A synthetic method for preparing a plant-derived cholesterol key intermediate

Abstract

The application discloses a synthetic method of preparing a plant source cholesterin key intermediate 20-formyl-pregn-4-ene-3-ketone. The method takes plant source 21-hydroxy-20-methyl-pregn-4-ene-3-ketone, also known as bisnorol or BA, as raw material, and oxidizes BA into aldehyde through a phase transfer catalyst under oxygen environment. The preparation method has the advantages of high yield, mild reaction condition, fast reaction time, cheap and recyclable solvent, relatively simple operation and the like, solves the problems of high production cost and serious pollution in the prior art, has high industrial production value and good agricultural application prospect, and provides a new method for synthesizing medicinal auxiliary materials of plant source cholesterin. The reaction formula is as follows.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for synthesizing 20-formylpregn-4-en-3-one, a key intermediate for plant-derived cholesterol, an important pharmaceutical excipient. Background Technology

[0002] Plant-derived cholesterol is a widely available and diverse natural substance, mainly found in plants, especially in plant oils, nuts, seeds, and legumes rich in phytosterols. Its structure is similar to animal cholesterol, but it has different physiological effects. Compared to animal-derived cholesterol, plant-derived cholesterol carries a lower risk of infection and is widely studied for lowering blood cholesterol levels, helping to reduce the risk of cardiovascular disease. It works by inhibiting the absorption of cholesterol in the intestines. The raw material BA (bisnoralcohol) used in this invention, also known as bisnorchol or progesterone intermediate, is a plant extract that appears as white to pale yellow needle-like crystals or crystalline powder. It is derived from the fermentation of phytosterols, a byproduct of oil processing, and is a green, plant-based raw material with an annual production of thousands of tons. It is inexpensive and effectively avoids the risk of pathogenic bacteria and viral infections that may exist with animal-derived cholesterol in existing technologies.

[0003] Currently, extracting plant-derived cholesterol from natural plants is extremely difficult, resulting in low yields and poor purity, which fails to meet the demands of the pharmaceutical market. 20-Formylpregn-4-en-3-one is a key intermediate in the synthesis of plant-derived cholesterol, and its synthesis is a crucial technical step in the entire synthetic route; most current methods are chemical synthesis. Therefore, developing a mild and efficient synthetic method for 20-formylpregn-4-en-3-one (compound 2), a key intermediate in the synthesis of plant-derived cholesterol, is crucial to solving the problems of production cost and environmental pollution associated with plant-derived cholesterol and realizing its industrial production.

[0004] The main reported methods for the chemical synthesis of 20-formylpregn-4-en-3-one are as follows.

[0005] Using BA as a raw material, NBS / NCS as an oxidant, and 2,2,6,6-tetramethylpiperidine oxide as a co-oxidant, 20-formylpregn-4-en-3-one was synthesized in a molar yield of 96.7% (CN 114874277A). This method requires a large amount of raw materials, an excess of phase transfer catalyst, and the post-treatment of large quantities of NBS / NCS consumes a large amount of solvent, resulting in significant subsequent wastewater discharge. Furthermore, the reaction requires low temperatures, leading to high energy consumption.

[0006] Summary of the Invention

[0007] To address the problems existing in the prior art, this invention provides a method for synthesizing 20-formylpregn-4-en-3-one. This method uses an iron salt, a co-oxidant 2,2,6,6-tetramethylpiperidine oxide, and a phase-transfer catalyst triethylbenzylammonium chloride to oxidize hydroxyl groups to aldehydes via oxygen. The availability of inexpensive oxygen, along with the presence of co-oxidants and phase-transfer catalysts in catalytic amounts, gives this reaction advantages such as low cost, a safe and mild reaction process, reduced energy consumption, and greater environmental friendliness compared to other oxidation methods. Furthermore, in practical plant-derived cholesterol synthesis routes, due to the high yield and high purity (up to 99.10%) of this step, further purification is not required in related routes before proceeding to the next reaction.

[0008] To solve the above technical problems, the proposed technical solution is as follows: Compound 2 is synthesized using BA as the raw material, oxygen as the oxidant, 2,2,6,6-tetramethylpiperidine oxide as the co-oxidant, iron salt, and a phase transfer catalyst. The mixture is stirred at room temperature for 3-12 hours. After the reaction is complete, sodium thiosulfate pentahydrate solution is added, and the mixture is stirred at 5-10°C for 15-30 minutes. The mixture is then separated, the aqueous phase is extracted with dichloromethane, the combined organic layers are washed with saturated brine, and the organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 2. The reaction route is shown below:

[0009] .

[0010] The iron salt is selected from one of FeCl2, FeBr2, FeSO4, Fe2(SO4)3, FeCl3, and FeBr3, preferably FeCl3.

[0011] The BA raw material to iron salt equivalent ratio is 1:(0.8-2.0). Preferably, it is 1:1.

[0012] The equivalence ratio of the BA raw material to 2,2,6,6-tetramethylpiperidine oxide is 1:(0.01-0.03), preferably 1:0.01.

[0013] The equivalent ratio of the BA raw material to triethylbenzylammonium chloride is 1:(0.01-0.06). Preferably, it is 1:0.05.

[0014] The reaction temperature range is 0-35℃, preferably 25℃. The solvent is selected from any one of acetonitrile, dichloromethane, dimethyl sulfoxide, and dimethylformamide, preferably dichloromethane.

[0015] The reaction time is 3-12 hours, preferably 6 hours.

[0016] Preferably, the iron salt is FeCl₂ 3，The solvent is dichloromethane, the reaction temperature is 25°C, and the reaction time is 6 hours; the equivalence ratio of BA raw material to iron salt is 1:1; the equivalence ratio of BA raw material to 2,2,6,6-tetramethylpiperidine oxide is 1:0.01; and the equivalence ratio of BA raw material to triethylbenzylammonium chloride is 1:0.05.

[0017] Preferably, dichloromethane (500 ml), 2,2,6,6-tetramethylpiperidine oxide (230 mg, 1.5 mmol), FeCl3 (24.3 g, 150 mmol), triethylbenzylammonium chloride (1.70 g, 7.5 mmol), and BA (49.6 g, 150 mmol) were added sequentially to a Schlenk flask, with an oxygen bulb as the oxygen source. The mixture was stirred at 25 °C for 6 h. After the reaction was completed as detected by TLC, sodium thiosulfate pentahydrate solution (11.2 g sodium thiosulfate pentahydrate / 220 ml water) was added, and the mixture was stirred at 5-10 °C for 30 min. The mixture was separated, and the aqueous phase was extracted with dichloromethane (200 ml × 2). The organic layers were combined, washed with saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 2 (49.12 g white solid, molar yield 99.13%).

[0018] Beneficial effects:

[0019] This invention uses a phase transfer catalyst to catalyze the oxidation of hydroxyl groups to aldehydes with oxygen. It has the advantages of low reaction cost, safe and mild reaction process, fast reaction rate, few side reactions, and high yield. Moreover, it can directly proceed to the next step of the reaction without further purification, which reduces energy consumption costs and is more environmentally friendly than other oxidation methods.

[0020] The preparation method of 20-formylpregn-4-en-3-one (compound 2) was described, in which the amounts of triethylbenzylammonium chloride, the type of iron salt, the amount of FeCl3, the amount of 2,2,6,6-tetramethylpiperidine oxide, temperature, and time were varied. Specific results are shown in Tables 1-6. In Example 1, the optimal yield of compound 2 (99.13%) was achieved when the amounts of 2,2,6,6-tetramethylpiperidine oxide, FeCl3, and triethylbenzylammonium chloride were 0.01 eq, the temperature was 25 °C, and the time was 6 h.

[0021] Comparing Examples 1, 4, 5, and 6, it was found that under different phase transfer catalysts, the reaction effect of triethylbenzylammonium chloride in Example 1 was the best, with a yield of 99.13% for compound 2. Attached Figure Description

[0022] Figure 1 The 1H NMR spectrum of 20-formylpregn-4-en-3-one prepared in Example 1. Detailed Implementation

[0023] Example 1

[0024] Preparation of 20-formylpregn-4-en-3-one

[0025] In a Schlenk flask, dichloromethane (500 ml), 2,2,6,6-tetramethylpiperidine oxide (230 mg, 1.5 mmol), FeCl3 (24.3 g, 150 mmol), triethylbenzylammonium chloride (1.7 g, 7.5 mmol), and BA (49.6 g, 150 mmol) were added sequentially. An oxygen bulb was used as the oxygen source. The mixture was stirred at 25 °C for 6 h. After the reaction was completed as detected by TLC, sodium thiosulfate pentahydrate solution (11.2 g sodium thiosulfate pentahydrate / 220 ml water) was added, and the mixture was stirred at 5-10 °C for 30 min. The mixture was separated into liquid and liquid phases. The aqueous phase was extracted with dichloromethane (200 ml × 2). The organic layers were combined and washed with saturated saline solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 2 (49.1 g white solid, molar yield 99.13%).

[0026] Example 2

[0027] Acetonitrile (500 ml), 2,2,6,6-tetramethylpiperidine oxide (230 mg, 1.5 mmol), FeCl3 (24.3 g, 150 mmol), and BA (49.6 g, 150 mmol), and triethylbenzylammonium chloride (1.70 g, 7.5 mmol) were added sequentially to a Schlenk flask. An oxygen bulb was used as the oxygen source. The mixture was stirred at 35 °C for 6 h. After the reaction was completed as detected by TLC, sodium thiosulfate pentahydrate solution (11.2 g sodium thiosulfate pentahydrate / 220 ml water) was added. The mixture was stirred at 5-10 °C for 30 min. The mixture was separated into liquid and liquid phases. The aqueous phase was extracted with dichloromethane (200 ml × 2). The organic layers were combined and washed with saturated saline solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 2 (45.13 g white solid, molar yield 90.7%).

[0028] Compared with Example 1, when the organic solvent dichloromethane in Example 1 was replaced with acetonitrile in Example 2, the yield of compound 2 decreased from 99.13% to 90.7%.

[0029] Example 3

[0030] In Example 1, screening experiments were conducted by varying only the amount of triethylbenzylammonium chloride, the type of iron salt, the amount of FeCl3, the amount of 2,2,6,6-tetramethylpiperidine oxide, the reaction temperature, and the reaction time. The results are shown in Tables 1-6 below:

[0031] Table 1 compares the addition amounts of triethylbenzylammonium chloride (reaction conditions: BA to FeCl3 and 2,2,6,6-tetramethylpiperidine oxide equivalent ratio of 1:1:0.01, temperature of 25℃, time of 6h).

[0032]

[0033] Table 2 shows the screening of iron salts (reaction conditions: BA to iron salt, 2,2,6,6-tetramethylpiperidine oxide and triethylbenzylammonium chloride equivalent ratio of 1:1:0.01:0.05, temperature of 25℃, time of 6h).

[0034]

[0035] Table 3 compares the different amounts of FeCl3 added (reaction conditions: BA, 2,2,6,6-tetramethylpiperidine oxide, and triethylbenzylammonium chloride added in an equivalent ratio of 1:0.01:0.05, temperature 25℃, time 6h).

[0036]

[0037] Table 4 compares the addition amounts of 2,2,6,6-tetramethylpiperidine oxide (reaction conditions: BA to FeCl3 and triethylbenzylammonium chloride equivalent ratio of 1:1:0.05, temperature of 25℃, and time of 6h).

[0038]

[0039] Table 5 compares the screening results at different temperatures (reaction conditions: BA to FeCl3,2,2,6,6-tetramethylpiperidine oxide and triethylbenzylammonium chloride equivalent ratio of 1:1:0.01:0.05, time of 6h).

[0040]

[0041] Table 6 compares the screening results at different times (reaction conditions: BA to FeCl3, 2,2,6,6-tetramethylpiperidine oxide and triethylbenzylammonium chloride equivalent ratio of 1:1:0.01:0.05, temperature of 25℃).

[0042]

[0043] Example 4

[0044] In a Schlenk flask, dichloromethane (500 ml), 2,2,6,6-tetramethylpiperidine oxide (230 mg, 1.5 mmol), FeCl3 (24.3 g, 150 mmol), tetrabutylammonium bromide (1.65 g, 7.5 mmol), and BA (4.96 g, 150 mmol) were added sequentially. An oxygen bulb was used as the oxygen source. The mixture was stirred at 25 °C for 6 h. After the reaction was completed as detected by TLC, sodium thiosulfate pentahydrate solution (11.2 g sodium thiosulfate pentahydrate / 220 ml water) was added, and the mixture was stirred at 5-10 °C for 20 min. The mixture was separated into two layers, and the aqueous phase was extracted with dichloromethane (200 ml × 2). The organic layers were combined, washed with saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 2 (47.10 g white solid, molar yield 95.32%).

[0045] Example 5

[0046] In a Schlenk flask, dichloromethane (500 ml), 2,2,6,6-tetramethylpiperidine oxide (230 mg, 1.5 mmol), FeCl3 (24.3 g, 150 mmol), tetramethylammonium iodide (1.54 g, 7.5 mmol), and BA (49.6 g, 150 mmol) were added sequentially. An oxygen bulb was used as the oxygen source. The mixture was stirred at 25 °C for 6 h. After the reaction was completed as detected by TLC, sodium thiosulfate pentahydrate solution (11.2 g sodium thiosulfate pentahydrate / 220 ml water) was added, and the mixture was stirred at 5-10 °C for 20 min. The mixture was separated into liquid and liquid phases. The aqueous phase was extracted with dichloromethane (200 ml × 2). The organic layers were combined and washed with saturated saline solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 2 (45.92 g white solid, molar yield 92.48%).

[0047] Example 6

[0048] In a Schlenk flask, dichloromethane (500 ml), 2,2,6,6-tetramethylpiperidine oxide (230 mg, 1.5 mmol), FeCl3 (24.3 g, 150 mmol), hexadecyltrimethylammonium bromide (2.78 g, 22.5 mmol), and BA (49.6 g, 150 mmol) were added sequentially. An oxygen bulb was used as the oxygen source. The mixture was stirred at 25 °C for 6 h. After the reaction was completed as detected by TLC, sodium thiosulfate pentahydrate solution (11.2 g sodium thiosulfate pentahydrate / 220 ml water) was added, and the mixture was stirred at 5-10 °C for 20 min. The mixture was separated into liquid and liquid phases. The aqueous phase was extracted with dichloromethane (200 ml × 2). The organic layers were combined and washed with saturated saline solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 2 (45.51 g white solid, molar yield 91.78%).

[0049] Conclusion: Comparing Examples 1, 4, 5, and 6, it was found that the triethylbenzylammonium chloride in Example 1 showed the best reaction effect under different phase transfer catalysts.

[0050] The present invention is not limited to the specific technical solutions described in the above embodiments. All technical solutions formed by equivalent substitutions are within the scope of protection claimed by the present invention.

Claims

1. A method for synthesizing 20-formylpregn-4-en-3-one, a key intermediate for preparing plant-derived cholesterol, characterized in that... The compound 20-formylpregn-4-en-3-one was synthesized by adding 500 ml of dichloromethane, 230 mg (1.5 mmol) of 2,2,6,6-tetramethylpiperidine oxide, 24.3 g (150 mmol) of FeCl3, 1.7 g (7.5 mmol) of triethylbenzylammonium chloride, and 21-hydroxy-20-methylpregn-4-en-3-one BA to a Schlenk flask in sequence. 49.6 g of compound thiosulfate was reacted with 150 mmol of oxygen bulb as the oxygen source at 25 °C for 6 h with stirring. After the reaction was completed as detected by TLC, 11.2 g of sodium thiosulfate pentahydrate / 220 ml of water was added, and the mixture was stirred at 5-10 °C for 30 min. The mixture was separated into two layers, and the aqueous phase was extracted with 200 ml of dichloromethane twice. The combined organic layers were washed with saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 2, a white solid of 49.1 g, with a molar yield of 99.13%. The reaction pathway is as follows: 。

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