Method for preparing 3alpha,7alpha-dyhydroxy-6alpha-ethyl-5beta-cholanic acid
A technology for cholanoic acid and cholanoic acid ester, which is applied in the field of preparing 3α,7α-di-hydroxy-6α-ethyl-5β-cholanoic acid, can solve the problem of carcinogenicity, difficult operation, small feeding amount, etc. problem, to achieve the effect of easy purification, high reaction yield and low cost
Inactive Publication Date: 2017-11-28
BEIJING KAWIN TECH SHARE HLDG
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Problems solved by technology
[0012] Although the synthesis steps of this route are shorter, there are also many shortcomings: (1) the amount of feedstock in the whole synthesis steps is very small, and the products of each step need to be purified by column chromatography; (2) the hexamethylene used in the synthesis step 3 Phosphate-based amide, which is carcinogenic; while LDA and n-BuLi are flammable and explosive reagents, and need to react at -78°C, the industrial operation is difficult, and the yield is low
[0019] It has to be noted that, in the preparation processes disclosed in WO2006122977A2 and CN201380043964.8, there are two common problems: (1) converting the ester into the corresponding acid product (3α-hydroxy-6-ethylene-7- Keto-5β-cholan-24 acid) yields are not high; (2) due to the intermediates 3α-hydroxyl-6α-ethyl-7-keto-5β-cholanic acid and 3α-hydroxyl- The helicoid of 6β-ethyl-7-keto-5β-cholanic acid cannot be completely converted into 3α-hydroxy-6α-ethyl-7-keto-5β-cholanic acid, resulting in the presence of 6-beta ethyl chenodeoxycholic acid impurity that is difficult to purify; (3) in the reaction process, since the hydroxyl and carboxyl groups in the structure are always exposed, it is easy to form esters and generate dimers, resulting in the presence of such impurities in the final product. dimeric impurity
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[0059] (a) Preparation of 3α-hydroxyl-6-ethylene-7-keto-5β-cholanoic acid ethyl ester (compound III)
[0060] Add 3α-hydroxy-6-ethylidene-7-keto-5β-cholanic acid (20.0g, 48.0mmol) and ethanol (200mL) into the reaction flask, magnetically stir evenly, add concentrated sulfuric acid (20D ), after the dropwise addition, was heated to reflux, reacted for 5 hours, and TLC detected that the reaction was complete. Evaporate off the solvent, add ethyl acetate (200mL) to dissolve the residue, wash the organic phase successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dry the organic phase over anhydrous sodium sulfate, and evaporate the solvent to obtain 21.1 g of yellow-brown oil , yield 98.9%.
[0061] 1 H NMR (400MHz, CDCl 3 -d 3 ): δ6.19 (1H, q, J = 7.2Hz), 4.12 (2H, q, J = 7.2Hz), 3.63-3.70 (1H, m), 2.58 (1H, dd, J = 13.2Hz, 4.4Hz ),2.17-2.43(4H,m),1.89-2.03(4H,m),1.59-1.85(6H,m),1.06-1.52(16H,m),1.01(3H,s),0.93(3H,d ...
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The invention discloses a novel method for preparing 3alpha,7alpha-dyhydroxy-6alpha-ethyl-5beta-cholanic acid (formula I). The method disclosed by the invention has the advantages of being less in types of impurities in preparation steps, high in yield, convenient in purification, easy to operate and capable of easily realizing industrialization. The compound is used for treating primary biliary cirrhosis and non-alcoholic fatty liver diseases.
Description
technical field [0001] The present invention relates to a new method for preparing 3α, 7α-di-hydroxy-6α-ethyl-5β-cholanic acid. Background technique [0002] 3α,7α-di-hydroxy-6α-ethyl-5β-cholanic acid, Chinese name: obeticholic acid (OCA), its structural formula is as follows: [0003] [0004] Obeticholic acid is a farnesoid X receptor agonist, which indirectly inhibits the gene expression of cytochrome 7A1 (CYP7A1) by activating farnesoid X receptor. Since CYP7A1 is the rate-limiting enzyme of bile acid biosynthesis, obeticholic acid can inhibit bile acid synthesis and is used for the treatment of primary biliary cirrhosis and nonalcoholic fatty liver disease. [0005] Obeticholic acid was successfully developed by Intercept Pharmaceutical Company of the United States. It is the first drug developed for the treatment of cholestatic liver disease in two decades. The study was performed in patients who did not respond adequately to or could not tolerate the older standa...
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Login to View More IPC IPC(8): C07J9/00C07J17/00
CPCC07J9/005C07J17/00
Inventor 张传玉杨利民韩永信高妍杨健
Owner BEIJING KAWIN TECH SHARE HLDG