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A kind of preparation method of 6-alpha-ethyl-7-keto gallstone acid

A ketocholic acid and ethyl technology, which is applied in the fields of synthetic chemistry and biomedicine, can solve the problems of complex product system, excessive side reactions, low actual yield and the like, and achieves simplified process, mild reaction conditions and high yield. Excellent effect

Active Publication Date: 2021-04-06
ZHONGSHAN BAILING BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This synthetic method has good reaction selectivity, less impurities, relatively easy purification, and the actual yield of the final qualified product is high. The disadvantage is that the synthetic route is relatively long
[0008] Some new patents adopt a relatively novel method, using ethyl electrophile to directly react with 7-ketocholelithic acid under metal catalysis to prepare 6-ethyl-7-ketocholelithic acid. There are too many reactions, the product system is complex, and the actual yield obtained after purification is very low, which is difficult to apply in production

Method used

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  • A kind of preparation method of 6-alpha-ethyl-7-keto gallstone acid
  • A kind of preparation method of 6-alpha-ethyl-7-keto gallstone acid
  • A kind of preparation method of 6-alpha-ethyl-7-keto gallstone acid

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Experimental program
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Effect test

Embodiment 1

[0035] Add 390g (about 1mol) of methyl 7-ketocholelithate (compound 1) into a 5L reaction flask, add 150g (5mol) of paraformaldehyde, 2.5L of toluene, and 276g (about 2mol) of potassium carbonate, at 60°C The reaction was vigorously stirred, followed by TLC spot plate (petroleum ether: ethyl acetate = 1:1, color developed by ammonium phosphomolybdate baked plate), the raw materials basically disappeared, and the reaction was stopped. After the reaction system was cooled, it was filtered. After the toluene solution was filtered out, it was evaporated to dryness to obtain methyl 6-methylene-7-ketocholelithate (compound 2). Methyl 6-methylene-7-ketocholelithate was purified by silica gel column chromatography.

[0036]Dissolve 2 mol of the methyl Grignard reagent MeMgBr in 2 L of anhydrous tetrahydrofuran, cool down to -20°C, add 217 g (2.2 mol) of cuprous chloride under nitrogen protection, stir for 10 minutes to half an hour, and a yellow solid suspension appears. This is the ...

Embodiment 2

[0038] Add 390g (about 1mol) of methyl 7-ketocholelithate to a 5L reaction flask, add 2.5L of DMF, 150g (5mol) of paraformaldehyde, and 357g (1.1mol) of cesium carbonate, and stir vigorously at 60°C. TLC plate tracking (petroleum ether: ethyl acetate = 1:1, ammonium phosphomolybdate baked plate for color development), the raw materials had disappeared, and the reaction was stopped.

[0039] The excess DMF solvent was distilled off under reduced pressure, and the residual material was extracted twice with diethyl ether (1.2 L). The diethyl ether solution was washed with water and dried over anhydrous sodium sulfate. After passing the drying, lower the temperature to -20°C, add the pre-cooled ether solution (11mol) of dimethyl copper lithium reagent at this temperature, raise the temperature to 0°C naturally, continue to react at about 0°C for 1 hour, add dropwise cold 2L of 5% dilute hydrochloric acid aqueous solution was used to quench the reaction, stirred for 2 hours, and th...

Embodiment 3

[0041] 390g (about 1mol) of ethyl 7-ketocholelithate (compound 1) was added in a 5L reaction flask, 5mol of anhydrous formaldehyde gas was fed into it, 2.5L of tetrahydrofuran was added, and 207g of potassium carbonate (about 1.5mol) was added at 20 The reaction was vigorously stirred at ℃, followed by TLC plate tracking (petroleum ether: ethyl acetate = 1:1, ammonium phosphomolybdate baked plate for color development), the raw materials basically disappeared, and the reaction was stopped. After the reaction system was cooled, it was filtered and evaporated to dryness to obtain ethyl 6-methylene-7-ketocholelithate (compound 2). Ethyl 6-methylene-7-ketocholelithate was purified by silica gel column chromatography.

[0042] Dissolve compound 2 in 800ml tetrahydrofuran, pre-cool to -30°C, then add it into dimethyl copper lithium reagent, stir for 0.5 hours, then slowly raise the temperature to 10°C, continue to stir for 1 hour, add cold 3% Quench the reaction with 2L of dilute h...

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Abstract

The invention discloses a preparation method of 6-α-ethyl-7-ketocholelithic acid, which belongs to the technical fields of synthetic chemistry application and biomedicine. Its synthetic route is shown in the following formula, including the following steps: (1) compound 1 undergoes condensation reaction with formaldehyde or paraformaldehyde to obtain compound 2; (2) compound 2 undergoes 1,4 addition reaction with methyl copper reagent to obtain 6‑α‑Ethyl‑7‑ketocholelithic acid. This method avoids the use of strong acid and strong alkali and some highly volatile reagents (such as trimethylchlorosilane and boron trifluoride) that are difficult to scale up. The production environment is safe and friendly, the reaction conditions are mild, the operation is simple, and the yield of each step is uniform. Excellent, less by-products, simple post-treatment and purification, very suitable for industrial applications,

Description

technical field [0001] The invention belongs to the technical fields of synthetic chemistry application and biomedicine, and specifically relates to a preparation method of 6-alpha-ethyl-7-ketocholelithic acid. Background technique [0002] Obeticholic acid (6-α-ethylchenodeoxycholic acid) can promote bile acid synthesis and is used for the treatment of primary biliary cirrhosis and non-alcoholic fatty liver disease. It has not yet been put into large-scale production and application . [0003] In recent years, more than half of the new routes for the synthesis of obeticholic acid published in domestic and foreign patents and public documents are improvements to the patented routes of original manufacturers, such as the adjustment and optimization of the types of silyl ether protecting groups, the protection methods of silyl ether protecting groups and Adjustment and improvement of strategies, new methods of hydroxyl and carboxyl protection, etc. Although these new routes a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J9/00
CPCC07J9/005Y02P20/55
Inventor 欧松
Owner ZHONGSHAN BAILING BIOTECHNOLOGY CO LTD
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