A process for the catalytic hydrogenation of cholesterols to dihydrocholesterols

Abstract

The present application relates to the field of organic synthesis, in particular to a kind of method for catalytic hydrogenation of cholesterols to synthesize dihydrocholesterol, with cholesterols as raw material, hydrogen donor, Pd / CuO-Al2O3 Catalyst occurs hydrogenation and generates dihydrocholesterol, the present application avoids directly using hydrogen as raw material, safety is good, meets the trend of green chemical industry, and reaction condition is mild, reaction temperature is low, reaction time is short, with good industrial production application prospect.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and more specifically to a method for catalytically synthesizing dihydrocholesterol from hydrogenated cholesterol. Background Technology

[0002] Dihydrocholesterol, also known as dihydrocholesterol, has the chemical formula C64-C ... 27 H 48 O, the structural formula is: As a fully saturated derivative of cholesterol, dihydrocholesterol undergoes selective catalytic hydrogenation of the double bond at the C5-C6 position in its molecular structure, forming a saturated choline skeleton. This slight structural change endows it with physicochemical properties and biological activities distinctly different from cholesterol. On one hand, dihydrocholesterol possesses higher chemical and oxidative stability, and is less prone to oxidation by air to produce harmful oxidation products. This makes it an excellent raw material for cosmetics and skincare products, used in the preparation of creams, lotions, etc., providing stable and safe skin-feeling adjustments. On the other hand, in the pharmaceutical field, dihydrocholesterol is an important intermediate or starting material for the synthesis of physiologically active substances such as bile acids, steroid hormones, adrenocortical hormones, estrogens, and androgens.

[0003] Currently, the main methods for synthesizing dihydrocholesterol using existing technologies are:

[0004] Zhang Gongcheng et al. from Lanzhou University used glacial acetic acid as a solvent and platinum oxide as a catalyst to synthesize dihydrocholesterol at 60-75℃. The crude product was purified and the yield reached 80%. However, the yield of this method was relatively low and the crude product needed to be recrystallized.

[0005] CN102212101A discloses a method for preparing dihydrocholesterol using cholesterol and hydrogen as raw materials. After the reaction, the mixture is hot-filtered, the filter cake is washed, the filtrate is concentrated, the solvent is recovered, and after cooling, dihydrocholesterol crystals precipitate. These crystals are then separated and dried to obtain dihydrocholesterol. However, the above method requires the use of hydrogen, which poses a certain degree of danger and is not suitable for industrial production. Furthermore, the yield and purity of the obtained product are low, with a purity of only 97%.

[0006] Catalytic transfer hydrogenation (CTH) is an effective reduction method in organic synthesis. It involves certain organic compounds acting as donors in the presence of a catalyst, quantitatively releasing hydrogen for a hydrogenation reaction. The fundamental difference between CTH and direct hydrogen-based catalytic hydrogenation is that CTH uses hydrogen-containing polyatomic molecules as the hydrogen source (called hydrogen donors). During the reaction, hydrogen is transferred from the hydrogen donor to the reaction substrate (hydrogen acceptor). The diversity of hydrogen sources in CTH provides a new pathway to improve reaction selectivity. Therefore, CTH has become a promising synthetic method for both laboratory and industrial applications. However, the choice of catalyst is crucial for the success of CTH; a suitable catalyst can significantly reduce the severity of reaction conditions and improve the yield and purity of the product.

[0007] Given the numerous problems associated with the direct use of hydrogen as a reaction raw material in existing technologies, developing a new method for synthesizing dihydrocholesterol using catalytic transfer hydrogenation is of great significance. Summary of the Invention

[0008] The purpose of this invention is to provide a method for the catalytic synthesis of dihydrocholesterol from cholesterol hydrogenation, solving the problems of low yield, low purity, and harsh reaction conditions in existing technologies. The main technical solution adopted is as follows:

[0009] A method for catalytically synthesizing dihydrocholesterol from cholesterol involves using cholesterol as a raw material and conducting a hydrogenation reaction to produce dihydrocholesterol in the presence of a hydrogen donor and a Pd / CuO-Al2O3 catalyst. The reaction formula is as follows:

[0010] .

[0011] In some embodiments, the hydrogen donor is selected from one or more of ammonium formate, formic acid, ammonium acetate, acetic acid, hydrazine, and triethylammonium formate.

[0012] In some embodiments, the hydrogen donor is selected from ammonium formate or formic acid.

[0013] In some embodiments, the mass ratio of active component Pd in ​​the Pd / CuO-Al2O3 catalyst is 1.0% to 10.0%.

[0014] In some embodiments, the preparation method of the Pd / CuO-Al2O3 catalyst includes the following steps:

[0015] Step S1: Add Cu(NO3)2·6H2O and Al(NO3)3·9H2O to deionized water, adjust the pH of the mixture to 11~12 with ammonia solution, filter and separate the precipitate, wash the filter cake with deionized water, and obtain the composite metal oxide CuO-Al2O3 after drying and calcination.

[0016] Step S2: The composite metal oxide CuO-Al2O3 is impregnated in PdCl2 aqueous solution, then evaporated and dried, and placed in a box muffle furnace to calcine at a heating rate of 5~10℃ / min to 450~500℃ for 5~10h. After cooling, it is transferred to a horizontal quartz tube furnace, where N2 is first introduced to remove air, and then H2 is continuously introduced. The temperature is raised to 400~500℃ at a rate of 5~10℃ / min and held for 5~10h. Then it is cooled to room temperature to obtain the Pd / CuO-Al2O3 catalyst.

[0017] In some embodiments, the reaction solvent is selected from one or more of methanol, ethanol, isopropanol, tert-butanol, water, tetrahydrofuran, chloroform, and dichloromethane.

[0018] In some embodiments, the reaction solvent is selected from one or more of methanol, ethanol, isopropanol, and tert-butanol.

[0019] In some embodiments, the molar ratio of cholesterol to hydrogen donor is 1:(2~3); the reaction temperature is 50~80℃; and the reaction time is 0.5~2h.

[0020] In some implementation schemes, after the reaction is completed, the catalyst is removed by filtration, the filtrate is concentrated under reduced pressure and water is added, then extracted with an organic solvent, the organic phases are combined, the organic phases are removed by rotary evaporation and vacuum drying to obtain dihydrocholesterol.

[0021] In some embodiments, the organic solvent is diethyl ether.

[0022] The present invention has achieved the following beneficial effects:

[0023] 1) This invention uses cholesterol as a raw material to produce dihydrocholesterol through a hydrogenation reaction in the presence of a hydrogen donor and a Pd / CuO-Al2O3 catalyst. This avoids the direct use of hydrogen, has good safety, conforms to the trend of green chemical industry, and has good prospects for industrial production applications.

[0024] 2) The Pd / CuO-Al2O3 catalyst used in this invention has high activity, with a dihydrocholesterol yield of up to 97.2% and a purity of up to 99.5%. Moreover, the reaction conditions are mild, with low reaction temperature and short reaction time, and the catalytic effect is better than that of the Pd / C catalyst used in the prior art. Detailed Implementation

[0025] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0026] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Every smaller range between any stated value or intermediate value within a stated range, and any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0027] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail. Furthermore, unless otherwise stated, all materials used in this invention are commercially available.

[0028] Preparation Example 1: Preparation of Pd / CuO-Al2O3 Catalyst

[0029] Cu(NO3)2·6H2O (10.0 g) and Al(NO3)3·9H2O (4.0 g) were added to deionized water (200 mL), stirred evenly, and the pH of the mixture was adjusted to 11-12 with ammonia solution (ammonia to water volume ratio of 1:1). The mixture was stirred for 10 h at room temperature. The resulting precipitate was filtered and separated. The filter cake was washed three times with deionized water and dried overnight in an oven at 120 °C. Finally, it was calcined at 550 °C for 5 h to obtain the composite metal oxide CuO-Al2O3.

[0030] CuO-Al2O3 (10.0 g) was impregnated in a calculated amount of a prepared 5% PdCl2 aqueous solution to achieve Pd loadings (mass ratios) of 2.0%, 3.0%, and 5.0%, respectively. The mixture was stirred at room temperature for 8 h, then evaporated and dried at 120 °C. The mixture was then placed in a box-type muffle furnace and calcined at 450 °C for 5 h at a heating rate of 5 °C / min. After cooling, the mixture was transferred to a horizontal quartz tube furnace. N2 was first introduced to purge air, followed by continuous introduction of H2. The temperature was increased to 500 °C at 5 °C / min and held for 10 h. The mixture was then cooled to room temperature to obtain Pd / CuO-Al2O3 catalysts with Pd loadings of 2.0%, 3.0%, and 5.0%, respectively.

[0031] Example 1 Synthesis of dihydrocholesterol

[0032]

[0033] Cholesterol (38.7 g, 0.1 mol) and ethanol (200 mL) were added to a double-necked round-bottom flask, followed by the addition of ammonium formate (12.6 g, 0.2 mol) as a hydrogen donor and 10.0 g of 5.0 wt% Pd / CuO-Al2O3 catalyst. The mixture was heated to 65 °C and stirred for 1 h. After the reaction was complete, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Water (150 mL) was added, followed by extraction with diethyl ether (300 mL × 3). The organic phases were combined, and the solvent was removed by rotary evaporation. The organic phase was then dried under vacuum to obtain 37.8 g of dihydrocholesterol as a white solid, with a yield of 97.2% and an HPLC purity of 99.5%.

[0034] 1 H-NMR (400 MHz, CDCl3): δ= 3.65-3.54 (m, 1H), 1.98-1.92 (m, 1H), 1.86-0.94 (m, 30 H), 0.91 (d, J = 6.5 Hz, 3H), 0.84 (dd, J = 6.6, 1.3 Hz, 6H), 0.79(s, 3H), 0.63 (s, 3H), 0.63-0.55 (m, 1H);

[0035] Example 2 Synthesis of dihydrocholesterol

[0036]

[0037] Cholesterol (38.7 g, 0.1 mol) and isopropanol (200 mL) were added to a double-necked round-bottom flask, followed by the addition of hydrogen donor formic acid (11.5 g, 0.25 mol) and 3.0 wt% Pd / CuO-Al2O3 catalyst (10.0 g). The mixture was heated to 70 °C and stirred for 1.5 h. After the reaction was complete, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Water (150 mL) was added, followed by extraction with diethyl ether (300 mL × 3). The organic phases were combined, and the solvent was removed by rotary evaporation. The organic phase was then dried under vacuum to obtain 37.0 g of dihydrocholesterol as a white solid, with a yield of 95.1% and an HPLC purity of 99.2%.

[0038] 1H-NMR (400 MHz, CDCl3): δ= 3.65-3.54 (m, 1H), 1.98-1.92 (m, 1H), 1.86-0.94 (m, 30 H), 0.91 (d, J = 6.5 Hz, 3H), 0.84 (dd, J = 6.6, 1.3 Hz, 6H), 0.79(s, 3H), 0.63 (s, 3H), 0.63-0.55 (m, 1H);

[0039] Example 3 Synthesis of dihydrocholesterol

[0040]

[0041] Cholesterol (38.7 g, 0.1 mol) and methanol (200 mL) were added to a double-necked round-bottom flask, followed by the addition of ammonium formate (13.8 g, 0.22 mol) as a hydrogen donor and 2.0 wt% Pd / CuO-Al2O3 catalyst (10.0 g). The mixture was heated to 60 °C and stirred for 2 h. After the reaction was complete, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Water (150 mL) was added, followed by extraction with diethyl ether (300 mL × 3). The organic phases were combined, and the solvent was removed by rotary evaporation. The organic phase was then dried under vacuum to obtain 37.3 g of dihydrocholesterol as a white solid, with a yield of 95.9% and an HPLC purity of 99.4%.

[0042] 1 H-NMR (400 MHz, CDCl3): δ= 3.65-3.54 (m, 1H), 1.98-1.92 (m, 1H), 1.86-0.94 (m, 30 H), 0.91 (d, J = 6.5 Hz, 3H), 0.84 (dd, J = 6.6, 1.3 Hz, 6H), 0.79(s, 3H), 0.63 (s, 3H), 0.63-0.55 (m, 1H);

[0043] Comparative Example 1

[0044] Based on Example 1, the 5.0 wt% Pd / CuO-Al2O3 catalyst was replaced with a 5.0 wt% Pd / C catalyst, as follows:

[0045] Cholesterol (38.7 g, 0.1 mol) and ethanol (200 mL) were added to a double-necked round-bottom flask, followed by the addition of ammonium formate (12.6 g, 0.2 mol) as a hydrogen donor and 5.0 wt% Pd / C catalyst (10.0 g). The mixture was heated to 65 °C and stirred for 1 h. After the reaction was complete, the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure, and water (150 mL) was added. The filtrate was then extracted with diethyl ether (300 mL × 3). The organic phases were combined, and the solvent was removed by rotary evaporation. The organic phase was then dried under vacuum to obtain 29.4 g of dihydrocholesterol as a white solid, with a yield of 75.6% and an HPLC purity of 97.1%.

[0046] Comparative Example 2

[0047] Based on Example 1, the 5.0 wt% Pd / CuO-Al2O3 catalyst was replaced with RuCl2(PPh3)3, as follows:

[0048] Cholesterol (38.7 g, 0.1 mol) and ethanol (200 mL) were added to a double-necked round-bottom flask, followed by the addition of hydrogen donors ammonium formate (12.6 g, 0.2 mol) and RuCl2(PPh3)3 (0.01 mol). The mixture was heated to 65 °C and stirred for 1 h. After the reaction was complete, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Water (150 mL) was added, followed by extraction with diethyl ether (300 mL × 3). The organic phases were combined, and the solvent was removed by rotary evaporation. The organic phase was then dried under vacuum to obtain 16.9 g of dihydrocholesterol as a white solid, with a yield of 43.4% and an HPLC purity of 96.5%.

[0049] Comparative Example 3

[0050] Based on Example 1, the 5.0 wt% Pd / CuO-Al2O3 catalyst was replaced with a 5.0 wt% Pd / Al2O3 catalyst (commercially available), as follows:

[0051] Cholesterol (38.7 g, 0.1 mol) and ethanol (200 mL) were added to a double-necked round-bottom flask, followed by the addition of ammonium formate (12.6 g, 0.2 mol) as a hydrogen donor and 10.0 g of 5.0 wt% Pd / Al₂O₃ catalyst. The mixture was heated to 65 °C and stirred for 1 h. After the reaction was complete, the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure, and water (150 mL) was added. The filtrate was then extracted with diethyl ether (300 mL × 3). The organic phases were combined, and the solvent was removed by rotary evaporation. The organic phase was then dried under vacuum to obtain 31.6 g of dihydrocholesterol as a white solid, with a yield of 81.2% and an HPLC purity of 98.6%.

[0052] The above embodiments are merely illustrative examples and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A method for catalytically synthesizing dihydrocholesterol from cholesterol hydrogenation, characterized in that, Using cholesterol as a raw material, a hydrogenation reaction occurs in the presence of a hydrogen donor and a Pd / CuO-Al2O3 catalyst to produce dihydrocholesterol. The reaction formula is as follows: ； The hydrogen donor is selected from ammonium formate or formic acid; The preparation method of the Pd / CuO-Al2O3 catalyst includes the following steps: Step S1: Add Cu(NO3)2·6H2O and Al(NO3)3·9H2O to deionized water, adjust the pH of the mixture to 11~12 with ammonia solution, filter and separate the precipitate, wash the filter cake with deionized water, and obtain the composite metal oxide CuO-Al2O3 after drying and calcination. Step S2: The composite metal oxide CuO-Al2O3 is impregnated in PdCl2 aqueous solution, then evaporated and dried, and placed in a box muffle furnace to calcine at a heating rate of 5~10℃ / min to 450~500℃ for 5~10h. After cooling, it is transferred to a horizontal quartz tube furnace, where N2 is first introduced to remove air, and then H2 is continuously introduced. The temperature is raised to 400~500℃ at a rate of 5~10℃ / min and held for 5~10h. Then it is cooled to room temperature to obtain the Pd / CuO-Al2O3 catalyst.

2. The method according to claim 1, characterized in that, The mass ratio of Pd, the active component, in the Pd / CuO-Al2O3 catalyst is 1.0% to 10.0%.

3. The method according to claim 1, characterized in that, The reaction solvent is selected from one or more of methanol, ethanol, isopropanol and tert-butanol.

4. The method according to claim 1, characterized in that, The molar ratio of cholesterol to hydrogen donor is 1:(2~3); the reaction temperature is 50~80℃, and the reaction time is 0.5~2h.

5. The method according to claim 1, characterized in that: After the reaction was completed, the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure and water was added. Then, it was extracted with an organic solvent. The organic phases were combined and the solvent was removed by rotary evaporation and vacuum drying to obtain dihydrocholesterol.

6. The method according to claim 5, characterized in that, The organic solvent is diethyl ether.

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