Preparation method of borneol alcohol ketone, dammarendiol II and intermediates of borneol alcohol ketone and dammarendiol II

Abstract

The invention belongs to the technical field of medicines, and provides a preparation method of borneol alcohol ketone and dammarendiol II as well as intermediates of the borneol alcohol ketone and the dammarendiol II. The preparation method comprises the following steps: mixing protopanoxadiol with a first additive and an anhydride compound, and reacting to obtain an intermediate 1; mixing the intermediate 1 with anhydrous potassium carbonate and a solvent for reaction to obtain an intermediate 2; mixing the intermediate 2 with a second additive and an oxidizing agent for reaction to obtain an intermediate 3; mixing the intermediate 3 with an alkaline compound and a mixed solvent for reaction to obtain a dammarendiol II intermediate; mixing the dammarendiol II intermediate with ethylene glycol, hydrazine hydrate and KOH for reaction to obtain dammarendiol II; and mixing the dammarendiol II with a third additive and an oxidizing agent, and reacting to obtain the borneol alcohol ketone. The method is simple, efficient, mild in condition and short in time consumption, high-purity borneol alcohol ketone, dammarendiol II and intermediates thereof are prepared, and industrial production of the products is greatly promoted.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a method for preparing borneol ketone and dammarene diol II and their intermediates. Background Technology

[0002] Ginsenosides are a series of glycosylated triterpenoid compounds, mainly distributed in the roots, stems, leaves, and flowers of plants. They are widely used in traditional Chinese medicine for the treatment of cancer, immune responses, mental stress, arteriosclerosis, hypertension, diabetes, and central nervous system diseases. Based on the differences in the structure of ginsenoside aglycones, ginsenosides can be divided into dammarane and oleanane types. Dammarane types are further subdivided into ginsenoside diols and ginsenoside triols, with ginsenoside diols containing the largest number of ginsenosides. The aglycones produced after the degradation of ginsenoside diols have various structures. Dammarenediol II and Dipterocarpol are important members of the ginsenoside diol aglycone family, widely used in various traditional Chinese medicines, and have been proven to possess rich biological activities. Studies show that dammarenediol II has anticancer activity, acetylcholinesterase inhibitory activity, antiviral activity, and hepatoprotective activity; Dipterocarpol has anticancer and antiviral activity. However, to date, both of these aglycones and their intermediates have mainly relied on plant extraction, which limits their sources and greatly hinders their further research and application.

[0003] Therefore, there is an urgent need to develop a simple and efficient method for preparing borneol ketone and dammarene diol II and their intermediates. Summary of the Invention

[0004] In view of this, the present invention provides a method for preparing borneol ketone and dammarene diol II and their intermediates, in order to solve the problem that existing dammarene diol II and borneol ketone mainly rely on plant extraction, which limits their sources.

[0005] To achieve the above objectives, the present invention adopts the following technical solution:

[0006] This invention provides a method for preparing dammarene diol II intermediate, comprising the following steps:

[0007] 1) The protopanaxadiol was mixed with the first additive and an acid anhydride compound and reacted to obtain intermediate 1;

[0008] 2) Intermediate 1 is mixed with anhydrous potassium carbonate and solvent and reacted to obtain intermediate 2;

[0009] 3) Intermediate 2 is mixed with the second additive and the oxidant, and reacted to obtain intermediate 3;

[0010] 4) Intermediate 3 is mixed with an alkaline compound and a mixed solvent and reacted to obtain dammarene glycol II intermediate;

[0011] The structural formula of the protopanaxadiol is as follows:

[0012] The structural formula of intermediate 1 is:

[0013] The structural formula of intermediate 2 is as follows:

[0014] The structural formula of the intermediate 3 is as follows:

[0015] The structural formula of the dammarene diol II intermediate is:

[0016] Preferably, the reaction temperature in step 1) is 80–100°C, and the reaction time is 8–10 h; the molar ratio of protopanaxadiol to acid anhydride is 1:2.0–4.0; the mass ratio of protopanaxadiol to the first additive is 1:5.0–10.0; the first additive includes one or more of pyridine, 2-methylpyridine, 2,6-dimethylpyridine, and 2,4,6-trimethylpyridine; and the acid anhydride includes one or more of acetic anhydride, propionic anhydride, butyric anhydride, and valeric anhydride.

[0017] Preferably, the reaction temperature in step 2) is -5 to 10°C, the time is 1 to 3 hours, and the atmosphere is an inert atmosphere; the molar ratio of intermediate 1 to anhydrous potassium carbonate is 1:0.2 to 2.0; the mass ratio of intermediate 1 to solvent is 1:4.0 to 8.0; and the solvent includes one or more of methanol, ethanol, and propanol.

[0018] Preferably, the reaction temperature in step 3) is 70–90°C, and the reaction time is 5–8 h; the mass ratio of intermediate 2 to the second additive and oxidant is 1:4.0–6.0:1.5–3.0; the oxidant includes chromium trioxide and / or sarette reagent; the second additive includes one or more of pyridine, 2-methylpyridine, 2,6-dimethylpyridine, and 2,4,6-trimethylpyridine.

[0019] Preferably, the reaction temperature in step 4) is 60–80°C, and the reaction time is 6–8 h; the mass-to-volume ratio of intermediate 3 to the basic compound and the mixed solvent is 1.0 g: 0.1–0.2 g: 5.0–15.0 mL; the basic compound includes one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, and sodium ethoxide; the mixed solvent includes one or more of aqueous solutions of tetrahydrofuran, 1,4-dioxane, acetone, methanol, and ethanol; and the volume concentration of the mixed solvent is 33.33–66.67%.

[0020] This invention also provides a method for preparing dammarene glycol II, comprising the following steps:

[0021] Dammarene glycol II intermediate was mixed with ethylene glycol, hydrazine hydrate and KOH and reacted to obtain dammarene glycol II;

[0022] The structural formula of the dammarene diol II is as follows:

[0023] The dammarene diol II intermediate is the dammarene diol II intermediate prepared by the above preparation method.

[0024] Preferably, the reaction includes a first reaction and a second reaction; the temperature of the first reaction is 160-180°C and the time is 0.5-1h; the temperature of the second reaction is 190-210°C and the time is 2-4h; the mass ratio of the dammarene glycol II intermediate to ethylene glycol, hydrazine hydrate and KOH is 1:8.0-15.0:2.0-4.0:1.0-1.5.

[0025] This invention also provides a method for preparing borneol ketone, comprising the following steps:

[0026] Dammarene glycol II was mixed with a third additive and an oxidizing agent and reacted to obtain borneol alcohol ketone.

[0027] The structural formula of the borneol ketone is as follows:

[0028] The dammarene diol II is the dammarene diol II prepared by the above preparation method.

[0029] Preferably, the reaction temperature is 70–90°C and the reaction time is 5–8 h; the mass ratio of dammarene glycol II to the third additive and the oxidant is 1:4.0–8.0:2.0–4.0; the oxidant includes chromium trioxide and / or sarette reagent; the third additive includes one or more of pyridine, 2-methylpyridine, 2,6-dimethylpyridine, and 2,4,6-trimethylpyridine.

[0030] As can be seen from the above technical solution, compared with the prior art, the beneficial effects of the present invention are as follows:

[0031] This invention uses protopanaxadiol as a starting material and prepares borneolone and dammarene diol II and their intermediates through organic synthesis. This method not only breaks through the limitation of relying on plant extraction for the source of borneolone and dammarene diol II and their intermediates, but also achieves efficient and high-purity preparation of these target products, avoiding the complex steps of the extraction process and the damage to the environment. At the same time, the preparation method described in this invention is simple, the reaction conditions are mild, and the reaction time is short, which can greatly promote the industrial production of borneolone and dammarene diol II and their intermediates. Attached Figure Description

[0032] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on the provided drawings without creative effort.

[0033] Figure 1 The 1H NMR spectrum of intermediate 1 in Example 1;

[0034] Figure 2 The hydrogen NMR spectrum of intermediate 2 in Example 1;

[0035] Figure 3 The 1H NMR spectrum of intermediate 3 in Example 1;

[0036] Figure 4 The 1H NMR spectrum of the dammarene diol II intermediate in Example 1;

[0037] Figure 5 The 1H NMR spectrum of dammarene glycol II in Example 4;

[0038] Figure 6 The mass spectrum of dammarene diol II in Example 4;

[0039] Figure 7 The high-performance liquid chromatogram of dammarene glycol II in Example 4;

[0040] Figure 8 The 1H NMR spectrum of borneol ketone in Example 7;

[0041] Figure 9 This is the mass spectrum of borneol ketone in Example 7;

[0042] Figure 10The image shows the high-performance liquid chromatogram of borneol ketone in Example 7. Detailed Implementation

[0043] This invention provides a method for preparing dammarene diol II intermediate, comprising the following steps:

[0044] 1) The protopanaxadiol was mixed with the first additive and an acid anhydride compound and reacted to obtain intermediate 1;

[0045] 2) Intermediate 1 is mixed with anhydrous potassium carbonate and solvent and reacted to obtain intermediate 2;

[0046] 3) Intermediate 2 is mixed with the second additive and the oxidant, and reacted to obtain intermediate 3;

[0047] 4) Intermediate 3 is mixed with an alkaline compound and a mixed solvent and reacted to obtain dammarene glycol II intermediate;

[0048] The structural formula of the protopanaxadiol is as follows:

[0049] The structural formula of intermediate 1 is:

[0050] The structural formula of intermediate 2 is as follows:

[0051] The structural formula of the intermediate 3 is as follows:

[0052] The structural formula of the dammarene diol II intermediate is:

[0053] In this invention, the reaction temperature in step 1) is 80–100°C, preferably 82–95°C, more preferably 85–92°C, and even more preferably 90°C; the reaction time is 8–10 h, preferably 8.5–9.8 h, more preferably 8.8–9.5 h, and even more preferably 9 h; the molar ratio of protopanaxadiol to the acid anhydride compound is 1:2.0–4.0, preferably 1:2.2–3.8, and even more preferably 1:2.5–3.5. More preferably, the ratio is 1:3.0; the mass ratio of protopanaxadiol to the first additive is 1:5.0 to 10.0, preferably 1:5.5 to 8.5, further preferably 1:6.0 to 8.0, and more preferably 1:6.5 to 7.0; the first additive includes one or more of pyridine, 2-methylpyridine, 2,6-dimethylpyridine, and 2,4,6-trimethylpyridine; the acid anhydride compound includes one or more of acetic anhydride, propionic anhydride, butyric anhydride, and valeric anhydride.

[0054] In this invention, the reaction temperature in step 2) is -5 to 10°C, preferably -2 to 8°C, more preferably -1 to 6°C, and even more preferably 0°C; the reaction time is 1 to 3 hours, preferably 1.2 to 2.8 hours, more preferably 1.5 to 2.5 hours, and even more preferably 2 hours; the reaction atmosphere is an inert atmosphere, preferably one of nitrogen atmosphere and argon atmosphere; the molar ratio of intermediate 1 to anhydrous potassium carbonate is 1:0.2 to 2.0, preferably 1:0.4 to 1.8, more preferably 1:0.5 to 1.5, and even more preferably 1:1; the mass ratio of intermediate 1 to solvent is 1:4.0 to 8.0, preferably 1:4.5 to 7.5, more preferably 1:5.0 to 7.0, and even more preferably 1:5.5 to 6.0; the solvent includes one or more of methanol, ethanol, and propanol.

[0055] In this invention, the anhydrous potassium carbonate in step 2) is used as a catalyst, and the solvent is used as a solvent and reagent to selectively remove acetyl groups.

[0056] In this invention, the reaction temperature in step 3) is 70–90°C, preferably 72–88°C, more preferably 75–85°C, and even more preferably 80°C; the reaction time is 5–8 h, preferably 5.5–7.5 h, more preferably 5.8–7 h, and even more preferably 6–6.5 h; the mass ratio of intermediate 2 to the second additive and oxidant is 1:4.0–6.0:1.5–3.0, preferably 1:4.2–5.8:1.6–2.8, more preferably 1:4.5–5.5:1.8–2.5, and even more preferably 1:4.8–5.0:2.0–2.2; the oxidant includes chromium trioxide and / or sarrit reagent; the second additive includes one or more of pyridine, 2-methylpyridine, 2,6-dimethylpyridine, and 2,4,6-trimethylpyridine.

[0057] In this invention, the reaction temperature in step 4) is 60–80°C, preferably 62–78°C, more preferably 65–75°C, and even more preferably 70°C; the reaction time is 6–8 h, preferably 6.2–7.8 h, more preferably 6.5–7.5 h, and even more preferably 7 h; the mass-to-volume ratio of intermediate 3 to the basic compound and the mixed solvent is 1.0 g : 0.1–0.2 g : 5.0–15.0 mL, preferably 1.0 g : 0.11–0.18 g : 6.0–14.0 mL, and even more preferably 1.0 g : 0.12–0.16 g The concentration of the mixed solvent is 8.0–12.0 mL, more preferably 1.0 g; 0.14–0.15 g; 9.0–10.0 mL; the alkaline compound includes one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, and sodium ethoxide, used for deacetylation; the mixed solvent includes one or more of aqueous solutions of tetrahydrofuran, 1,4-dioxane, acetone, methanol, and ethanol; the volume concentration of the mixed solvent is 33.33–66.67%, preferably 35–65%, more preferably 40–60%, and more preferably 50%.

[0058] This invention also provides a method for preparing dammarene glycol II, comprising the following steps:

[0059] Dammarene glycol II intermediate was mixed with ethylene glycol, hydrazine hydrate and KOH and reacted to obtain dammarene glycol II;

[0060] The structural formula of the dammarene diol II is as follows:

[0061] The dammarene diol II intermediate is the dammarene diol II intermediate prepared by the above preparation method.

[0062] In this invention, the reaction includes a first reaction and a second reaction; the temperature of the first reaction is 160–180°C, preferably 162–178°C, more preferably 165–175°C, and even more preferably 170°C; the time of the first reaction is 0.5–1 h, preferably 0.6–0.9 h, and even more preferably 0.7–0.8 h; the temperature of the second reaction is 190–210°C, preferably 192–208°C, more preferably 195–205°C, and even more preferably 200°C; the time of the second reaction is 2–4 h. The preferred time is 2.2–3.8 h, more preferably 2.5–3.5 h, and even more preferably 3 h; the mass ratio of the dammarene diol II intermediate to ethylene glycol, hydrazine hydrate, and KOH is 1:8.0–15.0:2.0–4.0:1.0–1.5, preferably 1:9.0–14.0:2.2–3.8:1.1–1.4, more preferably 1:9.5–12.0:2.5–3.5:1.15–1.35, and even more preferably 1:10.0–11.0:2.8–3.0:1.2–1.3.

[0063] This invention also provides a method for preparing borneol ketone, comprising the following steps:

[0064] Dammarene glycol II was mixed with a third additive and an oxidizing agent and reacted to obtain borneol alcohol ketone.

[0065] The structural formula of the borneol ketone is as follows:

[0066] The dammarene diol II is the dammarene diol II prepared by the above preparation method.

[0067] In this invention, the reaction temperature is 70–90°C, preferably 72–88°C, more preferably 75–85°C, and even more preferably 80°C; the reaction time is 5–8 h, preferably 5.2–7.8 h, more preferably 5.4–7.5 h, and even more preferably 6–6.5 h; the mass ratio of dammarene glycol II to the third additive and the oxidant is 1:4.0–8.0:2.0–4.0, preferably 1:4.5–7.5:2.2–3.8, more preferably 1:5.0–7.0:2.5–3.5, and even more preferably 1:5.5–6.0:2.8–3.2; the oxidant includes chromium trioxide and / or sarrit reagent; the third additive includes one or more of pyridine, 2-methylpyridine, 2,6-dimethylpyridine, and 2,4,6-trimethylpyridine.

[0068] In this invention, the first additive, the second additive, and the third additive can simultaneously serve as solvent, alkali, and catalyst in the reaction system.

[0069] In this invention, the principle for preparing the borneol alcohol ketone and dammarene glycol II and their intermediates is as follows: utilizing the different steric hindrance and reactivity of the three hydroxyl groups of protopanaxadiol, different hydroxyl groups are selectively protected and functional groups are transformed step by step: firstly, the hydroxyl groups at positions 3 and 12 are selectively acetylated for protection, and then the acetyl group at position 12 is selectively removed; the hydroxyl group at position 12 is oxidized to a carbonyl group, and then reduced by Ulf-Kashena-Huangminglong to remove the carbonyl oxygen at position 12 to obtain dammarene glycol II; the hydroxyl group at position 3 of dammarene glycol II is oxidized to obtain borneol alcohol ketone.

[0070] In this invention, the synthetic routes for the borneol ketone and dammarene diol II and their intermediates are as follows:

[0071]

[0072] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0073] Example 1: Preparation of dammarene diol II intermediate:

[0074] Acetic anhydride (60 mmol) was added to protopanaxadiol (9.2 g, 20 mmol) at room temperature (25 °C). The mixture was added to a solution of pyridine (50 g) and reacted at 100 °C for 8 hours, with the reaction monitored by TLC to ensure complete conversion of protopanaxadiol, yielding a reaction mixture. The reaction mixture was cooled to room temperature (25 °C) and concentrated using a rotary evaporator to remove pyridine and excess acetic anhydride, yielding a dark reddish-brown crude solid. The dark reddish-brown crude solid was recrystallized from methanol to obtain 10.4 g of intermediate 1 (white solid). At 0°C, intermediate 1 (9.8 g, 18 mmol) was added to a mixed solution of anhydrous potassium carbonate (18 mmol) and methanol (50 g), and the mixture was reacted at 0°C under a nitrogen atmosphere for 2 hours, with TLC monitoring to ensure complete conversion of intermediate 1, yielding a reaction mixture. The reaction mixture was filtered through diatomaceous earth, and the filtrate was diluted with 100 g of saturated ammonium chloride solution and extracted three times with 100 g of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain 8.3 g of intermediate 2 (white solid). At room temperature, intermediate 2 (7.5 g) was dissolved in pyridine (40 g), and chromium trioxide (15.0 g) was added. The mixture was then reacted at 70 °C for 6 hours to obtain a reaction solution. After cooling the reaction solution to room temperature, 15 g of silica gel was added and stirred for 1 hour. The mixture was then filtered through diatomaceous earth, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain 6.1 g of intermediate 3 (white solid). Sodium hydroxide (0.72 g) was dissolved in a 1:1 mixture of tetrahydrofuran and water (60 mL) at room temperature, and intermediate 3 (6.0 g) was added. The mixture was then reacted at 70 °C for 6 hours to obtain a reaction solution. After cooling the reaction solution to room temperature, it was neutralized to pH 7 with 1 mol / L HCl, and then extracted three times with 50 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was recrystallized from methanol to obtain 5.4 g of dammarene glycol II intermediate (white solid).

[0075]

[0076] Upon testing, the yield of intermediate 1 in Example 1 was 95%, and the 1H NMR spectrum of intermediate 1 is shown below. Figure 1 As shown, from Figure 1 As can be seen from the data, the 1H NMR spectrum of intermediate 1 is as follows: 1 H NMR(CDCl3,400MHz): δ0.85(s,6H),0.88(s,3H),0.95(s,3H),1.01(s,3H),1.13(s,3H),1.64(s,3H), 1.71(s,3H),2.04(s,3H),2.05(s,3H),3.05(s,1H),4.48(m,1H),4.73(m,1H),5.16(t,1H,J=6.5Hz);

[0077] The yield of intermediate 2 was 92%, and the 1H NMR spectrum of intermediate 2 is shown below. Figure 2 As shown, from Figure 2 As can be seen from the data, the 1H NMR spectrum of intermediate 2 is as follows: 1 H NMR(CDCl3,400MHz): δ0.86(s,6H),0.89(s,3H),0.91(s,3H),1.00(s,3H),1.20(s,3H),1. 65(s,3H),1.71(s,3H),2.06(s,3H),3.60(m,1H),4.48(m,1H,H-3u),5.17(t,1H,J=6.3Hz);

[0078] The yield of intermediate 3 was 81%, and the 1H NMR spectrum of intermediate 3 is shown below. Figure 3As shown, from Figure 3 As can be seen from the data, the 1H NMR spectrum of intermediate 3 is as follows: 1 H NMR(CDCl3,400MHz): δ0.85(s,3H),0.86(s,3H),0.87(s,3H),0.94(s,3H),1.11(s,3H),1.17(s,3H),1.61(s,3H),1.68(s,3H),2.0 4(s,3H),2.40(td,1H,J=10.5,6.8Hz),2.84(d,1H,J=10.5Hz),3.26(brs,1H),4.47(dd,1H,J=10.0,4.0Hz),5.09(t,1H,J=7.6Hz);

[0079] The yield of dammarene glycol II intermediate was 98%, and the 1H NMR spectrum of dammarene glycol II intermediate is shown below. Figure 4 As shown, from Figure 4 As can be seen from the data, the 1H NMR spectrum of the dammarene diol II intermediate is as follows: 1 H NMR(CDCl3,400MHz): δ0.81(s,3H),0.81(s,3H),0.94(s,3H),1.00(s,3H),1.12(s,3H),1.19(s,3H),1.63(s,3H),1.69(s,3 H), 2.42 (td, 1H, J = 10.5, 6.8Hz), 2.87 (d, 1H, J = 10.5Hz), 3.21 (dd, 1H, J = 10.0, 4.0Hz), 3.26 (brs, 1H), 5.11 (t, 1H, J = 7.6Hz).

[0080] Example 2: Preparation of dammarene diol II intermediate:

[0081] Acetic anhydride (40 mmol) was added to protopanaxadiol (9.2 g, 20 mmol) at room temperature (25 °C). The mixture was added to a solution of pyridine (90 g) and reacted at 90 °C for 9 hours, with the reaction monitored by TLC to ensure complete conversion of protopanaxadiol, yielding a reaction mixture. The reaction mixture was cooled to room temperature (25 °C) and concentrated using a rotary evaporator to remove pyridine and excess acetic anhydride, yielding a dark reddish-brown crude solid. The dark reddish-brown crude solid was recrystallized from methanol to give 10.2 g of intermediate 1 (white solid). At 0°C, intermediate 1 (9.8 g, 18 mmol) was added to a mixed solution of potassium carbonate (3.6 mmol) and methanol (40 g), and the mixture was reacted at 10°C for 3 hours under a nitrogen atmosphere while monitoring the reaction by TLC until intermediate 1 was completely converted, yielding a reaction mixture. The reaction mixture was filtered through diatomaceous earth, and the filtrate was diluted with 100 g of saturated ammonium chloride solution and extracted three times with 100 g of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain 8.5 g of intermediate 2 (white solid). At room temperature, intermediate 2 (7.5 g) was dissolved in pyridine (30 g), and chromium trioxide (12.0 g) was added. The mixture was then reacted at 70 °C for 8 hours to obtain a reaction solution. After cooling the reaction solution to room temperature, 15 g of silica gel was added and stirred for 1 hour. The mixture was then filtered through diatomaceous earth, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain 6.1 g of intermediate 3 (white solid). Sodium methoxide (0.65 g) was dissolved in a 1:0.5 mixture of methanol and water (80 mL) at room temperature, and intermediate 3 (6.0 g) was added. The mixture was then reacted at 60 °C for 8 hours to obtain a reaction solution. After cooling the reaction solution to room temperature, it was neutralized to pH 7 with 1 mol / L HCl, and then extracted three times with 50 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was recrystallized from methanol to obtain 5.2 g of dammarene glycol II intermediate (white solid).

[0082]

[0083] Example 3: Preparation of dammarene diol II intermediate:

[0084] Acetic anhydride (80 mmol) was added to protopanaxadiol (9.2 g, 20 mmol) at room temperature (25 °C). The mixture was added to a solution of pyridine (65 g) and reacted at 80 °C for 10 hours, with TLC monitoring to ensure complete conversion of protopanaxadiol, yielding a reaction mixture. The reaction mixture was cooled to room temperature (25 °C) and concentrated using a rotary evaporator to remove pyridine and excess acetic anhydride, yielding a dark reddish-brown crude solid. The dark reddish-brown crude solid was recrystallized from methanol to obtain 10.2 g of intermediate 1 (white solid). At -5°C, intermediate 1 (9.8 g, 18 mmol) was added to a mixed solution of potassium carbonate (36 mmol) and methanol (75 g), and the mixture was reacted at -5°C for 2 hours under a nitrogen atmosphere while monitoring the reaction by TLC until intermediate 1 was completely converted, yielding a reaction mixture. The reaction mixture was filtered through diatomaceous earth, and the filtrate was diluted with 100 g of saturated ammonium chloride solution and extracted three times with 100 g of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give 8.1 g of intermediate 2 (white solid). At room temperature, intermediate 2 (7.5 g) was dissolved in pyridine (45 g), and chromium trioxide (21.0 g) was added. The mixture was then reacted at 80 °C for 7 hours to obtain a reaction solution. After cooling the reaction solution to room temperature, 15 g of silica gel was added and stirred for 1 hour. The mixture was then filtered through diatomaceous earth, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain 6.2 g of intermediate 3 (white solid). At room temperature, potassium hydroxide (0.6 g) was dissolved in a 1:2 mixture of 1,4-dioxane and water (40 mL), and intermediate 3 (6.0 g) was added. The mixture was then reacted at 80 °C for 6 hours to obtain a reaction solution. After cooling the reaction solution to room temperature, it was neutralized to pH 7 with 1 mol / L HCl, and then extracted three times with 50 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was recrystallized from methanol to obtain 5.1 g of dammarene glycol II intermediate (white solid).

[0085]

[0086] Example 4: Preparation of dammarene diol II:

[0087] At room temperature (25°C), hydrazine hydrate (11.8 g) and KOH (5.6 g) were added to a mixed solution of dammarene glycol II intermediate (4.6 g) and ethylene glycol (50 g) prepared in Example 1. The mixture was then reacted at 165°C for 0.5 hours, followed by heating to 195°C and reacting for another 2 hours to obtain a reaction mixture. After cooling the reaction mixture to room temperature (25°C), it was poured into 50 mL of 3 mol / L HCl solution cooled in an ice-water bath. The precipitated white solid was washed with water until neutral to obtain a crude solid product. The crude solid product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain 3.4 g of dammarene glycol II (white solid).

[0088] The yield of dammarene glycol II prepared in Example 4 was 76% as determined by testing; the 1H NMR spectrum of dammarene glycol II is shown below. Figure 5 As shown, from Figure 5 As can be seen from the data, the 1H NMR spectrum of dammarene diol II is as follows: 1 ¹H NMR (CDCl₃, 400MHz): δ 0.78 (s, 3H), 0.85 (s, 3H), 0.89 (s, 3H), 0.97 (s, 3H), 0.98 (s, 3H), 1.15 (s, 3H), 1.63 (s, 3H), 1.70 (s, 3H), 2.03 (m, 1H), 3.21 (dd, 1H, J = 11.2, 5.2Hz), 5.11 (t, 1H, J = 7.2Hz); [M-OH]+ (ESI): m / z = 427.4. The mass spectrum of dammarene diol II prepared in Example 4 is shown below. Figure 6 As shown, from Figure 6 As can be seen from the data, the mass spectrometry data of dammarene diol II is: [M-OH]+(ESI): m / z=427.4.

[0089] The purity of dammarene glycol II in Example 4 was determined by high performance liquid chromatography (HPLC). The specific chromatographic conditions are as follows:

[0090] Agilent 1260 Infinity II HPLC system; Agilent InfinityLab poroshell 120EC-C18 column (4.6 × 100 mm, 2.7 μm); mobile phase: deionized water and acetonitrile; gradient elution: increasing the acetonitrile concentration of the eluent from 5% to 95% within 4 minutes; detector: ELSD; flow rate: 0.8 mL / min; column temperature: 30 °C; injection volume: 2 μL. HPLC results are as follows: Figure 7 As shown in Table 1 below.

[0091] Table 1. High-performance liquid chromatography purity results of dammarene diol II

[0092]

[0093]

[0094] Depend on Figure 7 As shown in Table 1, the purity of dammarene diol II prepared in Example 4 of this invention is 97.315%.

[0095] Example 5: Preparation of dammarene diol II:

[0096] At room temperature (25°C), hydrazine hydrate (18.0 g) and KOH (4.6 g) were added to a mixed solution of dammarene glycol II intermediate (4.6 g) and ethylene glycol (37 g) prepared in Example 1. The mixture was then reacted at 175°C for 0.6 hours, followed by heating to 190°C and reacting for another 2.5 hours to obtain a reaction mixture. After cooling the reaction mixture to room temperature (25°C), it was poured into 50 mL of 3 mol / L HCl solution cooled in an ice-water bath. The precipitated white solid was washed with water until neutral to obtain a crude solid. The crude solid was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain 3.2 g of dammarene glycol II (white solid).

[0097] Example 6: Preparation of dammarene diol II:

[0098] At room temperature (25°C), hydrazine hydrate (9.2 g) and KOH (6.8 g) were added to a mixed solution of dammarene glycol II intermediate (4.6 g) and ethylene glycol (65 g) prepared in Example 1. The mixture was then reacted at 180°C for 1.0 h, followed by heating to 210°C and reacting for another 4 h to obtain a reaction mixture. After cooling the reaction mixture to room temperature (25°C), it was poured into 50 mL of 3 mol / L HCl solution cooled in an ice-water bath. The precipitated white solid was washed with water until neutral to obtain a crude solid. The crude solid was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain 2.8 g of dammarene glycol II (white solid).

[0099] Example 7: Preparation of Borneol Ketone:

[0100] At room temperature (25°C), dammarene glycol II (3.3 g) prepared in Example 4 was dissolved in pyridine (20 g), and chromium trioxide (7.5 g) was added. The mixture was then reacted at 70°C for 6 hours to obtain a reaction solution. After cooling the reaction solution to room temperature (25°C), silica gel (7.5 g) was added and stirred for 1 hour. The solution was then filtered through diatomaceous earth. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain 3.0 g of borneol ketone (white solid).

[0101] The yield of borneol ketone prepared in Example 7 was 91% as tested; the 1H NMR spectrum of borneol ketone is shown below. Figure 8 As shown, from Figure 8 As can be seen from the data, the 1H NMR spectrum of borneol ketone is as follows: 1H NMR(CDCl3,400MHz): δ0.90(s,3H),0.95(s,3H),1.01(s,3H),1.05(s,3H),1.09(s,3H),1.16(s,3H), 1.64(s,3H),1.70(s,3H),2.07(m,2H),2.48(m,2H),5.13(t,1H,J=6.8Hz); [M+H]+(ESI): m / z=443.4.

[0102] The mass spectrum of the borneol ketone prepared in Example 7 is as follows: Figure 9 As shown, from Figure 9 As can be seen from the data, the mass spectrometry data of borneol ketone is: [M+H]+(ESI): m / z=443.4.

[0103] The purity of borneol ketone in Example 7 was determined by high performance liquid chromatography (HPLC). The specific chromatographic conditions are as follows:

[0104] Agilent 1260 Infinity II HPLC system; Agilent InfinityLab poroshell 120EC-C18 column (4.6 × 100 mm, 2.7 μm); mobile phase: deionized water and acetonitrile; gradient elution: increasing the acetonitrile concentration of the eluent from 5% to 95% within 4 minutes; detector: ELSD; flow rate: 0.8 mL / min; column temperature: 30 °C; injection volume: 2 μL. HPLC results are as follows: Figure 10 As shown in Table 2 below.

[0105] Table 2. High-performance liquid chromatography purity results of borneol ketones

[0106]

[0107]

[0108] Depend on Figure 10 As shown in Table 2, the purity of the borneol ketone prepared in Example 7 of the present invention is 98.44%, and the retention time is 3.000 minutes.

[0109] Example 8: Preparation of Borneol Ketone:

[0110] At room temperature (25°C), dammarene glycol II (3.3 g) prepared in Example 4 was dissolved in pyridine (15 g), and chromium trioxide (10.0 g) was added. The mixture was then reacted at 80°C for 8 hours to obtain a reaction solution. After cooling the reaction solution to room temperature (25°C), silica gel (7.5 g) was added and stirred for 1 hour. The solution was then filtered through diatomaceous earth. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain 2.9 g of borneol ketone (white solid).

[0111] Example 9: Preparation of Borneol Ketone:

[0112] At room temperature (25°C), dammarene glycol II (3.3 g) prepared in Example 4 was dissolved in pyridine (25 g), and chromium trioxide (13 g) was added. The mixture was then reacted at 90°C for 5 hours to obtain a reaction solution. After cooling the reaction solution to room temperature (25°C), silica gel (7.5 g) was added and stirred for 1 hour. The solution was then filtered through diatomaceous earth. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain 3.1 g of borneol ketone (white solid).

[0113] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing dammarene diol II intermediate, characterized in that, Includes the following steps: 1) The protopanaxadiol was mixed with the first additive and an acid anhydride compound and reacted to obtain intermediate 1; 2) Intermediate 1 is mixed with anhydrous potassium carbonate and solvent and reacted to obtain intermediate 2; 3) Intermediate 2 is mixed with the second additive and the oxidant, and reacted to obtain intermediate 3; 4) Intermediate 3 is mixed with an alkaline compound and a mixed solvent and reacted to obtain dammarene glycol II intermediate; The structural formula of the protopanaxadiol is as follows: The structural formula of intermediate 1 is: The structural formula of intermediate 2 is as follows: The structural formula of the intermediate 3 is as follows: The structural formula of the dammarene diol II intermediate is:

2. The method for preparing a dammarene diol II intermediate according to claim 1, characterized in that, The reaction in step 1) is carried out at a temperature of 80–100°C for 8–10 hours. The molar ratio of protopanaxadiol to acid anhydride compounds is 1:2.0 to 4.0; the mass ratio of protopanaxadiol to the first additive is 1:5.0 to 10.

0. The first additive includes one or more of pyridine, 2-methylpyridine, 2,6-dimethylpyridine and 2,4,6-trimethylpyridine; the acid anhydride compound includes one or more of acetic anhydride, propionic anhydride, butyric anhydride and valerate anhydride.

3. The method for preparing a dammarene diol II intermediate according to claim 2, characterized in that, The reaction in step 2) is carried out at a temperature of -5 to 10°C for 1 to 3 hours in an inert atmosphere. The molar ratio of intermediate 1 to anhydrous potassium carbonate is 1:0.2 to 2.0; the mass ratio of intermediate 1 to solvent is 1:4.0 to 8.0; the solvent includes one or more of methanol, ethanol and propanol.

4. A method for preparing a dammarene diol II intermediate according to any one of claims 1 to 3, characterized in that, The reaction in step 3) is carried out at a temperature of 70–90°C for 5–8 hours. The mass ratio of intermediate 2 to the second additive and oxidant is 1:4.0-6.0:1.5-3.0; the oxidant includes chromium trioxide and / or sarrit reagent; the second additive includes one or more of pyridine, 2-methylpyridine, 2,6-dimethylpyridine, and 2,4,6-trimethylpyridine.

5. The method for preparing a dammarene diol II intermediate according to claim 4, characterized in that, The reaction in step 4) is carried out at a temperature of 60–80°C for 6–8 hours. The mass-to-volume ratio of intermediate 3 to the basic compound and the mixed solvent is 1.0 g : 0.1–0.2 g : 5.0–15.0 mL; The alkaline compound includes one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, and sodium ethoxide; The mixed solvent includes one or more of the following: an aqueous solution of tetrahydrofuran, an aqueous solution of 1,4-dioxane, an aqueous solution of acetone, an aqueous solution of methanol, and an aqueous solution of ethanol. The volume concentration of the mixed solvent is 33.33% to 66.67%.

6. A method for preparing dammarene glycol II, characterized in that, Includes the following steps: Dammarene glycol II intermediate was mixed with ethylene glycol, hydrazine hydrate and KOH and reacted to obtain dammarene glycol II; The structural formula of the dammarene diol II is as follows: The dammarene diol II intermediate is the dammarene diol II intermediate prepared by the preparation method according to any one of claims 1 to 5.

7. The method for preparing dammarene glycol II according to claim 6, characterized in that, The reaction includes a first reaction and a second reaction; The temperature of the first reaction is 160–180°C, and the time is 0.5–1 h; the temperature of the second reaction is 190–210°C, and the time is 2–4 h. The mass ratio of the dammarene diol II intermediate to ethylene glycol, hydrazine hydrate and KOH is 1:8.0-15.0:2.0-4.0:1.0-1.

5.

8. A method for preparing borneol ketone, characterized in that, Includes the following steps: Dammarene glycol II was mixed with a third additive and an oxidizing agent and reacted to obtain borneol alcohol ketone. The structural formula of the borneol ketone is as follows: The dammarene diol II is the dammarene diol II prepared by the preparation method according to any one of claims 6 to 7.

9. The method for preparing borneol ketone according to claim 8, characterized in that, The reaction is carried out at a temperature of 70–90°C for 5–8 hours. The mass ratio of dammarene glycol II to the third additive and the oxidant is 1:4.0-8.0:2.0-4.0; the oxidant includes chromium trioxide and / or sarrit reagent; the third additive includes one or more of pyridine, 2-methylpyridine, 2,6-dimethylpyridine, and 2,4,6-trimethylpyridine.

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