Bile acid derivatives as fxr/tgr5 agonists and methods of use thereof
A compound, SO2R1 technology, applied in the field of bile acid derivatives and its preparation, can solve the problem of increasing energy consumption
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Embodiment 1
[0377]
[0378] Step 1-1
[0379]
[0380] at 0°C and N 2 MEMCl was added to a stirred solution of (1-1) (4.35 g, 10.0 mmol) and DIPEA (10.3 mL, 30 mmol) in DCM (100 mL). The resulting reaction mixture was allowed to warm to room temperature and stirred overnight, then quenched with water (50 mL) and 1 N HCl (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give 6.5 g of crude product (1-2), which was directly used in the next step. LC-MS observed value 2M+NH 4 = 1062.83 (calculated value 1062.81).
[0381] Step 1-2
[0382]
[0383] First at 0°C and N 2 The above mentioned crude product (1-2) (4.18 g, 8.0 mmol) was dissolved in THF (30 mL), anhydrous MeOH (1.28 ml, 32 mmol) was added followed by slow addition of LiBH 4 (697 mg, 32 mmol). The mixture was stirred at 0 °C for 6 h, TLC and LC-MS analysis showed partial conversion of starting material, then more LiBH was added 4 (348 mg, 16 mmol). The mixture was all...
Embodiment 2
[0391]
[0392] Step 2-1
[0393]
[0394] A solution of alcohol (1-3) (99 mg, 0.2 mmol) and CDI (65 mg, 0.4 mmol) in MeCN / THF (1 / 1, 1 mL) was stirred at room temperature for 1.5 h before addition of cyclohexanesulfonamide ( 98mg, 0.6mmol) and DBU (89μL, 0.6mmol). The resulting reaction mixture was stirred at room temperature for 1 h, then quenched with brine and extracted with ethyl acetate. The combined organic layers were washed with brine and concentrated. The residue was purified by silica gel chromatography using hexane / acetone (100 / 0 to 60 / 40, 10 min) to give sulfonylcarbamate (2-1) (100 mg, 73%) as a colorless oil . LC-MS observed M-1 = 682.36 (calculated 682.44).
[0395] Step 2-2
[0396]
[0397] Carbamate (2-1) (100 mg, 0.15 mmol) was first dissolved in THF (3 mL) at room temperature. Then 37% HCl (0.1 mL, 1.2 mmol) was added. The mixture was stirred at room temperature for 1 h, washed with saturated NaHCO 3Quenched and extracted with ethyl acetate...
Embodiment 3
[0399]
[0400] Step 3-1
[0401]
[0402] A solution of alcohol (1-3) (99 mg, 0.2 mmol) and CDI (65 mg, 0.4 mmol) in MeCN / THF (1 / 1, 1 mL) was stirred at room temperature for 1.5 h, then 4-tert-butylaniline was added (90 mg, 0.6 mmol) and DBU (89 μL, 0.6 mmol). The resulting reaction mixture was stirred at room temperature for 18 h, then quenched with brine and extracted with ethyl acetate. The combined organic layers were washed with brine and concentrated. The residue was purified by silica gel chromatography using hexane / acetone (100 / 0 to 60 / 20, 10 minutes) to give carbamate (3-1) (87 mg, 65%) as a colorless oil. LC-MS observation valueM+NH 4 =687.64 (calculated value 687.53).
[0403] Step 3-2
[0404]
[0405] Carbamate (3-1) (87 mg, 0.13 mmol) was first dissolved in THF (3 mL) at room temperature. Then 37% HCl (0.1 mL, 1.2 mmol) was added. The mixture was stirred at room temperature for 1 h, washed with saturated NaHCO 3 Quenched and extracted with ethyl...
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