Water → 1-(5,7-Dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl)-2-[2-(4-methoxy-phenyl)-6-methyl-imidazo[1,2-a]pyridin-3-yl]-ethanone

HRID 858895Notes

Reaction equation

HRID 858895 reaction equation
C([O:3][C:4](=O)[CH2:5][C:6]1[N:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]2=[N:8][C:7]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:35][C:36]1[CH:41]=[C:40]([CH3:42])[N:39]2[N:43]=[CH:44][C:45](C(Cl)=O)=[C:38]2[N:37]=1.O>C1COCC1.CCOC(C)=O>[CH3:35][C:36]1[CH:41]=[C:40]([CH3:42])[N:39]2[N:43]=[CH:44][C:45]([C:4](=[O:3])[CH2:5][C:6]3[N:10]4[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]4=[N:8][C:7]=3[C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[C:38]2[N:37]=1

Participants

7

Reactant 4

HCID 962Water2×HCID 3251421Potassium bis(trimethylsilyl)amideHCID 450819555,7-Dimethylpyrazolo[1,5-a]pyrimidine-3-carbonyl chlorideHCID 58763578[2-(4-Methoxy-phenyl)-6-methyl-imidazo[1,2-a]pyridin-3-yl]-acetic acid ethyl ester

Product 1

HCID 114530441-(5,7-Dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl)-2-[2-(4-methoxy-phenyl)-6-methyl-imidazo[1,2-a]pyridin-3-yl]-ethanoneYield 20.3%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-78 °C

Procedure

To a magnetically stirred solution of [2-(4-methoxy-phenyl)-6-methyl-imidazo[1,2-a]pyridin-3-yl]-acetic acid ethyl ester 13c (0.075 g, 0.231 mmol) in THF (3.0 mL) at −78° C. under Ar atmosphere was added potassium bis(trimethylsilyl)amide (KHMDS) (0.508 mL, 0.5M, 0.254 mmol). The reaction mixture was stirred for 15 min at −78° C., then a THF solution of 5,7-dimethyl-pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (0.053 g, 0.254 mmol) was added. After an additional 60 min at −78° C., water (20 mL) was added, and the reaction mixture was warmed to room temperature. Water was added, and the aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, dried (MgSO4), and concentrated in vacuo to the crude alkylated product. The crude adduct was dissolved in acetic acid (HOAc) (1 mL) and 12 N HCl (1 mL). The reaction mixture refluxed for 2 h. The mixture was cooled to room temperature and treated with aq Na2CO3 solution until basic. The aqueous solution was extracted with dichloromethane (2×50 mL). The combined organic layers were washed with water (20 mL), dried (MgSO4), and concentrated in vacuo to the crude product. The pure product was obtained by column chromatography over silica gel,(40:60 EtOAc/hexane, then 100% EtOAc as eluent), which gave the title compound (0.02 g, 20%) as an off white solid. 1H NMR (400 MHz, CDCl3) 2.28 (s, 3H), 2.62 (s, 3H), 2.82 (s, 3H), 3.81 (s, 3H), 4.98 (s, 2H), 6.80 (s, 1H), 6.91 (d, J=8.4 Hz, 2H), 7.02 (d, J=9.1 Hz, 1H), 7.54 (d, J=9.1 Hz, 1H), 7.68 (d, J=9.0 Hz, 2H), 7.76 (s, 1H), 8.62 (s, 1H). Mass spectrum m/e 426 (M+).

Workup

  1. waitAfter an additional 60 min at −78° C.
  2. temperaturethe reaction mixture was warmed to room temperature
  3. extractionthe aqueous phase was extracted with ethyl acetate (2×100 mL)
  4. washThe combined organic layers were washed with water
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated in vacuo to the crude alkylated product
  7. dissolutionThe crude adduct was dissolved in acetic acid (HOAc) (1 mL)
  8. temperatureThe reaction mixture refluxed for 2 h
  9. temperatureThe mixture was cooled to room temperature
  10. additiontreated with aq Na2CO3 solution until basic
  11. extractionThe aqueous solution was extracted with dichloromethane (2×50 mL)
  12. washThe combined organic layers were washed with water (20 mL)
  13. dry with materialdried (MgSO4)
  14. concentrationconcentrated in vacuo to the crude product
  15. customThe pure product was obtained by column chromatography over silica gel,(40:60 EtOAc/hexane

Sources & evidence

ORD record
ord-e9eb15e31ee24a7683ad8f7e48d6cf81
Source dataset
uspto-grants-2006_12
Patent number
US07148353B2

Reaction notes

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