Chlorotrimethylsilane → 2-[(4-Amino-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-hydroxy-methyl]-cyclopropanecarboxylic acid ethyl ester

HRID 1972874Notes

Reaction equation

HRID 1972874 reaction equation
Br[C:2]1[N:10]2[C:5]([C:6]([NH2:11])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl[Si](C)(C)C.CC([Mg]Cl)C.[CH2:22]([O:24][C:25]([CH:27]1[CH2:29][CH:28]1[CH:30]=[O:31])=[O:26])[CH3:23]>C1COCC1>[CH2:22]([O:24][C:25]([CH:27]1[CH2:29][CH:28]1[CH:30]([C:2]1[N:10]2[C:5]([C:6]([NH2:11])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)[OH:31])=[O:26])[CH3:23]

Participants

6

Reactant 4

HCID 6397ChlorotrimethylsilaneHCID 89334Ethyl 2-formylcyclopropanecarboxylateHCID 422813837-Bromopyrrolo[2,1-f][1,2,4]triazin-4-amineHCID 178418918HCID 178418918, compound

Product 1

HCID 585294272-[(4-Amino-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-hydroxy-methyl]-cyclopropanecarboxylic acid ethyl esterYield 30%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a stirred solution of 7-bromo-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (5.27 g, 24.7 mmol) in anhydrous THF (40 mL) was added chlorotrimethylsilane (5.9 g, 54.4 mmol) at rt. The reaction mixture was stirred at rt for 2 hours and cooled in an ice water bath. 2-propylmagnesium chloride in THF (52 mL, 104 mmol, 2.0 M) was added dropwise, and the reaction mixture was allowed stirred at rt for 2 hours. The reaction was cooled to 0° C. with an ice bath, and 2-formyl-cyclopropanecarboxylic acid ethyl ester (4.6 g, 32 mmol) was added. The reaction mixture was stirred at rt for 1 hour. The mixture was quenched with saturated, aqueous ammonium chloride (20 mL) In ice water bath. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was washed with water, brine, dried by Na2SO4, filtered and concentrated. The crude product was separated by column (30% EtOAc/70% Hexane) to give 2.0 g (30%) of product. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.75 (bs, 2 H), 6.80 (s, 1 H), 6.60 (m, 1 H), 5.40 (s, 1 H), 5.0-4.8 (m, 1 H), 4.0 (m, 2 H), 1.9-1.8 (m, 2 H), 1.2 (t, 3 H), 1.0 (m, 2 H); ES-MS m/z 277.34 [M+H]+, HPLC RT (min) 1.51.

Workup

  1. temperaturecooled in an ice water bath
  2. stirringthe reaction mixture was allowed stirred at rt for 2 hours
  3. temperatureThe reaction was cooled to 0° C. with an ice bath
  4. stirringThe reaction mixture was stirred at rt for 1 hour
  5. customThe mixture was quenched with saturated, aqueous ammonium chloride (20 mL) In ice water bath
  6. customThe organic layer was separated
  7. extractionthe aqueous layer was extracted with ethyl acetate (100 mL)
  8. washThe combined organic layer was washed with water, brine
  9. dry with materialdried by Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customThe crude product was separated by column (30% EtOAc/70% Hexane)

Sources & evidence

ORD record
ord-97a23a7e4e0a4305a30d1357c4059166
Source dataset
uspto-grants-2013_04
Patent number
US08431695B2

Reaction notes

Loading…