CN-121991017-A - Preparation method of optically pure glabridin

CN121991017ACN 121991017 ACN121991017 ACN 121991017ACN-121991017-A

Abstract

The invention discloses a preparation method of optically pure glabridin. In particular to a preparation method of a compound VII, which comprises the following steps of carrying out a photo-casting reaction on a compound V and a compound VI in a solvent in the presence of a phosphine reagent and an azo reagent to generate the compound VII. The preparation method has the advantages of cheap and easily obtained raw materials, mild reaction conditions and high total yield, and is favorable for realizing industrialization of the optical pure glabridin.

Inventors

LI MIN
WEI YIN
SHI MIN

Assignees

中国科学院上海有机化学研究所
华东理工大学

Dates

Publication Date: 20260508
Application Date: 20241108

Claims (10)

1. A preparation method of a compound VII is characterized by comprising the following steps of carrying out a photo-casting reaction on a compound V and a compound VI in a solvent in the presence of a phosphine reagent and an azo reagent to generate the compound VII; 。
2. The method of claim 1, wherein one or more of the following conditions are satisfied: (1) In the casting reaction, the solvent is selected from one or more of ether solvents, nitrile solvents, halogenated hydrocarbon solvents and aromatic hydrocarbon solvents, such as tetrahydrofuran, methyl tertiary butyl ether, acetonitrile, dichloromethane or toluene, and tetrahydrofuran; (2) In the casting reaction, the molar volume ratio of the compound V to the solvent is (0.1-0.8) mol/L, preferably 0.24 mol/L or 0.3 mol/L; (3) In the light delay reaction, the phosphine reagent is triphenylphosphine; (4) In the casting reaction, the molar ratio of the compound V to the phosphine reagent is 1 (0.8-2), for example 1:1.2 or 1:1.5, preferably 1 (1.1-1.3); (5) In the casting reaction, the azo reagent is diethyl azodicarboxylate or diisopropyl azodicarboxylate, such as diethyl azodicarboxylate; (6) In the casting reaction, the molar ratio of the compound V to the azo reagent is 1 (0.8-2), for example 1:1.2 or 1:1.5, preferably 1 (1.1-1.3); (7) In the casting reaction, the molar ratio of the compound V to the compound VI is 1 (0.8-2), preferably 1:1.1 or 1:1.2; (8) In the casting reaction, the temperature of the reaction is 10-60 o C, for example 25- o C or 50- o C, preferably 20-30- o C; (9) The materials of the photo-delay reaction are the compound V, the phosphine reagent, the compound VI, the azo reagent and the solvent.
3. The process according to claim 1, wherein the process further comprises the step of acetylating compound IV with an acetylating agent in the presence of a lipase in a solvent to produce compound V; ; preferably, it satisfies one or more of the following conditions: (1) In the acetylation reaction, the solvent is an ether solvent, preferably tetrahydrofuran; (2) In the acetylation reaction, the mol volume ratio of the compound IV to the solvent is (0.2-0.8) mol/L, preferably 0.45 mol/L; (3) In the acetylation reaction, the lipase is fungal lipase or bacterial lipase, preferably NoveXin 435 lipase; (4) In the acetylation reaction, the mass ratio of the lipase to the compound IV is 1 (50-500), for example 1 (70-150), and preferably 1:105; (5) In the acetylation reaction, the acetylating agent is vinyl acetate or acetic anhydride, preferably vinyl acetate; (6) In the acetylation reaction, the molar ratio of the compound IV to the acetylation reagent is 1 (0.8-2), for example 1 (1.2-1.5), preferably 1:1.2; (7) The temperature of the acetylation reaction is 20-80 o C, preferably 50- o C.
4. The process according to claim 3, wherein the process for producing compound VII further comprises the step of subjecting compound III, lithium chloride and sodium borohydride to a reduction reaction in a solvent to produce compound IV; ; the molar ratio of the compound III to the lithium chloride is 1 (2.1-5); The solvent is a mixed solvent of ethanol and tetrahydrofuran, wherein the volume ratio of the ethanol to the tetrahydrofuran in the mixed solvent is 1:1; preferably, it satisfies one or more of the following conditions: (1) In the reduction reaction, the molar volume ratio of the compound III to the solvent is (0.05-0.5) mol/L, preferably 0.11 mol/L; (2) In the reduction reaction, the molar ratio of the compound III to the lithium chloride is 1:3; (3) In the reduction reaction, the molar ratio of the compound III to the sodium borohydride is 1 (3-9), preferably 1:6; (4) The temperature of the reduction reaction is 10-40 o C, preferably 25- o C.
5. The process according to claim 4, wherein the process for producing compound VII further comprises the step of subjecting compound II to substitution reaction with diethyl malonate in the presence of an alkaline agent, a catalyst and 2-picolinic acid in a solvent to produce compound III; ; preferably, it satisfies one or more of the following conditions: (1) In the substitution reaction, the solvent is an ether solvent, preferably 1, 4-dioxane; (2) In the substitution reaction, the molar volume ratio of the compound II to the solvent is (0.3-1.5) mol/L, preferably 0.9 mol/L; (3) In the substitution reaction, the alkaline reagent is cesium carbonate, potassium carbonate or potassium phosphate, preferably cesium carbonate; (4) In the substitution reaction, the molar ratio of the compound II to the alkaline reagent is 1 (1-4), preferably 1:2; (5) In the substitution reaction, the catalyst is cuprous iodide or cuprous bromide, preferably cuprous iodide; (6) In the substitution reaction, the molar ratio of the compound II to the catalyst is 1 (0.01-0.2), preferably 1:0.05; (7) In the substitution reaction, the molar ratio of the compound II to the diethyl malonate is 1 (0.8-2), preferably 1:1.2; (8) In the substitution reaction, the molar ratio of the compound II to the 2-picolinic acid is 1 (0.005-0.3), preferably 1:0.1; (9) The temperature of the substitution reaction is 70-130 o C, preferably 100 o C.
6. The process according to claim 5, wherein the process for producing compound VII further comprises the step of reacting compound I with bromomethyl methyl ether in the presence of an alkaline agent in a solvent to form compound II; ; preferably, it satisfies one or more of the following conditions: (1) In the reaction of the upper protecting group, the solvent is an amide solvent, preferably N, N-dimethylformamide; (2) In the reaction of the upper protecting group, the mol volume ratio of the compound I to the solvent is (0.1-0.6) mol/L, preferably 0.3 mol/L; (3) In the reaction of the upper protecting group, the alkaline reagent is cesium carbonate, potassium carbonate or potassium phosphate, preferably potassium carbonate; (4) In the reaction of the upper protecting group, the molar ratio of the compound I to the alkaline reagent is 1 (2-6), preferably 1:4; (5) In the reaction of the upper protecting group, the mol ratio of the compound I to the bromomethyl methyl ether is 1 (1-4), for example 1 (2.1-2.5), and is preferably 1:2.1; (6) The reaction temperature of the upper protecting group is 0-90 o C, preferably 60- o C.
7. The process according to claim 6, wherein the process for producing compound VII further comprises the step of iodinating resorcinol with potassium iodide in the presence of ammonium persulfate in a mixed solvent to produce compound I; ; preferably, it satisfies one or more of the following conditions: (1) The iodination reaction is carried out, wherein the mixed solvent is a mixed solvent of an alcohol solvent and water, preferably a mixed solvent of methanol and water, and the volume ratio of the alcohol solvent to the water in the mixed solvent is more preferably 6:1; (2) The mass volume ratio of the resorcinol to the mixed solvent is (10-40 g/L), preferably 20g/L; (3) The molar ratio of the resorcinol to the potassium iodide is 1 (0.5-2), preferably 1:1; (4) The molar ratio of the resorcinol to the ammonium persulfate is 1 (1-5), preferably 1:2.5; (5) The temperature of the iodination reaction is 10-40 o C, preferably 25- o C.
8. A method for preparing a compound TM, comprising the steps of: S1, preparing a compound VII by the preparation method of the compound VII according to any one of claims 1-7; S2, preparing the compound VII into the compound TM according to the following route; ; in the step 1 of S2, the compound VII is reacted with an alkaline reagent in a solvent to generate a compound VIII; In step 2 of S2, compound VIII is reacted with pyridine dichromate in the presence of SiO 2 in a solvent to produce compound IX; in step 3 of S2, in the presence of a catalyst, reacting a compound IX with oxalyl chloride in a mixed solvent to generate a compound X; in step 4 of S2, compound X, triethylsilane and trifluoroacetic acid are reacted in a solvent to form compound TM.
9. A method for preparing compound TM according to claim 8, characterized in that it satisfies one or more of the following conditions: (1) In the preparation method of the compound TM, in the step 1 of S2, the solvent is an alcohol solvent, preferably methanol; (2) In the preparation method of the compound TM, in the step 1 of S2, the molar volume ratio of the compound VII to the solvent is (0.2-0.6) mol/L, preferably 0.4 mol/L; (3) In the preparation method of the compound TM, in the step 1 of S2, the alkaline reagent is cesium carbonate, potassium carbonate or potassium phosphate, preferably potassium carbonate; (4) In the preparation method of the compound TM, in the step 1 of S2, the molar ratio of the compound VII to the alkaline reagent is 1 (1-4), preferably 1:1.4; (5) In the preparation method of the compound TM, in the step 1 of S2, the reaction temperature is 10-40 o C, preferably 25- o C; (6) In the preparation method of the compound TM, in the step 2 of S2, the solvent is an amide solvent, preferably N, N-dimethylformamide; (7) In the preparation method of the compound TM, in the step 2 of S2, the molar volume ratio of the compound VIII to the solvent is (0.2-0.8) mol/L, preferably 0.42 mol/L; (8) In the preparation method of the compound TM, in the step 2 of S2, the molar ratio of the compound VIII to the pyridine dichromate is 1 (1-4), preferably 1:2; (9) In the preparation method of the compound TM, in the step 2 of S2, the molar ratio of the compound VIII to the SiO 2 is 1 (2-6), preferably 1:4.7; (10) In the preparation method of the compound TM, in the step 2 of S2, the reaction temperature is 10-40 o C, preferably 25- o C; (11) In the preparation method of the compound TM, in the step 3 of S2, the mixed solvent is a mixed solvent of a halogenated alkane solvent and an amide solvent, preferably dichloromethane and N, N-dimethylformamide, and the volume ratio of the halogenated alkane solvent to the amide solvent in the mixed solvent is further preferably 1:0.005; (12) In the preparation method of the compound TM, in the step 3 of S2, the molar volume ratio of the compound IX to the mixed solvent is (0.08-0.3) mol/L, preferably 0.17 mol/L; (13) In the preparation method of the compound TM, in the step 3 of S2, the catalyst is a Lewis acid catalyst, preferably aluminum trichloride; (14) In the preparation method of the compound TM, in the step 3 of S2, the molar ratio of the compound IX to the catalyst is 1 (0.5-4), preferably 1:1.2; (15) In the preparation method of the compound TM, in the step 3 of S2, the molar ratio of the compound IX to the oxalyl chloride is 1 (0.5-4), preferably 1:1.1; (16) In the preparation method of the compound TM, in the step 3 of S2, the reaction temperature is 0-40 o C, preferably 25- o C; (17) In the preparation method of the compound TM, in the step 4 of S2, the solvent is an ether solvent, preferably tetrahydrofuran; (18) In the preparation method of the compound TM, in the step 4 of S2, the molar volume ratio of the compound X to the solvent is (0.05-0.3) mol/L, preferably 0.13 mol/L; (19) In the preparation method of the compound TM, in the step 4 of S2, the molar ratio of the triethylsilane to the compound X is 1 (0.05-0.5), preferably 1:0.13; (20) In the preparation method of the compound TM, in the step 4 of S2, the molar ratio of the compound X to the trifluoroacetic acid is 1 (1-6), preferably 1:3.8; (21) In the preparation method of the compound TM, in the step 4 of S2, the reaction temperature is 10-90 o C, preferably 25- o C or 70- o C.
10. A compound of any one of: 。

Description

Preparation method of optically pure glabridin Technical Field The invention relates to the field of organic chemistry, in particular to a preparation method of optically pure glabridin. Background Glycyrrhiza glabra is a perennial herb, growing in the southern Europe, asia, mediterranean and widely cultivated in Russian, spanish, iran and India areas. Glabridin is a natural whitening agent separated from licoflavone, the glabridin is extracted from rhizomes of specific types of liquorice plants (such as uralensis, glycyrrhiza distenosa, glabridin and the like), is natural, pollution-free and free of any side effect on human bodies, is known as whitening gold by people due to the high-efficiency active oxygen and melanin inhibiting capability, has the praise on whitening efficacy, has the price of glabridin in one gram equivalent to gold, and is only used as a whitening component by a few brands. At present, the glabridin in China is mainly distributed in northern Xinjiang, qinghai, gansu and other provinces, and is limited in harvesting along with the execution of the policies of sand prevention and sand fixation in China, and secondly, the glabridin has lower content in the glabridin and higher cost for extracting and separating glabridin with higher purity, so that the development of chemical synthesis for synthesizing the optical pure glabridin in green and high efficiency is particularly important. In 2018, patent document CN 108440553a discloses a method for preparing optically pure glabridin by catalyzing isoflavone intermediate with chiral ruthenium complex, wherein chirality is introduced by dynamic asymmetric hydrogen transfer, and hydroxy and protecting group are removed to obtain optically pure glabridin, but the chiral ruthenium complex is expensive and the cost of large scale production is high. In 2020, patent document CN 111362961a discloses a method for preparing (R) -glabridin by 7 steps using 7-hydroxychroman-4-one as a starting material, wherein the total yield is 30%, chiral palladium complex is required for key steps, and the starting material 7-hydroxychroman-4-one is not a bulk chemical product, is expensive, and does not have the value of scale-up production. In 2023, patent CN 116284031 discloses a method for preparing chiral glabridin from optically active glabridin by bromination, elimination and asymmetric hydrogenation under the catalysis of chiral palladium complex, the method is a synthesis method for the optical-rotation-eliminating glycyrrhizin, and also needs to use a noble metal palladium catalyst, so that the cost is high. In 2021, patent document CN 113651832a discloses a method for constructing optically pure glabridin by biological enzyme catalysis, but according to the published reaction conditions, the yield is found to be poor after repeated experiments, even the target product cannot be obtained, in the synthetic method, some reagents used in the synthetic method are dangerous, such as lithium aluminum hydride used in the reduction reaction, a large amount of reagents are dangerous to explode, and further such as boron tribromide used in the deprotection process is expensive, has strong corrosiveness, has high requirements on a reaction kettle, and brings challenges to industrial production. How to prepare optical pure glabridin with high efficiency by using cheaper raw materials, milder conditions, shorter routes and the like is a problem to be solved at present. Disclosure of Invention Aiming at the defects of higher synthesis cost and harsh reaction conditions in the prior art, the invention provides the preparation method of the optical pure glabridin, which has the advantages of low-cost and easily-obtained raw materials, mild reaction conditions and high total yield, and is favorable for realizing industrialization of the optical pure glabridin. The invention provides a preparation method of a compound VII, which comprises the following steps of carrying out a photo-delay reaction on a compound V and a compound VI in a solvent in the presence of a phosphine reagent and an azo reagent to generate the compound VII; 。 in the casting reaction, the solvent may be a solvent conventional in such a reaction in the art, preferably one or more selected from ether solvents, nitrile solvents, halogenated hydrocarbon solvents and aromatic hydrocarbon solvents, such as tetrahydrofuran, methyl t-butyl ether, acetonitrile, methylene chloride or toluene, and further such as tetrahydrofuran. In the casting reaction, the solvent may be used in an amount conventional in the art, preferably, the molar volume ratio of the compound V to the solvent is (0.1 to 0.8) mol/L, preferably 0.24 mol/L or 0.3 mol/L. In the casting reaction, the phosphine reagent may be a phosphine reagent conventional in such reactions in the art, such as triphenylphosphine (PPh 3). In the casting reaction, the molar ratio of the compound V to the phosphine reagent is 1 (0.8-2), for example 1:1.2 or 1:1.5,