Histone deacetylase inhibitor and its preparation method and use
A technology of inhibitors and uses, applied in the field of histone deacetylase inhibitors and their preparation, to achieve good effect of sirtuin inhibitory activity
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Embodiment 1
[0074] Example 1 Synthesis of target products 1-7
[0075] The routes for synthesizing target products 1 to 7 are as follows:
[0076]
[0077] 1. Synthesis of Intermediate 1
[0078] (1) Synthesis of Intermediate 1a:
[0079]
[0080] Chlorosulfonyl isocyanate (11.8 g, 83.2 mmol) was dissolved in dry dichloromethane (220 mL), cooled to 0°C, and 2-chloroethanol (6.70 g, 83.2 mmol) in dichloromethane was added dropwise under argon protection (220 mL) solution. After stirring the reaction for 30 minutes, a solution of aniline (8.53 g, 91.5 mmol) and triethylamine (16.8 g, 166 mmol, 23.1 mL) in dichloromethane (220 mL) was slowly added, and the reaction was stirred for 1 hour after warming to room temperature. The reaction was quenched by the addition of 0.2N hydrochloric acid (10 mL), and the pH was adjusted to 2.0 with concentrated hydrochloric acid. The organic layer was separated, washed with 0.05mol / L hydrochloric acid and water in turn, and dried by adding anhydro...
Embodiment 2
[0110] Example 2 Synthesis of target compounds 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, the obtained intermediates 5a and 5b and their corresponding structures and yields are shown in Table 4. Wherein, the molar weight of the 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, other unmentioned raw materials or solvents and reaction conditions thereof are related to the preparation of Same as in 1a.
[0116] Table 4 Raw materials and final yields for the synthesis of intermediates 5a and 5b
[0117]
[0118] 2. Synthesi...
Embodiment 3
[0127] Example 3 Synthesis of target compounds 10-15
[0128] The routes for synthesizing target products 10 to 15 are as follows:
[0129]
[0130] 1. Synthesis of Intermediate 7
[0131]
[0132] 2,3-Dihydro-1H-pyrrolo[2,3-b]pyridine (5.00 g, 41.6 mmol) was dissolved in DMF (140 mL) and N-bromosuccinimide (8.89 g, 49.9 mmol) was added ), the reaction was stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and purified by column chromatography (eluent: petroleum ether / ethyl acetate=10:1 to 1:1) to obtain Intermediate 7 (3.60 g, 18.1 mmol, yield 43%).
[0133] 2. Synthesis of Intermediate 8:
[0134]
[0135] Intermediate 7 (2.00 g, 10.1 mmol), zinc cyanide (1.77 g, 15.1 mmol) and tetrakis(triphenylphosphine)palladium (1.16 g, 1.00 mmol) were dissolved ...
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