Difused piperidine compounds as well as preparation method, application and intermediate thereof
A technology of double-condensed piperidine and compound, which is applied in the field of double-condensed piperidine compounds and can solve problems such as poor curative effect and the like
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Embodiment 1
[0079] Example 1: Preparation of Compound III-1
[0080]
[0081] Put carbon disulfide 8g (100mmol) and 4-Boc aminopiperidine 16g (80mmol) in a 500ml reaction flask, add H 2 O 300ml, add 12.3g (50mmol) of sophocarpine (compound IV) under stirring, nitrogen protection, 60 ℃ of reaction 12 hours, after completion of the reaction, add ethyl acetate extraction, saturated sodium chloride solution washing, organic layer anhydrous sulfuric acid Dry over sodium, concentrate under reduced pressure, and then perform silica gel column chromatography with dichloromethane:methanol (50:1) as the eluent to obtain 22 g of solid (ie compound III-1) with a yield of 81.2% and a purity of ≥95%. M+H + = 523.3.
Embodiment 2
[0082] Example 2: Preparation of Compound II-1
[0083]
[0084] 22 g of compound III-1 prepared in Example 1 was dissolved in 100 ml of ethyl acetate, and 200 ml (2M / L) of hydrochloric acid ethyl acetate solution was added dropwise at 0° C., under nitrogen protection, and reacted at room temperature for 12 hours. After the reaction was completed, Filtration, adding ethyl acetate to wash the solid, and vacuum drying at room temperature to obtain 18 g of a white solid (ie compound II) with a yield of 85.2% and a purity of ≥95%. M+H + = 423.2.
Embodiment 3
[0085] Example 3: Preparation of Compounds 1-10
[0086]
[0087] Preparation of compound 1:
[0088] Place 244mg (2mmol) of benzoic acid and 422mg (1mmol) of compound II-1 in a 25ml reaction flask, add 420mg (2mmol) of DCC and 270mg (2mmol) of HOBt, 20ml of dichloromethane, under nitrogen protection, react at room temperature for 6 hours, and the reaction is complete Then, dichloromethane was added for extraction, washed with saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography, eluent dichloromethane:methanol (50:1), to obtain 442 mg of white solid (ie compound 1) in 85.5% yield. Purity ≥95%.
[0089] The preparation methods of compounds 2-10 refer to the preparation method of compound 1, and only change R to prepare compounds 2-10.
[0090] Structures, Yields, Mass Spectra and Molecular Formulas of Compounds 1-10
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