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A kind of method that takes Ba as raw material to synthesize ursodeoxycholic acid

A technology for ursodeoxycholic acid and raw materials, applied in chemical instruments and methods, steroids, organic chemistry, etc., can solve the problems of low yield, cumbersome steps, expensive raw materials and the like

Active Publication Date: 2021-09-14
JIANGSU JIAERKE PHARMA GRP CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] The reported ursodeoxycholic acid synthesis route not only has problems such as too complicated steps, low yield, high pollution, and expensive raw materials, but the existing ursodeoxycholic acid synthesis route reported above all uses animal bile acids ( Cattle, sheep cholic acid, chenodeoxycholic acid, ursolic acid, hyodeoxycholic acid, hyodeoxycholic acid) as starting materials, but due to the emergence of diseases such as avian influenza, mad cow disease, porcine streptococcal disease and African swine fever, People have doubts about the safety of animal-derived raw materials. Therefore, it is of great significance and industrial value to develop a high-efficiency synthesis method of ursodeoxycholic acid based on plant-derived raw materials

Method used

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  • A kind of method that takes Ba as raw material to synthesize ursodeoxycholic acid
  • A kind of method that takes Ba as raw material to synthesize ursodeoxycholic acid
  • A kind of method that takes Ba as raw material to synthesize ursodeoxycholic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0117] Example Preparation of a compound of formula (2) Embodiment

[0118] In 250mL single-necked flask were added sequentially BA (10.0g, 30.26mmol), p-toluenesulfonic acid (57mg, 0.30mmol), ethylene glycol (16.8mL, 302.60mmol), triethyl orthoformate (15.1mL, 90.78mmol) 150mL of tetrahydrofuran and stirred at rt for 8h. After completion of the reaction was concentrated under reduced pressure, water was added 100mL ethyl acetate (60mL × 3) extracted with water (50mL × 2) wash with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, silica gel column chromatography (PE / EA = 3 / 1, v / v) to give the formula (2) compound (5.0g, white solid) in a yield of 44 mol%.

[0119] In 250mL single-necked flask were added sequentially BA (10.0g, 30.26mmol), p-toluenesulfonic acid (57mg, 0.30mmol), ethylene glycol (16.8mL, 302.60mmol) and 300mL of benzene, refluxing reaction was 24h. After completion of the addition the react...

Embodiment 2

[0121] Example Two Preparation of the compound of formula (3) Embodiment

[0122] In 250mL single-necked flask were added sequentially the formula (2) compound (5.0g, 13.35mmol), IBX (7.5g, 26.70mmol), 50mLTHF and 50mLDMSO, room temperature 5h. After completion of the reaction by TLC was added water, filtered off with suction, dichloromethane (50mL × 3) extracted with water (50mL × 2) wash with saturated sodium bicarbonate solution (50mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, silica gel column chromatography (PE / EA = 3 / 1, v / v) to give the formula (3) compound (4.9 g of, as a white solid), yield 98% mol.

[0123] In 500mL single-necked flask were added sequentially the formula (2) compound (10.1g, 26.96mmol), TEMPO (42mg, 0.27mmol), 100mL methylene chloride, sodium bicarbonate (3.1g, 36.40mmol) and tetrabutylammonium bromide (870mg, 2.70mmol) in water (40 mL) solution, NCS (4.1g, 31.00mmol), 0 ℃ reaction 5h. After completion of the reacti...

Embodiment 3

[0125] Example Three Preparation of the compound of formula (6) Embodiment

[0126] In 100mL single-necked flask were added sequentially the formula (3) compound (1.0g, 2.68mmol), carbomethoxy methylene triphenyl phosphine (1.7g, 5.36mmol) and 15mL of toluene, the reaction was refluxed for 4h. Concentrating the reaction was complete by TLC (PE / EA = 3 / 1, v / v) was purified by column chromatography on silica compound (1.13 g of, as a white solid) of formula (6), the molar yield 98% under reduced pressure.

[0127] After successively added to 100mL single-necked flask, sodium hydride (161mg, 4.02mmol) and 10mL of tetrahydrofuran, stirred for 15min trimethyl phosphonoacetate (0.65 mL, 4.02 mmol), the formula (3) compound (1.0g, 2.68mmol), 0 ℃ reaction 4h. Concentrating the reaction was complete by TLC (PE / EA = 3 / 1, v / v) was purified by column chromatography on silica compound (1.12 g of, as a white solid) of formula (6), 97% molar yield after reduced pressure. mp: 161-162 ℃. 1 ...

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Abstract

The invention discloses a method for synthesizing ursodeoxycholic acid. The plant-derived compound BA is used as a raw material to synthesize the ursodeoxycholic acid through the steps of ethylene glycol protection, oxidation, side chain extension reaction, removal of ethylene glycol protection, reduction, hydrolysis and other steps. ursodeoxycholic acid. The raw materials used in the synthesis of ursodeoxycholic acid in the invention are cheap and easy to obtain, the synthesis steps are simple and easy to operate, the yield is high, the environment is friendly, and the industrial production is convenient.

Description

Technical field [0001] The present invention belongs to the field of synthetic organic chemistry synthesis techniques / drugs, to a method for the synthesis of ursodeoxycholic acid, particularly relates to a 21-hydroxy-20-methyl-pregn-4-en-3-one (BA) the method of deoxycholic acid was synthesized bears. Background technique [0002] Ursodeoxycholic acid (Ursodeoxycholic acid, UDCA) (as shown in Formula 1), chemical name 3α, 7β- -5β- cholesteric dihydroxy-24-oic acid (3α, 7β-dihydroxy-5β-cholan-24- oic acid), CAS No. 128-13-2, molecular formula C 24 Hide 40 O 4 , The molecular weight of 392.56, as a white powder, odorless, bitter taste, mp 203-204 ℃. Ursodeoxycholic acid is a major component of bear bile contains valuable medicine is FDA approved primary biliary cirrhosis (PBC) first-line therapy, can also be effective in the clinical treatment of gallstones and chronic liver diseases , it has broad market prospects. [0003] Currently, the preparation of ursodeoxycholic acid with...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J9/00C07J21/00
CPCC07J9/005C07J21/006C07J9/00
Inventor 仇文卫王杰
Owner JIANGSU JIAERKE PHARMA GRP CORP