Heterocyclic compound and application thereof in medicine
A technology of compounds, mixtures of isomers, applied in the field of medicine
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[0178] Preparation of intermediate compounds
[0179] Preparation of Intermediate I-100':
[0180]
[0181] 1-(2,3-Difluoropropyl)azetidine-3-amine ( I-100’-1 )
[0182]
[0183] first step
[0184] 2-benzyloxymethyloxirane ( I-100’-1-a )
[0185]
[0186] NaOH (3.7 g), tetra-n-butylammonium iodide TBAI (3.43 g) and DMF (150 mL) were added to the reaction flask, cooled in an ice-water bath, and then oxiran-2-ylmethanol (CAS: 556- 52-5; 6.85 g) was dropped into the reaction flask and stirred for 2 hours; then benzyl bromide BnBr (17.3 g) was slowly added dropwise; after the addition, the reaction was kept at room temperature overnight. Then, water was added to quench the reaction and extracted with ethyl acetate; the ethyl acetate layer was collected, washed twice with dilute aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated; the residue was purified by silica gel column chromatography to obtain oily product, I-...
Embodiment 1
[0261] 1-(3-Fluoropropyl)-N-(4-((6R,7S)-7-isobutyl-8-methyl-6,7,8,9-tetrahydro-3H-pyrazolo [3,4-h]isoquinolin-6-yl)phenyl)azetidine-3-amine ( 1 )
[0262]
[0263] first step
[0264] (2S)-2-(((1H-Indazol-4-yl)methyl)(methyl)amino)-1-(4-bromophenyl)-4-methylpentan-1-ol ( 1a )
[0265]
[0266] compound I-60-1 (839 mg), 4-(chloromethyl)-1H-indazole (ADV947321888 from Advanced ChemBlocks Inc., 739 mg), potassium carbonate (1.8 g) and sodium iodide (39 mg) were mixed at room temperature in no water in DMF. The reaction solution was stirred at room temperature overnight. Then, ethyl acetate and water were added for extraction; the organic phase was separated, and the organic phase was washed twice with dilute aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated; the residue was purified by silica gel column chromatography to obtain a yellow solid product 1a (950 mg). 1 H NMR (500 MHz, DMSO-d6) δ (ppm): 13.00 (1H, s), 8.07 (...
Embodiment 2
[0288] N-(3,5-Difluoro-4-((6S,7S)-7-isobutyl-8-methyl-6,7,8,9-tetrahydro-3H-pyrazolo[3,4 -h]isoquinolin-6-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine ( 2 )
[0289]
[0290] first step
[0291] (2S)-2-(((1H-Indazol-4-yl)methyl)(methyl)amino)-1-(4-chloro-2,6-difluorophenyl)-4-methylpentan -1-ol ( 2a )
[0292]
[0293] compound I-60-2 (1130 mg), 4-(chloromethyl)-1H-indazole (ADV947321888 from Advanced ChemBlocks Inc., 630 mg), potassium carbonate (2.5 g) and sodium iodide (54 mg) were mixed at room temperature in no water in DMF. The reaction solution was stirred at room temperature overnight. Then, ethyl acetate and water were added for extraction; the organic phase was separated, and the organic phase was washed twice with dilute aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated; the residue was purified by silica gel column chromatography to obtain a yellow solid product 2a (1660 mg). 1 H NMR (500MHz, dmso-d6) ...
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