Preparation method of glabridin, chiral intermediate and preparation method of chiral intermediate
By constructing a chiral center through asymmetric epoxidation reaction using a chiral catalyst, the problems of low extraction efficiency and purity of glycyrrhizin were solved, and the synthesis of glycyrrhizin with high yield and high optical purity was achieved.
Patent Information
- Application Number
- CN202510803759.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-17
- Publication Date
- 2025-10-28
AI Technical Summary
In existing technologies, the extraction efficiency of glycyrrhizin is low and the cost is high. The glycyrrhizin molecule synthesized by total synthesis is a racemic mixture, which makes it difficult to achieve high optical purity and chiral resolution.
A chiral catalyst was used to carry out an asymmetric epoxidation reaction to construct a chiral center, avoiding chiral resolution, and glycyrrhizin was synthesized through a series of chemical reactions.
A high-yield, high-optical-purity synthesis of glycyrrhizin was achieved, avoiding the chiral separation step and improving synthesis efficiency and purity.
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Figure CN120842233A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of organic synthesis, specifically to a method for preparing glycyrrhizin, a chiral intermediate, and a method for preparing the chiral intermediate. Background Technology
[0002] Glabridin is a type of glycyrrhizin. According to the literature (The inhibitory effect of glabridin from licorice extracts on melanogenesis and inflammation Pigment. Cell Res 1998, 11: 355–361), glabridin can significantly inhibit tyrosinase activity, thereby controlling melanin production and achieving a skin whitening effect.
[0003] In existing technologies, the most common method for producing glycyrrhizin is direct extraction from plants. Traditional extraction methods include water extraction, organic solvent extraction, microwave extraction, and ultrasonic extraction. However, these methods generally have disadvantages such as low extraction efficiency and high extraction costs.
[0004] In addition, some literature reports the preparation of glycyrrhizin by total synthesis. However, due to various limitations, the glycyrrhizin molecules synthesized by total synthesis are all racemic and must be obtained by chiral resolution. However, according to the literature (Synthetic Communication, 2014, 44, 540-546), such resolution is difficult to achieve for glycyrrhizin with optical purity. Even if the analytical amount of racemic mixture is resolved by chiral column, it is difficult to obtain glycyrrhizin with optical purity. Summary of the Invention
[0005] This invention is made to solve the above-mentioned problems, and aims to provide a method for preparing glycyrrhizin by directly constructing chiral centers through a chiral catalyst to avoid polar chiral separation, as well as a chiral intermediate synthesized by a chiral catalyst and its preparation method.
[0006] This invention provides a method for preparing glycyrrhizin, characterized by the following reaction formula:
[0007]
[0008] The steps include:
[0009] Step 1: Compound 1 reacts with benzyl halide to give compound 2;
[0010] Step 2: Compound 2 reacts with 3-halopropanal dialkyl acetal to give compound 3;
[0011] Step 3: Compound 3 undergoes an intramolecular cyclization reaction in the presence of p-toluenesulfonic acid to give compound 4;
[0012] Step 4: Compound 4 undergoes an asymmetric epoxidation reaction catalyzed by a chiral catalyst to yield compound 5;
[0013] Step 5: Compound 5 reacts with a nucleophile to give compound 6; the nucleophile is selected from any one of 2,4-dimethoxyphenyl magnesium halide, 2,4-dimethoxyphenylboronic acid, 2,4-dimethoxybromobenzene, 2,4-dimethoxyiodobenzene, or 2,4-dimethoxychlorobenzene.
[0014] Step 6: In the presence of triethylsilane and trifluoroacetic acid, compound 6 undergoes a dehydroxylation reaction to give compound 7;
[0015] Step 7: In the presence of a reducing catalyst, compound 7 reacts with hydrogen to obtain compound 8;
[0016] Step 8: Compound 8 reacts with 3-chloro-3-methylbutyne to give compound 9;
[0017] Step 9: In the presence of boron tribromide, compound 9 undergoes a demethylation reaction to give compound 10.
[0018] The method for preparing glycyrrhizin provided by this invention may also have the following feature: wherein, in step 4, the chiral catalyst is selected from any one of the following compounds:
[0019]
[0020] The method for preparing glycyrrhizin provided by this invention may also have the following feature: in step 5, when the nucleophile is 2,4'-dimethoxyphenyl magnesium halide, a cuprous salt is also added to the reaction.
[0021] When the nucleophile is any one of 2,4-dimethoxyphenylboronic acid, 2,4-dimethoxybromobenzene, 2,4-dimethoxyiodobenzene, or 2,4-dimethoxychlorobenzene, a divalent palladium salt is also added to the reaction.
[0022] The method for preparing glycyrrhizin provided by the present invention may also have the following feature: in step 7, the reduction catalyst is Pd / C, Pt / C, Pd(OH)2 / C, or Raney nickel.
[0023] This invention provides a chiral intermediate characterized by being any one of the following compounds:
[0024]
[0025] The method for preparing glycyrrhizin provided by this invention may also have the following feature, with the following structural formula:
[0026]
[0027] The method for preparing glycyrrhizin provided by this invention may also have the following feature, with the following structural formula:
[0028]
[0029] This invention provides a method for preparing a chiral intermediate, characterized by the following reaction formula:
[0030]
[0031] The steps include:
[0032] Compound 4 undergoes an asymmetric epoxidation reaction catalyzed by a chiral catalyst to yield compound 5.
[0033] The method for preparing the chiral intermediate provided by this invention may also have the following feature: the chiral catalyst is selected from any one of the following compounds:
[0034]
[0035] This invention provides a method for preparing a chiral intermediate, characterized by the following reaction formula:
[0036]
[0037] The steps include:
[0038] Compound 5 reacts with a nucleophile to give compound 6; the nucleophile is selected from any one of 2,4-dimethoxyphenyl magnesium halide, 2,4-dimethoxyphenylboronic acid, 2,4-dimethoxybromobenzene, 2,4-dimethoxyiodobenzene, or 2,4-dimethoxychlorobenzene.
[0039] When the nucleophile is 2,4'-dimethoxyphenyl magnesium halide, a cuprous salt is also added to the reaction.
[0040] When the nucleophile is any one of 2,4-dimethoxyphenylboronic acid, 2,4-dimethoxybromobenzene, 2,4-dimethoxyiodobenzene, or 2,4-dimethoxychlorobenzene, a divalent palladium salt is also added to the reaction.
[0041] The role and effect of invention
[0042] According to the method for preparing glycyrrhizin of the present invention, because a chiral fructose derivative is used as a catalyst for asymmetric epoxidation reaction followed by ring opening, a chiral center is cleverly constructed. Therefore, the present invention can obtain glycyrrhizin with a high ee value in a high yield without chiral resolution. Attached Figure Description
[0043] Figure 1 This is a photograph of compound 10 obtained in Example 9 of the present invention. Detailed Implementation
[0044] To make the technical means, creative features, objectives and effects of this invention easy to understand, the invention will be specifically described below in conjunction with embodiments and accompanying drawings.
[0045] In the following embodiments, unless otherwise stated, all raw materials are commercially available products.
[0046] <Example 1>
[0047] Preparation of compound 2
[0048] This embodiment provides a method for preparing compound 2, and the reaction formula is as follows:
[0049]
[0050] The steps include:
[0051] 50 g of compound 1 (0.454 mol, 1.3 eq) was dissolved in 650 mL of acetonitrile, and then 125.5 g of potassium carbonate (0.908 mmol, 2.0 eq) was added. 100.9 g of benzyl bromide (0.590 mmol, 1.0 eq) was added dropwise at room temperature. The mixture was heated to 60 °C and stirred for 2 h. Water and ethyl acetate were added to the reaction system, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to give 61.5 g of compound 2, with a yield of 67.6%.
[0052] <Example 2>
[0053] Preparation of compound 3
[0054] This embodiment provides a method for preparing compound 3, and the reaction formula is as follows:
[0055]
[0056] The steps include:
[0057] 50 g of compound 2 (0.25 mol, 1.0 eq) and 12 g of sodium hydroxide (0.30 mol, 1.2 eq) were added to 300 mL of tetrahydrofuran. A solution of 69 g of 3-iodopropionaldehyde dimethyl acetal (0.3 mol, 1.2 eq) in 300 mL of tetrahydrofuran was added dropwise at room temperature. After the addition was complete, the mixture was heated to 70 °C and refluxed for 12 h. After the reaction was complete, the mixture was allowed to return to room temperature and washed once with 10 wt% sodium hydroxide aqueous solution and once with saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, and subjected to column chromatography to give 62.4 g of compound 3, with a yield of 82.5%.
[0058] <Example 3>
[0059] Preparation of compound 4
[0060] This embodiment provides a method for preparing compound 4, and the reaction formula is as follows:
[0061]
[0062] The steps include:
[0063] Under nitrogen protection, 50 g of compound 3 and 5 g of p-toluenesulfonic acid were added to 500 mL of 1,4-dioxane, and the mixture was refluxed at 100 °C for 8 h. After the reaction was complete, 200 mL of 10 wt% sodium hydroxide aqueous solution and 100 mL of tert-butyl methyl ether were added to the reaction system, mixed thoroughly, and extracted. The organic phase was collected and washed once each with 10 wt% sodium hydroxide aqueous solution and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to give 32.9 g of compound 4, with a yield of 83.6%.
[0064] <Example 4>
[0065] Preparation of compound 5
[0066] This embodiment provides a method for preparing compound 5, and the reaction formula is as follows:
[0067]
[0068] The steps include:
[0069] 10 g of compound 4 (42.0 mmol, 1.0 eq) and 4.3 g of compound 11 (12.6 mmol, 0.3 eq) were added to a mixed solvent consisting of 40 mL of acetonitrile and 20 mL of buffer aqueous solution (containing 2 mol / L potassium carbonate and 4 mmol / L EDTA). The mixture was cooled to -10 °C, and 21.4 g of 30% hydrogen peroxide aqueous solution (189 mmol, 4.5 eq) was slowly added dropwise. After the addition was complete, the mixture was stirred at 0 °C for 6 h. After the reaction was completed, the reaction was quenched with saturated sodium thiosulfate aqueous solution, extracted with ethyl acetate, and the organic phase was collected. The phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and subjected to column chromatography to give 8.16 g of compound 5, with a yield of 76.5% and an ee value of 97%.
[0070] <Example 5>
[0071] Preparation of compound 6
[0072] This embodiment provides a method for preparing compound 5, and the reaction formula is as follows:
[0073]
[0074] The steps include:
[0075] Under nitrogen protection, 0.4 g of cuprous bromide-dimethyl sulfide complex (1.9 mmol, 0.1 eq) and 15 mL of tetrahydrofuran were added to the reaction vessel. At room temperature, 36.9 mL of freshly prepared tetrahydrofuran solution of 2,4-dimethoxyphenyl magnesium bromide (0.8 mol / L, 29.5 mmol, 1.5 eq) was added dropwise to the reaction vessel. After the addition was complete, the reaction system was cooled to -35°C to -30°C, and 19.7 mL of tetrahydrofuran solution of compound 5 (1 mol / L, 19.7 mmol, 1.0 eq) was added dropwise. After the addition was complete, the mixture was allowed to return to room temperature naturally, and the reaction was stirred for 2 h.
[0076] After the reaction was completed, a saturated ammonium chloride aqueous solution was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was then washed once with a saturated ammonium chloride aqueous solution and once with a saturated brine solution, dried over anhydrous sodium sulfate, subjected to column chromatography, and then separated by supercritical fluid chromatography to obtain 3.0 g of compound 6, with a yield of 38.8% and an ee value > 99%.
[0077] <Example 6>
[0078] Preparation of compound 7
[0079] This embodiment provides a method for preparing compound 7, and the reaction formula is as follows:
[0080]
[0081] The steps include:
[0082] 5 g of compound 6 (12.7 mmol, 1.0 eq) was added to 10 mL of dichloromethane, followed by 1.77 g of triethylsilane (15.2 mmol, 1.2 eq) and 3.48 g of trifluoroacetic acid (30.5 mmol, 2.4 eq). The mixture was refluxed at 40 °C for 3 h. The solvent was removed by vacuum concentration, and the mixture was extracted with ethyl acetate and saturated sodium bicarbonate aqueous solution. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and subjected to column chromatography to give 4.4 g of compound 7, with a yield of 92.0%.
[0083] <Example 7>
[0084] Preparation of compound 8
[0085] This embodiment provides a method for preparing compound 8, the reaction formula of which is as follows:
[0086]
[0087] The steps include:
[0088] 10 g of compound 7 was dissolved in 20 mL of methanol, 0.5 g of Pd / C catalyst (Pd content 5%) was added, hydrogen gas was substituted, the mixture was stirred at room temperature for 12 h, filtered, the filtrate was concentrated and column chromatography was performed to obtain 7.29 g of compound 8, with a yield of 95.8%.
[0089] <Example 8>
[0090] Preparation of compound 9
[0091] This embodiment provides a method for preparing compound 9, and the reaction formula is as follows:
[0092]
[0093] The steps include:
[0094] Under nitrogen protection, 5 g of compound 8 (17.5 mmol, 1.0 eq), 4.08 g of sodium carbonate (38.5 mmol, 2.2 eq), 2.9 g of potassium iodide (17.5 mmol, 1.0 eq), and 4.48 g of 3-chloro-3-methylbutyne (43.7 mmol, 2.5 eq) were added to 30 mL of LDM. The mixture was heated to 80 °C and stirred for 24 h. After cooling to room temperature, the mixture was filtered. The filtrate was heated to 160 °C and refluxed for 3 h. After cooling to room temperature, ethyl acetate was added. The organic phase was washed once with 1 mol / L hydrochloric acid aqueous solution and once with saturated brine. The solution was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to give 4.85 g of compound 9, with a yield of 78.6%.
[0095] <Example 9>
[0096] Preparation of compound 10
[0097] This embodiment provides a method for preparing compound 10, the reaction formula of which is as follows:
[0098]
[0099] The steps include:
[0100] 5 g of compound 9 (14.2 mmol, 1.0 eq) was dissolved in 200 mL of dichloromethane, cooled to -78 °C, and 71.0 mL of a boron tribromide solution in dichloromethane (1 mol / L, 71.0 mmol, 5 eq) was added dropwise. After the addition was complete, the mixture was allowed to return to room temperature and stirred for 2 h. The reaction mixture was quenched in a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to give 4.05 g of compound 10, with a yield of 87.8% and an ee value > 95%.
[0101] Figure 1 This is a photograph of compound 10 obtained in this embodiment.
[0102] The role and effect of the embodiments
[0103] According to the method for preparing glycyrrhizin of the present invention, because a chiral fructose derivative is used as a catalyst for asymmetric epoxidation reaction followed by ring opening, a chiral center is cleverly constructed. Therefore, the present invention can obtain glycyrrhizin with a high ee value in a high yield without chiral resolution.
[0104] The above embodiments are preferred embodiments of the present invention and are not intended to limit the scope of protection of the present invention.
Claims
1. A method for preparing glycyrrhizin, characterized in that, The reaction formula is as follows: Includes the following steps: Step 1: Compound 1 reacts with benzyl halide to give compound 2; Step 2: Compound 2 reacts with 3-halopropanal dialkyl acetal to give compound 3; Step 3: Compound 3 undergoes an intramolecular cyclization reaction in the presence of p-toluenesulfonic acid to give compound 4; Step 4: Compound 4 undergoes an asymmetric epoxidation reaction catalyzed by a chiral catalyst to yield compound 5; Step 5: Compound 5 reacts with a nucleophile to give compound 6; the nucleophile is selected from any one of 2,4-dimethoxyphenyl magnesium halide, 2,4-dimethoxyphenylboronic acid, 2,4-dimethoxybromobenzene, 2,4-dimethoxyiodobenzene, or 2,4-dimethoxychlorobenzene. Step 6: In the presence of triethylsilane and trifluoroacetic acid, compound 6 undergoes a dehydroxylation reaction to give compound 7; Step 7: In the presence of a reducing catalyst, compound 7 reacts with hydrogen to obtain compound 8; Step 8: Compound 8 reacts with 3-chloro-3-methylbutyne to give compound 9; Step 9: In the presence of boron tribromide, compound 9 undergoes a demethylation reaction to give compound 10.
2. The method for preparing glycyrrhizin according to claim 1, characterized in that: in, In step 4, the chiral catalyst is selected from any one of the following compounds:
3. The method for preparing glycyrrhizin according to claim 1, characterized in that: in, In step 5, when the nucleophile is 2,4'-dimethoxyphenyl magnesium halide, a cuprous salt is also added to the reaction. When the nucleophile is any one of 2,4-dimethoxyphenylboronic acid, 2,4-dimethoxybromobenzene, 2,4-dimethoxyiodobenzene, or 2,4-dimethoxychlorobenzene, a divalent palladium salt is also added to the reaction.
4. The method for preparing glycyrrhizin according to claim 1, characterized in that: in, In step 7, the reduction catalyst is Pd / C, Pt / C, Pd(OH)2 / C, or Raney nickel.
5. A chiral intermediate for the preparation of glycyrrhizin, characterized in that, It is any one of the following compounds:
6. The chiral intermediate according to claim 5, characterized in that, The structural formula is as follows:
7. The chiral intermediate according to claim 5, characterized in that, The structure is as follows:
8. A method for preparing a chiral intermediate, characterized in that, The reaction formula is as follows: Includes the following steps: Compound 4 undergoes an asymmetric epoxidation reaction catalyzed by a chiral catalyst to yield compound 5.
9. The method for preparing the chiral intermediate according to claim 8, characterized in that: in, The chiral catalyst is selected from any one of the following compounds:
10. A method for preparing a chiral intermediate, characterized in that, The reaction formula is as follows: Includes the following steps: Compound 5 reacts with a nucleophile to give compound 6; the nucleophile is selected from any one of 2,4-dimethoxyphenyl magnesium halide, 2,4-dimethoxyphenylboronic acid, 2,4-dimethoxybromobenzene, 2,4-dimethoxyiodobenzene, or 2,4-dimethoxychlorobenzene. When the nucleophile is 2,4'-dimethoxyphenyl magnesium halide, a cuprous salt is also added to the reaction. When the nucleophile is any one of 2,4-dimethoxyphenylboronic acid, 2,4-dimethoxybromobenzene, 2,4-dimethoxyiodobenzene, or 2,4-dimethoxychlorobenzene, a divalent palladium salt is also added to the reaction.