阅读说明：本技术 一种合成光甘草定的方法 (Method for synthesizing glabridin ) 是由 古国贤 李明凯 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甘草定的方法。该方法利用2,4-二甲氧基溴苯和丙二酸二乙酯为起始原料,通过碘化亚铜催化偶联反应、还原反应、溴代反应制得关键中间体化合物Ⅲ,再通过亲核取代和傅克反应制得甲基保护的光甘草定,脱除甲基后得到光甘草定。本发明为一种原料廉价易得,总收率高的合成光甘草定的方法。(The invention relates to a method for synthesizing glabridin. The method uses 2, 4-dimethoxy bromobenzene and diethyl malonate as starting materials, a key intermediate compound III is prepared through cuprous iodide catalytic coupling reaction, reduction reaction and bromination reaction, methyl-protected glabridin is prepared through nucleophilic substitution and Friedel-crafts reaction, and the glabridin is obtained after methyl is removed. The invention relates to a method for synthesizing glabridin, which has cheap and easily obtained raw materials and high total yield.)

1. A method for synthesizing glabridin, which is characterized by comprising the following steps:

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

wherein the mass of the first solvent is 2-8 times of that of the 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-dimethoxybromobenzene is 1: 25-1: 5; the molar ratio of the alkali to the 2, 4-dimethoxybromobenzene 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) adding a compound II, N-bromosuccinimide and triphenylphosphine into dichloromethane at 0 ℃, and reacting the mixture at 20-50 ℃ for 3-6 hours to obtain a compound III;

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

(4) reacting the second solvent, the compound III, the compound VII and potassium carbonate at the temperature of 20-70 ℃ for 8-16 hours to obtain a compound IV;

wherein the mass of the second solvent is 2-8 times of that of the compound III; the molar ratio of the compound VII to the compound III is 1: 1; the molar ratio of the potassium carbonate to the compound III is 1: 1-3: 1;

the compound VII is 2, 2-dimethyl-dihydro-5-naphthol;

(5) reacting the third solvent, the compound IV and the second catalyst at 25-70 ℃ for 8-16 hours to obtain a compound V;

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

(6) in the nitrogen atmosphere, dichloromethane, a compound V and boron tribromide react for 0.5-3 hours at the temperature of-5 ℃ to obtain a compound VI, namely racemic glabridin;

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

2. The method for synthesizing glabridin according to claim 1, wherein said first solvent is methyl t-butyl ether, 1, 4-dioxane or tetrahydrofuran; the second solvent is N, N-dimethylformamide or dimethyl sulfoxide, and the third solvent is dichloromethane, 1, 2-dichloroethane, nitromethane or nitroethane.

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

4. The method for synthesizing glabridin according to claim 1, wherein said base is potassium carbonate, cesium carbonate or potassium phosphate.

Technical Field

The invention belongs to the field of organic synthesis and fine chemicals, and particularly relates to a method for synthesizing 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 and the like, 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 that the total yield of the method for preparing the racemic glabridin by using resorcinol as a raw material through 10 steps of reaction is only 14%; in 2018, patent document CN109232603A 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 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, with a total yield of 30%, although optically pure glabridin can be prepared by the method, the starting material 7-hydroxychroman-4-one is not a large amount of chemical products 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 glabridin aiming at the defects in the prior art. The method uses 2, 4-dimethoxy bromobenzene and diethyl malonate as starting materials, a key intermediate compound III is prepared through cuprous iodide catalytic coupling reaction, reduction reaction and bromination reaction, methyl-protected glabridin is prepared through nucleophilic substitution and Friedel-crafts reaction, and the glabridin is obtained after methyl is removed. 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 glabridin comprises the following steps:

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

wherein the mass of the first solvent is 2-8 times of that of the 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-dimethoxybromobenzene is 1: 25-1: 5; the molar ratio of the alkali to the 2, 4-dimethoxybromobenzene 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 alkali is potassium carbonate, cesium 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) adding a compound II, N-bromosuccinimide and triphenylphosphine into dichloromethane at 0 ℃, and reacting the mixture at 20-50 ℃ for 3-6 hours to obtain a compound III;

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

(4) reacting the second solvent, the compound III, the compound VII and potassium carbonate at the temperature of 20-70 ℃ for 8-16 hours to obtain a compound IV;

the second solvent is N, N-dimethylformamide or dimethyl sulfoxide, and the mass of the second solvent is 2-8 times that of the compound III; the molar ratio of the compound VII to the compound III is 1: 1; the molar ratio of the potassium carbonate to the compound III is 1: 1-3: 1;

the compound VII is 2, 2-dimethyl-dihydro-5-naphthol;

(5) reacting the third solvent, the compound IV and the second catalyst at 25-70 ℃ for 8-16 hours to obtain a compound V;

wherein the mass of the third solvent is 2-8 times of that of the compound V; the molar ratio of the second catalyst to the compound IV is 1: 100-1: 5;

the second catalyst is aluminum trichloride or ferric trichloride; the third solvent is dichloromethane, 1, 2-dichloroethane, nitromethane or nitroethane;

(6) and (3) in a nitrogen atmosphere, reacting dichloromethane, the compound V and boron tribromide for 0.5-3 hours at the temperature of-5 ℃ to obtain a compound VI, namely racemic glabridin.

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

The invention has the substantive characteristics that:

the invention provides a method for synthesizing glabridin, which is different from the method reported in the literature, and the glabridin can be prepared by taking 2, 4-dimethoxy bromobenzene and diethyl malonate as starting raw materials and carrying out six-step chemical reaction.

The invention has the beneficial effects that:

1. the invention provides a method for synthesizing glabridin by using cheap and easily-obtained 2, 4-dimethoxybromobenzene and diethyl malonate as starting raw materials, wherein the preparation cost of each kilogram of glabridin is about 1.3 ten thousand yuan, which is far lower than the production cost of the method provided by patent document CN 109232603A;

2. the method has high reaction yield, and the total yield of the six steps is 55 percent;

3. 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 until a large amount of solid was precipitated, and filtered to obtain 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) 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 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 (125 g, 0.59 mol) was dissolved in dichloromethane (875 ml), triphenylphosphine (340 g, 1.3 mol) and N-bromosuccinimide (231 g, 1.3 mol) were added in sequence, stirred at room temperature for 4.5 hours, filtered and concentrated to give compound iii (162 g, yield 81%, yellow oil).¹H NMR(CDCl₃,400MHz)：δ7.08(d,1H,J＝7.2Hz,Ar-H),6.60-6.44(m,2H,Ar-H),3.82-3.78(m,8H,OMe+CH₂Br),3.73(dd,J＝10.3,6.3Hz,2H,CH₂Br),3.39(m,1H,PhCH).HRMS:m/z:[M+H]⁺calcd.for C₁₁H₁₅Br₂O₂ ⁺,336.9428.Found,336.9433.

4. Synthesis of Compound IV:

compound iii (160 g, 0.47 mol) and compound vii (83 g, 0.47 mol) were dissolved in N, N-dimethylformamide (0.8 l), potassium carbonate (65 g, 0.47 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 (4.0 l), extracted with methyl tert-butyl ether (300 ml × 3), the organic phases were combined, washed with saturated brine (150 ml × 1), and concentrated to give compound iv (203 g, 100% yield, white solid, m.p. 88-90 ℃).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),3.82-3.78(m,8H,OMe+CH₂Br),3.70(dd,J＝10.3,6.3Hz,2H,OCH₂),3.39(m,1H,Ar-CH),1.59(s,6H,CH₃).HRMS:m/z:[M+H]⁺calcd.for C₂₂H₂₆BrO₄ ⁺,433.1006.Found,433.1009.

The compound VII is 2, 2-dimethyl-dihydro-5-naphthol, cas:6537-43-5, and is prepared according to a literature method (Molecules2013,18, 11485-11495).

5. Synthesis of Compound V:

compound IV (200 g, 0.46 mol) was dissolved in 1, 2-dichloroethane (1.0L), ferric trichloride (3 g, 0.02 mol) was added, and the mixture was stirred at 50 ℃ for 16 hours with complete consumption of starting material by TLC. The reaction was slowly poured into cold 1M dilute hydrochloric acid (1.0L), stirred for 0.5 h, separated, the aqueous phase extracted with 1, 2-dichloroethane (150 mL. times.3), the organic phases combined, washed with saturated brine (150 mL. times.1), and the organic phase concentrated to give Compound V (118 g, 73% yield, white solid, mp 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.

6. Synthesis of Compound VI:

in nitrogen atmosphere, dissolving compound V (118 g, 0.33 mol) in dichloromethane (600 ml), cooling to 0 ℃, dropwise adding boron tribromide (499 g, 2 mol), stirring for 1.5 hours, detecting the complete consumption of raw materials by TLC, dropwise adding methanol (192 g, 6.0 mol) into the reaction system, stirring for 0.5 hours, and concentrating to obtain compound VI (107 g, yield 100%, white solid, melting point 155-.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, tetrahydrofuran is substituted by 1, 4-dioxane; replacement of cesium carbonate with potassium carbonate; in step 4, replacing N, N-dimethylformamide with dimethyl sulfoxide; in step 5, ferric trichloride is replaced by aluminum trichloride.

Example 3

The other steps were the same as in example 1 except that in step 5, dichloromethane was replaced with nitromethane.

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.