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A kind of preparation method of obeticholic acid

A technology for obeticholic acid and compound, which is applied in the field of preparation of obeticholic acid and can solve the problems of low separation yield and the like

Active Publication Date: 2018-06-26
JIANGSU HENGRUI MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Although this synthesis process can realize the large-scale synthesis, however, a large amount of by-products are produced in the process of preparing compound XI under the palladium-carbon hydrogenation reduction of compound Vb under strong basic conditions and strong basic high-temperature treatment, which leads to the separation and recovery of this step reaction. The yield is low (about 60%), and the low yield of this step reaction may be due to the dehydration of the unprotected hydroxyl group in the compound Vb and XI under the conditions of strong basicity (30% NaOH) and high temperature (95-105 ° C), etc. caused by side reactions

Method used

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  • A kind of preparation method of obeticholic acid
  • A kind of preparation method of obeticholic acid
  • A kind of preparation method of obeticholic acid

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Embodiment 1: preparation compound IVa

[0062] Compound Va (646 grams, prepared according to the method in WO2006122977) was dissolved in 7 liters of dichloromethane, 762 milliliters of diisopropylethylamine was added, cooled to 0°C, 166 milliliters of MOMCl was added, and the reaction system was heated to 20°C , reacted for 16 hours, added water to quench the reaction, added 10 liters of ethyl acetate for extraction, separated the organic phase, dried the organic phase with anhydrous sodium sulfate, filtered and concentrated to obtain 696 g of compound Iva, with a yield of 98%. 1 H NMR (400MHz, CDCl 3 )δ6.16(q,1H),4.76–4.59(m,2H),4.28–4.01(m,2H),3.70–3.48(m,1H),3.42–3.29(m,3H),2.56(dd, 1H),2.46–2.14(m,4H),2.07–1.87(m,4H),1.87–1.68(m,5H),1.55–1.04(m,16H),1.00(s,3H),0.92(t, 3H),0.78–0.62(m,3H).

Embodiment 2

[0063] Embodiment 2: Preparation of compound IIIa

[0064] Compound IVa (696g) is dissolved in ethanol (7 liters), adds palladium carbon (76g, 10wt%) and 500 grams of 30% sodium hydroxide aqueous solution, reacts 16h under hydrogen (1.5 atmospheric pressure) and 20 ℃, then warming up to 95°C, stirred for 16 hours, cooled to 20°C, filtered, the concentrated mother liquor was neutralized with 2N hydrochloric acid, extracted with 10 liters of ethyl acetate, the extract was concentrated, crystallized, filtered, and dried to obtain 606 grams of compound IIIa, 92% yield.

[0065] 1 H NMR (400MHz, CDCl 3 )δ4.74–4.55(m,2H),3.52–3.39(m,1H),3.38–3.30(m,3H),2.68(dd,1H),2.49–2.13(m,4H),2.02–1.65( m,9H),1.58–1.02(m,15H),0.95(dd,4H),0.86–0.77(m,3H),0.67(d,3H).

Embodiment 3

[0066] Embodiment 3: preparation compound IIa

[0067] Compound IIIa (606 grams) was dissolved in 7 liters of ethanol, cooled to 0°C, added 50 grams of sodium borohydride, heated to 20°C, reacted for 8 hours, slowly added phosphoric acid until pH = 6, solid precipitated, filtered, solid After washing with water and drying, 584 g of compound IIa was obtained with a yield of 96%.

[0068] 1HNMR (400MHz, CDCl 3 )δ4.66(s,2H),3.72(m,2H),3.35(m,4H),2.25-1.07(m,28H),0.90(m,8H),0.65(s,3H).

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Abstract

Provided are a compound represented by formula (III) and a preparation method therefor, wherein R1 is a hydroxyl protective group and preferably is MOM; and also provided is a method for preparing obeticholic acid by using the compound. The preparation method has moderate reaction conditions, few by-products and simple and convenient operation, and is suitable for large-scale production.

Description

technical field [0001] The invention relates to a preparation method of obeticholic acid. Background technique [0002] Obeticholic acid (formula I) is a semi-synthetic chenodeoxycholic acid derivative indicated for the treatment of portal hypertension and liver disorders, including primary biliary cirrhosis, bile acid diarrhea, nonalcoholic Steatohepatitis. Obeticholic acid acts by activating the FXR receptor, a nuclear receptor mainly expressed in the liver, intestine, and kidney. It can regulate the expression of genes related to bile acid, fat, and glucose metabolism, and can also regulate immune response. Activation of FXR can inhibit bile acid synthesis and prevent toxic reactions caused by excessive accumulation of bile acids. [0003] [0004] WO2002072598 discloses the preparation method of obeticholic acid for the first time (as shown below), the method obtains compound VII through direct alkylation of compound VI with ethyl iodide under strong basic conditio...

Claims

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Application Information

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IPC IPC(8): C07J9/00A61K31/575A61P9/10
CPCA61P9/10C07J9/005Y02P20/55
Inventor 张富尧陈谦益刘鹏
Owner JIANGSU HENGRUI MEDICINE CO LTD