Acetic Acid → (R)-tert-Butyl(1-(2-(1-ethyl-5-methoxy-1H-pyrrolo[2,3-c]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carbonyl)piperidin-3-yl)carbamate

1-Ethyl-5-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (200 mg, 0.908 mmol, reported in WO 2010/118208) and HATU (380 mg, 0.999 mmol) were dissolved in DMF (2 mL) and stirred at rt for 5 min. To this was added a solution of (R)-tert-butyl(1-(4-(methylamino)-3-nitrobenzoyl)piperidin-3-yl)carbamate (316 mg, 0.908 mmol) and DIPEA (0.476 ml, 2.72 mmol) in DMF (2 ml), and the resulting mixture stirred under nitrogen at rt for 3.5 hr. The reaction mixture was diluted with water (40 ml) and partitioned with ether (50 ml). The organic layer was isolated then the aqueous layer re-extracted with ether (2×50 ml). Combined organic layers were washed with water (2×30 ml) then dried over sodium sulfate then passed through a hydrophobic frit and concentrated under reduced pressure to give the crude amide intermediate as a blue solid. The solid was dried under reduced pressure overnight then dissolved in toluene (12.5 ml). Acetic acid (0.052 ml, 0.908 mmol) was added to the reaction mixture which was refluxed for 5 hr. Sodium bicarbonate (40 ml) was added to the reaction mixture and the organic layer isolated. The aqueous layer was reextracted with toluene (2×40 ml) and combined organic layers were concentrated under reduced pressure to give 238 mg of the crude product as a red-brown gum. The crude material was purified with column chromatography (eluted with 100% EtOAc) then further purified by high pH MDAP (Method E) to give the title compound as an off-white solid (106 mg, 22%).

1. stirringthe resulting mixture stirred under nitrogen at rt for 3.5 hr
2. custompartitioned with ether (50 ml)
3. customThe organic layer was isolated
4. extractionthe aqueous layer re-extracted with ether (2×50 ml)
5. washCombined organic layers were washed with water (2×30 ml)
6. dry with materialthen dried over sodium sulfate
7. concentrationconcentrated under reduced pressure
8. customto give the crude amide intermediate as a blue solid
9. customThe solid was dried under reduced pressure overnight
10. dissolutionthen dissolved in toluene (12.5 ml)
11. temperaturewas refluxed for 5 hr
12. customthe organic layer isolated
13. concentrationwere concentrated under reduced pressure
14. customto give 238 mg of the crude product as a red-brown gum
15. customThe crude material was purified with column chromatography (eluted with 100% EtOAc)
16. customthen further purified by high pH MDAP (Method E)

ORD record

ord-d82ada1475e84370b0058b3b81cab709

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09127003B2