A method for the catalytic oxidation of tetraenes to diols

Abstract

This invention belongs to the field of pharmaceutical chemical synthesis technology and relates to a method for the catalytic oxidation of acetate tetraenes to synthesize dihydroxy compounds. The method uses acetate tetraenes as a raw material, acetone as a solvent, Ru-X-Y as a catalyst, and sodium hypochlorite as an oxidant. Under alkaline conditions, catalytic oxidation yields the product dihydroxy compound. In Ru-X-Y, X is Pt or Pd, and Y is any one of Fe, Mn, and Cu. This invention uses solid Ru-X-Y as a catalyst, utilizing the synergistic activation and polarization properties of metals. It only requires sodium hypochlorite, which has relatively weak oxidizing power, as an oxidant to catalytically oxidize acetate tetraenes to the target product dihydroxy compound, effectively avoiding the use of strong oxidants such as potassium permanganate. This not only prevents over-oxidation and improves product yield and quality but also increases production efficiency, resulting in significant economic and social benefits.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical synthesis technology, and relates to a method for synthesizing dihydroxy compounds by catalytic oxidation of acetate tetraenes. Background Technology

[0002] The dihydroxy compound, chemically named 16α,17a-dihydroxypregn-1,4,9(11)-triene-3,20-dione-21-acetate, has the following structural formula: .

[0003] Dihydroxy compounds are key intermediates in the synthesis of 16α-hydroxyprednisolone, and are also intermediates in the synthesis of glucocorticoid raw materials. They are intermediates in the synthesis of approved nydroid drugs, including triamcinolone, budesonide, ciroxonide, and desoxind. Nydroid drugs belong to the class of inhaled glucocorticoids, characterized by local administration, low dosage, strong local anti-inflammatory effects, and few systemic side effects, and are widely used to treat refractory asthma and inflammation. Prednisolone is a synthetic intermediate-acting glucocorticoid with similar effects to prednisone, possessing anti-inflammatory and anti-allergic properties. It has a stronger anti-inflammatory effect, very weak water and electrolyte metabolism, and good efficacy when applied locally. It is also suitable for patients with hepatic impairment. It is rapidly and completely absorbed orally, reaching peak plasma concentration within 1 hour, with a plasma protein binding rate of 90%–95% and a half-life of approximately 200 minutes. It can enter fetal circulation, and the amount appearing in breast milk is 0.07%–0.23%. It is metabolized in the liver and mainly excreted by the kidneys, with more than 20% being the unchanged drug. It is suitable for treating allergic diseases such as eczema and dermatitis, as well as connective tissue diseases such as lupus erythematosus and dermatomyositis.

[0004] Existing methods for preparing dihydroxy compounds generally use acetate tetraenes as raw materials, which are oxidized in the presence of formic acid and potassium permanganate to obtain the dihydroxy compounds. However, these methods suffer from over-oxidation due to the strong oxidizing power of potassium permanganate, which affects the yield and quality of the dihydroxy compounds, thus increasing the preparation cost. Summary of the Invention

[0005] To address the aforementioned shortcomings, this invention provides a method for synthesizing dihydroxy compounds by catalytic oxidation of acetate tetraenes. This method is low-cost, safer, more environmentally friendly, and improves product yield and quality.

[0006] The purpose of this invention is to provide a method for synthesizing dihydroxy compounds by catalytic oxidation of acetate tetraenes, using acetate tetraenes as raw materials, acetone as solvent, Ru-XY as catalyst, and sodium hypochlorite as oxidant, to obtain the product dihydroxy compounds through catalytic oxidation under alkaline conditions; In the Ru-XY, X is Pt or Pd, and Y is any one of Fe, Mn, and Cu.

[0007] This invention uses solid Ru-XY as a catalyst, leveraging the synergistic activation and polarization properties of metals. It requires only sodium hypochlorite, a relatively weak oxidant, to catalytically oxidize acetate tetraenes to the target product, dihydroxyl, effectively avoiding the use of strong oxidants like potassium permanganate. This not only prevents over-oxidation and improves product yield and quality but also increases production efficiency. Furthermore, the solid catalyst can be recycled, reducing costs and resulting in significant economic and social benefits. The reaction principle is as follows: C 23 H 26 O4+ NaClO + H2O → C 23 H 28 O6+ NaCl Preferably, in the above technical solution, the preparation method of Ru-XY is as follows: first, ruthenium salt is loaded onto activated carbon and dried; then, soluble salts of X and Y are loaded onto the ruthenium-loaded activated carbon using the same method; and finally, the Ru-XY catalyst is obtained by filtration, washing, and vacuum drying. Specifically, activated carbon is placed in a reaction vessel, and an aqueous solution of ruthenium salt is added dropwise. After the addition is complete, the temperature is raised to 60-80°C with stirring, and stirring is continued for 2-4 hours. Then, the pH is adjusted to be greater than 12.5, and stirring is continued for 1-2 hours. After cooling and standing for 1-2 hours, the mixture is filtered under reduced pressure. The filter cake is washed with deionized water until the filtrate is neutral, and then vacuum dried to obtain ruthenium-loaded activated carbon. Then, the ruthenium salt is replaced with a combination of soluble salts of X and Y, and the soluble salts of X and Y are loaded onto the ruthenium-loaded activated carbon using the aforementioned operation. After filtration, washing, and vacuum drying, the Ru-XY catalyst is obtained.

[0008] Preferably, the ruthenium salt can be RuCl3·nH2O or ruthenium acetate; the soluble salt of X can be any one or more of PdCl2, Pd(NO3)2, H2PtCl5, and Pd(NO3)2(NH3)2. The soluble salt of Y can be FeCl3, Fe(NO3)3, Cu(NO3)2, Cu(CH3COO)2·H2O, MnCl2, or Mn(CH3COO)2.

[0009] Preferably, during the preparation of the catalyst, a sodium hydroxide solution is used to adjust the pH value.

[0010] Preferably, in the above technical solution, the loadings of Ru, X, and Y in the Ru-XY catalyst are 3wt%, 1wt%, and 1wt%, respectively.

[0011] Preferably, in the above technical solution, the pH of the alkaline condition is 8 to 9.

[0012] Preferably, in the above technical solution, the method specifically involves: adding acetate tetraene and acetone into a clean reaction flask, adding Ru-XY catalyst under stirring, cooling, adding sodium hypochlorite / sodium bicarbonate / aqueous solution dropwise, maintaining the temperature for 30-40 minutes after the addition is complete, filtering, adjusting the pH of the filtrate to 6-7, concentrating under negative pressure to remove acetone, adding water, stirring for 1-1.5 hours, filtering, and drying at 60°C to obtain the dihydroxy compound.

[0013] Preferably, in the above technical solution, the reaction and rinsing temperatures are both 0 to 5°C.

[0014] Preferably, in the above technical solution, the mass ratio of the acetate tetraene, acetone, water, Ru-XY catalyst, sodium hypochlorite, and sodium bicarbonate is 1:15-20:2-3:0.1-0.2:0.5:0.2.

[0015] Preferably, in the above technical solution, glacial acetic acid is used to adjust the pH.

[0016] Preferably, in the above technical solution, the Ru-XY catalyst is any one of Ru-Pt-Fe, Ru-Pt-Mn, Ru-Pt-Cu, Ru-Pd-Fe, and Ru-Pd-Mn; more preferably, it is Ru-Pt-Fe.

[0017] Advantages compared to existing technologies: This invention uses a self-made solid Ru-XY catalyst, leveraging its metal-synergistic activation and polarization properties, to catalytically oxidize acetate tetraenes to the target product, dihydroxyl, using sodium hypochlorite, which has relatively weak oxidizing properties. This effectively avoids the use of strong oxidants like potassium permanganate. This not only prevents excessive oxidation during the reaction process, improving product yield and quality, but also increases production efficiency and enhances the product's market competitiveness. Furthermore, the solid catalyst used can be recycled without affecting product yield and purity, significantly reducing costs and facilitating the industrial production of dihydroxyl, thus yielding substantial economic and social benefits. Detailed Implementation

[0018] The above-described technical features of the present invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. However, the present invention is not limited to these embodiments, nor are these embodiments limited in any way.

[0019] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the formulations involved in the following examples are all commercially available products and can be purchased from the market.

[0020] The present invention will be further described in detail below with reference to embodiments: Example 1 The preparation of a 3wt%Ru-1wt%Pt-1wt%Fe catalyst includes the following steps: (1) Weigh 5g of activated carbon and place it in a 100mL three-necked round-bottom flask. Add 14.7mL of RuCl3.nH2O solution with a concentration of 0.01022g / mL dropwise. Add magnetic stirring, heat to 80℃, and continue stirring for 4h. (2) Add 20% NaOH solution dropwise to adjust the pH to >12.5, and continue stirring for 2 hours; (3) Cool and stand for 1 hour, filter the liquid in the three-necked flask under reduced pressure, wash the filter cake with deionized water until the washing liquid is neutral, and dry the filter cake under vacuum at 120°C for 9 hours. (4) Transfer the filter cake from step (3) to a 100mL three-necked round-bottom flask, add 20mL of deionized water, stir, and slowly add 6.6mL of chloroplatinic acid solution with a concentration of 0.00725g / mL and 10mL of ferric chloride solution with a concentration of 0.005014g / mL, raise the temperature to 80℃, and continue stirring for 4h; (5) Add 20% NaOH solution dropwise to adjust the pH to >12.5, and continue stirring for 2 hours; (6) Cool and stand for 1 hour, filter the liquid in the three-necked flask under reduced pressure, wash the filter cake with deionized water until the washing liquid is neutral, and dry the filter cake under vacuum at 120°C for 9 hours to obtain 3wt%Ru-1wt%Pt-1wt%Fe catalyst.

[0021] Example 2 The preparation method of the 3wt%Ru-1wt%Pt-1wt%Mn catalyst is the same as that in Example 1, except that the soluble salt of Y used is MnCl2.

[0022] Example 3 The preparation method of the 3wt%Ru-1wt%Pt-1wt%Cu catalyst is the same as that in Example 1, except that the soluble salt of Y used is Cu(NO3)2.

[0023] Example 4 The preparation method of the 3wt%Ru-1wt%Pd-1wt%Fe catalyst is the same as that in Example 1, except that the soluble salt of X used is Pd(NO3)2.

[0024] Example 5 The preparation method of the 3wt%Ru-1wt%Pd-1wt%Mn catalyst is the same as that in Example 1, except that the soluble salt of X used is Pd(NO3)2 and the soluble salt of Y used is MnCl2.

[0025] Example 6 A method for catalytically oxidizing acetate tetraenes to synthesize dihydroxy compounds includes the following steps: (1) Add 10g of acetate tetraene and 180mL of acetone to a clean reaction flask, add 1.5g of the 3wt%Ru-1wt%Pt-1wt%Fe catalyst prepared in Example 1 while stirring, and cool to 0-5℃; (2) Add 4.5g sodium hypochlorite / 2g sodium bicarbonate / 20mL aqueous solution. After the addition is complete, react at 0-5℃ for 30min. Filter and add glacial acetic acid to the filtrate to adjust the pH to 6-7. (3) The filtrate was concentrated with negative pressure in a rotary evaporator to dry acetone, 50 mL of water was added, the temperature was lowered to 0-5℃ and stirred for 1 hour, filtered, and dried at 60℃ to obtain the dihydroxy compound. The purity of the product was tested to be 98.5% (HPLC) and the product yield was 105.6%.

[0026] Example 7 A method for catalytically oxidizing acetate tetraenes to synthesize dihydroxy compounds includes the following steps: (1) Add 10g of acetate tetraene and 180mL of acetone to a clean reaction flask, add 1.5g of the 3wt%Ru-1wt%Pt-1wt%Mn catalyst prepared in Example 2 under stirring, and cool to 0-5℃; (2) Add 5g sodium hypochlorite / 2g sodium bicarbonate / 20mL aqueous solution. After the addition is complete (pH is 8-9), react at 0-5℃ for 30min, filter, and add glacial acetic acid to the filtrate to adjust the pH to 6-7. (3) The filtrate was concentrated with negative pressure in a rotary evaporator to dry acetone, 50 mL of water was added, the temperature was lowered to 0-5℃ and stirred for 1 hour, filtered, and dried at 60℃ to obtain the dihydroxy compound. The purity of the product was tested to be 98.2% (HPLC) and the product yield was 104.8%.

[0027] Example 8 A method for catalytically oxidizing acetate tetraenes to synthesize dihydroxy compounds includes the following steps: (1) Add 10g of acetate tetraene and 180mL of acetone to a clean reaction flask, add 1.5g of the 3wt%Ru-1wt%Pt-1wt%Cu catalyst prepared in Example 3 under stirring, and cool to 0-5℃; (2) Add 4.5g sodium hypochlorite / 2g sodium bicarbonate / 20mL aqueous solution. After the addition is complete (pH is 8-9), react at 0-5℃ for 30min, filter, and add glacial acetic acid to the filtrate to adjust the pH to 6-7. (3) The filtrate was concentrated with negative pressure in a rotary evaporator to dry acetone, 50 mL of water was added, the temperature was lowered to 0-5℃ and stirred for 1 hour, filtered, and dried at 60℃ to obtain the dihydroxy compound. The purity of the product was tested to be 98.3% (HPLC) and the product yield was 104.9%.

[0028] Example 9 A method for catalytically oxidizing acetate tetraenes to synthesize dihydroxy compounds includes the following steps: (1) Add 10g of acetate tetraene and 180mL of acetone to a clean reaction flask, add 1.5g of the 3wt%Ru-1wt%Pd-1wt%Fe catalyst prepared in Example 4 under stirring, and cool to 0-5℃; (2) Add 4g sodium hypochlorite / 2g sodium bicarbonate / 20mL aqueous solution. After the addition is complete (pH is 8-9), react at 0-5℃ for 30min, filter, and add glacial acetic acid to the filtrate to adjust the pH to 6-7. (3) The filtrate was concentrated with negative pressure in a rotary evaporator to dry acetone, 50 mL of water was added, the temperature was lowered to 0-5℃ and stirred for 1 hour, filtered, and dried at 60℃ to obtain the dihydroxy compound. The purity of the product was tested to be 97.8% (HPLC) and the product yield was 104.5%.

[0029] Example 10 A method for catalytically oxidizing acetate tetraenes to synthesize dihydroxy compounds includes the following steps: (1) Add 10g of acetate tetraene and 180mL of acetone to a clean reaction flask, add 1.5g of the 3wt%Ru-1wt%Pd-1wt%Mn catalyst prepared in Example 5 while stirring, and cool to 0-5℃; (2) Add 6g sodium hypochlorite / 2g sodium bicarbonate / 20mL aqueous solution. After the addition is complete (pH is 8-9), react at 0-5℃ for 30min, filter, and add glacial acetic acid to the filtrate to adjust the pH to 6-7. (3) The filtrate was concentrated with negative pressure in a rotary evaporator to dry acetone, 50 mL of water was added, the temperature was lowered to 0-5℃ and stirred for 1 hour, filtered, and dried at 60℃ to obtain the dihydroxy compound. The purity of the product was tested to be 98.1% (HPLC) and the product yield was 104.7%.

[0030] Example 11 A method for catalytically oxidizing acetate tetraenes to synthesize dihydroxy compounds includes the following steps: (1) Add 10g of acetate tetraene and 180mL of acetone to a clean reaction flask, add 1.5g of the 3wt%Ru-1wt%Pt-1wt%Fe catalyst prepared in Example 1 while stirring, and cool to 0-5℃; (2) Add 6.5g sodium hypochlorite / 2g sodium bicarbonate / 20mL aqueous solution. After the addition is complete (pH is 8-9), react at 0-5℃ for 30min, filter, and add glacial acetic acid to the filtrate to adjust the pH to 6-7. (3) The filtrate was concentrated with negative pressure in a rotary evaporator to dry acetone, 50 mL of water was added, the temperature was lowered to 0-5℃ and stirred for 1 hour, filtered, and dried at 60℃ to obtain the dihydroxy compound. The purity of the product was tested to be 98.4% (HPLC) and the product yield was 105.6%.

[0031] Meanwhile, taking the catalyst used in this method as an example, the filter cake was washed with deionized water until the washing liquid was neutral. After the filter cake was vacuum dried at 120°C for 9 hours, it was added to the next reaction. Each time, 0.075g of 3wt%Ru-1wt%Pt-1wt%Fe fresh catalyst was added. The reaction was repeated a total of 20 times. The product quality and yield results are shown in Table 1.

[0032] Table 1

[0033] As can be seen from the results in Table 1, the solid catalyst prepared by this invention can be reused after simple processing following the catalytic reaction. Furthermore, only a small amount of new catalyst needs to be added subsequently to achieve the same effect as the first use. The yield of the dihydroxy compound is good, which also proves that the solid catalyst has excellent stability and activity, can be recycled, and saves costs.

[0034] Comparative Example 1 A method for synthesizing dihydroxy compounds from acetate tetraenes includes the following steps: 15g of acetate tetraene and 415mL of acetone were added to a clean reaction flask. 2.7g of formic acid and 25g of water were added with stirring, and the mixture was cooled to -5℃. A potassium permanganate aqueous solution prepared with 7.5g of potassium permanganate / 106g of water was added dropwise at -5℃ over 15 minutes. After the addition was complete, the reaction was allowed to proceed for 20 minutes. Then, a potassium permanganate aqueous solution prepared with 7.5g of sodium bisulfite / 75g of water was added dropwise. After the addition was complete, the mixture was stirred at 30℃ for 1 hour. The mixture was filtered, and the filtrate was concentrated to dryness with acetone under negative pressure. 375mL of water was added for water separation, followed by filtration and drying at 60℃ to obtain the dihydroxy compound. The purity of the product was determined to be 92.5% (HPLC), and the product yield was 95%.

[0035] Comparative Example 2 A method for synthesizing dihydroxy compounds from acetate tetraenes includes the following steps: 15g of acetate tetraene and 430mL of acetone were added to a clean reaction flask. 2.7g of formic acid and 25g of water were added with stirring, and the mixture was cooled to -5℃. A potassium permanganate aqueous solution prepared with 8g of potassium permanganate / 106g of water was added dropwise at -5℃ over 15 minutes. After the addition was complete, the reaction was allowed to proceed for 20 minutes. Then, a potassium permanganate aqueous solution prepared with 7.5g of sodium bisulfite / 75g of water was added dropwise. After the addition was complete, the mixture was stirred at 30℃ for 1 hour. The mixture was filtered, and the filtrate was concentrated to dryness with acetone under negative pressure. 375mL of water was added for water precipitation, followed by filtration and drying at 60℃ to obtain the dihydroxy compound. The purity of the product was determined to be 92.1% (HPLC), and the product yield was 94.5%.

[0036] Comparative Example 3 A method for synthesizing dihydroxy compounds from acetate tetraenes includes the following steps: 15g of acetate tetraene and 450mL of acetone were added to a clean reaction flask. 2.7g of formic acid and 25g of water were added with stirring, and the mixture was cooled to -5℃. A potassium permanganate aqueous solution prepared with 7g of potassium permanganate / 106g of water was added dropwise at -5℃ over 15 minutes. After the addition was complete, the reaction was allowed to proceed for 20 minutes. Then, a potassium permanganate aqueous solution prepared with 7.5g of sodium bisulfite / 75g of water was added dropwise. After the addition was complete, the mixture was stirred at 30℃ for 1 hour. The mixture was filtered, and the filtrate was concentrated to dryness with acetone under negative pressure. 375mL of water was added for water precipitation, followed by filtration and drying at 60℃ to obtain the dihydroxy compound. The purity of the product was determined to be 92.8% (HPLC), and the product yield was 93.2%.

[0037] Comparative Example 4 A method for synthesizing dihydroxy compounds by catalytic oxidation of acetate tetraenes differs from that in Example 6 in that the catalyst used is 1.5g of 3wt%Ru-1wt%Pt catalyst, and the purity of the obtained dihydroxy compound is 95.2% (HPLC), with a product yield of 101.2%.

[0038] Comparative Example 5 A method for synthesizing dihydroxy compounds by catalytic oxidation of acetate tetraenes differs from that in Example 6 in that the catalyst used is 1.5g of 3wt%Ru-1wt%Fe catalyst, and the purity of the obtained dihydroxy compound is 94.9% (HPLC), with a product yield of 100.8%.

[0039] Comparative Example 6 A method for synthesizing dihydroxy compounds by catalytic oxidation of acetate tetraenes, differing from Example 6 in that the catalyst used is 1.5g of 3wt% Ru catalyst, and the purity of the obtained dihydroxy compound is 83.9% (HPLC), with a product yield of 86.2%.

[0040] Comparative analysis revealed that the purity and yield of the dihydroxy compound prepared by the method of this invention were higher than those obtained by using conventional potassium permanganate as an oxidant. Even increasing the amount of potassium permanganate could not achieve the purity and yield of the product obtained by the method of this invention. Furthermore, a comparison of the results of Example 6 with Comparative Examples 4-6 showed that the ternary catalyst of this invention was more effective than binary or monocatalysts. Moreover, the solid catalyst prepared by this invention can be recycled more than 20 times without loss of yield and quality, exhibiting good activity and stability.

[0041] In summary, this invention, through improved preparation process, using solid Ru-XY as a catalyst and sodium hypochlorite with weak oxidizing power as an oxidant, can catalytically oxidize acetate tetraenes to the target product dihydroxy compounds. This method is low-cost, safer and more environmentally friendly, and improves product yield and quality, making the product highly competitive in the market.

[0042] Finally, it should be emphasized that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention can have various changes and modifications. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for catalytically oxidizing acetate tetraenes to synthesize dihydroxy compounds, characterized in that, Using acetate tetraene as a raw material, acetone as a solvent, Ru-XY as a catalyst, and sodium hypochlorite as an oxidant, the product dihydroxy compound was obtained by catalytic oxidation under alkaline conditions. In the Ru-XY, X is Pt or Pd, and Y is any one of Fe, Mn, and Cu.

2. The method according to claim 1, characterized in that, The Ru-XY preparation method is as follows: first, ruthenium salt is loaded onto activated carbon and dried, and then soluble salts of X and Y are loaded onto the ruthenium-loaded activated carbon in the same way. Then, the Ru-XY catalyst is obtained by filtration, washing and vacuum drying.

3. The method according to claim 2, characterized in that, In the Ru-XY catalyst, the loadings of Ru, X, and Y are 3 wt%, 1 wt%, and 1 wt%, respectively.

4. The method according to claim 1, characterized in that, The pH of the alkaline conditions is 8 to 9.

5. The method according to any one of claims 1 to 4, characterized in that, The method is as follows: Acetate tetraene and acetone are added to a clean reaction flask, Ru-XY catalyst is added under stirring, the temperature is lowered, sodium hypochlorite / sodium bicarbonate / aqueous solution is added dropwise, after the addition is complete, the reaction is kept at the temperature for 30-40 minutes, filtered, the pH of the filtrate is adjusted to 6-7, the acetone is removed by negative pressure concentration, water is added, the mixture is stirred for 1-1.5 hours, filtered, and dried at 60°C to obtain the dihydroxy compound.

6. The method of claim 5, wherein, The reaction and rinsing temperatures are both 0–5°C.

7. The method according to claim 5, characterized in that, The mass ratio of the acetate tetraene, acetone, water, Ru-XY catalyst, sodium hypochlorite, and sodium bicarbonate is 1:15-20:2-3:0.1-0.2:0.5:0.

2.

8. The method according to claim 5, characterized in that, Glacial acetic acid was used to adjust the pH.

9. The method of claim 5, wherein, The Ru-XY catalyst is any one of Ru-Pt-Fe, Ru-Pt-Mn, Ru-Pt-Cu, Ru-Pd-Fe, and Ru-Pd-Mn.

10. The method of claim 5, wherein, The Ru-XY catalyst is Ru-Pt-Fe.

Images