A kind of refining method of obeticholic acid
A technology of obeticholic acid and a refining method, which is applied to the refining field of obeticholic acid, can solve the problems of low total yield, high production cost, poor product purity and the like, and achieves simple and safe operation, low production cost and environmental friendliness. Effect
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Embodiment 1
[0036] Example 1: Synthesis of obeticholic acid intermediate III (refer to the method reported in patent CN201380043964.8)
[0037]
[0038] In a 500L hydrogenation kettle, add obeticholic acid starting material II (commercially available) 20.6Kg, mass percent is 10% palladium-carbon catalyst 2.1Kg (the mass percent refers to the quality of palladium in the palladium-carbon reagent The percentage of total mass), 200L mass percentage is 2.5% sodium hydroxide aqueous solution (the described mass percentage refers to the percentage that the quality of sodium hydroxide accounts for the total mass of sodium hydroxide aqueous solution). After nitrogen replacement, hydrogen replacement was carried out, and hydrogenation was carried out at 45° C. for 24 hours at 5 to 7 atm. Reaction liquid is filtered, and filtrate is heated to 100 ℃ and stirred for 16 hours, and after cooling, add 50% phosphoric acid aqueous solution to be adjusted to pH value to be 2~3 (the described mass percent...
Embodiment 2
[0039] Example 2: Synthesis of crude obeticholic acid (refer to the method reported in patent CN201380043964.8)
[0040]
[0041] Take 28.3Kg of obeticholic acid intermediate III, 400L of purified water, and 9.5Kg of sodium hydroxide into the reaction flask, stir, and heat to an internal temperature of about 80°C. Dissolve 8.8Kg of sodium borohydride in 60L of water to form a solution , was added dropwise to the above system, and after the dropwise addition was completed, the reaction was carried out at about 80°C for 3 hours. TLC spot plate (petroleum ether: ethyl acetate = 1:1) the reaction is complete, cool down to room temperature, add 1mol / L hydrochloric acid to quench, adjust the pH value to 5-6, stir at 15-20°C for 1 hour, After centrifugal filtration, an off-white solid was obtained, which was dried in a blast oven at 50°C. Add 200L of dichloromethane and heat to 40°C and stir for 3 hours. The white insoluble matter is borate and other inorganic substances. After f...
Embodiment 3
[0042] Embodiment 3: the refining of obeticholic acid I
[0043] Take obeticholic acid crude product 15.04Kg (can be obtained by Example 2, HPLC purity 92.44%), 82L n-butyl acetate, 8.2L dichloromethane, heated to 40°C and stirred (120rpm) for 2 hours to make it completely dissolved, The temperature was then lowered to 5° C. within 3 hours and stirred (120 rpm) for 2 hours. After centrifugal filtration, the obtained white solid was vacuum-dried (-0.01 to -0.1 MPa, 45 to 55° C.) for 12 hours to obtain 12.44 Kg of purified obeticholic acid. Get purified obeticholic acid 12.44Kg, add 150L mass percentage and be 25% ammonia solution (the said mass percentage refers to the percentage that the quality of ammonia gas accounts for the total mass of ammonia solution), stir (120rpm) to make it dissolve. Then add mass percentage and be 1.0% sodium dihydrogen phosphate aqueous solution 50L (the described mass percentage refers to the mass percentage of the mass of sodium dihydrogen phosp...
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