Oxalyl chloride → HCID 46200930, Verbindung

Temperatur

150 °C

To a solution of 1,1-dimethylethyl(2S)-2-(3-bromo-2-oxopropyl)-1-piperidinecarboxylate D2 (0.140 g, 0.44 mmol) in DMF (2 ml) was added 3,5-dimethyl-2-pyrazinamine (0.054 g, 0.44 mmol) and the mixture was stirred at 150° C. for 30 min. The reaction mixture was charged into a SCX column and was eluted with methanol and ammonia 2 M in methanol. Collected fractions gave 0.115 g of a crude containing the desired 6,8-dimethyl-2-[(2S)-2-piperidinylmethyl]imidazo[1,2-a]pyrazine. UPLC: rt=0.34, peak observed: 245 (M+1). C14H20N4 requires 244. Into a 7 ml screw capped vial 2-methyl-5-phenyl-1,3-thiazole-4-carboxylic acid (0.114 g, 0.52 mmol) was dissolved in DCM (1 ml), Oxalyl chloride (0.100 ml, 1.14 mmol) then DMF (0.036 ml, 0.47 mmol) were added and the resulting mixture was stirred for 30 min at rt. The solvent was removed under reduced pressure and the resulting yellow solid dissolved in DCM (1 ml) and added dropwise to the solution containing the crude (0.115 g) 6,8-dimethyl-2-[(2S)-2-piperidinylmethyl]imidazo[1,2-a]pyrazine and TEA (0.197 ml, 0.47 mmol) in DCM (1 ml) cooled at 0° C. The ice-bath was removed and the reaction mixture left under stirring at rt for 1 h. DCM was added and the mixture washed with a saturated NaHCO3 aqueous solution, the organic phase was separated, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica gel (Biotage 25 M, DCM/MeOH, 90/01) and by fraction lynx (basic method). The free base of the title compound was obtained (0.039 g, 0.079 mmol, 20% yield from D2, three steps) as a yellow solid. UPLC: rt=0.58, peak observed: 446 (M+1). C25H27N5OS requires 445. 1H NMR [the product is present as a mixture of conformers (ratio c.ca 60/40)] (500 MHz, DMSO-d6). The free base (0.037 g, 0.08 mmol) was transferred into a 7 ml screw capped vial with anhydrous DCM (1 ml) and the solution cooled to 0° C. HCl (0.125 ml of a 1 M solution in Et2O, 0.13 mmol) was added dropwise and the mixture stirred for 15 min. The solvent was removed under reduced pressure and the resulting solid triturated with anhydrous Et2O. The title compound was obtained (0.041 g, 0.08 mmol, 98% yield) as a white solid. UPLC: rt=0.58, peak observed: 446 (M+1-HCl). C25H28ClN5OS requires 482.

1. additionThe reaction mixture was charged into a SCX column
2. washwas eluted with methanol and ammonia 2 M in methanol
3. customCollected fractions gave 0.115 g of a crude
4. customrt=0.34, peak
5. stirringthe resulting mixture was stirred for 30 min at rt
6. customThe solvent was removed under reduced pressure
7. dissolutionthe resulting yellow solid dissolved in DCM (1 ml)
8. additionadded dropwise to the solution
9. temperaturecooled at 0° C
10. customThe ice-bath was removed
11. waitthe reaction mixture left
12. stirringunder stirring at rt for 1 h
13. additionDCM was added
14. washthe mixture washed with a saturated NaHCO3 aqueous solution
15. customthe organic phase was separated
16. dry with materialdried (Na2SO4)
17. filtrationfiltered
18. concentrationconcentrated
19. customThe residue was purified by column chromatography on silica gel (Biotage 25 M, DCM/MeOH, 90/01) and by fraction lynx (basic method)

ORD-Eintrag

ord-5f17b0bb626e42a19b3aa998ce98dc1c

Quelldatensatz

uspto-grants-2012_03

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08129384B2