Preparation method of medical intermediate 6-methoxy-1-tetralone

Abstract

The invention discloses a preparation method of a medical intermediate 6-methoxy-1-tetralone, which comprises the following steps: S1, carrying out hydrogenation reduction on 2-naphthol under the action of a catalyst and a promoter to prepare 5, 6, 7, 8-tetrahydro-2-naphthol; s2, 5, 6, 7, 8-tetrahydro-2-naphthol and an oxidizing agent X are subjected to a reaction, and 6-hydroxy-3, 4-dihydronaphthalene-1-one is prepared; s3, enabling the 6-hydroxyl-3, 4-dihydronaphthalene-1-ketone to react with a methylation reagent in an alkaline environment, so as to prepare 6-methoxyl-1-tetralone, and enabling the 6-hydroxyl-3, 4-dihydronaphthalene-1-ketone to react with a methylation reagent in an alkaline environment; wherein the oxidizing agent X comprises at least one of oxygen, hydrogen peroxide, tert-butyl hydroperoxide, potassium permanganate, tetrabutylammonium perchlorate, pyridine chlorochromate, 2, 3-dichloro-5, 6-dicyanobenzoquinone, chromium trioxide, ceric ammonium nitrate, potassium persulfate, 1, 4-benzoquinone and chloranil; the feeding molar ratio of the oxidizing agent X to the 5, 6, 7, 8-tetrahydro-2-naphthol is (1.0 to 2.5): 1.0. The method has the advantages of mild reaction conditions, high molar total yield, high purity, low cost and toxicity of raw materials, less discharge of three wastes, and clean process, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of compound preparation, and in particular relates to a preparation method of a pharmaceutical intermediate 6-methoxy-1-tetralone. Background Art

[0002] Steroids are natural chemical substances that are widely present in nature and were first discovered in animals and plants. The applications of steroid compounds involve multiple aspects such as health care, birth control, medicine, agriculture, and animal husbandry, and play a crucial role in the life activities of animals and plants. The research on steroid compounds has a history of more than 100 years. Therefore, steroid drugs have also become the second largest category of drugs after antibiotics.

[0003] Reacting 6-methoxy-1-tetralone with methyl D-ring and ethyl D-ring respectively, and then through multiple-step chemical synthesis, most of the current steroid drugs can be prepared. Moreover, the compounds with an ethyl group at the 13th position in steroid progestins must be prepared by the total synthesis of 6-methoxy-1-tetralone and ethyl D-ring. Therefore, 6-methoxy-1-tetralone, as a crucial basic raw material in the total synthesis field of steroid drugs such as 18-methyl norethindrone and gestrinone, has high economic value in the development of cleaner synthesis routes with higher selectivity, higher yield, and lower cost in modern steroid drug preparation.

[0004] According to the "Compilation of Pharmaceutical Processes", the traditional preparation method of 6-methoxy-1-tetralone uses 2-naphthol as the raw material, which is prepared through methylation, high-pressure catalytic hydrogenation, and oxidation with chromium trioxide. This reaction requires the use of a large amount of concentrated sulfuric acid and the toxic oxide chromium trioxide, generating a large amount of acid-containing wastewater and heavy metal pollutants, making it difficult for the three wastes to meet the regulatory requirements. Moreover, the total yield is not high, about 35%.

[0005] With the innovation and development of technology, some new methods have emerged in the industry. For example, the Chinese patent with the publication number CN116730810A reports that 2-naphthol is used as the raw material, catalytically hydrogenated and reduced by activated carbon supported Ni, then salted with sodium hydroxide for separation to obtain an intermediate, methylated with dimethyl carbonate, and oxidized with potassium permanganate in a concentrated sulfuric acid environment to obtain 6-methoxy-1-tetralone. This route has a total of 3 steps of reaction, and the reported molar yield is 87.07%. Although the yield is relatively high, the acid-containing wastewater generated by the reaction is not conducive to the clean production of the process, and this route does not mention the recovery problem of manganese dioxide.

[0006] For another example, the Chinese patent with the publication number CN114436790A reports the preparation of 6-methoxy-1-tetralone using 3-bromoanisole as the raw material through Grignard reaction, acylation, reduction, hydrolysis, acylation, and ring closure. This route involves a total of 5 reaction steps, and the reported mass yield is approximately 67%. In this process, the safety risk in the step of preparing the Grignard reagent is relatively high, the cost of the silicon-containing reagent used is relatively high, and the aluminum ion-containing wastewater and chloride ion-containing wastewater generated after the reaction of the Lewis acid aluminum trichloride in the acylation step are difficult to treat.

[0007] For another example, the Chinese patent with the publication number CN117088765A reports the preparation of 6-hydroxytetralone by catalytic hydrogenation of 1,6-dihydroxynaphthalene as the raw material, and then preparing 6-methoxy-1-tetralone by methylation with dimethyl sulfate under the catalysis of manganese acetate tetrahydrate and an organic palladium cocatalyst. This process involves a microchannel reaction, in which the organic palladium cocatalyst needs to be prepared by itself, and the raw material cost is relatively high.

[0008] For another example, the Chinese patent with the publication number CN111333494B reports the preparation of an intermediate by Friedel-Crafts acylation reaction of anisole as the raw material with a Lewis acid and an acylating reagent, and then obtaining 6-methoxy-1-tetralone by ring closure by controlling the reaction temperature. This process needs to use aluminum trichloride as the Lewis acid for the reaction, and the generated aluminum ion-containing wastewater and chloride ion-containing wastewater are difficult to treat.

[0009] As well as the Chinese patents with the publication numbers CN116874359A and CN116924896A, which use aromatic aldehydes as raw materials, react them with a self-prepared Wittig reagent to obtain olefin compounds, and can prepare naphthone compounds through steps such as reduction (or reduction and oxidation), ring closure, etc. These two methods are similar, both using a self-prepared Wittig reagent, with relatively high costs, long reaction steps, and low yields. SUMMARY OF THE INVENTION

[0010] To solve the above technical problems, the present invention provides a method for preparing the pharmaceutical intermediate 6-methoxy-1-tetralone.

[0011] The technical solution adopted by the present invention is: a method for preparing the pharmaceutical intermediate 6-methoxy-1-tetralone, which includes the steps:

[0012] S1. Hydrogenating and reducing 2-naphthol under the action of a catalyst and a cocatalyst to obtain 5,6,7,8-tetrahydro-2-naphthol;

[0013] S2. Reacting 5,6,7,8-tetrahydro-2-naphthol with oxidant X to obtain 6-hydroxy-3,4-dihydronaphthalen-1-one;

[0014] S3. React 6-hydroxy-3,4-dihydronaphthalen-1-one with a methylation reagent in an alkaline environment to obtain 6-methoxytetralone;

[0015] Among them, the oxidizing agent X includes at least one of oxygen, hydrogen peroxide, tert-butyl hydroperoxide, potassium permanganate, tetrabutylammonium perchlorate, pyridinium chlorochromate, 2,3-dichloro-5,6-dicyanobenzoquinone, chromium trioxide, ammonium cerium nitrate, potassium persulfate, 1,4-benzoquinone, and tetrachlorobenzoquinone; the molar ratio of the oxidizing agent X to 5,6,7,8-tetrahydro-2-naphthol is (1.0 - 2.5):1.0.

[0016] Preferably, the catalyst includes at least one of palladium on carbon, rhodium on carbon, platinum on carbon, ruthenium on carbon, Raney nickel, Ni supported on activated carbon, and Ni supported on aluminum oxide, and the mass ratio of the catalyst to 2-naphthol is (0.01 - 0.1):1.0.

[0017] Preferably, the cocatalyst includes at least one of formic acid, acetic acid, propionic acid, butyric acid, aluminum trichloride, zinc chloride, and phosphoric acid, and the mass ratio of the cocatalyst to 2-naphthol is (0.001 - 0.01):1.0.

[0018] Preferably, the specific operation of step S1 is as follows:

[0019] Place 2-naphthol, Raney nickel, and formic acid in a first solvent, react under the conditions of a temperature of 50 - 100°C, a hydrogen pressure of 3 MPa - 6 MPa, and a stirring speed of 300 - 1000 rpm, and then separate 5,6,7,8-tetrahydro-2-naphthol by vacuum distillation;

[0020] The mesh number of Raney nickel is 60 - 100 mesh;

[0021] The first solvent includes at least one of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, and 2-methyltetrahydrofuran, and the mass ratio of the first solvent to 2-naphthol is (1.5 - 4.5):1.0.

[0022] Preferably, the first solvent is ethanol, and the mass ratio of Raney nickel, formic acid, the first solvent to 2-naphthol is (0.05 - 0.1):(0.005 - 0.01):(2.0 - 3.0):1.0; the temperature of step S1 is 75 - 85°C.

[0023] Preferably, the specific operation of step S2 is as follows:

[0024] Place 5,6,7,8-tetrahydro-2-naphthol and tetrachlorobenzoquinone in a second solvent, react under the conditions of a temperature of -5 - 30°C and a stirring speed of 300 - 1000 rpm to obtain 6-hydroxy-3,4-dihydronaphthalen-1-one;

[0025] The second solvent includes at least one of water, methanol, ethanol, isopropanol, acetonitrile, 1,4-dioxane, dichloromethane, tetrahydrofuran, and 2-methyltetrahydrofuran. The mass ratio of the second solvent to 5,6,7,8-tetrahydro-2-naphthol in the feeding is (2.0 - 5.0):1.0.

[0026] Preferably, the molar ratio of chloranil to 5,6,7,8-tetrahydro-2-naphthol in the feeding is (2.0 - 2.5):1.0; the second solvent includes water and tetrahydrofuran, and the mass ratio of water, tetrahydrofuran to 5,6,7,8-tetrahydro-2-naphthol in the feeding is (0.3 - 0.5):(2.7 - 4.5):1.0; the temperature of step S2 is 0 - 25°C.

[0027] Preferably, the methylation reagent includes at least one of methyl iodide, methyl bromide, dimethyl sulfate, and dimethyl carbonate. The basic environment is provided by sodium hydroxide. The molar ratio of the methylation reagent, sodium hydroxide to 6-hydroxy-3,4-dihydronaphthalen-1-one in the feeding is (1.0 - 2.5):(1.0 - 2.5):1.0.

[0028] Preferably, the specific operation of step S3 is as follows:

[0029] 6-Hydroxy-3,4-dihydronaphthalen-1-one, dimethyl carbonate, and sodium hydroxide are placed in a third solvent, and reacted under the conditions of a temperature of 25 - 40°C and a stirring speed of 300 - 1000 rpm to obtain 6-methoxytetralone;

[0030] The third solvent includes at least one of water, methanol, ethanol, isopropanol, acetone, dichloromethane, acetonitrile, 1,4-dioxane, tetrahydrofuran, and 2-methyltetrahydrofuran. The mass ratio of the third solvent to 6-hydroxy-3,4-dihydronaphthalen-1-one in the feeding is (2.0 - 8.0):1.0.

[0031] Preferably, the molar ratio of dimethyl carbonate, sodium hydroxide to 6-hydroxy-3,4-dihydronaphthalen-1-one in the feeding is (1.1 - 1.5):(1.0 - 1. — 1.5):1.0; the third solvent includes water and tetrahydrofuran, and the mass ratio of water, tetrahydrofuran to 6-hydroxy-3,4-dihydronaphthalen-1-one in the feeding is (2.0 - 4.0):(2.0 - 4.0):1.0; the temperature of step S3 is 30 - 35°C.

[0032] The advantages and positive effects of the present invention are as follows: The preparation method successively includes three steps of reduction-oxidation-methylation. The steps are short, the operation is simple, and it avoids the problem in the prior art that the reduction product is first methylated, and after methylation, the oxidation reaction site is affected, resulting in the generation of impurities and the reduction of the reaction yield and purity. The reaction conditions of the present preparation method are mild, the total molar yield is high (up to 89% or more), and the purity is high (up to 98% or more). Using inexpensive 2-naphthol as the starting material, it is catalytically hydrogenated to obtain 5,6,7,8-tetrahydro-2-naphthol with Raney nickel of 60-100 mesh as the catalyst, and formic acid is used as a co-catalyst to improve its selectivity. Moreover, Raney nickel can be recycled more than 3 times, which can significantly reduce costs and increase the yield. The product in step S2 contains tetrachlorohydroquinone, which is the reduction product of tetrachlorobenzoquinone. It can be oxidized and regenerated for recycling, which can also reduce costs. In step S3, dimethyl carbonate with low toxicity is selected to replace traditional methylation reagents (such as methyl iodide, dimethyl sulfate, etc.), and there is no need for Lewis acid and acylating reagents in the existing process, avoiding the treatment of waste water containing aluminum ions, chloride ions, etc., and the three wastes discharge is relatively small, and the process is cleaner and greener, which is suitable for industrial production. Detailed implementation manners

[0033] The following describes the embodiments of the present invention.

[0034] The present invention relates to a preparation method of a pharmaceutical intermediate 6-methoxy-1-tetralone, and the preparation scheme includes the following steps:

[0035] S1. Hydrogenate and reduce 2-naphthol under the action of a catalyst and a co-catalyst to obtain 5,6,7,8-tetrahydro-2-naphthol;

[0036] S2. React 5,6,7,8-tetrahydro-2-naphthol with an oxidant X to obtain 6-hydroxy-3,4-dihydronaphthalen-1-one;

[0037] S3. React 6-hydroxy-3,4-dihydronaphthalen-1-one with a methylation reagent in an alkaline environment to obtain 6-methoxy-1-tetralone.

[0038] The chemical reaction formula of the above method is as follows:

[0039]

[0040] The specific operation of step S1 is as follows: Put 2-naphthol, a catalyst and a co-catalyst into a first solvent, and react under the conditions of a temperature of 50-100 °C, a hydrogen pressure of 3 MPa-6 MPa, and a stirring speed of 300-1000 rpm, and then separate 5,6,7,8-tetrahydro-2-naphthol by vacuum distillation.

[0041] Among them, the catalyst includes at least one of palladium-carbon, rhodium-carbon, platinum-carbon, ruthenium-carbon, Raney nickel, Ni supported on activated carbon, and Ni supported on aluminum oxide, preferably Raney nickel, and the mesh number is preferably 60-100 meshes; the mass ratio of the catalyst to 2-naphthol in the feed is (0.01-0.1):1.0, preferably (0.05-0.1):1.0.

[0042] Among them, the cocatalyst includes at least one of formic acid, acetic acid, propionic acid, butyric acid, aluminum trichloride, zinc chloride, and phosphoric acid, preferably formic acid; the mass ratio of the cocatalyst to 2-naphthol in the feed is (0.001-0.01):1.0; preferably (0.005-0.01):1.0.

[0043] Among them, the first solvent includes at least one of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, and 2-methyltetrahydrofuran, preferably ethanol; the mass ratio of the first solvent to 2-naphthol in the feed is (1.5-4.5):1.0, preferably (2.0-3.0):1.0.

[0044] Among them, the temperature condition of step S1 is preferably 75-85°C.

[0045] The specific operation of step S2 is: placing 5,6,7,8-tetrahydro-2-naphthol and oxidant X in a second solvent, and reacting under the conditions of a temperature of -5-30°C and a stirring speed of 300-1000 rpm to obtain 6-hydroxy-3,4-dihydronaphthalen-1-one.

[0046] Among them, oxidant X includes at least one of oxygen, hydrogen peroxide, tert-butyl hydroperoxide, potassium permanganate, tetrabutylammonium perchlorate, pyridinium chlorochromate, 2,3-dichloro-5,6-dicyanobenzoquinone, chromium trioxide, ammonium cerium nitrate, potassium persulfate, 1,4-benzoquinone, and tetrachlorobenzoquinone, preferably tetrachlorobenzoquinone; the molar ratio of oxidant X to 5,6,7,8-tetrahydro-2-naphthol in the feed is (1.0-2.5):1.0, preferably (2.0-2.5):1.0.

[0047] Among them, the second solvent includes at least one of water, methanol, ethanol, isopropanol, acetonitrile, 1,4-dioxane, dichloromethane, tetrahydrofuran, and 2-methyltetrahydrofuran. The mass ratio of the second solvent to 5,6,7,8-tetrahydro-2-naphthol in the feed is (2.0-5.0):1.0; the second solvent is preferably a mixed solvent of water and tetrahydrofuran, and the mass ratio of water, tetrahydrofuran to 5,6,7,8-tetrahydro-2-naphthol in the feed is preferably (0.3-0.5):(2.7-4.5):1.0.

[0048] Among them, the temperature condition of step S2 is preferably 0-25°C.

[0049] The specific operation of Step 3 is as follows: 6-Hydroxy-3,4-dihydronaphthalen-1-one, a methylation reagent, and sodium hydroxide are placed in a third solvent. Using sodium hydroxide to provide an alkaline environment, the reaction is carried out at a temperature of 25 - 40 °C and a stirring speed of 300 - 1000 rpm to obtain 6-methoxy-1-tetralone.

[0050] Among them, the methylation reagent includes at least one of methyl iodide, methyl bromide, dimethyl sulfate, and dimethyl carbonate, preferably dimethyl carbonate; the molar feeding ratio of the methylation reagent, sodium hydroxide, and 6-hydroxy-3,4-dihydronaphthalen-1-one is (1.0 - 2.5):(1.0 - 2.5):1.0, preferably (1.0 - 1.5):(1.0 - 1.5):1.0.

[0051] Among them, the third solvent includes at least one of water, methanol, ethanol, isopropanol, acetone, dichloromethane, acetonitrile, 1,4-dioxane, tetrahydrofuran, and 2-methyltetrahydrofuran. The mass feeding ratio of the third solvent to 6-hydroxy-3,4-dihydronaphthalen-1-one is (2.0 - 8.0):1.0; the third solvent is preferably a mixed solvent of water and tetrahydrofuran, and the mass feeding ratio of water, tetrahydrofuran, and 6-hydroxy-3,4-dihydronaphthalen-1-one is preferably (2.0 - 4.0):(2.0 - 4.0):1.0.

[0052] Among them, the temperature condition of Step S3 is preferably 30 - 35 °C.

[0053] The reaction conditions of the above technical solution are mild, the total molar yield is high (up to 89% and above), and the purity is high (up to 98% and above). Using inexpensive 2-naphthol as the starting material, it is catalytically hydrogenated with Raney nickel of 60 - 100 mesh as the catalyst to obtain 5,6,7,8-tetrahydro-2-naphthol, and formic acid is used as a co-catalyst to improve its selectivity. Moreover, Raney nickel can be recycled more than 3 times, which can significantly reduce costs and increase the yield; the product in Step S2 contains an oxidant X derivative, which is the reduction product of oxidant X. It can be oxidized and regenerated for recycling, which can also reduce costs; in Step S3, dimethyl carbonate with low toxicity is selected to replace traditional methylation reagents (such as methyl iodide, dimethyl sulfate, etc.), and there is no need for Lewis acid and acylating reagents in the existing process, avoiding the treatment of waste water containing aluminum ions, chloride ions, etc., and the three wastes emissions are relatively small. The process is cleaner and greener, and is suitable for industrial production.

[0054] The following list some specific examples. Among them, for the experimental methods where the operation steps are not specifically described, they are all carried out according to the corresponding product specifications. For the instruments, reagents, and consumables used in the examples, if not otherwise specified, they can all be purchased from commercial companies.

[0055] Example 1: Preparation of 6-methoxy-1-tetralone

[0056] S1. Add 147.11 g (purity 98%, 1.00 mol) of 2-naphthol, 14.75 g of Raney nickel with a mesh size of 60 - 100, 0.75 g of formic acid, and 300.00 g of absolute ethanol into a 1000 mL autoclave. After purging with hydrogen three times, charge it to 5.0 MPa. Set the rotation speed to 800 - 900 rpm, turn on the heating, and control the internal temperature at 80 °C ± 1 °C for the reaction. After reacting for 8 h, cool down to 25 °C, let it stand for 30 minutes, extract the supernatant, filter it through a 0.45 μm filter membrane, and the residual liquid at the bottom of the autoclave and the Raney nickel catalyst can be recycled.

[0057] In this step, Raney nickel with a mesh size of 60 - 100 is used as the catalyst, and formic acid is used as the co-catalyst for the hydrogenation of the benzene ring of 2-naphthol. The hydrogenated benzene ring can be obtained with high selectivity, while the content of the reduced phenol ring is very small. And 5,6,7,8-tetrahydro-2-naphthol can be separated by vacuum distillation.

[0058] Through experimental exploration and verification, it is found that when the Raney nickel specification is changed and 100 - 200 mesh is used, the reaction rate is accelerated, the reaction molar yield is about 70%, and at the same time, the content of the reduced phenol ring increases and the selectivity decreases; when 20 - 40 mesh or 40 - 60 mesh is used, the reaction rate is slower, the reaction time is prolonged, the reaction molar yield is about 65%, and at the same time, the content of the reduced phenol ring increases and the selectivity decreases.

[0059] Concentrate the filtrate obtained after filtering through a 0.45 μm filter membrane to obtain 148.98 g of concentrate with a GC content of 95% (the area normalization is basically the same as the external standard content). Then, separate 5,6,7,8-tetrahydro-2-naphthol colorless transparent liquid by vacuum distillation. Check its purity to be 98%, and the yield is 142.90 g (0.94 mol). Calculate its molar yield to be 94%.

[0060] S2. Add 142.90 g (purity 98%, 0.94 mol) of 5,6,7,8-tetrahydro-2-naphthol, 300.00 g of tetrahydrofuran, and 50.00 g of water into a 2000 mL four-necked round-bottom flask. Set the rotation speed to 400 - 600 rpm. After purging with nitrogen three times, use a low-temperature reaction bath to cool the reaction system to 0 °C ± 1 °C. Use a peristaltic pump to pump the tetrahydrofuran (200 g) solution containing tetrachlorobenzoquinone (2.00 mol) into the reaction system, which takes about 1 h. After the feeding is completed, slowly restore the temperature of the reaction system to 25 °C ± 1 °C and react for 5 h.

[0061] After monitoring the reaction by HPLC and finding no raw materials, the reaction was terminated. After removing the solvent under reduced pressure, 300 g of dichloromethane and 30 g of 10% sodium bisulfite solution were added, and stirring was continued until yellow tetrachlorohydroquinone (the reduction product of tetrachlorobenzoquinone) precipitated out in the system. It was separated by suction filtration under reduced pressure (the filter cake) for regeneration and recycling. The organic phase separated from the filtrate was stripped of the solvent under reduced pressure to obtain a light yellow solid, the crude product of 6-hydroxy-3,4-dihydronaphthalen-1-one. Its yield was examined to be 152.21 g, and the HPLC content was 96% (basically consistent with the area normalization and the external standard content), and it could be directly put into use in S3.

[0062] In this step, the filter cake obtained by suction filtration under reduced pressure contains the oxidant X derivative - tetrachlorohydroquinone, which can be regenerated by oxidation and continue to be used in this step of the reaction. Moreover, this tetrachlorobenzoquinone can significantly reduce the formation of other oxidation impurities; in addition, the tetrahydrofuran and dichloromethane distilled off under reduced pressure can be recycled and applied to the reaction and extraction processes of the next batch.

[0063] S3: Into a 2000 mL four-necked round-bottom flask, 152.21 g of the crude product of 6-hydroxy-3,4-dihydronaphthalen-1-one, 600 g of tetrahydrofuran, 600 g of water, and 56.31 g of sodium hydroxide were added; the rotation speed was set at 400 - 600 rpm. After purging with nitrogen three times, heating was started, and the reaction system was heated to 30 °C ± 1 °C, and the reaction system was controlled to maintain at this temperature. 126.81 g of dimethyl carbonate was added dropwise; after the dropwise addition was completed, the reaction was kept warm for 1 h.

[0064] After monitoring the reaction by HPLC and finding no raw materials, the reaction was terminated. The solvent was removed under reduced pressure to obtain a beige solid; it was stirred and slurried with 300 g of water for 1 h, and then suction filtered to obtain a filter cake. 200 g of isopropanol was heated to 45 °C to dissolve the filter cake. After it was completely dissolved, the temperature was lowered to 0 °C and stirred and slurried for 1 h; it was filtered and the filter cake was rinsed with 20 g of ice-cold isopropanol, and vacuum dried at 40 °C for 3 h to obtain 6-methoxy-1-tetralone. Its purity was examined to be 99% (HPLC content, basically consistent with the area normalization and the external standard content), and the yield was 159.21 g (0.89 mol).

[0065] In this step, the tetrahydrofuran distilled off under reduced pressure can be applied to the reaction process of the next batch, and the filtrate (mother liquor) is used in the next slurrying batch. The methylation reagent used in this step is dimethyl carbonate, which has lower toxicity compared to methyl iodide and dimethyl sulfate, and produces less three wastes, which can reduce costs.

[0066] In this embodiment, 6-methoxy-1-tetralone is prepared through three steps of reduction-oxidation-methylation in sequence. The steps are short and the operation is simple. Compared with the prior art scheme of methylation first and then oxidation, this embodiment avoids the problem that the methylation of the reduction product affects the oxidation reaction site, resulting in the generation of impurities and reducing the reaction yield and purity. The above is only a preferred embodiment of the present invention and does not impose any form of limitation on the present invention. Although the present invention has been disclosed as above with a preferred embodiment, it is not intended to limit the present invention. Any person skilled in the art can make many possible changes and modifications to the technical solution of the present invention by using the above-disclosed methods and technical contents, or modify it into an equivalent embodiment with equivalent changes. Therefore, any simple modification, equivalent replacement, equivalent change and modification made to the above embodiments based on the technical essence of the present invention without departing from the technical solution of the present invention still fall within the scope of protection of the technical solution of the present invention.

Claims

1. A preparation method of a pharmaceutical intermediate 6-methoxy-1-tetralone, characterized in that, It includes the steps as follows: S1. Hydrogenate and reduce 2-naphthol under the action of a catalyst and a cocatalyst to obtain 5,6,7,8-tetrahydro-2-naphthol; S2. React 5,6,7,8-tetrahydro-2-naphthol with oxidant X to obtain 6-hydroxy-3,4-dihydronaphthalen-1-one; S3. React 6-hydroxy-3,4-dihydronaphthalen-1-one with a methylation reagent in an alkaline environment to obtain 6-methoxytetralone; Among them, the oxidant X includes at least one of oxygen, hydrogen peroxide, tert-butyl hydroperoxide, potassium permanganate, tetrabutylammonium perchlorate, pyridinium chlorochromate, 2,3-dichloro-5,6-dicyanobenzoquinone, chromium trioxide, ammonium cerium nitrate, potassium persulfate, 1,4-benzoquinone, and tetrachlorobenzoquinone; the molar ratio of the oxidant X to 5,6,7,8-tetrahydro-2-naphthol in the feed is (1.0 - 2.5):1.

0.

2. The preparation method of a pharmaceutical intermediate 6-methoxy-1-tetralone according to claim 1, characterized in that: The catalyst includes at least one of palladium on carbon, rhodium on carbon, platinum on carbon, ruthenium on carbon, Raney nickel, Ni supported on activated carbon, and Ni supported on aluminum oxide, and the mass ratio of the catalyst to 2-naphthol in the feed is (0.01 - 0.1):1.

0.

3. The preparation method of a pharmaceutical intermediate 6-methoxy-1-tetralone according to claim 2, characterized in that: The cocatalyst includes at least one of formic acid, acetic acid, propionic acid, butyric acid, aluminum trichloride, zinc chloride, and phosphoric acid, and the mass ratio of the cocatalyst to 2-naphthol in the feed is (0.001 - 0.01):1.

0.

4. The preparation method of a pharmaceutical intermediate 6-methoxy-1-tetralone according to claim 3, characterized in that, The specific operation of step S1 is as follows: Place 2-naphthol, Raney nickel, and formic acid in a first solvent, and react under the conditions of a temperature of 50 - 100°C, a hydrogen pressure of 3 MPa - 6 MPa, and a stirring speed of 300 - 1000 rpm, and then separate 5,6,7,8-tetrahydro-2-naphthol by vacuum distillation; The mesh number of Raney nickel is 60 - 100 mesh; The first solvent includes at least one of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, and 2-methyltetrahydrofuran, and the mass ratio of the first solvent to 2-naphthol in the feed is (1.5 - 4.5):1.

0.

5. The preparation method of a pharmaceutical intermediate 6-methoxy-1-tetralone according to claim 4, characterized in that: The first solvent is ethanol, and the mass ratio of Raney nickel, formic acid, the first solvent to 2-naphthol in the feed is (0.05 - 0.1):(0.005 - 0.01):(2.0 - 3.0):1.0; the temperature of step S1 is 75 - 85°C.

6. A preparation method of a pharmaceutical intermediate 6-methoxy-1-tetralone according to any one of claims 1-2, 4-5, characterized in that, The specific operation of step S2 is as follows: Place 5,6,7,8-tetrahydro-2-naphthol and the tetrachlorobenzoquinone in a second solvent, and react under the conditions of a temperature of -5 - 30°C and a stirring speed of 300 - 1000 rpm to obtain 6-hydroxy-3,4-dihydronaphthalen-1-one; The second solvent includes at least one of water, methanol, ethanol, isopropanol, acetonitrile, 1,4-dioxane, dichloromethane, tetrahydrofuran, and 2-methyltetrahydrofuran, and the mass ratio of the second solvent to 5,6,7,8-tetrahydro-2-naphthol in the feed is (2.0 - 5.0):1.

0.

7. The preparation method of a pharmaceutical intermediate 6-methoxy-1-tetralone according to claim 6, characterized in that: The molar ratio of tetrachlorobenzoquinone to 5,6,7,8-tetrahydro-2-naphthol is (2.0 - 2.5):1.0; the second solvent includes water and tetrahydrofuran, and the mass ratio of water, tetrahydrofuran to 5,6,7,8-tetrahydro-2-naphthol is (0.3 - 0.5):(2.7 - 4.5):1.0; the temperature of step S2 is 0 - 25 °C.

8. A preparation method of a pharmaceutical intermediate 6-methoxy-1-tetralone according to any one of claims 1-2, 4-5, and 7, characterized in that: The methylation reagent includes at least one of methyl iodide, methyl bromide, dimethyl sulfate and dimethyl carbonate, the alkaline environment is provided by sodium hydroxide, and the molar ratio of the methylation reagent, sodium hydroxide to 6-hydroxy-3,4-dihydronaphthalen-1-one is (1.0 - 2.5):(1.0 - 2.5):1.

0.

9. The preparation method of a pharmaceutical intermediate 6-methoxy-1-tetralone according to claim 8, characterized in that, The specific operation of step S3 is as follows: 6-Hydroxy-3,4-dihydronaphthalen-1-one, dimethyl carbonate and sodium hydroxide are placed in a third solvent and reacted under the conditions of a temperature of 25 - 40 °C and a stirring speed of 300 - 1000 rpm to obtain 6-methoxy-1-tetralone; The third solvent includes at least one of water, methanol, ethanol, isopropanol, acetone, dichloromethane, acetonitrile, 1,4-dioxane, tetrahydrofuran and 2-methyltetrahydrofuran, and the mass ratio of the third solvent to 6-hydroxy-3,4-dihydronaphthalen-1-one is (2.0 - 8.0):1.

0.

10. The preparation method of a pharmaceutical intermediate 6-methoxy-1-tetralone according to claim 9, characterized in that: The molar ratio of dimethyl carbonate, sodium hydroxide to 6-hydroxy-3,4-dihydronaphthalen-1-one is (1.1 - 1.5):(1.0 - 1.5):1.0; the third solvent includes water and tetrahydrofuran, and the mass ratio of water, tetrahydrofuran to 6-hydroxy-3,4-dihydronaphthalen-1-one is (2.0 - 4.0):(2.0 - 4.0):1.0; the temperature of step S3 is 30 - 35 °C.

Images