A new method for preparing an intermediate of arylabein C

Abstract

The application discloses a novel method for preparing an intermediate of an aryl abietane diterpene Plebein C, and specifically comprises the following steps: substituting a carbonyl alpha position of 4,4-dimethyl-2-cyclohexen-1-ketone to obtain compound I; protecting the compound I by TBS to obtain compound II; performing a Luche reduction reaction on the compound II to obtain compound III; performing an iodination reaction on 3-hydroxy-4-methoxybenzaldehyde to obtain compound IV; performing a Wittig reaction on the compound IV to obtain compound V; performing a Mitsunobu reaction between the compound III and the compound V to obtain compound VI; performing a radical cyclization reaction on the compound VI to obtain compound VII; performing an oxidation on a benzyl position of the compound VII to obtain compound VIII; and finally performing an oxidation and a ring closure on the compound VIII to obtain a five-ring intermediate compound IX of a Plebein C molecule; the preparation method has the advantages of simple synthetic route, low-cost and easily-obtained reagents, high yield, favorability for industrial preparation of the intermediate, and strong popularization potential.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a new method for preparing an aryl abietane diterpene Plebein C intermediate. BACKGROUND

[0002] Aromatic abietane diterpenes are a kind of natural products that have been studied and focused on by scientists in recent years. The abietane diterpenes to which the aromatic abietane diterpenes belong contain a [6-6-6] tricyclic skeleton, and are oxidized to different degrees in the B ring and the C ring. The aromatic abietane diterpenes account for the largest category. The family of the aromatic abietane diterpenes is widely distributed in various terrestrial plants, and the characteristic aromatic C ring makes the aromatic abietane diterpenes have diverse and significant biological activities. For example, the first aromatic abietane diterpene Dehydroabietic acid discovered in the 1950s has antibacterial, anti-inflammatory, antitumor, anti-ulcer and other biological activities such as improving diabetes and hyperlipidemia; another aromatic abietane diterpene Ferruginol discovered subsequently not only has antibacterial, anti-inflammatory, antitumor and anti-ulcer activities, but also has antioxidant, anti-SARS, anti-trypanosoma, antimalarial and other biological activities. With the progress of science and technology, in recent years, the aromatic abietane diterpene compounds Isoabietenin A, Epoxyhinokiol, Plebein C and Huperphlegmarin B having a rare epoxy bridge ring between the A ring and the C ring have been discovered. In 2015, Epoxyhinokiol was first isolated from Chinese fir leaves, and then was isolated from the Chinese folk medicinal plant Lanxiangcao (used for relieving cough and rheumatic pain). It is thus speculated that the aromatic abietane diterpene compound having the rare epoxy bridge ring may be a kind of compound having potential drug activity. At present, there is no research report on the five-ring aromatic abietane diterpene Plebein C.

[0003] Therefore, the application designs a new method for preparing the aryl abietane diterpene Plebein C intermediate through a free radical tandem cyclization reaction and an oxidative ring closure reaction. The preparation method has a simple synthesis route, the reagents are cheap and easy to obtain, and the yield is high, which is very beneficial to the mass preparation of the aromatic abietane diterpene Plebein C intermediate, and facilitates the further research on the biological activity of the series of molecules of the aromatic abietane diterpene having the rare epoxy bridge ring. SUMMARY

[0004] The present application mainly overcomes the deficiencies in the prior art, and provides a new method for preparing an aryl abietane diterpene Plebein C intermediate, which is a skeleton construction method based on the Plebein C molecule; specifically comprising: substituting 4,4-dimethyl-2-cyclohexen-1-ketone at the alpha position of the carbonyl group to obtain compound I; protecting by TBS to obtain compound II; performing Luche reduction reaction to obtain compound III; performing iodination at the 2-position of 3-hydroxy-4-methoxybenzaldehyde to obtain compound IV; performing Wittig reaction to obtain compound V; performing Mitsunobu reaction between compound III and compound V to obtain compound VI; performing a key radical cyclization reaction to obtain compound VII; performing benzyl oxidation to obtain compound VIII; and finally performing ring closure after oxidation to obtain the five-ring intermediate compound IX of the Plebein C molecule. The preparation method has a simple synthesis route, the reagents are cheap and easy to obtain, and the yield is high, which is very beneficial to the mass preparation of the aryl abietane diterpene Plebein C intermediate, and facilitates the mass production of the Plebein C series molecules and the more in-depth study of the biological activity. Meanwhile, the convergent and tandem high-efficiency chemical reaction method is suitable for industrial preparation and has strong popularization potential.

[0005] In order to achieve the above technical purposes, the technical scheme adopted by the present application is:

[0006] A new method for preparing an aryl abietane diterpene Plebein C intermediate, and the reaction process route is as follows:

[0007]

[0008] The synthesis method comprises steps one to nine:

[0009] Specifically, step one: using 4,4-dimethyl-2-cyclohexen-1-ketone as a raw material, reacting with 4-dimethylaminopyridine and aqueous formaldehyde at room temperature to obtain compound I;

[0010] Step two: reacting compound I with 4-dimethylaminopyridine, tert-butyldimethylsilyl chloride and pyridine at room temperature to obtain compound II;

[0011] Step three: performing Luche reduction reaction on compound II and cerium chloride heptahydrate using sodium borohydride to obtain compound III;

[0012] Step four: using 3-hydroxy-4-methoxybenzaldehyde as a raw material, reacting with iodine dissolved in 1,4-dioxane in pyridine at room temperature in the dark to obtain compound IV;

[0013] Step five: performing Wittig reaction on compound IV using methyltriphenylphosphonium bromide and sodium bis(trimethylsilyl)amide to obtain V;

[0014] Step six: compound III and compound V undergo Mitsunobu reaction with triphenyl phosphine and diisopropyl azodicarboxylate to obtain VI;

[0015] Step seven: compound VI is treated with tris(trimethylsilyl)silane and triethylboron in deoxotoluene to obtain compound VII;

[0016] Step eight: compound VII undergoes benzylic oxidation with chromium trioxide and 3,5-dimethylpyrazole to obtain compound VIII;

[0017] Step nine: compound VIII is oxidized with selenium dioxide and cyclized to obtain compound IX, which is an intermediate of the aryl abietane diterpene Plebein C.

[0018] Further, the structural formulae of the compound 4,4-dimethyl-2-cyclohexen-1-one, 3-hydroxy-4-methoxybenzaldehyde and compounds I-IX are as follows:

[0019]

[0020] Further, the specific synthesis method of step one is as follows:

[0021] Compound 4,4-dimethyl-2-cyclohexen-1-one is used as a raw material, and 4-dimethylaminopyridine and aqueous formaldehyde are reacted at room temperature to obtain compound I, which specifically includes:

[0022] 4-dimethylaminopyridine is added to a reaction bottle at room temperature, and argon atmosphere is added to the reaction bottle. Solvent tetrahydrofuran, raw material 4,4-dimethyl-2-cyclohexen-1-one and aqueous formaldehyde are added, and stirred at room temperature for 24 hours under normal pressure. After the reaction is completed, 1N HCl is added at room temperature to quench the reaction, extracted with dichloromethane, washed with saturated brine, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and then separated and purified by column chromatography. The eluent is petroleum ether: ethyl acetate = 3:1, and compound I is obtained.

[0023] The molar ratio of 4,4-dimethyl-2-cyclohexen-1-one, 4-dimethylaminopyridine and aqueous formaldehyde is 100:55:300.

[0024] Further, the specific synthesis method of step two is as follows:

[0025] Compound I is reacted with 4-dimethylaminopyridine, tert-butyldimethylchlorosilane and pyridine at room temperature to obtain compound II, which specifically includes:

[0026] The reaction bottle is added with 4-dimethylaminopyridine and tert-butyl dimethyl chlorosilane at room temperature, and solvent dichloromethane and pyridine are added under an argon atmosphere at 0°C; after stirring at 0°C for 5 minutes, compound I dissolved in dichloromethane is added, and after stirring at 0°C for 30 minutes, reaction is carried out at room temperature for 2 hours under normal pressure; after the reaction is completed, saturated ammonium chloride solution is added at 0°C for quenching, and extraction is carried out with ethyl acetate; after washing with saturated brine and drying with anhydrous sodium sulfate, concentration is carried out under reduced pressure, and then column chromatography is used for separation and purification, and the eluent volume ratio is petroleum ether: ethyl acetate = 20:1, so that compound II is obtained.

[0027] The molar ratio of the compound I, 4-dimethylaminopyridine, tert-butyl dimethyl chlorosilane, and pyridine is 82.7:24.8:165.3:206.6.

[0028] Further, the specific synthesis method of step three is as follows:

[0029] Luche reduction reaction of compound II and cerium chloride heptahydrate with sodium borohydride at 0°C to obtain compound III, which specifically includes:

[0030] The reaction bottle is added with compound II, cerium chloride heptahydrate, and solvent methanol at room temperature, and sodium borohydride is added in three batches at 0°C; after stirring at 0°C for 10 minutes after each addition of sodium borohydride, reaction is carried out under normal pressure; after the reaction is completed, ice water is added for quenching, and extraction is carried out with ethyl acetate; after washing with saturated brine and drying with anhydrous sodium sulfate, concentration is carried out under reduced pressure, and then column chromatography is used for separation and purification, and the eluent volume ratio is petroleum ether: ethyl acetate = 20:1, so that compound III is obtained.

[0031] The molar ratio of the compound II, cerium chloride heptahydrate, and sodium borohydride is 41.8:41.8:25.

[0032] Further, the specific synthesis method of step four is as follows:

[0033] Compound 3-hydroxy-4-methoxybenzaldehyde is used as a raw material, and reaction is carried out with iodine monochloride dissolved in 1,4-dioxane in pyridine at room temperature in the dark to obtain compound IV, which specifically includes:

[0034] The reaction bottle is added with 3-hydroxy-4-methoxybenzaldehyde, and solvent pyridine is added under an argon atmosphere at 0°C; then iodine monochloride dissolved in 1,4-dioxane is added, and reaction is carried out at room temperature in the dark for 6 days under normal pressure; after the reaction is completed, the solvent is removed by concentration under reduced pressure, and then water and HCl are added to adjust the pH to 1; extraction is carried out with ethyl acetate, and washing is carried out with saturated brine; drying is carried out with anhydrous magnesium sulfate, and then concentration is carried out under reduced pressure, so that compound IV is obtained.

[0035] The molar ratio of the 3-hydroxy-4-methoxybenzaldehyde and iodine monochloride is 120:156.

[0036] Further, the specific synthesis method of step five is:

[0037] Compound IV is subjected to Wittig reaction with methyltriphenylphosphonium bromide and sodium bis(trimethylsilyl)amide to obtain V, which specifically includes:

[0038] Methyltriphenylphosphonium bromide is added into a reaction bottle at room temperature, tetrahydrofuran is added under argon atmosphere, sodium bis(trimethylsilyl)amide is added at 0°C, compound IV dissolved in tetrahydrofuran is added after stirring at 0°C for 30 minutes, reaction is carried out at room temperature for 30 minutes under normal pressure; after the reaction is completed, saturated ammonium chloride solution is added for quenching, ethyl acetate is used for extraction, saturated brine is used for washing, anhydrous magnesium sulfate is used for drying, and compound V is obtained after column chromatography separation and purification under reduced pressure, with the eluent volume ratio of petroleum ether: ethyl acetate being 5:1-3:1.

[0039] The molar ratio of compound IV, methyltriphenylphosphonium bromide and sodium bis(trimethylsilyl)amide is 72:172.8:158.4.

[0040] Further, the specific synthesis method of step six is:

[0041] Compound III and compound V are subjected to Mitsunobu reaction with triphenylphosphine and diisopropyl azodicarboxylate to obtain VI, which specifically includes:

[0042] Compound III and compound V are subjected to Mitsunobu reaction with triphenylphosphine and diisopropyl azodicarboxylate to obtain VI, which specifically includes:

[0043] The molar ratio of compound III, compound V, triphenylphosphine and diisopropyl azodicarboxylate is 51.2:56.3:58.8:58.8.

[0044] Further, the specific synthesis method of step seven is:

[0045] Compound VI is treated with tri(trimethylsilyl)silane and triethylboron in deoxymethylbenzene to obtain compound VII, which specifically includes:

[0046] The compound VI, tri (trimethylsilyl) silane and triethyl boron are added into a reaction bottle under normal temperature, deoxymethylbenzene is added under argon atmosphere, the temperature is raised to 85 degrees Celsius, and the reaction is carried out for 5 hours under normal pressure; after the reaction is completed, the toluene is removed by concentration under reduced pressure; ethyl acetate is extracted, washed with water and saturated brine; dried with anhydrous sodium sulfate, concentrated under reduced pressure, and then separated and purified by column chromatography, so that the compound VII is obtained, wherein the volume ratio of the eluent is petroleum ether: ethyl acetate = 40:1~30:1.

[0047] The molar ratio of the compound VI, tri (trimethylsilyl) silane and triethyl boron is 26:52:6.5.

[0048] The specific synthesis method of step eight is as follows:

[0049] The compound VII is subjected to a benzyl oxidation reaction with chromium trioxide and 3,5-dimethylpyrazole at minus 15 degrees Celsius to obtain the compound VIII, which specifically includes the following steps:

[0050] The compound VII is subjected to a benzyl oxidation reaction with chromium trioxide and 3,5-dimethylpyrazole at minus 15 degrees Celsius to obtain the compound VIII, which specifically includes the following steps:

[0051] The molar ratio of the compound VII, chromium trioxide and 3,5-dimethylpyrazole is 5:40:40.

[0052] Further, the specific synthesis method of step nine is as follows:

[0053] The compound VIII is treated in selenium dioxide to obtain the compound IX:

[0054] Specifically includes the following steps:

[0055] The compound VIII is treated in selenium dioxide to obtain the compound IX:

[0056] The molar ratio of the compound VIII and selenium dioxide is 0.2:1.

[0057] Beneficial effects

[0058] Compared with the prior art, the present application has the following advantages:

[0059] The application discloses a novel method for preparing an aryl abietane diterpene Plebein C intermediate, designs a synthesis method for an aryl abietane diterpene Plebein C five-ring skeleton through a free radical tandem cyclization reaction, oxidation and cyclization, and the method is a skeleton construction method taking the Plebein C molecule as the first; specifically, 4,4-dimethyl-2-cyclohexen-1-ketone is subjected to alpha position substitution of a carbonyl group to obtain a compound I; TBS protection is performed to obtain a compound II; a Luche reduction reaction is performed to obtain a compound III; 3-hydroxy-4-methoxybenzaldehyde is subjected to 2-position iodination to obtain a compound IV; a Wittig reaction is performed to obtain a compound V; Mitsunobu reaction between the compound III and the compound V is performed to obtain a compound VI; a key free radical cyclization reaction is performed to obtain a compound VII; benzyl oxidation is performed to obtain a compound VIII; and finally, oxidation and ring closure are performed to obtain a five-ring intermediate compound IX of the Plebein C molecule. The preparation method has the advantages of a simple synthesis route, cheap and easily obtained reagents and high yield; taking the Plebein C molecule as the guide, a convergent synthesis scheme is designed through a chemical synthesis method, a Mitsunobu etherification reaction is used to construct an aryl iodide precursor, a free radical tandem cyclization initiated by tris(trimethylsilyl)silane and triethyl boron is used as a key reaction, an aryl abietane diterpene Plebein C five-ring skeleton is quickly and efficiently constructed, and a novel method for constructing the structural unit is developed. The method has the advantages of simple operation, cheap and easily obtained raw materials and a simple synthesis route, lays a foundation for the synthesis of other types of aromatic abietane diterpene compounds, embodies the superiority of the method, has high practical value, is very favorable for the mass preparation of the aryl abietane diterpene Plebein C intermediate, is convenient for further research on the biological activity of the rare epoxy bridge ring aromatic abietane diterpene series molecule, is applicable to industrial preparation, and has strong popularization potential. BRIEF DESCRIPTION OF DRAWINGS

[0060] Figure 1 A synthesis path diagram of the novel method for preparing the aryl abietane diterpene Plebein C intermediate in the embodiments of the application;

[0061] Figure 2 Structural formulas of the compound 4,4-dimethyl-2-cyclohexen-1-ketone, the compound 3-hydroxy-4-methoxybenzaldehyde and the compounds I to IX in the embodiments of the application;

[0062] Figure 3 A nuclear magnetic hydrogen spectrum diagram of the compound IX in the embodiments of the application;

[0063] Figure 4 The carbon nuclear magnetic resonance spectrum of compound IX in the embodiments of the present application. DETAILED DESCRIPTION

[0064] In order to make the objects, technical solutions and advantages of the present application clearer, the present application will be further described in details below in combination with embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application and do not limit the present application.

[0065] According to the synthetic path shown in the following table, the compounds in the following embodiments are synthesized, and the structural formula of each compound involved in the synthesis is shown in the following table. Figure 1 Figure 2

[0066] Example 1:

[0067] Step one:

[0068] Take 250ml dry two-port bottle and add a stirring rod. Weigh compound 4-dimethylaminopyridine (6.7g, 55mmol, 0.6e.q) and add it to the reaction bottle. Replace argon three times and protect with a balloon. Place the device at room temperature, dissolve the substrate in tetrahydrofuran (20ml), and then add raw material 4,4-dimethyl-2-cyclohexen-1-one (13.1ml, 100mmol) and aqueous formaldehyde (37%~40%, 29ml, 300mmol, 3.0e.q) to the reaction bottle. After dropwise addition, place it at room temperature for 24 hours. After the reaction is completed, add 1N HCl (15ml) at room temperature to quench the reaction, extract with dichloromethane (30ml x 3), wash with saturated brine (20ml x 3), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and then separate and purify by column chromatography. The eluent volume ratio is petroleum ether: ethyl acetate = 3:1, and colorless oil is obtained as compound I (11.7g, 76%). R f = 0.25 (petroleum ether: ethyl acetate = 3:1).

[0069] Step two:

[0070] ​​Take 500 ml dry two-port bottle to add stirring son, take compound 4-dimethylaminopyridine (3 g, 24.8 mmol, 0.3 e.q), t-butyl dimethyl chlorosilane (24.9 g, 165.3 mmol, 2 e.q) into the reaction bottle, replace argon three times, insert the ball protection. The device is placed in zero Celsius, add dry dichloromethane (250 ml) to dissolve the substrate, then add pyridine (16.6 ml, 206.6 mmol, 2.5 e.q) into the reaction bottle, stir for 5 minutes at zero Celsius, then add compound I (12.7 g, 82.7 mmol) into the reaction bottle, stir for 30 minutes at zero Celsius, then place the device in normal temperature for 2 hours. After the reaction is completed, add saturated ammonium chloride solution (150 ml) at zero Celsius to quench the reaction, and extract with ethyl acetate (150 ml x 3), wash with saturated brine (100 ml x 3), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography, eluent volume ratio petroleum ether: ethyl acetate = 20:1, to obtain colorless oil compound II (20 g, 90%). R f = 0.30 (petroleum ether: ethyl acetate = 20:1).

[0071] Step three:

[0072] Take 250 ml dry two-port bottle to add stirring son, take compound II (11.2 g, 41.8 mmol) and cerium chloride heptahydrate (15.6 g, 41.8 mmol, 1.0 e.q) into the reaction bottle. The device is placed in zero Celsius, add methanol (100 ml) to dissolve the substrate, then add sodium borohydride (0.9 g, 25 mmol, 0.6 e.q) into the reaction bottle in three batches, react for 10 minutes at zero Celsius after each addition of sodium borohydride. After the reaction is completed, quench with ice water (60 ml), extract with ethyl acetate (60 ml x 3), wash with saturated brine (50 ml x 3), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography, eluent volume ratio petroleum ether: ethyl acetate = 20:1, to obtain colorless oil compound III (10.5 g, 93%). R f = 0.25 (petroleum ether: ethyl acetate = 20:1).

[0073] Step four:

[0074] Take 500ml dry two-port reaction bottle, add a stirring rod, weigh compound 3-hydroxy-4-methoxybenzaldehyde (18.2g, 120mmol) into the reaction bottle, replace argon three times, and insert a balloon for protection. Place the device in zero degrees Celsius, dissolve the substrate in pyridine (70ml), and then add iodine monochloride (8ml, 156mmol, 1.3e.q) dissolved in 1,4-dioxane (120ml) into the reaction bottle, and react at room temperature for 6 days in the dark. After the reaction is completed, remove the solvent under reduced pressure, then add water (200ml) and HCl to adjust the PH to 1 in the reaction bottle. Extract with ethyl acetate (120ml x 3), wash with saturated brine (120ml x 3), dry over anhydrous magnesium sulfate, and concentrate under reduced pressure to obtain a light yellow solid as compound IV (31.1g, 94%). f = 0.45 (petroleum ether: ethyl acetate = 3:1).

[0075] Step five:

[0076] Take 250ml dry two-port reaction bottle, add a stirring rod, weigh compound methyltriphenylphosphonium bromide (61.9g, 172.8mmol, 2.4e.q) into the reaction bottle, replace argon three times, and insert a balloon for protection. Place the device at room temperature, dissolve the substrate in freshly distilled tetrahydrofuran (100ml), then add sodium bis(trimethylsilyl)amide (71.2ml, 158.4mmol, 2.2e.q) into the reaction bottle at zero degrees Celsius, stir for 30 minutes at zero degrees Celsius, then add compound IV (20g, 72mmol) dissolved in freshly distilled tetrahydrofuran (30ml), and react at room temperature for 30 minutes. After the reaction is completed, quench with saturated ammonium chloride solution (70ml), extract with ethyl acetate (60ml x 3), wash with saturated brine (60ml x 3), dry over anhydrous magnesium sulfate, concentrate under reduced pressure, and purify by column chromatography with eluent volume ratio petroleum ether: ethyl acetate = 3:1 to obtain a light yellow solid as compound V (16.7g, 84%). f = 0.40 (petroleum ether: ethyl acetate = 3:1).

[0077] Step six:

[0078] Into a 500ml dry two necked reaction flask, add a stir bar, weigh compound III (13.8g, 51.2mmol), compound V (15.5g, 56.3mmol, 1.1e.q) and triphenyl phosphine (15.4g, 58.8mmol, 1.2e.q) into the flask, replace argon gas for three times, and insert a balloon for protection. Place the apparatus at room temperature, add re-distilled tetrahydrofuran (200ml) to dissolve the substrate, stir for 10 minutes at room temperature, and then place the apparatus at 0 degree Celsius, and add diisopropyl azodicarboxylate (9.9ml, 58.8mmol, 1.2e.q) into the flask, and react for 3 hours at room temperature. After the reaction is completed, quench the reaction with water (120ml), extract with ethyl acetate (100ml x 3), wash with saturated brine (100ml x 3), dry over anhydrous magnesium sulfate, concentrate under reduced pressure, and purify by column chromatography with eluent volume ratio of petroleum ether: ethyl acetate = 20:1. Compound VI (21g, 78%) is obtained as colorless oil. Rf = 0.40 (petroleum ether: ethyl acetate = 20:1). f

[0079] Step Seven:

[0080] Into a 500ml dry two necked reaction flask, add a stir bar, weigh compound VI (13.7g, 26mmol) into the flask, and install a condenser reflux apparatus, replace argon gas for three times, and insert a balloon for protection. Place the apparatus at room temperature, add dehydrated and deoxygenated toluene (250ml) to dissolve the substrate, and then place the apparatus at 110 degree Celsius, and slowly drop tri(trimethylsilyl)silane (12.93g, 52mmol, 2.0e.q) and triethylboron (0.637g, 6.5mmol, 0.25e.q) into the flask, and react for 5 hours at 85 degree Celsius. After the reaction is completed, cool to room temperature, extract with ethyl acetate (100ml x 2), wash with saturated brine (100ml x 2), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography with eluent volume ratio of petroleum ether: ethyl acetate = 40:1. Compound VII (4.2g, 40%) is obtained as colorless oil. Rf = 0.50 (petroleum ether: ethyl acetate = 40:1). f

[0081] Step Eight:

[0082] ​​Add a stir bar to a 100 ml dry double-necked reaction flask, weigh out chromium trioxide (4 g, 40 mmol, 8 e.g.) and 3,5-dimethylpyrazole (3.8 g, 40 mmol, 8 e.g.), and add them to the flask. Replace the gas with argon three times, and insert a balloon for protection. Place the apparatus at -15°C and stir for 30 minutes. Add 20 ml of redistilled dichloromethane to dissolve the substrate. Then place the apparatus at -10°C and add compound VII (2 g, 5 mmol) dissolved in 10 ml of dichloromethane to the reaction flask. Stir for 5 minutes to stop the reaction. Filter through a diatomaceous earth funnel, concentrate under reduced pressure, and purify by column chromatography with a petroleum ether:ethyl acetate volume ratio of 10:1. The white solid obtained is compound VIII (1.4 g, 68%). f =0.50 (petroleum ether: ethyl acetate = 10:1).

[0083] like Figure 3 As shown, its structure was characterized by TLC (thin-layer chromatography) and NMR data. Details are as follows: 1 HNMR(601MHz, CDCl3) δ7.40(d,J=8.5Hz,1H),6.83(d,J=8.4Hz,1H),4.97(dd,J=10.2,7.7Hz,1H),3.94 (s,3H),3.53(q,J=10.0Hz,2H),2.81(dd,J=18.7,7.0Hz,1H),2.63(d,J=18.7Hz,1H),2.46(d,J=6.9Hz ,1H),2.00(ddt,J=14.1,7.3,3.4Hz,1H),1.50(tdd,J=13.8,10.1,3.3Hz,1H),1.27(dt,J=13.8,3.7Hz ,1H),1.14(td,J=14.3,2.8Hz,1H),0.95(s,3H),0.89(s,9H),0.46(s,3H),0.01(d,J=13.6Hz,6H)ppm; 13 C NMR (151MHz, CDCl3) δ196.1,149.5,144.4,137.6,124.2,119.3,113.1,87.6,65.4 ,56.2,47.8,43.2,36.5,35.4,32.7,31.2,25.8,24.4,21.1,18.1,-5.5,-5.6ppm.

[0084] Step Nine:

[0085] Take 50 ml dry two-port bottle to add stirring rod, take compound VIII (83 mg, 0.2 mmol) and selenium dioxide (111 mg, 1 mmol, 5e.q) and add to the reaction bottle. At room temperature, add acetic acid (1.5 ml) and water (0.5 ml) mixed solvent to the reaction bottle, and then place the device in 110 degrees Celsius for 2 hours. After the reaction is completed, the device is placed at room temperature to cool, diluted with ethyl acetate (3 ml), then saturated sodium bicarbonate solution (6 ml) is added to quench the reaction, and extracted with ethyl acetate (10 ml x 3), washed with saturated brine (10 ml x 3), dried with anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography, eluent volume ratio petroleum ether: ethyl acetate = 5:1, to obtain white solid compound IX (55 mg, 70%). R f = 0.25 (petroleum ether: ethyl acetate = 5:1).

[0086] As shown in Figure 4 , characterized by TLC thin layer chromatography and nuclear magnetic data. The specific as follows: 1 HNMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.5 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 4.58-4.51 (m, 2H), 3.98 (s, 3H), 3.68-3.64 (m, 2H), 3.31 (d, J = 1.4 Hz, 1H), 2.10 (ddd, J = 14.2, 7.6, 3.4 Hz, 1H), 1.63-1.51 (m, 1H), 1.42-1.36 (m, 2H), 0.96 (s, 3H), 0.48 (s, 3H) ppm; 13 C NMR (101 MHz, CDCl3) δ 189.3, 150.9, 143.6, 136.4, 125.0, 120.1, 114.0, 86.1, 70.1, 66.1, 56.5, 45.3, 42.5, 35.1, 31.9, 29.7, 24.3, 22.1 ppm.

[0087] The structural formulas of the compounds 4,4-dimethyl-2-cyclohexen-1-one, 3-hydroxy-4-methoxybenzaldehyde and compounds I-IX described in this example are shown in Figure 2 .

[0088] In conclusion, the application discloses a new method for preparing an aryl abietane diterpene Plebein C intermediate, which specifically comprises the following steps: substituting 4, 4-dimethyl-2-cyclohexen-1-one at an alpha position of a carbonyl group to obtain compound I; protecting the compound I by TBS to obtain compound II; performing Luche reduction reaction on the compound II to obtain compound III; performing 2-position iodination on 3-hydroxy-4-methoxybenzaldehyde to obtain compound IV; performing Wittig reaction on the compound IV to obtain compound V; performing Mitsunobu reaction between the compound III and the compound V to obtain compound VI; performing a key radical cyclization reaction on the compound VI to obtain compound VII; performing benzyl oxidation on the compound VII to obtain compound VIII; and performing oxidation and then closing a lactone ring on the compound VIII to obtain a five-ring intermediate compound IX of a Plebein C molecule. The preparation method has the advantages of simple synthesis route, low-cost and easily-obtained reagents and high yield, is very favorable for mass preparation of the aryl abietane diterpene Plebein C intermediate, and is convenient for mass production of the Plebein C series molecules and further research on biological activities. Meanwhile, the convergent and serial high-efficiency chemical reaction method is applicable to industrial preparation and has strong popularization potential.

[0089] Finally, it should be noted that the terms "comprising", "including", or any other variant thereof are intended to cover non-exclusive inclusions, such that processes, methods, articles, or apparatuses that comprise a list of elements are not limited to those elements, but can also include other elements not expressly listed, or inherent to such processes, methods, articles, or apparatuses.

[0090] Although preferred embodiments of the application have been described, those skilled in the art will be able to make additional changes and modifications without departing from the spirit and scope of the application. Therefore, the appended claims are intended to cover all such changes and modifications that fall within the scope of the application.

[0091] Obviously, those skilled in the art can make various modifications and variations to the application without departing from the spirit and scope of the application. Thus, if these modifications and variations of the application fall within the scope of the claims of the application and equivalent technologies thereof, the application is also intended to include these modifications and variations.

Claims

1. A novel process for the preparation of arylabein C intermediate characterized in that, The reaction process route of the method is as follows: The synthesis method comprises steps 1 to 9: Specifically, step 1: compound 4,4-dimethyl-2-cyclohexen-1-one is used as a raw material, and 4-dimethylaminopyridine and aqueous formaldehyde are reacted at room temperature to obtain compound I; Step 2: compound I is reacted with 4-dimethylaminopyridine, tert-butyl dimethylchlorosilane and pyridine at room temperature to obtain compound II; Step 3: Luche reduction reaction of compound II and cerium trichloride heptahydrate with sodium borohydride to obtain compound III; Step 4: compound 3-hydroxy-4-methoxybenzaldehyde is used as a raw material, and 1,4-dioxane-soluble iodine monochloride is reacted at room temperature in the dark to obtain compound IV; Step 5: Wittig reaction of compound IV with methyl triphenylphosphonium bromide and sodium bis(trimethylsilyl)amide to obtain V; Step 6: Mitsunobu reaction of compound III and compound V with triphenylphosphine and diisopropyl azodicarboxylate to obtain VI; Step 7: treatment of compound VI with tris(trimethylsilyl)silane and triethylboron in deoxymethylbenzene to obtain compound VII; Step 8: benzyl oxidation reaction of compound VII with chromium trioxide and 3,5-dimethylpyrazole to obtain compound VIII; Step 9: oxidation of compound VIII with selenium dioxide to obtain compound IX, which is an intermediate of the aryl abietane diterpene Plebein C.

2. A novel method for preparing the aryl rosinane diterpene Plebein C intermediate as described in claim 1, characterized in that, The structural formulas of the compound 4,4-dimethyl-2-cyclohexen-1-one, 3-hydroxy-4-methoxybenzaldehyde and compounds I-IX are as follows:

3. A novel method for preparing the aryl rosinane diterpene Plebein C intermediate as described in claim 1, characterized in that, The specific synthesis method of step 1 is as follows: Compound 4,4-dimethyl-2-cyclohexen-1-one is used as a raw material, and 4-dimethylaminopyridine and aqueous formaldehyde are reacted at room temperature to obtain compound I, which specifically comprises: At room temperature, 4-dimethylaminopyridine is added to a reaction bottle, and argon atmosphere is added to the reaction bottle. Solvent tetrahydrofuran, raw material 4,4-dimethyl-2-cyclohexen-1-one and aqueous formaldehyde are added to the reaction bottle, and stirred at room temperature for 24 hours under normal pressure. After the reaction is completed, 1N HCl is added to quench the reaction at room temperature, and extracted with dichloromethane. After washing with saturated brine, drying with anhydrous sodium sulfate, concentrating under reduced pressure and purifying by column chromatography, the eluent is petroleum ether: ethyl acetate = 3:1, and compound I is obtained. The molar ratio of 4,4-dimethyl-2-cyclohexen-1-one, 4-dimethylaminopyridine and aqueous formaldehyde is 100:55:

300.

4. A novel method for preparing the aryl rosinane diterpene Plebein C intermediate as described in claim 1, characterized in that, The specific synthesis method of step 2 is as follows: Compound I is reacted with 4-dimethylaminopyridine, tert-butyl dimethylchlorosilane and pyridine at room temperature to obtain compound II, which specifically comprises: The 4-dimethylaminopyridine and tert-butyl dimethyl chlorosilane are added into a reaction bottle at room temperature, the solvent dichloromethane and pyridine are added under an argon atmosphere at 0 ℃, and then the compound I dissolved in dichloromethane is added after stirring at 0 ℃ for 5 minutes, and then the stirring is continued at 0 ℃ for 30 minutes, and then the reaction is continued at room temperature for 2 hours under normal pressure; after the reaction is completed, the saturated ammonium chloride solution is added at 0 ℃ for quenching, and then the extraction is carried out with ethyl acetate, and then the washing is carried out with saturated brine, and then the drying is carried out with anhydrous sodium sulfate, and then the concentration is carried out under reduced pressure, and then the separation and purification are carried out through column chromatography, and then the eluent volume ratio of petroleum ether to ethyl acetate is 20:1, so that the compound II is obtained. The molar ratio of the compound I, 4-dimethylaminopyridine, tert-butyl dimethyl chlorosilane and pyridine is 82.7:24.8:165.3:206.

6.

5. A novel method for preparing the aryl rosinane diterpene Plebein C intermediate as described in claim 1, characterized in that, The specific synthesis method of the step three is as follows: The Luche reduction reaction of the compound II and cerium trichloride heptahydrate with sodium borohydride at 0 ℃ obtains the compound III, and the specific process includes: The compound II, cerium trichloride heptahydrate and the solvent methanol are added into a reaction bottle at room temperature, and then the sodium borohydride is added in three batches at 0 ℃, and then the stirring is continued at 0 ℃ for 10 minutes after the addition of the sodium borohydride is completed each time, and then the reaction is carried out under normal pressure; after the reaction is completed, the ice water is added for quenching, and then the extraction is carried out with ethyl acetate, and then the washing is carried out with saturated brine, and then the drying is carried out with anhydrous sodium sulfate, and then the concentration is carried out under reduced pressure, and then the separation and purification are carried out through column chromatography, and then the eluent volume ratio of petroleum ether to ethyl acetate is 20:1, so that the compound III is obtained. The molar ratio of the compound II, cerium trichloride heptahydrate and sodium borohydride is 41.8:41.8:

25.

6. A novel method for preparing the arylrosinane diterpene Plebein C intermediate as described in claim 1, characterized in that, The specific synthesis method of the step four is as follows: The compound 3-hydroxy-4-methoxybenzaldehyde is used as a raw material, and the reaction is carried out with iodine monochloride dissolved in 1,4-dioxane in pyridine at room temperature in the dark, so that the compound IV is obtained, and the specific process includes: The 3-hydroxy-4-methoxybenzaldehyde is added into a reaction bottle, and then the solvent pyridine is added under an argon atmosphere at 0 ℃, and then the iodine monochloride dissolved in 1,4-dioxane is added, and then the reaction is carried out at room temperature in the dark for 6 days under normal pressure; after the reaction is completed, the solvent is removed through concentration under reduced pressure, and then the water and HCl are added to adjust the PH to 1, and then the extraction is carried out with ethyl acetate, and then the washing is carried out with saturated brine, and then the drying is carried out with anhydrous magnesium sulfate, and then the concentration is carried out under reduced pressure, so that the compound IV is obtained. The molar ratio of the 3-hydroxy-4-methoxybenzaldehyde and iodine monochloride is 120:

156.

7. A novel method for preparing the arylrosinane diterpene Plebein C intermediate as described in claim 1, characterized in that, The specific synthesis method of the step five is as follows: The Wittig reaction of the compound IV with methyl triphenyl phosphonium bromide and sodium bis(trimethylsilyl)amide obtains V, and the specific process includes: The methyl triphenyl phosphonium bromide is added into a reaction bottle at room temperature, and then the solvent tetrahydrofuran is added under an argon atmosphere at 0 ℃, and then the sodium bis(trimethylsilyl)amide is added at 0 ℃, and then the stirring is continued at 0 ℃ for 30 minutes, and then the compound IV dissolved in tetrahydrofuran is added at room temperature, and then the reaction is carried out at room temperature for 30 minutes under normal pressure; after the reaction is completed, the saturated ammonium chloride solution is added for quenching, and then the extraction is carried out with ethyl acetate, and then the washing is carried out with saturated brine, and then the drying is carried out with anhydrous magnesium sulfate, and then the concentration is carried out under reduced pressure, and then the separation and purification are carried out through column chromatography, and then the eluent volume ratio of petroleum ether to ethyl acetate is 5:1-3:1, so that the compound V is obtained. The molar ratio of the compound IV, methyl triphenyl phosphonium bromide, sodium bis(trimethylsilyl)amide is: 72: 172.8: 158.

4.

8. A novel method for preparing the aryl rosinane diterpene Plebein C intermediate as described in claim 1, characterized in that, The specific synthesis method of the step six is: The compound III and the compound V are subjected to Mitsunobu reaction with triphenyl phosphine and diisopropyl azodicarboxylate to obtain VI, and the specific method includes: The compound III, the compound V and triphenyl phosphine are added into a reaction bottle at room temperature, and tetrahydrofuran is added in an argon atmosphere; after stirring for 10 minutes at room temperature, diisopropyl azodicarboxylate is added at 0 degree Celsius, and reaction is carried out at room temperature for 3 hours under normal pressure; after the reaction is completed, the reaction is quenched with ice water, extracted with ethyl acetate, washed with saturated brine, dried with anhydrous magnesium sulfate, concentrated under reduced pressure, and then separated and purified by column chromatography; the eluent volume ratio is petroleum ether: ethyl acetate = 20:1 to 10:1, and the compound VI can be obtained; The molar ratio of the compound III, the compound V, triphenyl phosphine and diisopropyl azodicarboxylate is: 51.2: 56.3: 58.8: 58.

8.

9. A novel method for preparing the arylrosinane diterpene Plebein C intermediate as described in claim 1, characterized in that, The specific synthesis method of the step seven is: The compound VI is treated with tri(trimethylsilyl)silane and triethyl boron in deoxotoluene to obtain the compound VII, and the specific method includes: The compound VI, tri(trimethylsilyl)silane and triethyl boron are added into a reaction bottle at room temperature, and deoxotoluene is added in an argon atmosphere; after being heated to 85 degrees Celsius, reaction is carried out for 5 hours under normal pressure; after the reaction is completed, toluene is removed by concentration under reduced pressure; ethyl acetate is used for extraction, and the obtained mixture is washed with water and saturated brine; the mixture is dried with anhydrous sodium sulfate, concentrated under reduced pressure, and then separated and purified by column chromatography; the eluent volume ratio is petroleum ether: ethyl acetate = 40:1 to 30:1, and the compound VII can be obtained; The molar ratio of the compound VI, tri(trimethylsilyl)silane and triethyl boron is: 26: 52: 6.

5. The specific synthesis method of the step eight is: The compound VII is subjected to benzyl oxidation reaction with chromium trioxide and 3,5-dimethylpyrazole at minus 15 degrees Celsius to obtain the compound VIII, and the specific method includes: The compound VII, tri(trimethylsilyl)silane and triethyl boron are added into a reaction bottle at room temperature, and deoxotoluene is added in an argon atmosphere; after being heated to 85 degrees Celsius, reaction is carried out for 5 hours under normal pressure; after the reaction is completed, toluene is removed by concentration under reduced pressure; ethyl acetate is used for extraction, and the obtained mixture is washed with water and saturated brine; the mixture is dried with anhydrous sodium sulfate, concentrated under reduced pressure, and then separated and purified by column chromatography; the eluent volume ratio is petroleum ether: ethyl acetate = 40:1 to 30:1, and the compound VII can be obtained; The molar ratio of the compound VII, chromium trioxide and 3,5-dimethylpyrazole is: 5: 40:

40.

10. A novel method for preparing the arylrosinane diterpene Plebein C intermediate as described in claim 1, characterized in that, The specific synthesis method of the step nine is: The compound VIII is treated in selenium dioxide to obtain the compound IX: The specific method includes: At normal temperature, compound VIII and selenium dioxide are added into a reaction bottle, acetic acid and water mixed solvent is added at normal temperature, reaction is carried out at 110 degrees Celsius for 2 hours under normal pressure; after the reaction is completed, the reaction bottle is cooled to normal temperature, diluted with ethyl acetate, saturated sodium bicarbonate solution is added for quenching, extracted with ethyl acetate, washed with saturated brine, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and then separated and purified by column chromatography to obtain compound IX, wherein the eluent volume ratio is petroleum ether: ethyl acetate = 5:

1. The molar ratio of the compound VIII to selenium dioxide is 0.2:1.

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