Formamide → tert-butyl 4-(5-vinyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate

Temperatur

140 °C

Ethyl 2-amino-5-vinylcyclopent-1-enecarboxylate (2.132 g, 12.75 mmol) was mixed with ammonium formate (4.02 g, 63.75 mmol) and formamide (5.56 mL, 127.5 mmol) and heated at 140° C. for 16 hours. The mixture was diluted with water (50 mL) and 20% IPA-DCM (100 mL). Solids were filtered off (Celite). The organic layer was separated. The aqueous layer was extracted with 20% IPA-DCM (3×50 mL). The combined organic solutions were washed with brine (20 mL) and dried (Na2SO4). After filtration and concentration, toluene (10 mL) was added to the crude (1.543 g), mixed, and evaporated. The resulting 5-vinyl-6,7-dihydro-3H-cyclopenta[d]pyrimidin-4(5H)-one was mixed with acetonitrile (30 mL) and POCl3 (2.62 mL, 28.54 mmol) and heated at 80° C. for 20 hours. The mixture was cooled to 0° C. 50% KOH (11.25 mL, 142.7 mmol) was added dropwise. t-Butyl piperazine-1-carboxylate (5.31 g, 28.53 mmol) was added. The mixture was heated at 80° C. for 24 hours. The contents were concentrated. Water was added. The mixture was extracted with DCM (2×) and dried (Na2SO4). The crude material was purified with flash chromatography to give tert-butyl 4-(5-vinyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (855 mg, 20% for 2 steps). 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.47 (s, 1H), 5.95-5.86 (m, 1H), 5.12-5.09 (m, 1H), 4.92-4.87 (m, 1H), 3.98-3.93 (m, 1H), 3.67-3.60 (m, 4H), 3.-3.39 (m, 4H), 2.94-2.76 (m, 2H), 2.35-2.27 (m, 1H), 1.90-1.82 (m, 1H), 1.47 (d, 1.47 (s, 9H). MS: 331.3 (M+1).

1. filtrationSolids were filtered off (Celite)
2. customThe organic layer was separated
3. extractionThe aqueous layer was extracted with 20% IPA-DCM (3×50 mL)
4. washThe combined organic solutions were washed with brine (20 mL)
5. dry with materialdried (Na2SO4)
6. filtrationAfter filtration and concentration, toluene (10 mL)
7. additionwas added to the crude (1.543 g)
8. additionmixed
9. customevaporated
10. temperatureheated at 80° C. for 20 hours
11. temperatureThe mixture was cooled to 0° C
12. temperatureThe mixture was heated at 80° C. for 24 hours
13. concentrationThe contents were concentrated
14. additionWater was added
15. extractionThe mixture was extracted with DCM (2×)
16. dry with materialdried (Na2SO4)
17. customThe crude material was purified with flash chromatography

ORD-Eintrag

ord-50eca08b00e24e02a142dc563dedd3a1

Quelldatensatz

uspto-grants-2014_09

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08846681B2