c ] phenanthridine alkaloid intermediate compound prepared by the preparation method according to any one of claims 8-17 for the synthesis of sanguinarine, chelerythrine or nitine chloride.
CN202310220698.7A 2022-03-07 2023-03-03 Preparation method and application of aromatic benzo [ c ] phenanthridine alkaloid intermediate compound Pending CN116444478A (en)

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