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A cholic acid and cornerstone technology, applied in the field of organic chemical synthesis, can solve problems such as low yield, high equipment requirements, and unsuitability for large-scale production
Inactive Publication Date: 2017-08-11
EAST CHINA NORMAL UNIV
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This method needs to use the high-temperature Huangminglong reaction in the process of preparing 7-ketolithocholic acid, which has higher requirements on equipment, low yield (58.94%), and is not suitable for large-scale production. The reaction formula is as follows:
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Embodiment 1
[0111]
[0112] 1. Synthesis of the compound of formula (2): Dissolve cholic acid (9g, 22.0mmol) in 200mL of acetone / water (v / v=3:1), protect from light, slowly add NBS (5.7g, 31.9mmol), Reaction at room temperature 25°C for 2h. After TLC detects that the reaction is complete, add 100mL saturated sodium bisulfite solution to quench the reaction, remove the solvent under reduced pressure until a white solid appears, stop when poured into 1L of water, and precipitate a large amount of white solid, stand for crystallization, filter and dry to obtain Formula (2) compound (8.5g white solid, yield 95%). used directly in the next step.
[0113]
[0114] 2. Synthesis of the compound of formula (3-1): Dissolve the compound of formula (2) (8.5g, 20.8mmol) in 100mL of methanol, add 1mL of concentrated sulfuric acid dropwise, heat to reflux for 2h, remove methanol under reduced pressure, add 30mL of water , the aqueous phase was extracted with dichloromethane (30 mL×3). Combine t...
Embodiment 2
[0128]
[0129] 1. Synthesis of the compound of formula (2): Dissolve cholic acid (9g, 22.0mmol) in 200mL acetone / water (v / v=3:1), stir in the dark, slowly add NBS (5.7g, 31.9mmol) , room temperature 25 ℃ reaction 2h. After TLC detects that the reaction is complete, add 100 mL of saturated sodium bisulfite solution to quench the reaction, concentrate under reduced pressure until a white solid appears, pour it into 1L of water, and precipitate a large amount of white solid, leave it to crystallize, filter and dry to obtain the formula ( 2) Compound (8.5g white solid, yield 95%). used directly in the next step.
[0130]
[0131] 2. Synthesis of the compound of formula (3-1): Dissolve the compound of formula (2) (8.5g, 20.8mmol) in 100mL of methanol, add 1mL of concentrated sulfuric acid dropwise, heat to reflux for 2h, remove methanol under reduced pressure, add 30mL of water , the aqueous phase was extracted with dichloromethane (30 mL×3). Combine the organic phases, w...
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Abstract
The invention discloses a chemical synthetic method of an intermediate 7-keto-lithocholic acid (3alpha-hydroxyl-7-ketone-5beta-cholestane-24-acid) of obeticholic acid, and belongs to the field of organic chemical synthesis. According to the chemical synthetic method of the intermediate 7-keto-lithocholic acid (3alpha-hydroxyl-7-ketone-5beta-cholestane-24-acid) of obeticholic acid, cholic acid is adopted as a raw material, and through reactions of selective oxidization of 7alpha-hydroxyl, esterification of side chain carboxyl groups, esterification of 3alpha-hydroxyl, methanesulfonic acid esterification, elimination, hydrogenation, and hydrolysis of 12alpha-hydroxyl, the intermediate 7-keto-lithocholic acid (3alpha-hydroxyl-7-ketone-5beta-cholestane-24-acid) of obeticholic acid is synthesized. According to the chemical synthetic method of the intermediate 7-keto-lithocholic acid (3alpha-hydroxyl-7-ketone-5beta-cholestane-24-acid) of obeticholic acid, cheap cholic acid is adopted as the raw material, the synthesis method is novel, low in cost, high in yield and environmentally friendly, which facilitates industrialized production.
Description
technical field [0001] The invention relates to a chemical synthesis method of obeticholic acid intermediate 7-ketolithocholic acid (3α-hydroxy-7-keto-5β-cholestane-24-acid), belonging to the field of organic chemical synthesis. Background technique [0002] Obeticholic Acid, the chemical name is 6α-ethyl-3α,7α-dihydroxy-5β-cholestane-24-acid, also known as 6-ethylchenodeoxycholic acid or INT-747, It is a semi-synthetic chenodeoxycholic acid, which is a new derivative of chenodeoxycholic acid in human primary bile acids. [0003] Obeticholic acid is a potent agonist of farnesoid receptor X (Farnesoid Xreceptor, FXR) developed by American Intercept Pharmaceutical Company. effect. In May 2016, obeticholic acid (trade name Ocaliva) was approved by the US FDA for the treatment of primary biliary cirrhosis. Currently, the chemical synthesis of obeticholic acid mainly uses 7-ketolithocholic acid as the starting material. Therefore, it is particularly important to develop a syn...
Claims
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