Histone deacetylase inhibitor as well as preparation method and application thereof
A technology of compound and solvate, applied in the field of histone deacetylase inhibitor and its preparation
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Embodiment 1
[0074] Embodiment 1 synthetic target product 1~7
[0075] The route for synthesizing target products 1-7 is as follows:
[0076]
[0077] 1. Synthesis of Intermediate 1
[0078] (1) Synthesis of intermediate 1a:
[0079]
[0080] Dissolve chlorosulfonyl isocyanate (11.8g, 83.2mmol) in dry dichloromethane (220mL), cool to 0°C, add 2-chloroethanol (6.70g, 83.2mmol) dropwise in dichloromethane under the protection of argon (220 mL) solution. After stirring and reacting for 30 minutes, a solution of aniline (8.53g, 91.5mmol) and triethylamine (16.8g, 166mmol, 23.1mL) in dichloromethane (220mL) was slowly added, and the reaction was stirred for 1 hour after rising to room temperature. The reaction was quenched by adding 0.2N hydrochloric acid (10 mL), and the pH was adjusted to 2.0 with concentrated hydrochloric acid. The organic layer was separated, washed successively with 0.05mol / L hydrochloric acid and water, and dried by adding anhydrous sodium sulfate. The solvent ...
Embodiment 2
[0110] Embodiment 2 synthetic target compound 8 and 9
[0111] The synthetic routes of target products 8 and 9 are as follows:
[0112]
[0113] 1. Synthesis of Intermediate 5
[0114] Synthesis of intermediates 5a and 5b:
[0115] Using the raw materials in Table 4, other conditions are the same as the synthesis method of intermediate 1a, and the obtained intermediates 5a and 5b and their corresponding structures and yields are shown in Table 4. Among them, the molar amount of raw material 1 corresponds to the aniline used in the preparation of 1a, the raw material 2 corresponds to the chlorosulfonyl isocyanate used in the preparation of 1a, the raw material 3 corresponds to the 2-chloroethanol used in the preparation of 1a, and other unmentioned raw materials or solvents and their reaction conditions are related to the preparation Same as in 1a.
[0116] Table 4 The raw materials used for the synthesis of intermediates 5a and 5b and the final yield
[0117]
[0118...
Embodiment 3
[0127] Embodiment 3 synthetic target compound 10~15
[0128] The route of synthesizing target products 10-15 is as follows:
[0129]
[0130] 1. Synthesis of intermediate 7
[0131]
[0132] Dissolve 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (5.00g, 41.6mmol) in DMF (140mL), add N-bromosuccinimide (8.89g, 49.9mmol ), stirred at room temperature for 3 hours. Add saturated ice-cold sodium bicarbonate solution, extract with ethyl acetate, wash with saturated sodium chloride solution, and add anhydrous sodium sulfate to dry. The solvent was evaporated under reduced pressure, and intermediate 7 (3.60 g, 18.1 mmol, yield 43%) was obtained after purification by column chromatography (eluent: petroleum ether / ethyl acetate=10:1 to 1:1).
[0133] 2. Synthesis of Intermediate 8:
[0134]
[0135] Intermediate 7 (2.00g, 10.1mmol), zinc cyanide (1.77g, 15.1mmol) and tetrakis(triphenylphosphine)palladium (1.16g, 1.00mmol) were dissolved in DMSO (30.0mL) under nitrogen protection ,...
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