反应详情

温度

60 °C

A 0.25 M solution of SEM-Boc protected aminopyrrolopyrazole, E1(III-2) was prepared using anhydrous DMF as solvent. A 0.25 M solution of 3-ethylisoxazole-5-carboxylic acid was prepared using anhydrous DMF as solvent. A fresh 0.5 M solution of o-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyl uronium hexafluorophosphate (HATU) was prepared in anhydrous DMF. To the reaction tube were added 320 μL (0.08 mmol, 1 equiv, 0.25M) of the 3-ethylisoxazole-5-carboxylic acid DMF solution prepared, 320 μL (0.080 mmol, 1 equiv, 0.25M) of SEM-Boc protected aminopyrrolopyrazole DMF solution prepared, and 40 μL (0.288 mmol, 3.6 equiv) neat TEA followed by the 160 μL (0.080 mmol, 1 equiv) of the HATU DMF solution. The reaction mixtures were stirred at 60° C. for 16 h. Then the tube was allowed to cool to room temperature. The solvents and volatiles from the tubes were removed in vacuo. To the residue were added 1 mL of EtOAc and 1 mL of 2M aqueous NaOH. After the tube was covered with Parafilm, the covered test tube was vigorously shaken until all residues have dissolved or the mixtures are completely homogenized. The agitation was stopped and the phases were allowed to separate completely. The supernatant organic layer (EtOAc layer) of each test tube was transferred into its corresponding receiving tube. EtOAc (0.5 mL) was added to the tube and extracted the organic layers after the agitation of the mixtures and these procedures were repeated twice. The solvent (EtOAc) and volatiles from the receiving tube were removed in vacuo until they were dry. To the residue was added 0.6 mL (2.4 mmol, 30 equiv) of 4M HCl in dioxane and the mixtures were stirred at room temperature for 2 h. Then the solvent, volatiles and HCl from the tube were removed in vacuo. To the residue were added 500 μL anhydrous DMA, 70 μL neat DIPEA (0.400 mmol, 5 equiv.). A 0.25 M solution of (3S,8aS)-3-methylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carbonyl chloride, E1(VI), in anhydrous CH2Cl2 was prepared.

1. customwas prepared
2. customprepared
3. customprepared
4. customThe reaction mixtures
5. temperatureto cool to room temperature
6. customThe solvents and volatiles from the tubes were removed in vacuo
7. additionTo the residue were added 1 mL of EtOAc and 1 mL of 2M aqueous NaOH
8. stirringthe covered test tube was vigorously shaken until all residues
9. dissolutionhave dissolved
10. stirringthe mixtures are completely homogenized
11. customto separate completely
12. customThe supernatant organic layer (EtOAc layer) of each test tube was transferred into its corresponding receiving tube
13. additionEtOAc (0.5 mL) was added to the tube
14. extractionextracted the organic layers after the agitation of the mixtures
15. customThe solvent (EtOAc) and volatiles from the receiving tube were removed in vacuo until they
16. customwere dry
17. stirringthe mixtures were stirred at room temperature for 2 h
18. customThen the solvent, volatiles and HCl from the tube were removed in vacuo