反应详情

Methyl 6-cyclohexyl-5-[2-({[(3S)-1-isopropylpyrrolidin-3-yl]amino}methyl)phenyl]-4-(2-methoxy-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate was dissolved in MeOH/THF/water and LiOH monohydrate (1.04 eq.) was added to the solution. The mixture was left stirring at RT for 5 h. All volatiles were evaporated i. vac. and the residual material was dried i. vac. The crude material was redissolved in DMF, HATU (1.2 eq.) and DIPEA (3.6 eq.) were added and the mixture was left stirring overnight. All volatiles were evaporated i. vac. and the residual material was filtered with EtOAc/PE+1% NEt3 through silica gel. After evaporation of the solvents the crude product was dissolved in THF and 2M borane dimethylsulfide complex in THF (20 eq.) was added. After 1 h all volatiles were evaporated i. vac. and the residual material was dissolved in an excess of 1.25M HCl in MeOH. The solution was warmed to 70° C. and evaporated slowly to dryness. The crude residue was dissolved in dioxane and an excess of 1N aq. KOH-solution was added. The mixture was left stirring over night and then warmed for 2 h to 50° C. The product was then isolated by prep. RP-HPLC. After lyophilisation of the product fractions a colourless solid was obtained (42%). 1H-NMR (400 MHz, DMSO-d6, 330 K, mixture of atropisomers, δ) 7.90-7.88 (2s, 1H); 7.53-7.47 (m, 3H), 7.39-7.37 (2s, 1H), 4.59-4.48 (m, 1H), 3.91-3.42 (m, 5H), 3.30-3.18 (m, 1H), 3.10-2.67 (m, 2H), 2.60-2.51 (m, 3H), 2.33-2.15 (m, 2H), 2.03-2.00 (m, 1H), 1.85-1.82 (m, 1H), 1.74-1.65 (m, 3H), 1.59-1.43 (m, 2H), 1.36-1.10 (m, 10H); MS (ES+) m/z 492 (M+H)+; [α]D20−4.8° (c=1.0 in MeCN).

1. waitThe mixture was left
2. customAll volatiles were evaporated i
3. customand the residual material was dried i
4. dissolutionThe crude material was redissolved in DMF
5. waitthe mixture was left
6. stirringstirring overnight
7. customAll volatiles were evaporated i
8. filtrationand the residual material was filtered with EtOAc/PE+1% NEt3 through silica gel
9. customAfter evaporation of the solvents the crude product
10. dissolutionwas dissolved in THF
11. customAfter 1 h all volatiles were evaporated i
12. dissolutionand the residual material was dissolved in an excess of 1.25M HCl in MeOH
13. temperatureThe solution was warmed to 70° C.
14. customevaporated slowly to dryness
15. dissolutionThe crude residue was dissolved in dioxane
16. additionan excess of 1N aq. KOH-solution was added
17. waitThe mixture was left
18. stirringstirring over night
19. temperaturewarmed for 2 h to 50° C
20. customThe product was then isolated by prep
21. customAfter lyophilisation of the product fractions a colourless solid was obtained (42%)