Octahydropyrrolo[3,4-c]pyrrole derivative and use thereof
A compound, CH3 technology, applied in the field of medicine, can solve the problem of safety refusal to approve, and achieve the effect of high safety, improved tolerance and good bioavailability
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Embodiment 1
[0190] Example 1 2-(5-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2( Synthesis of 1H)-yl)-4-methylthiazole-5-carboxamide
[0191]
[0192] 2-Bromo-4-methylthiazole-5-carboxamide (295mg, 1.33mmol), (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(hexa Hydrogen pyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone hydrochloride (500mg, 1.34mmol) (reference patent CN105949203 A, synthesis of Example 3), sodium carbonate (0.569g, 5.34 mmol) and acetonitrile (15 mL) were added into a 100 mL reaction flask, and reacted at 80° C. under reflux for 12 hours. The completion of the reaction was monitored by TLC, the reaction was stopped, cooled to room temperature, and spin-dried. Purification by silica gel column (dichloromethane / methanol (v / v)=40 / 1) gave the title compound as a yellow solid (510 mg, yield: 86.5%).
[0193] MS(ESI,pos.ion)m / z:442.50[M+H] + ;
[0194] 1 H NMR (400MHz, CDCl 3 )δ(ppm): 7.90–7.73(m,3H), 7.50(dt, J=14.3,7.3Hz,1H), 7.17(t,J=8.5Hz,1H), 5.67...
Embodiment 2
[0196] Example 2 2-(5-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2( Synthesis of 1H)-yl)-4-methylthiazole-5-carbonitrile
[0197]
[0198] 2-Bromo-4-methylthiazole-5-carbonitrile (325mg, 1.60mmol), (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)( Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone hydrochloride (600mg, 1.60mmol) (refer to patent CN 105949203A, synthesis of Example 3), sodium carbonate (0.683g, 6.41 mmol) and acetonitrile (15 mL) were added into a 100 mL reaction flask, and reacted at 80° C. under reflux for 12 hours. The reaction was monitored by TLC, the reaction was stopped, cooled to room temperature, and spin-dried. Purification by silica gel column (dichloromethane / methanol (v / v)=50 / 1) gave the title compound as a white solid (623 mg, yield: 91.7%).
[0199] MS(ESI,pos.ion)m / z:424.05[M+H] + ;
[0200] 1 H NMR (400MHz, CDCl 3 )δ (ppm): 7.90–7.75 (m, 3H), 7.51 (dd, J = 14.3, 8.2Hz, 1H), 7.17 (td, J = 8.5, 2.7Hz, 1H), 3.96 (d...
Embodiment 3
[0202] Example 3 4-methyl-2-(5-(5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4- c] Synthesis of pyrrole-2 (1H) base) thiazole-5-carboxylic acid ethyl ester
[0203]
[0204] 2-Bromo-4-methylthiazole-5-carboxylic acid ethyl ester (220mg, 0.88mmol), (hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(5-methyl Base-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrochloride (293mg, 0.88mmol) (refer to patent CN 105949203 A, the synthesis of Example 1), triethyl Amine (445mg, 4.4mmol) and N,N-dimethylformamide (8mL) were added into a 50mL reaction flask and reacted at 60°C for 12 hours. TLC detects that the reaction is complete, and the reaction is stopped. Water (50 mL) was added, extracted with dichloromethane (50 mL*2), the organic layer was washed twice with saturated brine, dried over anhydrous sodium sulfate, and spin-dried. Purified by silica gel column (dichloromethane / methanol (v / v)=50 / 1), concentrated and dried to obtain the title compound as a tan solid (350 mg, ...
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