A halogen-modified supported noble metal catalyst and its application in the synthesis of oxaragoli key intermediates

Abstract

This invention belongs to the fields of catalytic chemistry and fine chemicals, and discloses a halogen-modified supported noble metal catalyst and its application in the synthesis of oxaragoli key intermediates. The catalyst uses alumina or modified alumina as a support, loads the active component (noble metal), and modifies its surface electronic structure through halide ions. The preparation method includes precursor conversion of the support, impregnation and reduction of the active metal, and post-modification and regulation of halide ions. The catalyst obtained by this invention exhibits excellent hydrogenation reduction activity and selectivity for compounds containing C=N or C≡N bonds under mild conditions. Under room temperature and low-pressure hydrogen conditions, this catalyst can efficiently catalyze the conversion of 2-fluoro-6-trifluoromethylbenzaldehyde oxime to the oxaragoli key intermediate 2-fluoro-6-trifluoromethylbenzylamine, showing promising industrial application prospects.

Description

Technical Field

[0001] This invention belongs to the field of catalytic chemistry and fine chemical technology, specifically relating to a halogen-modified supported noble metal catalyst and its application in the synthesis of oxaragoli key intermediates. Background Technology

[0002] Elagolix is ​​the only orally administered gonadotropin-releasing hormone (GnRH) receptor antagonist approved by the U.S. Food and Drug Administration (FDA), widely used to relieve pain associated with moderate to severe endometriosis. This drug works by selectively inhibiting GnRH receptors, reducing the release of gonadotropins, thereby lowering estrogen levels, inhibiting the growth of endometriosis lesions, and relieving pain symptoms. However, the synthesis of elagolix involves the reduction reactions of several key intermediates, and these reduction steps are crucial to the synthesis of the final product. In the synthesis of elagolix, 2-fluoro-6-trifluoromethylbenzaldehyde oxime is a key intermediate that needs to be reduced to 2-fluoro-6-trifluoromethylbenzylamine. The choice of catalyst for this reduction reaction directly affects the efficiency of the reaction and the purity of the product. In the prior art, the synthesis of 2-fluoro-6-trifluoromethylbenzylamine often employs borane reduction or Raney nickel catalytic hydrogenation. However, borane reagents are highly toxic and difficult to process; ordinary palladium on carbon or Raney nickel catalysts are prone to dehalogenation side reactions when reducing haloaromatic oximes, leading to decreased product purity and catalyst poisoning and deactivation. Therefore, developing a catalyst that can both suppress dehalogenation side reactions and maintain high hydrogenation activity is a key technical challenge in this field.

[0003] Its chemical structural formula is shown in the figure:

[0004] 2-Fluoro-6-trifluoromethylbenzylamine is one of the key intermediates in the synthesis of elagolix. Existing techniques typically use 2-fluoro-6-trifluoromethylbenzonitrile as a starting material to prepare this compound via a borane reduction reaction (as described in PCT patent WO2005007165A). However, borane reagents have high toxicity and safety risks, and the reduction process of nitrile compounds often relies on high-pressure hydrogen, lithium aluminum hydride, or sodium borohydride, resulting in harsh operating conditions, poor safety, significant environmental burden, and limitations on industrial scale-up, making it difficult to meet the requirements of green chemistry and large-scale production. Based on these problems, the purpose of this invention is to provide a novel method for preparing 2-fluoro-6-trifluoromethylbenzylamine. This method can achieve efficient conversion of the target compound under relatively mild reaction conditions, avoiding the use of highly toxic reducing reagents or high-risk operating conditions, thereby improving the safety and environmental friendliness of the reaction and possessing good prospects for industrial application. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of the prior art and provide a halogen-modified supported noble metal catalyst and its preparation method, as well as the application of this catalyst in the selective hydrogenation reduction reaction of oxaragoli intermediates. This catalyst, by introducing halide ions to modify the electronic structure of the active metal palladium, significantly improves the activity and selectivity of the catalyst in the hydrogenation reaction of haloaromatic oximes.

[0006] To achieve the above objectives, the present invention adopts the following technical solution: A halogen-modified supported noble metal catalyst; the catalyst includes a support, an active metal supported on the support, and a modifier; the support is alumina or modified alumina; the active metal is a noble metal; The modifier is a halogen element, which exists on the catalyst surface in the form of chemical adsorption or coordination. The molar ratio of the halogen element to the active metal palladium is 0.1:1 to 5:1.

[0007] The preparation method of the above-mentioned halogen-modified supported noble metal catalyst includes the following steps: 1) Carrier preparation: Using aluminum source as precursor, alumina-based carrier precursor is prepared by precipitation method, and the carrier is obtained by drying and calcination; 2) Noble metal loading: The active noble metal precursor solution is loaded onto the carrier obtained in step 1) by impregnation, and then dried, calcined and reduced to obtain the intermediate material loaded with noble metal. 3) Halogen modification: The intermediate material obtained in step 2) is dispersed in a liquid system containing a halogen source for modification treatment. After washing and drying, the halogen-modified supported noble metal catalyst X-Pd / Al2O3 (X is a halogen) is obtained.

[0008] Further, the aluminum source used in step 1) is selected from one or more of hydrated aluminum nitrate, hydrated aluminum chloride, aluminum sulfate, sodium aluminate, or aluminum sol; the precipitant in the precipitation method can be selected from one or more of ammonia, sodium hydroxide, potassium hydroxide, ammonium sulfide, diammonium hydrogen phosphate, or sodium oxalate; the heating rate of the calcination can be 5~20℃. o C·min -1 The calcination temperature can be 400-600℃. o C, the calcination time can be 6-8 h.

[0009] Furthermore, the noble metal precursor mentioned in step 2) is a noble metal salt, including but not limited to chloropalladium acid, palladium chloride, palladium nitrate, palladium acetate, tetrachloropalladium salt, ruthenium chloride, rhodium chloride, and platinum chloride.

[0010] The mass ratio of alumina support to loaded metal is 10-100:1; the reducing agent is selected from one or more of sodium borohydride, hydrazine hydrate, formaldehyde, hydrogen, or methanol; the mass ratio of support to reducing agent is 5-20:1-3; the heating rate of the reduction treatment is 3-15°C. o C·min -1 Calcination temperature 400-600 o C, calcination time 3-6 h.

[0011] Further, the halogen source in step 3) is selected from one or more of alkali metal halides or ammonium halides; the solvent for modification is water, C1-C4 alcohol, or a mixture of water and n-hexane. Even further, the alkali metal halides include, but are not limited to, sodium fluoride, sodium chloride, and potassium bromide.

[0012] The resulting halogen-modified noble metal-supported alumina catalyst exhibited excellent catalytic activity at room temperature for the reduction of the key oxaragoli intermediate (2-fluoro-6-trifluoromethylbenzaldehyde oxime) to 2-fluoro-6-trifluoromethylbenzylamine. Therefore, it can be used for efficient catalytic reduction of 2-fluoro-6-trifluoromethylbenzaldehyde oxime to 2-fluoro-6-trifluoromethylbenzylamine under mild conditions. The reaction formula is as follows:

[0013] Specifically, it uses 2-fluoro-6-trifluoromethylbenzaldehyde oxime as a raw material, hydrogen as a hydrogen source, alcohol and water mixed in a certain proportion as a reaction solvent, and bromine-modified palladium-supported alumina as a catalyst to react at room temperature for a certain time to generate 2-fluoro-6-trifluoromethylbenzylamine.

[0014] Furthermore, the volume ratio of the oxaragone key intermediate, alcohol, and water used is 1:1, and the alcohol is one or more of isopropanol, ethanol, or ethylene glycol; the reaction temperature is 25-100 °C; and the reaction time is 3-4 h.

[0015] The significant advantages of this invention are: (1) The halogen-modified palladium-supported alumina catalyst prepared in this invention exhibits excellent reactivity. Under mild reaction conditions, this catalyst can efficiently catalyze the conversion of fine compounds containing functional groups such as nitriles, imines, or aldehydes. For example, in the reduction of 2-fluoro-6-trifluoromethylbenzaldehyde oxime to 2-fluoro-6-trifluoromethylbenzylamine, a conversion rate of 98% and a yield of 96% can be achieved, demonstrating excellent catalytic performance. Therefore, this catalyst is a highly efficient catalytic hydrogenation material suitable for the reduction reactions of various organic compounds.

[0016] (2) The catalytic material prepared by the present invention has good chemical stability.

[0017] (3) The entire production process of this invention is simple, easy to control, and has low energy consumption and low cost, which meets the actual production needs and is conducive to large-scale promotion. Attached Figure Description

[0018] Figure 1 The XRD patterns are those of the Br-Pd / Al2O3, F-Pd / Al2O3, and Cl-Pd / Al2O3 catalysts prepared in Example 1.

[0019] Figure 2 The images show a comparison of Raman spectra of different halogen-modified catalysts prepared in Example 1. Left: Full Raman spectra of different halogen-modified catalysts; Right: Enlarged view of a localized halogen-metal bond.

[0020] Figure 3 The image shows the SEM morphology of the catalyst prepared in Example 1.

[0021] Figure 4 This is an HPLC chromatogram of the product from the Br-Pd / Al2O3 catalytic reduction reaction in Example 2.

[0022] Figure 5 This is a comparison chart of the catalytic reduction activities of 2-fluoro-6-trifluoromethylbenzaldehyde oxime by different catalyst samples in Example 2. Detailed Implementation

[0023] The present invention will be further described in detail below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto.

[0024] Example 1: Preparation of Halogen-Modified Metal Catalysts 1) Carrier Preparation: Weigh 7.0 g of aluminum nitrate nonahydrate and dissolve it in deionized water to prepare solution A. Separately, use ammonium carbonate solution as a precipitant, adding it dropwise to solution A with stirring, controlling the final pH to 8.0 to obtain a suspension. Age the resulting suspension in a 50 ℃ water bath for 3-6 hours. Filter the solution, wash the filter cake with deionized water until neutral, dry it at 100 ℃, and then place it in a muffle furnace, calcining it at 600 ℃ for 6 hours at a rate of 10 ℃ / min. After natural cooling, grind the mixture to obtain the alumina carrier.

[0025] 2) Preparation of active metal-supported alumina (Pd / Al2O3): Palladium chloride (0.06 g) was dissolved in dilute hydrochloric acid (0.1 M hydrochloric acid solution, 20 mL) to prepare a chloropalladic acid solution. The alumina support (1.2 g) prepared in step 1) was immersed in the chloropalladic acid solution, stirred evenly, and then the water was evaporated. The dried powder was placed in a muffle furnace and calcined at 600 °C for 4 hours. After cooling, the sample was dispersed in deionized water, and an aqueous solution containing sodium borohydride (0.18 g) was added dropwise under vigorous stirring for liquid-phase reduction. After reduction, the sample was filtered, washed with a large amount of water, and dried under vacuum to obtain the Pd / Al2O3 intermediate.

[0026] 3) Halogen modification (X-Pd / Al2O3): The above Pd / Al2O3 intermediate was dispersed in aqueous solutions containing appropriate amounts of potassium bromide (KBr), sodium fluoride (NaF), or sodium chloride (NaCl) (controlling the molar ratio of halogen to Pd to be 0.7:1), and stirred at room temperature for 6-8 hours to carry out chemisorption modification. The mixture was filtered, washed with an ethanol-water mixture to remove physically adsorbed ions, and dried under vacuum at 100 °C to obtain Br-Pd / Al2O3, F-Pd / Al2O3, and Cl-Pd / Al2O3 catalysts, respectively.

[0027] Figure 1 The synthesized Br-Pd / Al2O3 and F-Pd / Al2O3 3、 XRD comparison of Cl-Pd / Al2O3 modified with different halogens. Figure 1 The XRD patterns showed that all samples retained the characteristic diffraction peaks of alumina, and the crystal structure remained stable before and after modification, proving that the support structure was not damaged.

[0028] Figure 2 The synthesized Br-Pd / Al2O3 and F-Pd / Al2O3 3、 Raman comparison of Cl-Pd / Al2O3. Figure 2 Raman spectroscopy confirmed the interaction between halogens and the palladium surface.

[0029] Figure 3 The images show the SEM morphology of the synthesized Br-Pd / Al2O3, F-Pd / Al2O3, and Cl-Pd / Al2O3.

[0030] Example 2 Preparation of halogen-modified metal catalysts In step 3) of Example 1, the molar ratio of halogen to Pd is controlled to 0.1:1, and the remaining steps are the same as in Example 1.

[0031] Example 3 Preparation of halogen-modified metal catalysts In step 3) of Example 1, the molar ratio of halogen to Pd is controlled to 5:1, and the remaining steps are the same as in Example 1.

[0032] Example 4 Preparation of halogen-modified metal catalysts Replace the active metal compound in step 2) of Example 1 with nickel chloride, and the remaining steps are the same as in Example 1.

[0033] Example 5 Preparation of halogen-modified ruthenium catalyst Replace the active metal compound in step 2) of Example 1 with ruthenium chloride, and the remaining steps are the same as in Example 1.

[0034] Example 6: Preparation of Halogen-Modified Rhodium Catalyst Replace the active metal compound in step 2) of Example 1 with rhodium chloride, and the remaining steps are the same as in Example 1.

[0035] Example 7: Preparation of Halogen-Modified Platinum Catalyst Replace the active metal compound in step 2) of Example 1 with platinum chloride, and the remaining steps are the same as in Example 1.

[0036] Example 8: Evaluation of Catalytic Performance Take 5 mg each of the catalysts Br-Pd / Al₂O₃, F-Pd / Al₂O₃, and Cl-Pd / Al₂O₃ prepared in Example 1 and place them in reaction flasks. Add 3 mL of methanol / water (1:1 volume ratio) mixed solvent to each flask, and add 0.015 mmol of the substrate 2-fluoro-6-trifluoromethylbenzaldehyde oxime. After purging with hydrogen three times, stir the reaction under atmospheric pressure and hydrogen atmosphere at 25 °C for 4 hours. After the reaction is complete, separate the catalysts by centrifugation. Figure 4 The results of HPLC analysis of the supernatant after the Br-Pd / Al2O3 catalytic reaction are shown in the figure. The results indicate that the substrate conversion rate reached 98%, the selectivity of the target product 2-fluoro-6-trifluoromethylbenzylamine was 99%, and no obvious defluorination byproducts were detected.

[0037] Figure 5 The diagram shows a comparison of the catalytic activity of the catalyst samples in the reduction of 2-fluoro-6-trifluoromethylbenzaldehyde oxime. The results indicate that all three halogen-modified catalysts exhibit activity, with the Br-modified catalyst (Br-Pd / Al2O3) showing the highest yield (96%), which is superior to the Cl-modified and F-modified samples. This may be related to the varying strengths of the electronic modification effect caused by differences in the atomic radii and electronegativity of the different halogens.

[0038] The halogen-modified palladium-supported alumina catalyst prepared by this invention is simple in process and low in cost. Under mild conditions (room temperature and atmospheric pressure), it exhibits excellent activity and chemoselectivity for the reduction of the key intermediate of oxaragoli, solving the problem of dehalogenation side reactions easily caused by traditional catalysts, and has good prospects for industrial application.

[0039] The above description is only a preferred embodiment of the present invention. All equivalent changes and modifications made within the scope of the claims of the present invention should be included in the scope of the present invention.

Claims

1. A halogen-modified supported noble metal catalyst, characterized in that: The catalyst includes a support, an active metal supported on the support, and a modifier; 1) The carrier is alumina or modified alumina; 2) The active metal is a noble metal; 3) The modifier is a halogen element, which exists on the catalyst surface in the form of chemical adsorption or coordination; The molar ratio of the halogen element to the active metal is 0.1:1 to 5:

1.

2. A method for preparing a halogen-modified supported noble metal catalyst as described in claim 1, characterized in that, Includes the following steps: 1) Carrier preparation: Using aluminum source as precursor, alumina-based carrier precursor is prepared by precipitation method, and the carrier is obtained by drying and calcination; 2) Noble metal loading: The active noble metal precursor solution is loaded onto the carrier obtained in step 1) by impregnation, and then dried, calcined and reduced to obtain the intermediate material loaded with noble metal. 3) Halogen modification: The intermediate material obtained in step 2) is dispersed in a liquid system containing a halogen source for modification treatment. After washing and drying, the halogen-modified supported noble metal catalyst is obtained.

3. The preparation method according to claim 2, characterized in that: The aluminum source mentioned in step 1) is selected from one or more of aluminum nitrate, aluminum chloride, aluminum sulfate, sodium aluminate, boehmite, or aluminum sol; the calcination temperature is 400-800 ℃.

4. The preparation method according to claim 2, characterized in that: The noble metal precursor mentioned in step 2) is a noble metal salt, including but not limited to chloropalladium acid, palladium chloride, palladium nitrate, palladium acetate, tetrachloropalladium salt, ruthenium chloride, rhodium chloride, and platinum chloride.

5. The preparation method according to claim 2, characterized in that: The mass ratio of the carrier to the active metal in step 2) is 10-100:

1.

6. The preparation method according to claim 2, characterized in that: The reduction treatment described in step 2) adopts liquid-phase reduction or gas-phase reduction; the reducing agent is selected from one or more of sodium borohydride, hydrazine hydrate, formaldehyde, hydrogen or methanol; the mass ratio of carrier to reducing agent is 5-20:1-3.

7. The preparation method according to claim 2, characterized in that: The halogen source mentioned in step 3) is selected from one or more of alkali metal halides or ammonium halides; the solvent for modification is water, C1-C4 alcohol, or a mixed solvent of water and n-hexane.

8. The preparation method according to claim 7, characterized in that: The alkali metal halides include, but are not limited to, sodium fluoride, sodium chloride, and potassium bromide.

9. The application of the catalyst as described in claim 1 in the hydrogenation reduction reaction of carbon-nitrogen unsaturated compounds.

10. The application according to claim 9, characterized in that: The carbon-nitrogen unsaturated compound is a benzaldehyde oxime compound; using 2-fluoro-6-trifluoromethylbenzaldehyde oxime as a substrate, in the presence of hydrogen, with an alcohol or an alcohol-water mixture as a solvent, and under the action of the catalyst, the oxaragoli intermediate 2-fluoro-6-trifluoromethylbenzylamine is prepared by reduction; the reaction temperature is 25-100℃, and the reaction pressure is atmospheric pressure to 5.0 MPa.

Images