A preparation process of (indol-4-yl)methanol

Abstract

The invention belongs to the field of organic preparation, and is specifically related to a preparation process of (indole-4-yl) methanol, wherein indole-4-carboxylic acid methyl ester is dissolved in a solvent, a catalyst is added at 15-25 DEG C, and under the protection of a protective gas, after the completion of the hydrogenation reaction, the solvent is filtered and evaporated, and (indole-4-yl) methanol is obtained after stirring, crystallizing and drying; the catalyst includes a palladium carbon complex and a porous nickel-aluminum alloy. The yield of the method of the present invention is much greater than the prior art, and the purity of the prepared (indole-4-yl) methanol is much higher than commercially available goods.

Description

Technical Field

[0001] The invention belongs to the field of organic matter preparation, and specifically relates to a preparation process of (indole-4-yl)methanol. Background Art

[0002] (Indole-4-yl)methanol is an important pharmaceutical research and development reagent, but its product price is high, and the commercial purity is generally 95~97%, which is difficult to meet the high-precision experimental requirements. The existing preparation process of (indole-4-yl)methanol generally adopts the method disclosed in the European patent: Imidazole pyridazine and imidazole thiadiazole compounds (International Publication No.: WO 2016 / 134450 A1), which is synthesized by indole-4-carboxylic acid methyl ester through two steps, and the first step reaction yield is only 48%, and the second step reaction yield is only 61%. The catalytic hydrogenation reaction seems simple, but the existing catalytic hydrogenation reaction can only be a single indole parent for hydrogenation reduction or ester group reduction, and it is impossible to achieve simultaneous reduction of two groups at the same time. The multi-step reaction makes the product yield less than 40%, the production cost is high, and impurities and by-products are difficult to separate, which limits the purification of the product.

[0003] Palladium carbon is a commonly used hydrogenation reduction catalyst, but palladium metal is extremely expensive, and the feasibility of using palladium carbon in the industrial production of (indol-4-yl) methanol has not been studied. The metal palladium crystals of the palladium carbon catalyst are generally distributed in the micropores close to the surface of the activated carbon. The loading depth of the palladium carbon catalyst surface is only tens of microns. Any friction and impact during use will cause the catalyst to wear. In addition, due to the influence of temperature and other environmental factors during use, the catalyst is constantly washed by the material, and some of it will become finer particles, resulting in palladium loss and the catalyst gradually losing its activity. At present, the supply and demand of palladium metal is seriously unbalanced. In order to reduce the adverse effects of the rising price of palladium metal on fine chemicals, medicine, and environmental protection industries, it is necessary to focus on the full use and recovery of palladium. Summary of the invention

[0004] The present invention mainly provides a process for preparing (indol-4-yl)methanol with high yield and high purity. The technical scheme is as follows:

[0005] A preparation process of (indol-4-yl)methanol comprises the following steps: dissolving indole-4-carboxylic acid methyl ester in a solvent, adding a catalyst at 15-25°C, filtering and distilling off the solvent after the hydrogenation reaction is completed under the protection of a protective gas, stirring, crystallizing, and drying to obtain (indol-4-yl)methanol; the catalyst comprises a palladium carbon complex and a porous nickel-aluminum alloy. The reaction equation is as follows:

[0006] .

[0007] Furthermore, the yield of the (indol-4-yl)methanol is above 90% and the purity is greater than 99%.

[0008] Furthermore, the concentration of indole-4-carboxylic acid methyl ester in the solvent is 0.3-0.4 g / mL; the solvent is anhydrous tetrahydrofuran; the mass ratio of the catalyst to indole-4-carboxylic acid methyl ester is 1:50-150; and the weight ratio of the palladium carbon composite to the porous nickel-aluminum alloy is 1:0.8-1.2.

[0009] Further, the following steps are included:

[0010] a. adding indole-4-carboxylic acid methyl ester and a solvent into a reaction vessel, and stirring until the materials are completely dissolved to obtain an indole-4-carboxylic acid methyl ester solution;

[0011] b. Maintain the temperature in the system at 15-25°C, add the catalyst into the reaction system, protect the reaction system with nitrogen, then start to add hydrogen to start the reaction, react for 10-16 hours, and detect by HPLC that the raw materials react completely to obtain a reaction liquid;

[0012] c. Separate the catalyst from the reaction solution; concentrate the reaction solution to remove the solvent, and after more than 80% of the volume of the solvent has been evaporated, add n-heptane to make up the volume of the reaction solution, cool to 0-5°C, and stir to crystallize; after the crystallization is completed, filter and dry the crystals to obtain (indol-4-yl)methanol.

[0013] Furthermore, after the reaction is completed, the catalyst is separated by magnetic attraction.

[0014] Furthermore, the preparation of the palladium-carbon composite comprises the following steps:

[0015] Take the carbon precursor and place it in water to fully disperse it, then use ammonia water to adjust the pH to 8-9, stir at 40-60°C for 1-3 hours, separate the precipitate, mix the precipitate with dichlorotetraamminepalladium solution, fully disperse it and remove the air, use sodium hydroxide to adjust the pH to 9.5-11, then add sodium borohydride solution dropwise, stir the reaction for 0.5-2 hours, separate the precipitate, wash it thoroughly and then vacuum dry it to obtain a palladium-carbon complex.

[0016] Furthermore, the specific surface area of ​​the carbon precursor is 300 m 2 / g or above.

[0017] Furthermore, the mass ratio of the dichlorotetraamminepalladium to the carbon precursor is 1:5-20; the molar ratio of the dichlorotetraamminepalladium to sodium borohydride is 1:4-5; and the concentration of the dichlorotetraamminepalladium solution is 1.5-3 mg / mL.

[0018] Furthermore, the preparation of the carbon precursor comprises the following steps:

[0019] Tetraethyl orthosilicate is dissolved in an ethanol aqueous solution to obtain a tetraethyl orthosilicate solution, chitosan is fully dispersed in the tetraethyl orthosilicate solution to obtain a dispersion, and then 3-aminopropyltrimethoxysilane and ferrous chloride are added in sequence. After being fully dispersed, the solvent is evaporated; the mixture is frozen to a central temperature below -18°C; the mixture is then freeze-dried at -88°C to -50°C; after drying, the mixture is heated to 1300°C to 1500°C in an inert gas atmosphere, kept warm for 2 to 6 hours, and then cooled to room temperature to obtain a carbon precursor.

[0020] Furthermore, the mass ratio of the tetraethyl orthosilicate to chitosan is 1:12-18; the mass ratio of the ferrous chloride to chitosan is 1:10-20; and the mass ratio of the ferrous chloride to 3-aminopropyltrimethoxysilane is 1:2-4.

[0021] By adopting the above scheme, the method of the present invention has the following advantages:

[0022] 1. The prior art for preparing (indol-4-yl)methanol can only carry out hydrogenation reduction of the indole matrix and reduction of the ester group separately, and it is not possible to reduce the two groups simultaneously. However, the present invention can prepare it directly in a one-step reaction.

[0023] 2. The yield of the present invention reaches more than 90%, which is significantly improved compared with 29.3% of the prior art, can greatly reduce production costs, and is suitable for industrial promotion.

[0024] 3. The purity of the sample prepared by the process of the present invention is high, which is much higher than the 95-97% of commercially available products. Products with a purity of more than 99.5% can be directly obtained, with few difficult-to-separate by-products and no need for additional purification operations, thus avoiding the adverse effects of difficult-to-separate impurities on subsequent research and development experiments or production applications.

[0025] 4. The catalyst of the present invention is insoluble in water, and the catalyst and the product can be separated by simple filtration. The operation is simple and the separation efficiency is high, with little residue. While improving the purity of the product, the loss of the catalyst is reduced.

[0026] 5. The catalyst of the present invention contains nickel or iron, both of which are magnetically conductive. The use of magnetic separation can further improve the separation efficiency and ensure the full recovery of the catalyst, especially the palladium-carbon complex with high production cost, and is suitable for application in large-scale production.

[0027] 6. Silicon is doped into the carbon precursor of the palladium-carbon composite catalyst of the present invention to improve the strength of the palladium-carbon composite and reduce the breakage of fine catalyst particles on the surface caused by material scouring and environmental factors during the working process of the catalyst, thereby reducing the loss of palladium.

[0028] 7. When preparing the palladium-carbon composite, the present invention introduces amino groups into the carbon precursor through coupling agents and ammonia water. When palladium is compounded, palladium is attracted to penetrate into the pores of the carbon precursor, so that the palladium is loaded deeper in the pores, the effective contact between the palladium and the carbon precursor carrier is greater, the loading is more uniform, and it is not easy to fall off, and more catalytic active sites can be exposed, thereby improving the catalytic efficiency and increasing the yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 It is the liquid chromatogram of the product of Example 1 of the present invention;

[0030] Figure 2 The liquid chromatographic peak table of the product of Example 1 of the present invention;

[0031] Figure 3 is the hydrogen nuclear magnetic resonance spectrum of the product of Example 1 of the present invention;

[0032] Figure 4 It is a comparison chart of the catalyst cycle stability of Examples 1 to 3 of the present invention. DETAILED DESCRIPTION

[0033] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0034] Example 1: (1) 175 g of indole-4-carboxylic acid methyl ester and 500 mL of anhydrous tetrahydrofuran were added to a reaction bottle and stirred for 10 min until the materials were completely dissolved;

[0035] (2) maintaining the internal temperature at 15-25°C, adding 1.75 g of a 1:1 mixture of Raney nickel and 5% palladium carbon catalyst to the reaction system, protecting the reaction system with nitrogen, and then adding hydrogen to start the reaction, and reacting for 12 hours; HPLC detection showed that the raw materials reacted completely, and the catalyst was removed by filtration to obtain a reaction liquid;

[0036] (3) The reaction solution was concentrated to remove the tetrahydrofuran solvent. After 400-450 mL of tetrahydrofuran was evaporated, 500 mL of n-heptane was added and the temperature was lowered to 0-5°C. The mixture was stirred for 2 hours to crystallize. After the crystallization was completed, the product was filtered and dried to obtain 138.2 g of the product with a yield of 92.6%.

[0037] Depend on Figure 1 and Figure 2 It can be seen from the liquid chromatogram that the purity of the obtained product reaches 99.8% and there are very few impurities, indicating that the method of the present invention can produce high-purity (indol-4-yl) methanol.

[0038] Depend on Figure 3 It can be seen that the signals on the spectrum correspond to (indol-4-yl)methanol, and there are no obvious unknown signals, indicating that the purity of the product is extremely high.

[0039] Example 2: (1) Take 1g of tetraethyl orthosilicate and dissolve it in an ethanol aqueous solution to obtain a tetraethyl orthosilicate solution, and then place 15g of chitosan in the tetraethyl orthosilicate solution and fully disperse it to obtain a dispersion, and then add 3g of 3-aminopropyltrimethoxysilane and 1g of ferrous chloride in sequence. After fully dispersing, evaporate the solvent; freeze until the center temperature is below -18°C. Then freeze-dry at -60°C; after drying, heat to 1400°C in an inert gas atmosphere, keep warm for 4 hours, and then cool to room temperature to obtain a carbon precursor;

[0040] (2) Take 5 g of carbon precursor and place it in water to fully disperse it, then use ammonia water to adjust the pH to 8, stir at 40-60 ° C for 1-3 hours, separate the precipitate, mix the precipitate with 250 mL of 2 mg / mL dichlorotetraamminepalladium solution, fully disperse it and remove the air, use sodium hydroxide to adjust the pH to 10, then add dropwise a solution containing 0.35 g of sodium borohydride, stir the reaction for 0.5-2 hours, separate the precipitate, wash it thoroughly and dry it in vacuum to obtain a palladium-carbon complex;

[0041] (3) Add 175 g of indole-4-carboxylic acid methyl ester and 500 mL of anhydrous tetrahydrofuran into the reaction bottle and stir for 10 min until the materials are completely dissolved;

[0042] (4) maintaining the internal temperature at 15-25°C, adding 1.75 g of the above-mentioned palladium-carbon composite and Raney nickel catalyst in a 1:1 ratio to the reaction system, protecting the reaction system with nitrogen, and then adding hydrogen to start the reaction, and reacting for 12 hours; HPLC detection showed that the raw materials reacted completely; filtering to remove the catalyst, and obtaining a reaction solution;

[0043] (5) The reaction solution was concentrated to remove tetrahydrofuran solvent, and after 400-450 mL of tetrahydrofuran was evaporated, 500 mL of n-heptane was added to cool to 0-5°C and stirred for 2 h for crystallization; after the crystallization was completed, the product was filtered and dried to obtain 143.1 g, with a yield of 95.9%. The palladium-carbon composite of the present invention has a higher yield of the product.

[0044] Example 3: (1) Take 5 g of a sample with a specific surface area of ​​800 m 2 / g of activated carbon as a carbon precursor is placed in water and fully dispersed, and then ammonia water is used to adjust the pH to 8, and stirred at 40-60°C for 1-3h. After separating the precipitate, the precipitate is mixed with 250mL of a 2mg / mL dichlorotetraamminepalladium solution, and after fully dispersing and removing air, sodium hydroxide is used to adjust the pH to 10, and then a solution containing 0.35g of sodium borohydride is added dropwise, and after stirring the reaction for 0.5-2h, the precipitate is separated, and after fully washing, vacuum drying is performed to obtain a palladium-carbon complex;

[0045] (2) Add 175 g of indole-4-carboxylic acid methyl ester and 500 mL of anhydrous tetrahydrofuran into the reaction bottle and stir for 10 min until the materials are completely dissolved;

[0046] (3) maintaining the internal temperature at 15-25°C, adding 1.75 g of the above-mentioned palladium-carbon composite and Raney nickel catalyst in a 1:1 ratio to the reaction system, protecting the reaction system with nitrogen, and then adding hydrogen to start the reaction, and reacting for 12 hours; HPLC detection shows that the raw materials have reacted completely; filtering to remove the catalyst, and obtaining a reaction solution;

[0047] (4) The reaction solution was concentrated to remove the tetrahydrofuran solvent. After 400-450 mL of tetrahydrofuran was evaporated, 500 mL of n-heptane was added and the temperature was lowered to 0-5°C. The mixture was stirred for 2 h for crystallization. After the crystallization was completed, the product was filtered and dried to obtain 134.9 g of the product with a yield of 90.4%.

[0048] Example sample test:

[0049] After the completion of the first reaction, the commercial 5% palladium carbon catalyst of Example 1 and the catalyst containing the palladium carbon complex of Example 3 were centrifuged and collected, and the catalyst containing the palladium carbon complex of Example 2 was magnetically separated and collected, and then dispersed in water to prepare a 5 mg / mL dispersion, stirred at a speed of 120-150 rpm for 10 min, and then washed with water and ethanol, and then vacuum dried at 60 ° C., and then the preparation of (indol-4-yl) methanol was cyclically carried out according to the methods of each embodiment, and the product yield of each preparation was recorded to evaluate the catalytic performance. The results are as follows:

[0050]

[0051] Combining the above table with Figure 4It can be seen that in the process of preparing (indol-4-yl) methanol, the yield of the product obtained by using the palladium carbon complex of the present invention as a catalyst is close to or even exceeds the commercially available palladium carbon product, indicating that the palladium carbon complex of the present invention has high catalytic efficiency and strong selectivity for preparing (indol-4-yl) methanol. After multiple treatments and cyclic preparation processes that intensify catalyst damage, the yield of the product prepared by the palladium carbon complex of the present invention decreases significantly slower than that of commercially available palladium carbon, indicating that when the palladium carbon complex of the present invention is used as a catalyst for preparing (indol-4-yl) methanol, it has little loss, high strength, and can maintain activity well.

[0052] For those skilled in the art, various other corresponding changes and deformations can be made according to the technical solutions and concepts described above, and all of these changes and deformations should fall within the protection scope of the claims of the present invention.

Claims

1. A process for preparing (indol-4-yl)methanol, characterized in that: The following steps are involved: Indole-4-carboxylic acid methyl ester is dissolved in a solvent, a catalyst is added at 15-25° C., and after the hydrogenation reaction is completed under the protection of a protective gas, the solvent is filtered and evaporated, and (indole-4-yl) methanol is obtained after stirring, crystallization, and drying. The catalyst is composed of a palladium-carbon complex and a porous nickel-aluminum alloy. The concentration of the indole-4-carboxylic acid methyl ester in the solvent is 0.3-0.4 g / mL. The solvent is anhydrous tetrahydrofuran. The mass ratio of the catalyst to the indole-4-carboxylic acid methyl ester is 1:50-150. The weight ratio of the palladium-carbon complex to the porous nickel-aluminum alloy is 1:0.8-1.

2.

2. The process for preparing (indol-4-yl)methanol according to claim 1, characterized in that: The yield of the (indol-4-yl)methanol is above 90%, and the purity is greater than 99%.

3. The process for preparing (indol-4-yl)methanol according to claim 1, characterized in that: The following steps are involved: a. adding indole-4-carboxylic acid methyl ester and a solvent into a reaction vessel, and stirring until the materials are completely dissolved to obtain an indole-4-carboxylic acid methyl ester solution; b. Maintain the temperature in the system at 15-25°C, add the catalyst into the reaction system, protect the reaction system with nitrogen, then start to add hydrogen to start the reaction, react for 10-16 hours, and detect by HPLC that the raw materials react completely to obtain a reaction liquid; c. Separate the catalyst from the reaction solution; concentrate the reaction solution to remove the solvent, and after more than 80% of the volume of the solvent has been evaporated, add n-heptane to make up the volume of the reaction solution, cool to 0-5°C, and stir to crystallize; after the crystallization is completed, filter and dry the crystals to obtain (indol-4-yl)methanol.

4. The process for preparing (indol-4-yl)methanol according to claim 1, characterized in that: The preparation of the palladium-carbon composite comprises the following steps: Take the carbon precursor and place it in water to fully disperse it, then use ammonia water to adjust the pH to 8-9, stir at 40-60°C for 1-3 hours, separate the precipitate, mix the precipitate with dichlorotetraamminepalladium solution, fully disperse it and remove the air, use sodium hydroxide to adjust the pH to 9.5-11, then add sodium borohydride solution dropwise, stir the reaction for 0.5-2 hours, separate the precipitate, wash it thoroughly and then vacuum dry it to obtain a palladium-carbon complex.

5. The process for preparing (indol-4-yl)methanol according to claim 4, characterized in that: The specific surface area of ​​the carbon precursor is 300 m 2 / g or above.

6. The process for preparing (indol-4-yl)methanol according to claim 4, characterized in that: The mass ratio of the dichlorotetraamminepalladium to the carbon precursor is 1:5-20; the molar ratio of the dichlorotetraamminepalladium to sodium borohydride is 1:4-5; and the concentration of the dichlorotetraamminepalladium solution is 1.5-3 mg / mL.

7. The process for preparing (indol-4-yl)methanol according to claim 4, characterized in that: The preparation of the carbon precursor comprises the following steps: Tetraethyl orthosilicate is dissolved in an ethanol aqueous solution to obtain a tetraethyl orthosilicate solution, chitosan is fully dispersed in the tetraethyl orthosilicate solution to obtain a dispersion, and then 3-aminopropyltrimethoxysilane and ferrous chloride are added in sequence. After being fully dispersed, the solvent is evaporated; the mixture is frozen to a central temperature below -18°C; the mixture is then freeze-dried at -88°C to -50°C; after drying, the mixture is heated to 1300°C to 1500°C in an inert gas atmosphere, kept warm for 2 to 6 hours, and then cooled to room temperature to obtain a carbon precursor.

8. The process for preparing (indol-4-yl)methanol according to claim 7, characterized in that: The mass ratio of the tetraethyl orthosilicate to chitosan is 1:12-18; the mass ratio of the ferrous chloride to chitosan is 1:10-20; and the mass ratio of the ferrous chloride to 3-aminopropyltrimethoxysilane is 1:2-4.

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