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Preparation method of lithocholic acid and intermediates thereof

A technology for lithocholic acid and intermediates, which is applied in the field of synthesis of lithocholic acid and its intermediates, and can solve the problems of large material loss, difficulty, and cost increase

Inactive Publication Date: 2021-02-19
HUNAN KEREY BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The inventive method uses plant-derived androstenedione as a raw material, avoiding the use of various cholic acids extracted from animal viscera to synthesize lithocholic acid, but the method involves multiple Chirality needs to be controlled, which is difficult, and a large amount of materials will inevitably be lost in the refining process, resulting in increased costs

Method used

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  • Preparation method of lithocholic acid and intermediates thereof
  • Preparation method of lithocholic acid and intermediates thereof
  • Preparation method of lithocholic acid and intermediates thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] Embodiment 1 lithocholic acid synthetic method (synthetic route one)

[0085]

[0086] Add 20g of compound I, 100ml of tetrahydrofuran, 100ml of absolute ethanol, and 0.2g of piperazine into the reaction flask, dissolve it under stirring, and then add 2g of 10% Pd / C. The system was first replaced with nitrogen, then replaced with hydrogen, and finally hydrogenated at normal pressure to complete the reaction. After the reaction was completed, the system was replaced with nitrogen for hydrogen, and palladium carbon was filtered off. The filtrate was transferred to a reaction kettle and concentrated to a viscous state. Silica gel column chromatography, gradient elution, petroleum ether: ethyl acetate = 20:1 ~ 5:1, combined the pure products, and dried to obtain 17.2g of compound II, the yield 85.5%.

[0087] Add 45g of compound II, 45g of trimethyl orthoacetate, 5g of anhydrous methanol, and 2.2g of p-toluenesulfonic acid into the reaction flask, and stir the reaction...

Embodiment 2

[0093] Embodiment 2 synthetic method of lithocholic acid (synthetic route two)

[0094]

[0095] Add 100g of BA dissolved in 500ml of dichloromethane into the reaction bottle, add 1g of TEMPO, 5g of sodium bicarbonate, 4g of sodium bromide, cool down to -5 ~ 5 degrees, add dropwise 250ml of 9-10% sodium hypochlorite, dropwise, at 0 ~ React at 10 degrees for 1 to 2 hours. Take samples for TLC until the reaction is complete. Control the temperature at 0-10 degrees and add an aqueous solution of sodium thiosulfate dropwise until it is non-oxidizing, stir, separate layers, extract the water layer with dichloromethane, wash the combined organic layer with sodium thiosulfate, water, and saturated brine , concentrated under reduced pressure until a large amount of yellow solid precipitated, added acetonitrile twice, continued to concentrate under reduced pressure, added acetonitrile, stirred at room temperature, filtered, and dried the filter cake to obtain 96 g of compound F, wi...

Embodiment 3

[0099] Embodiment 3 lithocholic acid synthetic method (synthetic route three)

[0100]

[0101] Add 100g of BA dissolved in 500ml of dichloromethane into the reaction bottle, add 1g of TEMPO, 5g of sodium bicarbonate, 4g of sodium bromide, cool down to -5 ~ 5 degrees, add dropwise 250ml of 9-10% sodium hypochlorite, dropwise, at 0 ~ React at 10 degrees for 1 to 2 hours. Take samples for TLC until the reaction is complete. Control the temperature at 0-10 degrees and add an aqueous solution of sodium thiosulfate dropwise until it is non-oxidizing, stir, separate layers, extract the water layer with dichloromethane, wash the combined organic layer with sodium thiosulfate, water, and saturated brine , concentrated under reduced pressure until a large number of yellow solids precipitated, added acetonitrile twice, continued to concentrate under reduced pressure, added acetonitrile, stirred at room temperature, filtered, and dried the filter cake to obtain 96 g of compound F, wi...

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Abstract

The invention discloses a synthesis method of lithocholic acid and an intermediates thereof. According to the preparation method of the lithocholic acid intermediate, a compound I reacts with hydrogento generate a compound II in a mixed solvent by taking palladium on carbon as a catalyst and adding specific alkali; a low-price botanical bulk fermentation product BA is used as a raw material, andlithocholic acid is synthesized through side chain construction, hydrogenation, reduction, hydrolysis and other reactions; and the selectivity of 5beta hydrogen in the hydrogenation reaction is improved, high-toxicity reagents such as hydrazine hydrate are prevented from being used for hydroxyl due to removal of other animal-derived cholic acids, and the method is environmentally friendly, high insafety, simple in route, mild in reaction condition and suitable for industrial mass production.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, and in particular relates to a synthesis process and application of lithocholic acid and its intermediate. Background technique [0002] Lithocholic acid, also known as 3a-hydroxy-5β-cholanic acid, belongs to one of the bile acids and is a secondary bile acid. The structural formula is as follows. It exists in the bile of humans, cattle and rabbits, and the gallstones of cattle and pigs. In the liver, a binding reaction occurs in the liver, and it appears in the bile in the form of taurolithocholic acid or glycine lithocholic acid. The change of its content has important reference value in the diagnosis of liver lesions. Studies have shown that lithocholic acid and its derivatives have a variety of physiological activities, can selectively kill several types of cancer cells, and have no toxic effect on normal cells; other such as antibacterial, antifungal activity α-2,3 - Sialyltransferase inhib...

Claims

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Application Information

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IPC IPC(8): C07J9/00
CPCC07J9/00C07J9/005
Inventor 蒋红平郭志军李斌
Owner HUNAN KEREY BIOTECH
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