阅读说明：本技术 一种合成光学纯光甘草定的方法 (Method for synthesizing optically pure glabridin ) 是由 古国贤 王英明 韩恩山 章文军 何艳贞 刘洁翔 朱令之 李小菊 王瑞虎 于 2021-09-03 设计创作，主要内容包括：本发明为一种合成光学纯光甘草定的方法。该方法通过生物酶催化构建光学纯光甘草定的手性碳,结合有机合成方法制备了光学纯光甘草定,其关键步骤在于利用脂肪酶催化化合物Ⅱ生成手性中间体化合物Ⅲ,再经过溴代反应得到重要中间体化合物Ⅳ。本发明为一种原料廉价易得,总收率高的合成光学纯光甘草定的方法。(The invention relates to a method for synthesizing optically pure glabridin. The method comprises the steps of constructing chiral carbon of optically pure glabridin by biological enzyme catalysis, preparing the optically pure glabridin by combining an organic synthesis method, catalyzing a compound II by using lipase to generate a chiral intermediate compound III, and performing bromination reaction to obtain an important intermediate compound IV. The invention relates to a method for synthesizing optically pure glabridin with cheap and easily obtained raw materials and high total yield.)

1. A method for synthesizing optically pure glabridin is characterized in that the method comprises the following steps:

(1) reacting a first solvent, 2, 4-dimethoxy bromobenzene, diethyl malonate, a first catalyst, 2-picolinic acid and a first alkali at 20-120 ℃ for 3-20 hours in an argon atmosphere to obtain a compound I;

wherein the mass of the solvent is 2-8 times of that of 2, 4-dimethoxy bromobenzene; the molar ratio of diethyl malonate to 2, 4-dimethoxy bromobenzene is 1: 1-2: 1; the molar ratio of the first catalyst to the 2, 4-dimethoxybromobenzene is 1: 50-1: 10; the molar ratio of the 2-picolinic acid to the 2, 4-dimethoxy bromobenzene is 1: 25-1: 5; the molar ratio of the first alkali to the 2, 4-dimethoxy bromobenzene is 1: 1-5: 1;

(2) adding lithium aluminum hydride into a tetrahydrofuran solution of the compound I, and stirring at room temperature to obtain a compound II;

wherein the molar ratio of the lithium aluminum hydride to the compound I is 1: 1-4: 1; the mass of the tetrahydrofuran is 2-8 times of that of the compound I;

(3) reacting the second solvent, the compound II, an acetylation reagent and lipase at 20-90 ℃ for 0.5-3 hours to obtain a compound III;

wherein the ratio of water to any one of acetonitrile, N-dimethylformamide and dimethyl sulfoxide is 0: 1-1: 1; the dosage of the second solvent is 5-75 ml per gram of the compound II; the molar ratio of the acetylation reagent to the compound II is 1: 1-1: 5, and the mass ratio of the lipase to the compound II is 1: 50-1: 500;

(4) adding a compound III, N-bromosuccinimide and triphenylphosphine into dichloromethane at 0 ℃, and reacting the mixture at 20-50 ℃ for 3-6 hours to obtain a compound IV;

wherein the molar ratio of the N-bromosuccinimide to the compound III is 1: 1-10: 1; the molar ratio of triphenylphosphine to the compound III is 1: 1-10: 1; the mass of the dichloromethane is 2-8 times that of the compound II;

(5) reacting the third solvent, the compound IV, the compound V and potassium carbonate at the temperature of 20-70 ℃ for 8-16 hours to obtain a compound VI;

wherein the mass of the third solvent is 2-8 times of that of the compound III;

the compound V is 2, 2-dimethyl-dihydro-5-naphthol; the molar ratio of the compound V to the compound IV is 1: 1-2: 1;

(6) reacting the fourth solvent, the compound VI and the second alkali at 0-90 ℃ for 3-16 hours to obtain a compound VII;

wherein the mass of the fourth solvent is 2-8 times of that of the compound VI; the molar ratio of the second alkali to the compound VI is 1: 50-1: 5;

(7) adding the compound VII, N-bromosuccinimide and triphenylphosphine into dichloromethane at 0 ℃, and reacting the mixture at 20-50 ℃ for 3-6 hours to obtain a compound VIII;

wherein the molar ratio of the N-bromosuccinimide to the compound VII is 1: 1-10: 1; the molar ratio of the triphenylphosphine to the compound VII is 1: 1-10: 1; the mass of the dichloromethane is 2-8 times that of the compound II;

(8) reacting the fifth solvent, the compound VIII and a catalyst at the temperature of 25-70 ℃ for 8-16 hours to obtain a compound IX;

wherein the mass of the fifth solvent is 2-8 times of that of the compound VIII; the molar ratio of the catalyst to the compound VIII is 1: 100-1: 5;

(9) in a nitrogen atmosphere, dichloromethane is used as a solvent, and a compound IX and boron tribromide react for 0.5-3 hours at the temperature of-5 ℃ to obtain a compound X, namely (R) -euphorbia helioscopine.

Wherein the mass of the dichloromethane is 2-8 times of that of the compound IX; the molar ratio of boron tribromide to IX compound is 3: 1-10: 1.

2. The method of synthesizing optically pure glabridin according to claim 1, wherein said first solvent is methyl t-butyl ether, 1, 4-dioxane or tetrahydrofuran;

the second solvent is acetonitrile, N-dimethylformamide or dimethyl sulfoxide;

the third solvent is N, N-dimethylformamide or dimethyl sulfoxide;

the fourth solvent is one of methanol, ethanol, N-dimethylformamide, dimethyl sulfoxide and acetonitrile, or a mixed solution of one of the methanol, the ethanol, the N, N-dimethylformamide and the dimethyl sulfoxide and water;

the fifth solvent is dichloromethane, 1, 2-dichloroethane, nitromethane or nitroethane.

3. The method of synthesizing optically pure glabridin according to claim 1, wherein said first catalyst is cuprous iodide; the second catalyst is aluminum trichloride or ferric trichloride.

4. The method of synthesizing optically pure glabridin according to claim 1, wherein said first base is cesium carbonate, potassium carbonate or potassium phosphate;

the second alkali is potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide or lithium hydroxide.

5. The method of synthesizing optically pure glabridin according to claim 1, wherein said acetylating agent is vinyl acetate or acetic anhydride.

6. The method of synthesizing optically pure glabridin according to claim 1, wherein said lipase is a fungal lipase or a bacterial lipase.

Technical Field

The invention belongs to the field of organic synthesis and fine chemicals, and particularly relates to a synthesis method of optically pure glabridin.

Background

Glabradine (Glabridin) is a flavonoid substance, has the effects of whitening, resisting bacteria, allergy, cancer, oxidation and spasm, diminishing inflammation, protecting the liver, removing free radicals, reducing blood fat and lowering blood pressure, is more and more highly valued in the research and application fields of international beauty treatment, cosmetics, medicines, health care and the like, and shows good development prospect (Wang Xudong et al, fine chemical intermediates, 2021,51(3), 6-9.). At present, the obtaining way of glabridin in China is mainly to extract from a precious plant of glabrous licorice, and the glabrous licorice cannot be obtained in large quantity, but the glabrous licorice mainly grows in the south of Tianshan in China, and the harvesting of the glabrous licorice is limited along with the implementation of the policy of sand prevention and sand fixation in China, so that the development of an effective chemical synthesis method for preparing the glabridin becomes more important.

2013, Wenhua et al (Synthetic Communications,2014,44,540-546) reported a method for preparing racemic glabridin by 10 steps of reaction with resorcinol as a raw material, wherein the total yield is only 14%; in 2018, patent document CN 109232603a discloses a method for preparing racemic glabridin by using 7-hydroxycoumarin as a starting material through 8 steps of reaction, wherein the total yield is only 20%, the key step is Suzuki coupling reaction, and the price of a required boric acid reagent and a metal palladium catalyst is high; in 2018, patent document CN 108440553a discloses a method for preparing optically pure glabridin by using a metal ruthenium catalytic isoflavone intermediate, but the patent does not give a detailed synthesis method of the isoflavone intermediate; in 2020, patent document CN 111362961a discloses a method for preparing R-configuration glabridin by 7-step reaction using 7-hydroxychroman-4-one as a starting material, wherein the total yield is 30%, the key steps require a noble metal palladium catalyst and a chiral phosphine ligand, and the starting material 7-hydroxychroman-4-one is not a large-volume chemical product and is expensive (>20 ten thousand yuan/kg). How to prepare the glabridin with cheaper raw materials and shorter route with high efficiency still remains a problem which needs to be solved at present.

Disclosure of Invention

The invention aims to provide a method for synthesizing optically pure glabridin, aiming at the defects in the prior art. The method comprises the steps of constructing chiral carbon of optically pure glabridin by biological enzyme catalysis, preparing the optically pure glabridin by combining an organic synthesis method, catalyzing a compound II by using lipase to generate a chiral intermediate compound III, and performing bromination reaction to obtain an important intermediate compound IV. The invention relates to a method for synthesizing glabridin, which has cheap and easily obtained raw materials and high total yield.

The technical scheme of the invention is as follows:

a method for synthesizing optically pure glabridin comprises the following steps:

(1) reacting a first solvent, 2, 4-dimethoxy bromobenzene, diethyl malonate, a first catalyst, 2-picolinic acid and a first alkali at 20-120 ℃ for 3-20 hours in an argon atmosphere to obtain a compound I;

wherein the mass of the solvent is 2-8 times of that of 2, 4-dimethoxy bromobenzene; the molar ratio of diethyl malonate to 2, 4-dimethoxy bromobenzene is 1: 1-2: 1; the molar ratio of the first catalyst to the 2, 4-dimethoxybromobenzene is 1: 50-1: 10; the molar ratio of the 2-picolinic acid to the 2, 4-dimethoxy bromobenzene is 1: 25-1: 5; the molar ratio of the first alkali to the 2, 4-dimethoxy bromobenzene is 1: 1-5: 1;

the first solvent is methyl tert-butyl ether, 1, 4-dioxane or tetrahydrofuran;

the first catalyst is cuprous iodide;

the first alkali is cesium carbonate, potassium carbonate or potassium phosphate;

(2) adding lithium aluminum hydride into a tetrahydrofuran solution of the compound I, and stirring at room temperature to obtain a compound II;

wherein the molar ratio of the lithium aluminum hydride to the compound I is 1: 1-4: 1; the mass of the tetrahydrofuran is 2-8 times of that of the compound I;

(3) reacting the second solvent, the compound II, an acetylation reagent and lipase at 20-90 ℃ for 0.5-3 hours to obtain a compound III;

wherein the ratio of water to any one of acetonitrile, N-dimethylformamide and dimethyl sulfoxide is 0: 1-1: 1; the dosage of the second solvent is 5-75 ml per gram of the compound II; the molar ratio of the acetylation reagent to the compound II is 1: 1-1: 5, and the mass ratio of the lipase to the compound II is 1: 50-1: 500

The acetylation reagent is vinyl acetate or acetic anhydride;

the second solvent is acetonitrile, N-dimethylformamide or dimethyl sulfoxide;

(4) adding a compound III, N-bromosuccinimide and triphenylphosphine into dichloromethane at 0 ℃, and reacting the mixture at 20-50 ℃ for 3-6 hours to obtain a compound IV;

wherein the molar ratio of the N-bromosuccinimide to the compound III is 1: 1-10: 1; the molar ratio of triphenylphosphine to the compound III is 1: 1-10: 1; the mass of the dichloromethane is 2-8 times that of the compound II;

(5) reacting the third solvent, the compound IV, the compound V and potassium carbonate at the temperature of 20-70 ℃ for 8-16 hours to obtain a compound VI;

wherein the mass of the third solvent is 2-8 times of that of the compound III;

the compound V is 2, 2-dimethyl-dihydro-5-naphthol, and the molar ratio of the compound V to the compound IV is 1: 1-2: 1;

the third solvent is N, N-dimethylformamide or dimethyl sulfoxide;

(6) reacting the fourth solvent, the compound VI and the second alkali at 0-90 ℃ for 3-16 hours to obtain a compound VII;

wherein the mass of the fourth solvent is 2-8 times of that of the compound VI; the molar ratio of the second alkali to the compound VI is 1: 50-1: 5;

the second alkali is potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide or lithium hydroxide;

the fourth solvent is one of methanol, ethanol, N-dimethylformamide, dimethyl sulfoxide and acetonitrile, or a mixed solution of one of the methanol, the ethanol, the N, N-dimethylformamide and the dimethyl sulfoxide and water;

(7) adding the compound VII, N-bromosuccinimide and triphenylphosphine into dichloromethane at 0 ℃, and reacting the mixture at 20-50 ℃ for 3-6 hours to obtain a compound VIII;

wherein the molar ratio of the N-bromosuccinimide to the compound VII is 1: 1-10: 1; the molar ratio of the triphenylphosphine to the compound VII is 1: 1-10: 1; the mass of the dichloromethane is 2-8 times that of the compound II;

(8) reacting the fifth solvent, the compound VIII and a catalyst at the temperature of 25-70 ℃ for 8-16 hours to obtain a compound IX;

wherein the mass of the fifth solvent is 2-8 times of that of the compound VIII; the molar ratio of the catalyst to the compound VIII is 1: 100-1: 5;

the second catalyst is aluminum trichloride or ferric trichloride;

the fifth solvent is dichloromethane, 1, 2-dichloroethane, nitromethane or nitroethane;

(9) and in a nitrogen atmosphere, taking dichloromethane as a solvent, and reacting the compound IX with boron tribromide at the temperature of-5 ℃ for 0.5-3 hours to obtain a compound X, namely (R) -glabridin.

Wherein the mass of the dichloromethane is 2-8 times of that of the compound IX; the molar ratio of boron tribromide to IX compound is 3: 1-10: 1.

The invention has the substantive characteristics that:

the invention provides a method for synthesizing optically pure glabridin, which is different from the method reported in the literature, and the optically pure glabridin is prepared by taking 2, 4-dimethoxybromobenzene and diethyl malonate as starting raw materials through nine steps of reaction and 42% of total yield, and the key step is that chiral compound III is prepared by catalyzing achiral compound II with lipase.

The invention has the beneficial effects that:

1. the invention provides a method for preparing optically pure glabridin by combining lipase catalysis and chemical reaction;

2. the starting raw materials used in the invention are 2, 4-dimethoxy bromobenzene and diethyl malonate, and are cheap and easy to obtain;

3. the cost of the (R) -glabridin produced by the method is about 2.2 ten thousand yuan/kg, the cost is greatly reduced, and the method has potential commercial value.

Detailed Description

The reaction equation of the present invention is as follows:

example 1

1. Synthesis of Compound I:

2, 4-dimethoxybromobenzene (200 g, 0.92 mol) was dissolved in 1, 4-dioxane (1 l) under an argon atmosphere, cesium carbonate (330 g, 1.01 mol), cuprous iodide (3.8 g, 0.02 mol), 2-picolinic acid (4.9 g, 0.04 mol) and diethyl malonate (162 g, 1.01 mol) were added in this order, and stirred at 100 ℃ for 16 hours, and the consumption of the starting material was detected by TLC. The reaction solution was poured into ice water (1 l), stirred for 0.5 h, separated, the aqueous phase was extracted with ethyl acetate (200 ml × 3), the organic phases were combined, washed with saturated brine (200 ml × 1), the organic phase was concentrated to give a large amount of solid which was precipitated, and filtered to give compound i (254 g, yield 93%, white solid, m.p. 53-55 ℃).¹H NMR(CDCl₃,400MHz)：δ7.25(1H,br s,Ar-H),6.50(1H,dd,J＝6.6,1.6Hz,Ar-H),6.46(1H,dd,J＝1.6Hz,Ar-H),5.02(1H,s,Ar-CH),4.27-4.17(4H,m,-CH₂CH₃),3.80(3H,s,-OMe),3.79(3H,s,-OMe),1.26(6H,t,J＝5.6Hz,-CH₂CH₃).HRMS:m/z:[M+H]⁺calcd.for C₁₅H₂₁O₆ ⁺,297.1340.Found,297.1333.

2. Synthesis of Compound II:

lithium aluminum hydride (95 g, 2.52 mol) was divided into 5 portions on average, added in portions (1 hour apart for each portion) to a solution of compound i (250 g, 0.84 mol) in tetrahydrofuran (1.25 l), stirred at room temperature for 16 hours, and run-off of starting material was detected by TLC. The reaction was cooled to-5 ℃ and ice water (95 ml), 15% aqueous sodium hydroxide (95 ml) and ice water (285 ml) were added dropwise to the reaction mixture in that order, warmed to room temperature, stirred for 1 hour, filtered and concentrated to give compound ii (178 g, 100% yield, white solid, mp 84-86 ℃).¹H NMR(CDCl₃,400MHz)：δ7.07(d,1H,J＝7.2Hz,Ar-H),6.50-6.43(m,2H,Ar-H),4.05-3.85(m,4H,CH(CH₂OH)₂),3.81(s,3H,-OMe),3.79(s,3H,-OMe),3.50-3.39(m,1H,CH(CH₂OH)₂),2.01(t,2H,J＝6.0Hz,-OH).HRMS:m/z:[M+H]⁺calcd.for C₁₁H₁₇O₄ ⁺,213.1115.Found,213.1121.

3. Synthesis of Compound III:

compound ii (50 g, 0.24 mol) was dissolved in a mixed solvent of acetonitrile (1 l) and water (0.1 l), vinyl acetate (26 g, 0.30 mol) and lipase ((Novozyme 435, 1 g) were added, reacted at 70 ℃ for 0.5 hour, filtered, and concentrated to give a crude product (viscous oil), and column chromatography (ethyl acetate: petroleum ether ═ 1:1) gave pure compound iii (53 g, yield 87%, 98.5% ee, colorless oil).¹H NMR(CDCl₃ 400MHz)：δ7.10(dd,1H,J＝5.5,1.9Hz,Ar-H),6.49-6.43(m,2H,Ar-H),4.38(dd,1H,J＝8.9,4.6Hz,AcOCH₂-),4.34(dd,1H,J＝8.9,4.7Hz,AcOCH₂-),3.83(d,2H,J＝4.7,OHCH₂-),3.80(s,3H,OCH₃),3.79(s,3H,OCH₃),3.50(penta,1H,J＝4.7Hz,Ar-CH),2.04(s,3H,C(O)CH₃),1.90(br,1H,CH₂OH).HRMS:m/z:[M+Na]⁺calcd.for C₁₃H₁₈NaO₅ ⁺,277.1050.Found,277.1046.

4. Synthesis of Compound IV:

compound iii (52 g, 0.2 mol) was dissolved in dichloromethane (260 ml), triphenylphosphine (58 g, 0.22 mol), N-bromosuccinimide (39 g, 0.22 mol) were added in sequence, stirred at room temperature for 4.5 hours, filtered, and concentrated to give compound iv (52 g, 82% yield, 98.2% ee, yellow oil).¹H NMR(CDCl₃,400MHz)：δ7.32(dd,1H,J＝5.5,1.9Hz,Ar-H),6.58-6.53(m,2H,Ar-H),4.47(dd,1H,J＝8.9,4.6Hz,AcOCH₂-),4.22(dd,1H,J＝8.9,4.7Hz,AcOCH₂-),3.80(s,3H,OCH₃),3.79(s,3H,OCH₃),3.70(dd,1H,J＝8.9,4.7Hz,BrCH₂-),3.67(penta,1H,J＝4.7Hz,Ar-CH),3.44(dd,1H,J＝8.9,4.7Hz,BrCH₂-),2.05(s,3H,C(O)CH₃).HRMS:m/z:[M+Na]⁺calcd.for C₁₃H₁₇BrNaO₄ ⁺,339.0196.Found,339.0202.

5. Synthesis of Compound VI:

compound iv (51 g, 0.16 mol) and compound v (29 g, 0.16 mol) were dissolved in N, N-dimethylformamide (260 ml), potassium carbonate (22 g, 0.16 mol) was added, stirred at room temperature for 16 hours, TLC checked for complete consumption of starting material, the reaction solution was poured into ice water (1.5 l), extracted with methyl tert-butyl ether (100 ml × 3), the organic phases were combined, washed with saturated brine (50 ml × 1), and concentrated to give compound vi (66 g, 100% yield, 98.0% ee, white solid, m.p. 87-89 ℃).¹H NMR(CDCl₃,400MHz)：δ7.13(m,1H,Ar-H),7.08(d,1H,J＝7.2Hz,Ar-H),6.86(m,1H,Ar-H),6.60-6.44(m,3H,Ar-H),6.31(d,1H,J＝8.9Hz),5.91(d,1H,J＝9.1Hz),4.47(dd,1H,J＝8.9,4.7Hz,AcOCH₂-),4.34(dd,1H,J＝8.9,4.7Hz,ArOCH₂-),4.22(dd,1H,J＝8.9,4.7Hz,AcOCH₂-),4.09(dd,1H,J＝8.9,4.7Hz,ArOCH₂-),3.84(s,3H,OMe),3.72(s,3H,OMe),3.70(dd,J＝10.3,6.3Hz,2H,OCH₂),3.39(m,1H,Ar-CH),2.04(s,3H,C(O)CH₃),1.59(s,6H,CH₃).HRMS:m/z:[M+H]⁺calcd.For C₂₄H₂₉O₆ ⁺,413.1955.Found,413.1959.

The compound V is 2, 2-dimethyl-dihydro-5-naphthol, cas:6537-43-5, which is prepared by synthesis according to a Wen method (Molecules 2013,18, 11485-11495);

6. synthesis of compound vii:

compound VI (65 g, 0.16 mol) was dissolved in methanol (320 ml), potassium hydroxide (1.1 g, 0.02 mol) was added and reacted at 70 ℃ for 16 hours, TLC checked for complete consumption of starting material, concentrated and dissolved in dichloromethane (300 ml), washed successively with water (50 ml. times.3) and saturated ammonium chloride (50 ml. times.1), and the dichloromethane phase was concentrated to give compound VII (58 g, 98% yield, 97.8% ee, white solid, m.p. 85-88 ℃).¹H NMR(CDCl₃,400MHz)：δ7.13(m,1H,Ar-H),7.08(d,1H,J＝7.2Hz,Ar-H),6.86(m,1H,Ar-H),6.60-6.44(m,3H,Ar-H),6.31(d,1H,J＝8.9Hz),5.91(d,1H,J＝9.1Hz),4.33(dd,1H,J＝8.9,4.7Hz,ArOCH₂-),4.08(dd,1H,J＝8.9,4.7Hz,ArOCH₂-),3.83(s,3H,OMe),3.75(s,3H,OMe),3.71-3.58(m,2H,HOCH₂-),3.39(m,1H,Ar-CH),2.01(t,1H,J＝6.0Hz,-OH),1.59(s,6H,CH₃).HRMS:m/z:[M+H]⁺calcd.For C₂₂H₂₇O₅ ⁺,371.1863.Found,371.1853.

7. Synthesis of compound viii:

compound vii (56 g, 0.15 mol) was dissolved in dichloromethane (280 ml), triphenylphosphine (45 g, 0.17 mol), N-bromosuccinimide (30 g, 0.17 mol) were added sequentially, stirred at room temperature for 4.5 hours, filtered, and concentrated to give compound viii (60 g, 92% yield, 97.9% ee, white solid, m.p. 88-90 ℃).¹H NMR(CDCl₃,400MHz)：δ7.03(d,1H,J＝5.6Hz,Ar-H),6.82(d,1H,J＝5.6Hz,Ar-H),6.65(d,1H,J＝6.4Hz,Ar-CH＝CH-),6.45-6.48(m,2H,Ar-H),6.36(d,1H,J＝5.2Hz,Ar-H),5.55(d,1H,J＝6.4Hz,Ar-CH＝CH-),4.35(dd,1H,J＝4.8,1.2Hz,-OCH₂),3.97(t,1H,J＝7.2Hz,-OCH₂),3.80(s,3H,-OCH₃),3.79(s,3H,-OCH₃),3.53-3.57(m,1H,Ar-CH),2.96(dd,1H,J＝10.4,7.6Hz,Ar-CH₂-),2.83(dd,1H,J＝10.4,2.0Hz,Ar-CH₂-),1.42(s,3H,CH₃),1.40(s,3H,CH₃).HRMS:m/z:[M+H]⁺calcd.for C₂₂H₂₅O₄ ⁺,353.1755.Found,353.1747.

8. Synthesis of Compound IX:

compound VIII (60 g, 0.14 mol) was dissolved in 1, 2-dichloroethane (300 mL), ferric trichloride (0.5 g, 0.003 mol) was added and stirred at 50 ℃ for 16 hours with complete consumption of starting material by TLC. The reaction solution was slowly poured into cold 1M dilute hydrochloric acid (300 ml), stirred for 0.5 hour, separated, the aqueous phase extracted with 1, 2-dichloroethane (60 ml. times.3), the organic phases combined, washed with saturated brine (60 ml. times.1), the organic phase concentrated to precipitate a solid, and filtered to obtain compound IX (35 g, yield 71%, 97.8% ee, white solid, melting point 98-100 ℃).¹H NMR(CDCl₃,400MHz)：δ7.03(d,1H,J＝5.6Hz,Ar-H),6.82(d,1H,J＝5.6Hz,Ar-H),6.65(d,1H,J＝6.4Hz,Ar-CH＝CH-),6.45-6.48(m,2H,Ar-H),6.36(d,1H,J＝5.2Hz,Ar-H),5.55(d,1H,J＝6.4Hz,Ar-CH＝CH-),4.35(dd,1H,J＝4.8,1.2Hz,-OCH₂),3.97(t,1H,J＝7.2Hz,-OCH₂),3.80(s,3H,-OCH₃),3.79(s,3H,-OCH₃),3.53-3.57(m,1H,Ar-CH),2.96(dd,1H,J＝10.4,7.6Hz,Ar-CH₂-),2.83(dd,1H,J＝10.4,2.0Hz,Ar-CH₂-),1.42(s,3H,CH₃),1.40(s,3H,CH₃).HRMS:m/z:[M+H]⁺calcd.for C₂₂H₂₅O₄ ⁺,353.1755.Found,353.1747.

9. Synthesis of compound x:

dissolving a compound IX (35 g, 0.10 mol) in dichloromethane (200 ml) in a nitrogen atmosphere, cooling to 0 ℃, dropwise adding boron tribromide (150 g, 0.6 mol), stirring for 1 hour, detecting the complete consumption of raw materials by TLC, dropwise adding methanol (58 g, 1.8 mol) into the reaction system, stirring for 0.5 hour, and concentrating to obtain the compound IX, namely (R) -Glaucocalyxin (32 g, yield of 100%, 97.5% ee, white solid, melting point 155 ℃ 157 ℃).¹H NMR(CDCl₃ 400MHz)：δ9.39(s,1H，Ar-OH),9.11(s,1H,Ar-OH),6.86(d,1H,J＝5.2Hz,Ar-H),6.83(d,1H,J＝5.6Hz,Ar-H),6.54(d,1H,J＝6.4Hz,Ar-CH＝CH-),6.33(s,1H,Ar-H),6.29(d,1H,J＝5.6Hz,Ar-H),6.19(d,1H,J＝5.6Hz,Ar-H),5.64(d,1H,J＝6.8Hz,Ar-CH＝CH-),4.23(d,1H,J＝6.8Hz,-OCH₂),3.93(t,1H,J＝6.8Hz,-OCH₂),3.29(t,1H,J＝6.8Hz,Ar-CH),2.89(t,1H,J＝7.6Hz,Ar-CH₂-),2.69(dd,1H,J＝10.8,2.8Hz,Ar-CH₂-),1.76(s,6H,CH₃).HRMS:m/z:[M+Na]⁺calcd.for C₂₀H₂₀NaO₄ ⁺,347.1259.Found,347.1254.

Example 2

The other steps are the same as example 1, except that in step 1, 4-dioxane is replaced by methyl tert-butyl ether;

in step 3, acetonitrile is replaced by N, N-dimethylformamide.

In step 5, replacing N, N-dimethylformamide with dimethyl sulfoxide;

in step 6, methanol is replaced by a mixed solvent of N, N-dimethylformamide and water in a ratio of 0.2:1, and potassium hydroxide is replaced by potassium carbonate;

example 3

The other steps are the same as example 1, except that,

in the step 1, 4-dioxane is replaced by tetrahydrofuran; replacement of cesium carbonate for potassium phosphate;

in the step 3, acetonitrile is replaced by dimethyl sulfoxide, and vinyl acetate is replaced by acetic anhydride;

in step 6, methanol is replaced by ethanol, and potassium hydroxide is replaced by lithium hydroxide.

Example 4

The other steps are the same as example 1, except that,

in the step 8, ferric trichloride is replaced by aluminum trichloride, and the ratio of the aluminum trichloride to the compound VIII is 1: 5.

The above-mentioned embodiments are only preferred embodiments of the present invention, and the description thereof is more specific and detailed, but not to be construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention.

The invention is not the best known technology.