Synthetic method for preparing plant-derived cholesterol key intermediate

Abstract

The invention discloses a synthesis method for preparing a plant source cholesterol key intermediate 20-formyl pregna-4-ene-3-ketone, which comprises the following steps: by taking plant source 21-hydroxy-20-methyl pregna-4-ene-3-ketone, also known as dinorhydrin or BA as a raw material, oxidizing BA into aldehyde in an oxygen environment through a phase transfer catalyst. The preparation method disclosed by the invention has the advantages of high yield, mild reaction conditions, short reaction time, cheap and recyclable solvent, relatively simple operation and the like, solves the problems of high production cost, serious pollution and the like in the prior art, has relatively high industrial production value and good agricultural application prospect, and is suitable for industrial production. And a new method is provided for the synthesis of plant-derived cholesterol substances as pharmaceutic adjuvants. The reaction formula is as follows: # imgabs0 #.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a method for synthesizing 20-formylpregnane-4-ene-3-one, a key intermediate of plant-derived cholesterol, which is an important pharmaceutical auxiliary material. Background Art

[0002] Plant cholesterol is a natural substance with a wide and diverse source, mainly found in plants, especially plant oils, nuts, seeds and beans rich in plant sterols. Its structure is similar to that of animal cholesterol, but it has different physiological effects. Compared with animal cholesterol, plant cholesterol has a lower risk of infection. It is widely studied to reduce blood cholesterol levels and help reduce the risk of cardiovascular disease. They work by inhibiting the intestinal absorption of cholesterol. The raw material BA (bisnoralcohol) used in the present invention is also called bisnoralcohol or progesterone intermediate. It is a plant extract with a white to light yellow needle-shaped crystal or crystalline powder. It is obtained from the fermentation of plant sterols, which are waste materials of oil and fat processes. It is a plant-derived green raw material. The current annual output is thousands of tons, and the price is cheap. It can well avoid the risk of pathogenic bacteria and virus infection in animal cholesterol in the prior art.

[0003] At present, it is very difficult to extract plant-derived cholesterol from natural plants, with low yield and poor purity, which is difficult to meet the needs of the pharmaceutical market. 20-Formylpregnant-4-ene-3-one is a key intermediate for the synthesis of plant-derived cholesterol. The synthesis method of the compound is a key technical step in the entire synthesis route. Most of the synthesis methods currently used are chemical synthesis. Therefore, the development of a new method for the synthesis of 20-formylpregnant-4-ene-3-one (compound 2), a key intermediate of plant-derived cholesterol, is the key to solving the production cost and environmental pollution problems of plant-derived cholesterol and realizing its industrial production.

[0004] The chemical synthesis of 20-formylpregnane-4-en-3-one has been reported mainly in the following ways.

[0005] BA is used as raw material, NBS / NCS is used as oxidant, and 2,2,6,6-tetramethylpiperidinoxide is used as co-oxidant to synthesize 20-formylpregnane-4-ene-3-one with a molar yield of 96.7%. CN 114874277A, the method uses a large amount of raw materials, an excessive amount of phase transfer catalyst is required, and a large amount of solvent is consumed for post-treatment of a large amount of NBS / NCS, and subsequent waste liquid and wastewater discharge is large, and the reaction requires low temperature and high energy consumption.

[0006] Summary of the invention

[0007] In view of the problems existing in the prior art, the present invention provides a method for synthesizing 20-formylpregnane-4-ene-3-one. The method uses iron salt, oxidant 2,2,6,6-tetramethylpiperidinoxide, and phase transfer catalyst triethylbenzyl ammonium chloride to oxidize hydroxyl groups to aldehydes by oxygen. The cheap oxygen source, catalytic amounts of oxidants and phase transfer catalysts make the reaction have the advantages of low reaction cost, safe and mild reaction process, etc., reduce energy consumption costs, and be more environmentally friendly than other oxidation methods. In the actual synthesis route of plant-derived cholesterol, since this step has a high yield and high purity (purity of 99.10%), the next step reaction can be directly carried out without further purification in the relevant route.

[0008] In order to solve the above technical problems, the proposed technical scheme is as follows: Synthesize compound 2, use BA as raw material, solvent, oxygen as oxidant, 2,2,6,6-tetramethylpiperidinyl oxide as co-oxidant, iron salt, phase transfer catalyst, stir at room temperature for 3-12h. After the reaction, add sodium thiosulfate pentahydrate solution, stir at 5-10℃ for 15-30min, separate the liquids, extract the aqueous phase with dichloromethane, combine the organic layers, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain compound 2. The reaction route is as follows:

[0009] .

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

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

[0012] The equivalent ratio of the BA raw material to 2,2,6,6-tetramethylpiperidinyl 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° C., preferably 25° C. 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 FeCl 3，The solvent is dichloromethane, the reaction temperature is 25° C., and the reaction time is 6 hours; the equivalent ratio of the BA raw material to the iron salt is 1:1; the equivalent ratio of the BA raw material to 2,2,6,6-tetramethylpiperidinyl oxide is 1:0.01; and the equivalent ratio of the BA raw material to triethylbenzylammonium chloride is 1:0.05.

[0017] Preferably, dichloromethane (500 ml), 2,2,6,6-tetramethylpiperidinoxide (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) are added to a Schlenk bottle in sequence, an oxygen ball is used as an oxygen source, and the reaction is stirred at 25 ° C for 6 h. After the reaction is completed by TLC detection, a sodium thiosulfate pentahydrate solution (11.2 g sodium thiosulfate pentahydrate / 220 ml water) is added, and the mixture is stirred at 5-10 ° C for 30 min. The liquids are separated, and the aqueous phase is extracted with dichloromethane (200 ml×2). The organic layers are combined and washed with a saturated saline solution. The organic phase is 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] The present invention uses a phase transfer catalyst to catalyze the oxidation of hydroxyl groups to aldehydes by oxygen, which has the advantages of low reaction cost, safe and mild reaction process, fast reaction rate, few side reactions, and high yield. The next step of reaction can be directly carried out without further purification, which reduces energy consumption costs and is environmentally friendly compared to other oxidation methods.

[0020] The preparation method of 20-formylpregnane-4-ene-3-one (Compound 2) is provided, wherein the addition amount of triethylbenzylammonium chloride, the type of iron salt, the addition amount of FeCl3, the addition amount of 2,2,6,6-tetramethylpiperidinyl oxide, the temperature and the time are changed, and the specific results are shown in Table 1 to Table 6. In Example 1, the addition amount of 2,2,6,6-tetramethylpiperidinyl oxide is 0.01eq, the addition amount of FeCl3 is 1eq, the addition amount of triethylbenzylammonium chloride is 0.05eq, the temperature is 25°C, and the time is 6h. The yield of Compound 2 is the best, which is 99.13%.

[0021] By comparing Examples 1, 4, 5, and 6, it was found that under different phase transfer catalysts, the reaction effect of triethylbenzyl ammonium chloride in Example 1 was the best, and the yield of compound 2 was 99.13%. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is the H NMR spectrum of 20-formylpregnane-4-en-3-one prepared in Example 1. DETAILED DESCRIPTION

[0023] Example 1

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

[0025] Dichloromethane (500 ml), 2,2,6,6-tetramethylpiperidinoxide (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 to a Schlenk bottle in sequence, with an oxygen balloon as the oxygen source. The reaction was stirred at 25 °C for 6 h. After the reaction was completed 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 liquids were separated, and 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 obtain compound 2 (49.1 g white solid, molar yield 99.13%).

[0026] Example 2

[0027] Acetonitrile (500 ml), 2,2,6,6-tetramethylpiperidinoxide (230 mg, 1.5 mmol), FeCl3 (24.3 g, 150 mmol) and BA (49.6 g, 150 mmol), triethylbenzylammonium chloride (1.70 g, 7.5 mmol) were added to a Schlenk bottle in sequence, and an oxygen balloon was used as the oxygen source. The reaction was stirred at 35°C for 6 h. After the reaction was completed by TLC detection, 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 liquids were separated, and 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 obtain compound 2 (45.13 g white solid, molar yield 90.7%).

[0028] Comparative Example 1, the organic solvent dichloromethane in Example 1 was replaced by acetonitrile in Example 2, and the yield of Compound 2 decreased from 99.13% to 90.7%.

[0029] Example 3

[0030] In Example 1, only the amount of triethylbenzylammonium chloride, the type of iron salt, the amount of FeCl3, the amount of 2,2,6,6-tetramethylpiperidinyl oxide, the reaction temperature and the reaction time were changed, and a screening experiment was carried out, as shown in Tables 1 to 6 below:

[0031] Table 1 makes a screening comparison for the addition amount of triethylbenzylammonium chloride (reaction conditions: the equivalent ratio of BA to FeCl3 and 2,2,6,6-tetramethylpiperidinyl oxide is 1:1:0.01, the temperature is 25°C, and the time is 6h)

[0032]

[0033] Table 2 screened the types of iron salts (reaction conditions: BA and iron salt, 2,2,6,6-tetramethylpiperidinyl oxide and triethylbenzylammonium chloride equivalent ratio of 1:1:0.01:0.05, temperature of 25°C, time of 6h)

[0034]

[0035] Table 3 makes a screening comparison for the addition amount of FeCl3 (reaction conditions: the equivalent ratio of BA to 2,2,6,6-tetramethylpiperidinyl oxide and triethylbenzylammonium chloride is 1:0.01:0.05, the temperature is 25°C, and the time is 6h)

[0036]

[0037] Table 4 makes a screening comparison for the addition amount of 2,2,6,6-tetramethylpiperidinyl oxide (reaction conditions: the equivalent ratio of BA to FeCl3 and triethylbenzylammonium chloride is 1:1:0.05, the temperature is 25°C, and the time is 6h)

[0038]

[0039] Table 5 makes a screening comparison for different temperatures (reaction conditions: BA and FeCl3, 2,2,6,6-tetramethylpiperidinyl oxide and triethylbenzylammonium chloride equivalent ratio is 1:1:0.01:0.05, time is 6h)

[0040]

[0041] Table 6 makes a screening comparison for different times (reaction conditions: BA and FeCl3, 2,2,6,6-tetramethylpiperidinyl oxide and triethylbenzylammonium chloride equivalent ratio is 1:1:0.01:0.05, temperature is 25°C)

[0042]

[0043] Example 4

[0044] Dichloromethane (500 ml), 2,2,6,6-tetramethylpiperidinoxide (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 to a Schlenk bottle in sequence, with an oxygen balloon as the oxygen source. The reaction was stirred at 25°C for 6 h. After the reaction was completed 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 liquids were separated, and 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 obtain compound 2 (47.10 g white solid, molar yield 95.32%).

[0045] Example 5

[0046] Dichloromethane (500 ml), 2,2,6,6-tetramethylpiperidinoxide (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 to a Schlenk bottle in sequence, with an oxygen balloon as the oxygen source. The reaction was stirred at 25 ° C for 6 h. After the reaction was completed 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 liquids were separated, and 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 obtain compound 2 (45.92 g white solid, molar yield 92.48%).

[0047] Example 6

[0048] Dichloromethane (500 ml), 2,2,6,6-tetramethylpiperidinoxide (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 to a Schlenk bottle in sequence, with an oxygen balloon as the oxygen source. The reaction was stirred at 25°C for 6 h. After the reaction was completed by TLC detection, 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 liquids were separated, and 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 obtain compound 2 (45.51 g white solid, molar yield 91.78%).

[0049] Conclusion: By comparing Examples 1, 4, 5, and 6, it is found that the triethylbenzyl ammonium chloride of Example 1 has 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, and all technical solutions formed by equivalent replacement are within the protection scope required by the present invention.

Claims

1. A method for preparing a key intermediate of plant-derived cholesterol, 20-formylpregnane-4-ene-3-one, characterized in that :Synthesis of compound 20-formylpregnane-4-ene-3-one, using 21-hydroxy-20-methylpregnane-4-ene-3-one (BA) as a raw material, adding a reaction solvent, an iron salt, a phase transfer catalyst of triethylbenzylammonium chloride, an oxidant of oxygen, and a co-oxidant of 2,2,6,6-tetramethylpiperidinoxide (TEMPO), stirring at room temperature for 3-12 hours; after the reaction is completed, adding a sodium thiosulfate pentahydrate solution, stirring at 5-10° C. for 15-30 minutes, separating the liquids, extracting the aqueous phase with dichloromethane, combining the organic layers, washing with a saturated saline solution, drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain compound 20-formylpregnane-4-ene-3-one, the reaction route of which is as follows: 。 2. The method for synthesizing 20-formylpregnane-4-ene-3-one, a key intermediate of plant-derived cholesterol, according to claim 1, characterized in that: The iron salt is selected from one of FeC12, FeBr2, FeSO4, Fe2(SO4)3, FeC13, and FeBr3.

3. The method for synthesizing 20-formylpregnane-4-ene-3-one, a key intermediate of plant-derived cholesterol, according to claim 1, characterized in that: The equivalent ratio of the BA raw material to the iron salt is 1:0.8-2.

0.

4. The method for synthesizing 20-formylpregnane-4-ene-3-one, a key intermediate of plant-derived cholesterol, according to claim 1, characterized in that: The equivalent ratio of the BA raw material to 2,2,6,6-tetramethylpiperidinyl oxide is 1:0.01-0.

03.

5. The method for synthesizing 20-formylpregnane-4-ene-3-one, a key intermediate of plant-derived cholesterol, according to claim 1, characterized in that: The equivalent ratio of the BA raw material to triethylbenzylammonium chloride is 1:0.01-0.

06.

6. The method for synthesizing 20-formylpregnane-4-ene-3-one, a key intermediate of plant-derived cholesterol, according to claim 1, characterized in that: The reaction solvent is selected from any one of acetonitrile, dichloromethane, dimethyl sulfoxide and dimethylformamide.

7. The method for synthesizing 20-formylpregnane-4-ene-3-one, a key intermediate of plant-derived cholesterol, according to claim 1, characterized in that: The equivalent ratio of BA to phase transfer catalyst is 1:0.03-0.

06.

8. The method for synthesizing 20-formylpregnane-4-ene-3-one, a key intermediate of plant-derived cholesterol, according to claim 1, characterized in that: The iron salt is FeCl 3， The reaction solvent is dichloromethane, the reaction temperature is 25°C, and the reaction time is 6 hours; the equivalent ratio of BA to FeCl3, 2,2,6,6-tetramethylpiperidinyl oxide and triethylbenzylammonium chloride is 1:1:0.01:0.

05.

9. The method for synthesizing 20-formylpregnane-4-ene-3-one, a key intermediate of plant-derived cholesterol, according to claim 1, characterized in that: Dichloromethane (500 ml), 2,2,6,6-tetramethylpiperidinoxide (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 to a Schlenk bottle in sequence, with an oxygen balloon as the oxygen source. The reaction was stirred at 25 °C for 6 h. After the reaction was completed 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 liquids were separated, and 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 obtain compound 2 (49.1 g white solid, molar yield 99.13%).

Images