Dimethylformamide → HCID 58406376, compound

To generate the acid chloride, 3-methyl-1,2-oxazole-4-carboxylic acid (95.53 mg, 0.75 mmol) was dissolved in CH2Cl2 (10 mL). Oxalyl chloride (0.22 mL, 2.63 mmol) and a drop of DMF were added at 0° C. The ice bath was removed and the mixture stirred for 1 h before the solvent and the unreacting oxalyl chloride was removed with a stream of nitrogen. The residue was further dried in vacuo. 10a-[4-(difluoromethoxy)phenyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (60 mg, 0.19 mmol) was dissolved in pyridine (4 ml) and the solution added to the previously generated acid chloride in pyridine (1 mL) at 0° C. The ice bath was removed after 15 min and the mixture stirred at room temperature for 18 h. LCMS analysis showed only a trace amount of product. Further 4 equivalent of acid chloride were prepared as described above and added to the reaction mixture. The resultant mixture was then heated at 50° C. until completion (28 h, monitored by LCMS). The resultant suspension was then concentrated in vacuo and the residue partitioned between CH2Cl2 (20 mL) and a saturated aqueous solution of NaHCO3 (10 mL). The organic layers were washed with further a saturated aqueous solution of NaHCO3 (10 mL) and brine (5 mL), dried (MgSO4), filtered and concentrated in vacuo to give a yellow residue. This residue was purified by flash column chromatography (Biotage SP4, 12 g cartridge, 70-100% EtOAc gradient in n-hexanes) to give 10a-[4-(difluoromethoxy)phenyl]-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one compound (I) as a white solid (42 mg, yield 52%).

1. customThe ice bath was removed
2. customthe unreacting oxalyl chloride was removed with a stream of nitrogen
3. customThe residue was further dried in vacuo
4. customThe ice bath was removed after 15 min
5. stirringthe mixture stirred at room temperature for 18 h
6. additionadded to the reaction mixture
7. concentrationThe resultant suspension was then concentrated in vacuo
8. customthe residue partitioned between CH2Cl2 (20 mL)
9. washThe organic layers were washed with further a saturated aqueous solution of NaHCO3 (10 mL) and brine (5 mL)
10. dry with materialdried (MgSO4)
11. filtrationfiltered
12. concentrationconcentrated in vacuo
13. customto give a yellow residue
14. customThis residue was purified by flash column chromatography (Biotage SP4, 12 g cartridge, 70-100% EtOAc gradient in n-hexanes)

ORD record

ord-ec2c92443c3243f5ab1c97ef6934ef8f

Source dataset

uspto-grants-2015_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09163029B2