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Polymorphic substances of obeticholic acid and preparation method thereof

A technology for obeticholic acid and polymorphs, which is applied in the field of polymorphs of obeticholic acid and its preparation, and can solve problems such as poor repeatability and instability

Inactive Publication Date: 2016-07-20
厦门蔚扬药业有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The first object of the present invention is to provide polymorphs of obeticholic acid; the second object is to overcome the defects of poor reproducibility and instability in the disclosed preparation methods and provide the polymorphs of obeticholic acid preparation method

Method used

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  • Polymorphic substances of obeticholic acid and preparation method thereof
  • Polymorphic substances of obeticholic acid and preparation method thereof
  • Polymorphic substances of obeticholic acid and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Embodiment 1 Preparation of obeticholic acid crystal form I:

[0021] Add 4.5g of obeticholic acid into 35ml of n-butyl acetate, heat up to reflux, stir for 2 hours, add 100ml of heptane, filter with suction when the temperature is lowered to room temperature, rinse the filter cake with heptane, and dry the filter cake by air blowing. 4.1 g of obeticholic acid in I crystal form was obtained, with a yield of 91% and a purity of 99%.

[0022] The DSC spectrum of crystal form I is as follows figure 1 As shown, there is an endothermic peak at 94±2.0°C.

[0023] The XRPD spectrum of crystal form I (radiation source is CuKα1) is figure 1 As shown, there are diffraction peaks at 2θ values ​​of 4.2, 6.3, 12.4, and 15.8, and the error range of 2θ values ​​is ±0.2.

Embodiment 2

[0024] Embodiment 2 Preparation of obeticholic acid crystal form II:

[0025] Dissolve 30g of obeticholic acid in NaOH (8.3% NaOH, 45.0ml) solution, slowly add HCl (0.22mmol, 450ml) solution to the solution at 30-40°C, and adjust the pH to 2-5 , slowly cooled to room temperature, filtered the precipitate, and dried to obtain 28.4 g of crystal form II as a solid, with a yield of 94.6% and a purity of 99%.

[0026] The DSC spectrum of crystal form II is as follows image 3 As shown, there is an endothermic peak at 99±2.0°C.

Embodiment 3

[0027] Embodiment 3 Preparation of obeticholic acid crystal form I:

[0028] Add 10g of obeticholic acid into 5ml of toluene, heat up to reflux, stir for half an hour, add 50ml of petroleum ether under reflux, stir for 2 hours, and suction filter when cooling down to room temperature, and rinse the filter cake with cyclohexane. The filter cake was blast-dried to obtain 9.3 g of obeticholic acid crystal form I with a yield of 93% and a purity of 99%.

[0029] The DSC spectrum of crystal form I is as follows figure 1 As shown, there is an endothermic peak at 94±2.0°C.

[0030] The XRPD spectrum of crystal form I (radiation source is CuKα1) is figure 2 As shown, there are diffraction peaks at 2θ values ​​of 4.2, 6.3, 12.4, and 15.8, and the error range of 2θ values ​​is ±0.2

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Abstract

The invention relates to polymorphic substances of obeticholic acid and a preparation method thereof. According to the invention, a novel crystallization method is adopted to prepare obeticholic acid polymorphic substances. The preparation method for a crystal form I comprises the following steps: dissolving obeticholic acid in a good solvent, adding a certain proportion of a poor solvent when complete dissolving is just realized under the condition of refluxing, decreasing a temperature, carrying out cooling so as to allow a crystal to be precipitated, and carrying out filtering and drying. The preparation method for a crystal form II comprises the following steps: dissolving obeticholic acid in an organic solvent, carrying out refluxing, decreasing a temperature, carrying out cooling so as to allow a crystal to be precipitated, and carrying out filtering and drying. The method provided by the invention has the following advantages: the crystallized obeticholic acid polymorphic substances are stable; meanwhile, operation is simple and practicable, and a conventional solvent can be used; the disadvantages of complex steps, difficult crystallization, poor repeatability and instability of a disclosed preparation method are overcome; and the method is suitable for industrial production.

Description

1. Technical field: [0001] The invention belongs to the technical field of medicine, and in particular relates to a polymorph of obeticholic acid and a preparation method thereof. 2. Background technology: [0002] Obeticholic acid, also known as 6-ethylchenodeoxycholic acid, is a new derivative of chenodeoxycholic acid (CDCA) in human primary bile acids, and is a farnesoid derivative X receptor (FXR ) natural ligands. 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 for the treatment of primary biliary cirrhosis and nonalcoholic fatty liver disease. [0003] 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 decad...

Claims

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Application Information

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IPC IPC(8): C07J9/00
Inventor 顾世海密良
Owner 厦门蔚扬药业有限公司
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