18β-Glycyrrhetinic Acid (18β-Glycyrrhizic acid) is a natural triterpenoid mainly found in the root and rhizome of Glycyrrhiza. It is a white to light yellow crystalline powder with no odor and sweet taste. 18β-Glycyrrhetinic Acid has a wide range of pharmacological activities, including anti-virus, anti-oxidation, anti-inflammatory, anti-tumor, hypolipidemic, hypoglycemic, and hepatoprotective effects.
In recent years, 18β-Glycyrrhetinic Acid has also been widely used in the field of cosmetics and health care products for skin moisturizing, whitening, anti-aging and other aspects. At the same time, some studies have shown that 18β-Glycyrrhetinic Acid can also be used as a drug carrier or compound modification group, which has the potential to improve drug bioavailability and selectivity. Therefore, many researchers have been trying various methods many times to improve its purity. The following are the more common chemical synthesis routes:
method one:
1>, synthesis of 3-hydroxy-11-methyl-δ-lactic acid
3-Hydroxy-11-methyl-δ-lactic acid can be obtained by hydroxylation and methylation of 2-methylglutaric acid. The specific steps are:
(1) Add 2-methylglutaric acid to acetonitrile, and add catalysts such as H2O2 and NaOH to generate 3-hydroxy-2-methylglutaric acid.
(2) Add 3-hydroxy-2-methylglutaric acid to methyl iodide, and add catalysts such as potassium carbonate to generate 3-hydroxy-11-methyl-δ-lactic acid.
2>Synthesis of 18β-glycyrrhizic acid
(1) React 3-hydroxy-11-methyl-δ-lactic acid with methacrylate in the presence of an esterifying agent (such as DCC or EDC) to generate 3-hydroxy-11-methyl-δ-lactic acid Methacrylate.
(2) 3-Hydroxy-11-methyl-δ-lactate methyl acrylate is hydrolyzed to generate 18β-glycyrrhizic acid.
3>Purification of 18β-glycyrrhizic acid
After obtaining 18β-glycyrrhizic acid, further purification and crystallization are required, and techniques such as recrystallization or chromatography can be used for purification.
Method Two:
The detailed steps of the synthetic method starting from acetylacetone:
(1) Heat acetylacetone and butanone oxide ime (3-butanone alumina) in chloroform to generate 1,3-dibutyl-2,4-cyclohexanedione.
(2) Heat 1,3-dibutyl-2,4-cyclohexanedione and formaldehyde in acetic acid to generate 3-methoxy-1,5-hexanedione.
(3) React 3-methoxy-1,5-hexanedione and isobutyl magnesium solution in tetrahydrofuran to generate 4-isobutoxy-3-methoxy-1,5-hexanetrione.
(4) React 4-isobutoxy-3-methoxy-1,5-hexanetrione and potassium hydroxide in tetrahydrofuran to generate 4-isobutoxy-3-hydroxy-1,5-hexane Triketones.
(5) React 4-isobutoxy-3-hydroxy-1,5-hexanetrione and chloromethyl acetone in chloroform to generate 4-isobutoxy-3-hydroxy-1,5-hexanetrione Ketone-11-methanone.
(6) React 4-isobutoxy-3-hydroxy-1,5-hexanetrione-11-methanone and potassium hydroxide in ethanol to generate 18β-hydroxymethyl-11-keto-olean- 12-en-30-oic acid.
Method three:
The following is the synthesis method of 18β-Glycyrrhetinic Acid starting from potassium bicarbonate:
(1) Oxidation: Heating acetylacetone and chromium acidate together for oxidation reaction to obtain 3-hydroxypentanone.
(2) Carbonylation reaction: react 3-hydroxypentanone and formaldehyde under alkaline conditions for carbonylation reaction to obtain 3-hydroxy-5-methoxypentanone.
(3) Oxidative acylation: Heating 3-hydroxy-5-methoxypentanone and hydrogen chloride together for chlorination reaction to obtain 3-chloro-5-methoxypentanone. Then react 3-chloro-5-methoxypentanone and potassium bicarbonate in acetone for oxidative acylation to obtain 18β-Glycyrrhetinic Acid.
The overall reaction equation is as follows:
3-Hydroxypentanone + CrO3/H+ → 3-Hydroxy-5-methoxypentanone
3-Hydroxy-5-methoxypentanone + HCHO/NaOH → 3-hydroxy-5-methoxypentanone
3-Hydroxy-5-methoxypentanone + HCl → 3-chloro-5-methoxypentanone
3-Chloro-5-methoxypentanone + KHCO3 → 18β-Glycyrrhetinic Acid
Method four:
The following is the synthesis method of 18β-Glycyrrhetinic Acid starting from β-maltose:
(1) Dissolution: Dissolve β-maltose in water, add sodium hydroxide and styrene, and stir well.
(2) Oxidation: add hydrogen peroxide to carry out oxidation reaction to obtain 3,20-dihydroxy-11-keto-olean-12-ene.
(3) Chlorination: Heating 3,20-dihydroxy-11-keto-olean-12-ene and hydrogen chloride together for chlorination reaction to obtain 3-chloro-11-keto-olean-12-ene.
(4) Carboxylation: react 3-chloro-11-keto-olean-12-ene with hydrogen chloride in the presence of sodium chloride for carboxylation to obtain 3-chloro-11-carboxy-olean-12-ene .
(5) Hydroxylation: Heating 3-chloro-11-carboxy-olean-12-ene and sodium carbonate together for hydroxylation reaction to obtain 18β-Glycyrrhetinic Acid.
The overall reaction equation is as follows:
β-maltose + NaOH + C6H5CH=CH2 → 3,20-dihydroxy-11-keto-olean-12-ene
3,20-dihydroxy-11-keto-olean-12-ene + H2O2 → 3,20-dihydroxy-11-keto-olean-12-ene
3,20-dihydroxy-11-keto-olean-12-ene + HCl → 3-chloro-11-keto-olean-12-ene
3-chloro-11-keto-olean-12-ene + HCl + NaCl → 3-chloro-11-carboxy-olean-12-ene
3-Chloro-11-carboxy-olean-12-ene + Na2CO3 → 18β-Glycyrrhetinic Acid
Method five:
The following is the synthesis method of 18β-Glycyrrhetinic Acid starting from the steroid nucleus:
(1) Dissolution: Dissolve the steroid nucleus in acetic acid, add an acidulant, and stir well.
(2) Chlorination: add ferrous chloride or aluminum trichloride to carry out chlorination reaction to obtain chlorinated steroids.
(3) Carboxylation: Heating chlorinated steroids and sodium hydroxide together for carboxylation reaction to obtain carboxylic acid steroids.
(4) Hydroxylation: Heating carboxylic acid steroids and sodium hydroxide together for hydroxylation reaction to obtain 18β-Glycyrrhetinic Acid.
The overall reaction equation is as follows:
Steroid Core + CH3COOH + Acidulant → Chlorinated Steroid
Chlorinated Steroids + FeCl2/AlCl3 → Chlorinated Steroids
Chlorinated Steroid + NaOH → Carboxylic Steroid
Carboxylic acid steroid + NaOH → 18β-Glycyrrhetinic Acid
The above are the various methods of the laboratory, for reference only, and in the specific experiment, you need to choose different methods according to your own experimental situation.