Fluorinated bile acid derivatives
A compound, cholane technology, applied in the field of compounds for the treatment of liver diseases, compounds for the treatment of diseases such as non-alcoholic steatohepatitis and primary cholangitis, selective agonists
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Embodiment 1
[0329] Example 1 - 3α-hydroxy-4β-fluoro-6α-ethyl-7α-hydroxy-5β-cholane with a sulfonylurea-substituted side chain Synthesis of acid analogs
[0330] A. 6α-Ethyl-3α, 7α-dihydroxy-5β-cholan-24-oic acid methyl ester
[0331]
[0332] To a solution of OCA (23.5 g, 55.87 mmol) in MeOH (540 mL) was added p-toluenesulfonic acid (1.02 mg, 5.59 mmol, ~0.1 equiv) at RT and sonicated at 30 °C for 3 h. Upon completion, the reaction mixture was concentrated in vacuo. The residue was dissolved in chloroform (500 mL), washed with saturated NaHCO 3 (500mL), H 2 O (500 mL) and brine (500 mL), washed with MgSO 4 Dry, filter, and concentrate in vacuo to afford the title compound as a white solid in quantitative yield. The resulting solid was used without further purification.
[0333] 1 H NMR (400MHz, CDCl 3): δ3.70(1H, s), 3.67(3H, s,), 3.44-3.37(1H, m), 2.40-2.32(1H, m), 2.26-2.18(1H, m), 1.96(1H, dt, J=12.0, 2.6Hz), 1.92-1.76 (6H, m), 1.69-1.59 (3H, m), 1.58-1.12 (14H, m), 1.00...
Embodiment 2
[0482] Example 2 - Alternative Synthesis of Compounds with Sulfonylurea-Substituted Side Chains
[0483] The following methods are exemplified for 4β-fluoro derivatives, but can also be used for 2β-fluorinated, 4,4-difluorinated or 2,4-difluorinated compounds.
[0484] A. 6α-Ethyl-4β-fluoro-7α-trimethylsilyloxy-3-oxo-5β-cholane-24-oic acid methyl ester
[0485]
[0486] To a stirred, precooled solution of diisopropylamine (0.78 mL, 5.54 mmol, ~12 equiv) in dry THF (6.9 mL) was added n-BuLi in hexane dropwise at -78 °C under argon atmosphere solution (1.44 mL, 2.31 mmol, ~5.0 equiv) over 0.25 h. After the addition, trimethylsilyl chloride (0.29 mL, 2.31 mmol, ~5.0 equiv) was added and stirred for 1 h. 6α-Ethyl-7α-hydroxy-3-oxo-5β-cholan-24-oic acid methyl ester (200 mg, 0.46 mmol) from Example 1 Step B was then added in dry THF (3 mL) and triethylamine ( 1.16 mL, 8.32 mmol, ~18 equiv). After the addition, the reaction system was gradually warmed to -20 °C and stirred f...
Embodiment 3
[0519] Example 3 - Synthesis of compounds with sulfonamide-substituted side chains
[0520] The procedure below exemplifies 4β-fluoro derivatives, but can also be used with 2β-fluorinated, 4,4-difluorinated or 2,4-difluorinated compounds. Steps A and B are as described in Example 2.
[0521] C. 6α-Ethyl-4β-fluoro-7α-trimethylsilyloxy-3α-hydroxy-5β-cholanic acid
[0522]
[0523] 6α-Ethyl-4β-fluoro-7α-trimethylsilyloxy-3α-hydroxy-5β-cholan-24-oic acid methyl ester (162.3 mg) from Step B was dissolved in IPA ( 1.6mL). 0.5M NaOH (1.6 mL) was added and the reaction was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure to -half the volume, then water (5 mL) was added and the 2 SO 4 The solution was neutralized and diluted with EtOAc (10 mL). with 2M H 2 SO 4The mixture was acidified to pH 1, the phases were separated and the aqueous phase was extracted with EtOAc (10 mL). The combined extracts were washed with water (3 mL) and brine ...
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