Histone deacetylase inhibitor as well as preparation method and application thereof
A preparation and compound technology, applied in the field of histone deacetylase inhibitor and preparation thereof
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Embodiment 1
[0055] Embodiment 1 synthetic target product 1~8
[0056] The route for synthesizing target products 1-8 is as follows:
[0057]
[0058] 1. Synthesis of intermediate 1
[0059] (1) Synthesis of intermediate 1a:
[0060]
[0061] 4-iodoaniline (21.9g, 100mmol) was dissolved in acetonitrile (400mL), after adding ethyl acrylate (50.1g, 500mmol), palladium acetate (1.12g, 5.00mmol) and triethylamine (50.6g, 500mmol) , stirred and reacted at 80° C. for 2 days under the protection of nitrogen. After distilling off the solvent under reduced pressure, the intermediate 1a (11.0 g, 57.5 mmol, yield 58%) was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 10:1 to 1:1).
[0062] (2) Synthesis of intermediate 1b:
[0063] Using 3-iodoaniline as a raw material, other conditions are the same as the synthesis method of intermediate 1a, the obtained intermediate 1b and its yield, the yield is 80%; other unmentioned raw materials, solvents and reaction con...
Embodiment 2
[0116] Embodiment 2 synthetic target product 9~15
[0117] The route of synthesizing target products 9-15 is as follows:
[0118]
[0119] 1. Synthesis of Intermediate 6:
[0120]
[0121] Dissolve tert-butanol (3.46g, 46.6mmol) in dichloromethane (110mL), add dropwise chlorosulfonic acid isocyanate (6.00g, 42.4mmol), then add intermediate 1a (8.11g, 42.4mmol) and triethyl A solution of the amine (12.9 g, 127 mmol, 17.6 mL) in dichloromethane (110 mL). The temperature was raised to 20°C and the reaction was stirred for 1 hour, then the solvent was evaporated under reduced pressure, dichloromethane was added and washed with 1N hydrochloric acid, the solvent was evaporated under reduced pressure, and then the solvent was evaporated under reduced pressure and then subjected to column chromatography (eluent: petroleum ether: ethyl acetate = 10: 1 to 1:1) to obtain intermediate 6 (11.2 g, 30.2 mmol, yield 71%).
[0122] 2. Synthesis of intermediate 7:
[0123]
[0124]...
Embodiment 3
[0143] Embodiment 3 synthetic target product 16
[0144] The route of synthetic target product 16 is as follows:
[0145]
[0146] 1. Synthesis of Intermediate 10:
[0147]
[0148] Dissolve chlorosulfonic acid isocyanate (11.8g, 83.2mmol) in dry dichloromethane (92.0mL), and after cooling to 0°C, add 2-bromoethanol (4.82g, 59.9mmol) dropwise under nitrogen protection. Methane (30.0 mL) solution. After continuing to stir the reaction for 30 minutes, slowly add intermediate 1a (11.5g, 59.9mmol) and triethylamine (12.1g, 120mmol, 16.6mL) in dichloromethane (60.0mL) solution, slowly rise to room temperature and continue to stir the reaction 15 hours. The reaction was quenched with 0.2N hydrochloric acid (50.0 mL) and adjusted to pH 2.0 with 37 wt% concentrated hydrochloric acid. The organic layer was separated, washed successively with 0.05N hydrochloric acid (200 mL) and water, and dried by adding anhydrous sodium sulfate. The crude intermediate 2a (20.3 g, 59.6 mmol,...
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