A kind of hydrogenation catalyst of 4-acetylaminocyclohexanol and preparation method

Abstract

The invention belongs to the field of fine chemicals. Specifically, a 4-acetylaminocyclohexanol hydrogenation catalyst and a preparation method are provided, wherein the catalyst can hydrogenate benzene rings at a low pressure of 1-3 MPa and achieve complete conversion of raw materials, with a 4-acetylaminocyclohexanol selectivity of >99.0% and a trans-4-acetylaminocyclohexanol selectivity of >70.0%. Furthermore, the catalyst of the invention can be used multiple times and has high economic value.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, and in particular to a hydrogenation catalyst for 4-acetylaminocyclohexanol and a preparation method thereof. Background Art

[0002] Trans-4-acetylaminocyclohexanol is an important pharmaceutical intermediate and can be used in the synthesis of a variety of drugs.

[0003] The literature synthesis method of trans-4-aminocyclohexanol is mainly to obtain cis-trans mixed 4-acetylaminocyclohexanol by hydrogenation of acetaminophen, and then further separate the cis-trans isomers. Patent application CN101628879A discloses a method for separating cis-trans-4-acetylaminocyclohexanol, wherein acetic anhydride is first mixed with the cis-trans mixture, and the esterified product is recrystallized, and the purity of the trans product can be as high as more than 99%. However, direct hydrogenation and then separation are carried out without selectively obtaining the target configuration, and the final yield is low, and the separation step further requires manpower and material resources, which increases the process cost.

[0004] If the target configuration is directly modified on the cyclohexane ring, it is difficult. In the prior art, in order to obtain various cyclohexane derivatives, some researchers will use the important practical technology of aromatic ring reduction. However, due to the special stability of the aromatic ring due to its aromaticity, when using the existing hydrogenation reduction technology, the reaction requires a large amount of reagents and harsh conditions. Nickel has been widely and deeply studied as an effective benzene ring hydrogenation catalyst. Tang Xinyuan and others used Raney nickel as a catalyst to hydrogenate 4-acetaminophenol to trans-4-acetaminocyclohexanol at a high pressure of 7-9MPa and a high temperature of more than 150°C, but the conditions used were harsh, resulting in high difficulty in industrialization. Zhao Mengmeng et al. used 5% Ru / C as a catalyst to hydrogenate 4-acetaminophenol at 120°C and 5MPa. The selectivity of the obtained product 4-acetaminocyclohexanol was about 96%, and the ratio of trans to cis was 78:22. Although this process can use precious metal catalysts to achieve 4-acetaminophenol hydrogenation, the reaction pressure is relatively high, and a lower reaction pressure is required to achieve industrial application. The literature also involves some conversions of cis and trans isomers. Yang Nengwei et al. used Raney nickel as a catalyst to achieve the conversion of cis-4-acetaminocyclohexanol to trans-4-acetaminocyclohexanol, but the required reaction conditions were harsh, and the proportion of the trans target product obtained was not high enough, resulting in serious post-processing losses.

[0005] The use of metals such as nickel and ruthenium for catalytic reduction of aromatic rings can achieve certain results, but such metal catalysts are expensive and difficult to recycle. Therefore, more economically valuable catalysts and preparation methods that can obtain higher reaction yields are needed. Summary of the invention

[0006] In order to solve the above technical problems, the present invention provides a method for preparing a hydrogenation catalyst, comprising the steps of:

[0007] 1) Carrier pretreatment: Place the carrier in an alkaline aqueous solution with a pH of 8-9, stir, and then filter and dry;

[0008] 2) Dispersing the Ru precursor in ultrapure water, adding auxiliary metal ions X; preferably, the metal molar ratio of Ru:X=200:1-2:1, stirring to obtain a mixed solution of the precursor and the auxiliary metal ions;

[0009] 3) dispersing the carrier pretreated in step 1) in ultrapure water, adding dropwise the mixed solution of the precursor and the auxiliary metal ion in step 2), stirring, and obtaining a carrier solution for adsorbing the precursor; preferably, the mass fraction of Ru is 0.1-20wt%;

[0010] 4) Adding a reducing agent to the carrier solution of the adsorption precursor in step 3) to carry out a reduction reaction; preferably, the amount of the reducing agent is 0.05-5 wt %, relative to the mass ratio of the catalyst; the reduced catalyst is filtered and dried to obtain a hydrogenation catalyst.

[0011] In some implementations, the metal molar ratio Ru:X is 200:1, 180:1, 160:1, 140:1, 120:1, 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1 or 2:1.

[0012] In some embodiments, the mass fraction of Ru in the carrier solution of the adsorption precursor in step 3) is 0.1%, 0.2%, 0.3%, 0.5%, 0.8%, 1%, 1.5%, 2%, 2.5%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15% or 20%.

[0013] In some implementations, the amount of the reducing agent used in step 4) is related to the selection of the reducing agent, and the amount of the reducing agent used is the amount used in conventional reduction reactions.

[0014] In some embodiments, 0.05wt%, 0.1wt%, 0.2wt%, 0.5wt%, 1wt%, 1.5wt%, 2wt%, 2.5%, 3wt%, 3.5wt%, 4wt%, 4.5wt%, 5wt%.

[0015] In some implementations, the base in step 1) is one or more combinations of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate.

[0016] In some implementations, the stirring time in step 1) is 4-6 hours; the drying temperature is 60-80° C.; and the drying time is 12-18 hours.

[0017] In some implementations, the ruthenium metal precursor in step 2) is ruthenium trichloride or ruthenium acetate.

[0018] In some implementations, the stirring time in step 2) is 2-3 hours.

[0019] In some implementations, the auxiliary metal ion in step 2) comprises Fe 3+ , Cu 2+ , Pt 4+ , Pd 2+ One or more of.

[0020] In some implementations, the auxiliary metal ion in step 2) comprises Pt 4+ and Pd 2+ Preferably, the auxiliary metal ion Pt in step 2) 4+ and Pd 2+ and the molar ratio is (1:10) to (10:1). Preferably, the auxiliary metal ion Pt in step 2) 4+ and Pd 2+ and the molar ratio is (1:5) to (5:1). Preferably, the auxiliary metal ion Pt in step 2) 4+ and Pd 2+ The molar ratio is (1:2) to (2:1).

[0021] In some implementations, the co-metal ions are provided by the co-metal precursor, and the co-metal precursor is chloroplatinic acid, palladium chloride, palladium acetate, ferric chloride or cupric chloride.

[0022] In some implementations, the stirring time in step 3) is 3-5 hours.

[0023] In some implementations, the reducing agent in step 4) is one of hydrazine hydrate, sodium formate, formaldehyde, ethylene glycol, and potassium borohydride.

[0024] In some implementations, the drying temperature in step 4) is 100-150° C., and the drying time is 8-12 hours.

[0025] In another aspect, the present invention provides a catalyst prepared by the method for preparing the hydrogenation catalyst of the present invention.

[0026] On the other hand, the present invention provides the use of a catalyst prepared by the method for preparing a hydrogenation catalyst of the present invention in the hydrogenation of acetaminophen to prepare acetaminocyclohexanol.

[0027] On the other hand, the present invention provides a method for preparing acetaminocyclohexanol by hydrogenating acetaminophen, comprising the steps of: adding a catalyst prepared by the method for preparing the hydrogenation catalyst of the present invention to an aqueous solution of acetaminophen, and reacting at 100-200° C. in a hydrogen atmosphere to prepare acetaminocyclohexanol.

[0028] In some implementations, the reaction is carried out at a hydrogen pressure of 0.1-5 Ma and a temperature of 120-180° C. to produce acetylaminocyclohexanol.

[0029] In some implementations, the acetamidocyclohexanol is trans-acetamidocyclohexanol.

[0030] The amount of water, pure water or ultrapure water used in the various solutions described in the present invention is based on the ability to achieve the reaction of the present invention, and is generally a conventional amount.

[0031] Beneficial Effects

[0032] The present invention can realize hydrogenation of benzene ring under low pressure of 1-3MPa and complete conversion of raw materials, with selectivity of 4-acetylaminocyclohexanol greater than 99.0% and selectivity of trans-4-acetylaminocyclohexanol greater than 70.0%. Furthermore, the catalyst of the present invention can be applied multiple times and has high economic value.

[0033] Terminology

[0034] Certain embodiments of the present invention are now described in detail. The present invention is intended to cover all substitutions, modifications and equivalent technical solutions, which are all included in the scope of the present invention as defined in the claims. It should be appreciated by those skilled in the art that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is by no means limited to the methods and materials described herein. In the event that one or more of the combined documents, patents and similar materials are different from or contradictory to the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0035] It should be further appreciated that certain features of the invention, which for clarity are described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which for brevity are described in a single embodiment, may also be provided separately or in any suitable sub-combination.

[0036] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0037] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0038] In the following, all numbers disclosed herein are approximate, regardless of whether the word "about" or "approximately" is used. The value of each number may vary by 1%, 2%, 5%, 7%, 8%, 10%, 15% or 20%. Whenever a number with a value of N is disclosed, any number with a value of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, N+ / -10%, N+ / -15% or N+ / -20% will be explicitly disclosed, where "+ / -" means plus or minus.

[0039] wt% means weight percentage. DETAILED DESCRIPTION

[0040] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with embodiments. The specific embodiments described herein are only used to explain the present invention and are not intended to constitute any limitation of the present invention. In addition, in the following description, the description of known structures and technologies is omitted to avoid unnecessary confusion of the concepts of the present disclosure. Such structures and technologies are also described in many publications.

[0041] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0042] Example 1

[0043] Catalyst preparation:

[0044] 1) Carrier pretreatment: 10 g of alumina carrier was placed in a sodium hydroxide solution adjusted to pH 8-9 and stirred for 1 h. The carrier was filtered out by solid-liquid separation and dried at 60°C.

[0045] 2) Adding auxiliary metal ions: RuCl 3Dispersed in 50 mL of ultrapure water (ruthenium mass fraction 3%), add metal ion precursors chloropalladic acid and chloroplatinic acid, the metal mass ratio of Ru:Pd:Pt = 10:1:1, stir for 4 hours to obtain a mixed solution of precursor and metal ion.

[0046] 3) The carrier pretreated in step 1) was dispersed in 50 mL of ultrapure water, and a mixed solution of the precursor and the auxiliary metal ions in step 2) was added dropwise, and stirred at room temperature for 6 h.

[0047] 4) Reduction: slowly add 1 wt% hydrazine hydrate to the carrier solution of the adsorption precursor in step 3), slowly add and stir for 3 hours; filter the catalyst and dry it in an oven at 110° C. for 6 hours to obtain catalyst product A.

[0048] Preparation of 4-acetylaminocyclohexanol:

[0049] 40 g of acetaminophen raw material, 100 g of ultrapure water, and 1 g of catalyst product A were weighed and placed in a reactor. The reaction time was 5 h at 120° C. and 2 MPa pressure to achieve a raw material conversion rate of 99.99%, a selectivity of the target product 4-acetylaminocyclohexanol of 99.3%, and a selectivity of trans-4-acetylaminocyclohexanol of 75%.

[0050] Comparative Example 1

[0051] Comparative catalyst preparation:

[0052] 1) Adding auxiliary metal ions: 0.81g RuCl 3 Dispersed in 50 mL of ultrapure water (ruthenium mass fraction 3%), add the metal ion precursor copper chloride, the metal molar ratio Ru:Cu = 5:1, stir for 4 hours to obtain a mixed solution of the precursor and the metal ion.

[0053] 2) Disperse 10 g of alumina support in 50 mL of ultrapure water, slowly dropwise add the mixed solution of the precursor and auxiliary metal ions in step 1), and stir for 6 h.

[0054] 3) Reduction: Slowly add hydrazine hydrate to the carrier solution of the adsorbed precursor to carry out a reduction reaction; after filtering the catalyst, place it in an oven to dry for a certain period of time to obtain a catalyst product B.

[0055] Preparation of 4-acetylaminocyclohexanol:

[0056] 40g of acetaminophen raw material, 100g of ultrapure water, and 1g of catalyst product B were weighed and placed in a reactor. At 120°C and 3MPa pressure, the reaction time was 5h, and the raw material conversion rate was 95.87%, and the selectivity of the target product 4-acetylaminocyclohexanol was 94.63%. The selectivity of trans-4-acetylaminocyclohexanol was 55.2%.

[0057] Example 2

[0058] Catalyst product A obtained in Example 1 and catalyst product B obtained in Comparative Example 1 were subjected to catalyst application experiments to verify the effects of multiple applications.

[0059] 2.1 Experimental application of catalyst product A in Example 1

[0060] 40 g of acetaminophen raw material, 100 g of ultrapure water, and 1 g of catalyst product A in Example 1 were weighed and placed in a reaction kettle. The reaction was carried out at 120° C. and 2 MPa pressure for 5 h. The catalyst was applied ten times. The application data are shown in Table 1.

[0061] Table 1

[0062]

[0063]

[0064] 2.2 Experimental application of catalyst product B in comparative example 1

[0065] Weigh 40g of acetaminophen raw material, 100g of ultrapure water, and 1g of catalyst product B in the comparative example, place them in a reactor, and carry out catalyst application at 120°C, 2MPa pressure, and reaction time of 5h. The results of catalyst application are shown in Table 2 below, and the catalyst cannot be applied.

[0066] Table 2

[0067]

[0068] It can be seen from the above experiments that the catalyst involved in the present invention can change the properties of the catalyst by pretreating the carrier, so that the catalyst not only has a higher conversion rate and selectivity, but also can be used multiple times and has a higher economic value.

[0069] The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein within the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims

1. A method for preparing a hydrogenation catalyst, comprising the steps of: 1) Carrier pretreatment: placing the carrier in an alkaline aqueous solution with a pH of 8-9, stirring, filtering and drying; the carrier is alumina; 2) Dispersing the Ru precursor in ultrapure water, adding auxiliary metal ions X; the metal molar ratio of Ru:X=200:1-2:1, stirring, and obtaining a mixed solution of the precursor and the auxiliary metal ions; the auxiliary metal ions X include Pt 4+ and Pd 2+ ; 3) The carrier pretreated in step 1) is dispersed in ultrapure water, and the mixed solution of the precursor and the auxiliary metal ion in step 2) is added dropwise, and stirred to obtain a carrier solution for adsorbing the precursor; the mass fraction of Ru is 0.1-20 wt%; 4) Adding a reducing agent to the carrier solution of the adsorption precursor in step 3) to carry out a reduction reaction; the amount of the reducing agent is 0.05-5wt% relative to the mass ratio of the catalyst; filtering the reduced catalyst and drying it to obtain a hydrogenation catalyst.

2. The preparation method according to claim 1, characterized in that: The base in step 1) is one or more combinations of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate; and / or In step 1), the stirring time is 4-6 hours; the drying temperature is 60-80°C; and the drying time is 12-18 hours.

3. The preparation method according to claim 1, characterized in that: In step 2), the ruthenium metal precursor is ruthenium trichloride or ruthenium acetate; and / or In step 2), the stirring time is 2-3 hours.

4. The preparation method according to claim 1, characterized in that: The auxiliary metal ion X is provided by an auxiliary metal precursor, and the auxiliary metal precursor is chloroplatinic acid and palladium chloride or palladium acetate.

5. The preparation method according to claim 1, characterized in that: The reducing agent in step 4) is one of hydrazine hydrate, sodium formate, formaldehyde, ethylene glycol, and potassium borohydride; and / or In step 4), the drying temperature is 100-150° C. and the drying time is 8-12 hours.

6. A hydrogenation catalyst prepared by the preparation method according to any one of claims 1 to 5.

7. Use of the hydrogenation catalyst prepared by the method for preparing the hydrogenation catalyst according to any one of claims 1 to 5 in the preparation of acetaminocyclohexanol by hydrogenation of acetaminophen.

8. A method for preparing acetaminocyclohexanol by hydrogenating acetaminophen, comprising the steps of: A hydrogenation catalyst prepared by the method for preparing a hydrogenation catalyst according to any one of claims 1 to 5 is added to an aqueous solution of acetaminophen, and the mixture is reacted at 100 to 200° C. under a hydrogen atmosphere to obtain acetaminocyclohexanol.

9. The method according to claim 8, characterized in that The reaction is carried out under a hydrogen pressure of 0.1-5 Ma and at 120-180° C. to prepare acetylaminocyclohexanol.

10. The method according to claim 8 or 9, characterized in that: The acetylaminocyclohexanol is trans-acetylaminocyclohexanol.

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