Diisopropylethylamine → Ethyl5-chloro-6-(2-methoxy-2-oxoacetyl)-7-methylimidazo[1,2-a]pyridine-2-carboxylate

HRID 1481963Notes

Reaction equation

HRID 1481963 reaction equation
[Cl:1][C:2]1[N:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:6]2[CH:5]=[C:4]([CH3:16])[C:3]=1[C:17]([OH:19])=O.[Br-].C(C[S+]1CCCC1)#N.CCN(C(C)C)C(C)C.CN([C:41]([O:45]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:62]([O-])(O)=[O:63].[Na+].OOS([O-])=O.[K+]>C(Cl)Cl.O>[Cl:1][C:2]1[N:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:6]2[CH:5]=[C:4]([CH3:16])[C:3]=1[C:17](=[O:19])[C:62]([O:45][CH3:41])=[O:63]

Participants

9

Reactant 6

HCID 81531Diisopropylethylamine2×HCID 516892Sodium Bicarbonate2×HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 23707502Potassium hydroxy sulfite2×HCID 862488991-(cyanomethyl)tetrahydro-1H-thiophen-1-ium, bromide salt2×HCID 1176324075-Chloro-2-(ethoxycarbonyl)-7-methylimidazo[1,2-a]pyridine-6-carboxylic acid

Product 1

HCID 117631349Ethyl5-chloro-6-(2-methoxy-2-oxoacetyl)-7-methylimidazo[1,2-a]pyridine-2-carboxylate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

To a slurry of 5-chloro-2-(ethoxycarbonyl)-7-methylimidazo[1,2-a]pyridine-6-carboxylic acid (0.46 g, 1.623, 1 equiv) and 1-(cyanomethyl)tetrahydro-1H-thiophen-1-ium, bromide salt (0.47 g, 2.27 mmol, 1.4 equiv) in DCM (16 mL) was added DIPEA (1.13 mL, 6.49 mmol, 4 equiv) then HATU (0.86 g, 2.27 mmol, 1.4 equiv). After 2 h, more 1-(cyanomethyl)tetrahydro-1H-thiophen-1-ium, bromide salt (0.20 g) and DIPEA (0.5 mL) added. After stirring 18 h, the reaction was added to saturated aqueous NaHCO3 and extracted with DCM (×2). The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo. The crude sulfur ylide was taken up in MeOH (16 mL) and a solution of Oxone (2.4 g, 3.90 mmol, 2.4 equiv) in water (5 mL) was added. After 2 d, more Oxone (2.4 g, 3.90 mmol, 2.4 equiv) was added. After 6 h, the reaction was added cautiously to saturated aqueous NaHCO3 and extracted with DCM (×3). The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (20-100% EtOAc/hex) to provide the product (0.40, 76%) as a viscous yellow oil. 1H NMR (500 MHz, CDCl3) δ 8.37 (d, J=0.8 Hz, 1H), 7.55-7.52 (m, 1H), 4.51 (q, J=7.2 Hz, 2H), 4.01 (s, 3H), 2.40 (d, J=1.1 Hz, 3H), 1.47 (t, J=7.2 Hz, 3H); LCMS (ESI, M+1): 325.05.

Workup

  1. extractionextracted with DCM (×2)
  2. dry with materialThe combined DCM extracts were dried (Na2SO4)
  3. concentrationconcentrated in vacuo
  4. waitAfter 2 d
  5. waitAfter 6 h
  6. extractionextracted with DCM (×3)
  7. dry with materialThe combined DCM extracts were dried (Na2SO4)
  8. concentrationconcentrated in vacuo
  9. customThe crude product was purified by flash column chromatography (20-100% EtOAc/hex)
  10. customto provide the product (0.40, 76%) as a viscous yellow oil

Sources & evidence

ORD record
ord-83d930b0b2894a67a16aef0ce162f291
Source dataset
uspto-grants-2016_08
Patent number
US09409922B2

Reaction notes

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