Hydrochloric Acid → HCID 68750086, compound

A mixture of 2 g of Fmoc-Rink Amide AM polystyrene resin (0.61 mmol/g resin, 1.22 mmol) and 12 ml of 20% piperidine in DMF was stirred in a microwave reactor for 2 min at 35° C. The resin was filtered and washed with DMF (3×15 ml), isopropyl alcohol (3×15 ml) and DCM (3×15 ml). The resin was treated with a solution of bromoacetic acid (III, 840 mg, 5 eq.) and N,N′-diisopropylcarbodiimide (1.15 ml, 5 eq.) in DMF (12 ml). The reaction mixture was stirred for 2 min at 60° C. in a microwave reactor. The resin was filtered and washed with DMF (3×15 ml), isopropyl alcohol (3×15 ml) and DCM (3×15 ml). A solution of 2,4-dichlorophenethylamine (IVa, 1.035 ml, 5 eq.) and triethylamine (0.85 ml, 5 eq.) in 12 ml of DMF was added to the resin and the suspension was stirred for 2 min at 90° C. activated by microwaves. The supernatant was removed and the reaction was repeated in the same conditions. The resin V obtained was filtered and washed with DMF (3×15 ml), isopropyl alcohol (3×15 ml) and DCM (3×15 ml). Then, the resin was treated with a solution of (Z)-2-butenedioic acid allyl ester (VI, 957 mg, 5 eq.), HOBT (825 mg, 5 eq.) and DIC (770 μL, 5 eq.) in DCM:DMF (2:1, 123 ml). The reaction mixture was stirred at room temperature for 30 min and was filtered. The resin was dried and washed with DMF (3×15 ml), isopropyl alcohol (3×15 ml) and DCM (3×15 ml). Then, a solution of 3,3-diphenylpropylamine (IVb, 1.29 g, 5 eq.) and triethylamine (0.85 ml, 5 eq.) in 12 ml of DMF was added to the resin and the suspension was stirred for 3 h at room temperature. The resin was filtered and the reaction was repeated for 16 h at the same temperature. The supernatant was removed and the resin was dried and washed with DMF (3×15 ml), isopropyl alcohol (3×15 ml) and DCM (3×15 ml). Cleavage from the solid phase was performed by treatment with a 60:40:2 TFA/DCM/water mixture (20 ml) for 30 min at room temperature. The reaction mixture was filtered and the solvents were evaporated at reduced pressure. Cyclization was then performed by treating the residue obtained with 20 ml of dioxane for 1.5 h at reflux (monitoring the reaction by HPLC). A 1:2 solution (9 ml) of 4N sodium hydroxide and allyl alcohol was then added and the mixture was stirred for 45 min at reflux. The crude reaction product was acidified with 1N hydrochloric acid and the solvent was evaporated. The resulting solution was extracted with ethyl acetate (3×50 ml) and the organic extracts were washed with a saturated NaCl solution (2×100 ml); they were dried on anhydrous MgSO4 and were evaporated at reduced pressure to obtain 450 mg of the desired product (X, 70% purity, 95% yield at 210 nm). HRMS (M+H)+ calculated for C29H29Cl2N2O4, 539.1504, experimental, 539.1514.

1. filtrationwas filtered
2. washwashed with DMF (3×15 ml), isopropyl alcohol (3×15 ml) and DCM (3×15 ml)
3. filtrationwas filtered
4. customThe resin was dried
5. washwashed with DMF (3×15 ml), isopropyl alcohol (3×15 ml) and DCM (3×15 ml)
6. stirringthe suspension was stirred for 3 h at room temperature
7. filtrationThe resin was filtered
8. waitthe reaction was repeated for 16 h at the same temperature
9. customThe supernatant was removed
10. customthe resin was dried
11. washwashed with DMF (3×15 ml), isopropyl alcohol (3×15 ml) and DCM (3×15 ml)
12. waitCleavage from the solid phase was performed by treatment with a 60:40:2 TFA/DCM/water mixture (20 ml) for 30 min at room temperature
13. filtrationThe reaction mixture was filtered
14. customthe solvents were evaporated at reduced pressure
15. additionby treating the residue
16. customobtained with 20 ml of dioxane for 1.5 h
17. temperatureat reflux (
18. customthe reaction by HPLC)
19. stirringthe mixture was stirred for 45 min
20. temperatureat reflux
21. customThe crude reaction product
22. customthe solvent was evaporated
23. extractionThe resulting solution was extracted with ethyl acetate (3×50 ml)
24. washthe organic extracts were washed with a saturated NaCl solution (2×100 ml)
25. dry with materialthey were dried on anhydrous MgSO4
26. customwere evaporated at reduced pressure

ORD record

ord-0b2899b9b3504ad68edf1bb44729b266

Source dataset

uspto-grants-2015_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09040701B2