Pyrrolidone derivative serving as glucokinase activator as well as preparation method and application of pyrrolidone derivative
A compound, alkyl technology, applied in the field of medicine, can solve problems such as difficulty in achieving blood sugar control goals, weight gain, etc.
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Embodiment 1
[0129] The synthesis of embodiment 1 compound I-1
[0130]
[0131] a.
[0132] A solution of 3-aminopyrazole (1.22g, 14.68mmol) in ethyl acetate (10mL) was heated to 45°C, and then acetic anhydride (1.35g, 13.21mmol) was slowly added dropwise at this temperature. , Keep at this temperature for 6h. The mixture was cooled to 25 °C, ethyl acetate (20 mL) was added, and kept at this temperature for 2 h, then the solution was filtered to obtain insoluble material, and pure product 9-1 (1.80 g, 98%) was obtained: LR-ES-MS m / z calculated value C 5 h 7 N 3 O[M] + 125, measured value [M+H] + 126.
[0133] b.
[0134] A suspension of compound 9-1 (1.65g, 13.19mmol) and 2,4-difluorobenzyl bromide (3.01g, 14.53mmol) in N,N-dimethylformamide (DMF, 50mL) was dissolved in sodium carbonate (3.50 g, 32.98 mmol) was treated, then the mixture was heated to 50 °C and kept at this temperature for 5 h. The mixture was cooled to 25°C, and the insolubles were filtered off. The superna...
Embodiment 2
[0147] The synthesis of embodiment 2 compound I-2
[0148]
[0149] a.
[0150] 3-Acetamidopyrazole (prepared as in Example 1, 1.55 g, 12.40 mmol) and 2-fluoro-4-chlorobenzyl chloride (2.45 g, 13.66 mmol) were dissolved in N,N-dimethylformamide ( The suspension in DMF, 60 mL) was treated with potassium carbonate (4.28 g, 31.00 mmol), then the mixture was heated to 50 °C and maintained at this temperature for 5 h. The mixture was cooled to 25°C, and the insolubles were filtered off. The supernatant was concentrated and purified by column chromatography (0% to 100% ethyl acetate / petroleum ether) to give pure 11-2 (2.26 g, 68%): LR-ES-MS m / z calculated C 12 h 11 ClFN 3 O[M] + 267, measured value [M+H] + 268.
[0151] b.
[0152] Compound 11-2 (2.02g, 7.56mmol) was added to a solution made of sodium hydroxide (0.90g, 22.5mmol) and water (2.67g, 148.18mmol) and ethanol (24mL), then the mixture was heated to reflux , and kept at this temperature for 6h. The mixture was ...
Embodiment 3
[0163] The synthesis of embodiment 3 compound Ⅰ-3
[0164]
[0165] a.
[0166] To a stirred mixture of 2-chlorophenol (1.71 g, 15.26 mmol) and ethyl 2-butynoate (1.43. g, 12.70 mmol) in acetonitrile (15 mL) was added triethylenediamine gradually under nitrogen atmosphere (DABCO, 0.51 g, 4.58 mmol), after the addition was complete, the mixture was stirred at reflux for 10 h. After the completion of the reaction, add water (10mL) and methyl tert-butyl ether (20mL) to the mixture, adjust the pH of the aqueous phase with concentrated hydrochloric acid under stirring 12 h 13 FO 3 [M] + 224, measured value [M+H] + 225.
[0167] b.
[0168] To a stirred mixture of compound 3-3 (1.99 g, 8.88 mmol) dissolved in carbon tetrachloride (25 mL) was added N-bromosuccinimide (NBS, 2.72 g, 15.10 mmol) under nitrogen atmosphere ) and azobisisobutyronitrile (AIBN, 0.22 g, 1.33 mmol). After the addition was complete, the mixture was stirred at reflux for 20 h. The reaction mixture wa...
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