Chlorotrimethylsilane → Tert-butyl 3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3-hydroxypiperidine-1-carboxylate

HRID 578755Notes

Reaction equation

HRID 578755 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.[O:22]=[C:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1>C1COCC1>[NH2:11][C:6]1[C:5]2=[CH:4][CH:3]=[C:2]([C:23]3([OH:22])[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:24]3)[N:10]2[N:9]=[CH:8][N:7]=1

Participants

6

Reactant 4

HCID 6397ChlorotrimethylsilaneHCID 2756825Tert-butyl 3-oxopiperidine-1-carboxylateHCID 422813837-Bromopyrrolo[2,1-f][1,2,4]triazin-4-amineHCID 178418918HCID 178418918, compound

Product 1

HCID 58529617Tert-butyl 3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3-hydroxypiperidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

7-Bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (17.29 g, 81 mmol) was dissolved in THF (214 mL) under argon at room temperature. Chlorotrimethylsilane (20.60 mL, 17.63 g, 162 mmol, 2 eq.) was added, and the mixture was stirred at room temperature for 3 h. Then, it was cooled to 0° C., and 2-propyl magnesium chloride (170 mL of a 2.0 M solution in THF, 340 mmol, 4.2 eq.) was added. The mixture was stirred for further 3 h while warming up to room temperature. Then, tert-butyl 3-oxopiperidine-1-carboxylate (25.00 g, 121 mmol, 1.5 eq.) was added, and stirring was continued for another 16 h. The reaction was quenched with a 1:1 mixture of concentrated aqueous ammonium chloride solution and ice until the pH value reached 6-7. The mixture was extracted with two portions of ethyl acetate, and the combined organic extracts were dried over anhydrous sodium carbonate and concentrated to dryness. The title compound crystallized upon trituration of the residue with diethyl ether (50 mL). The crystals were washed with diethyl ether and dried to give 17.20 g (64% of th.).

Workup

  1. temperatureThen, it was cooled to 0° C.
  2. stirringThe mixture was stirred for further 3 h
  3. temperaturewhile warming up to room temperature
  4. stirringstirring
  5. waitwas continued for another 16 h
  6. customThe reaction was quenched with a 1:1 mixture of concentrated aqueous ammonium chloride solution and ice until the pH value
  7. extractionThe mixture was extracted with two portions of ethyl acetate
  8. dry with materialthe combined organic extracts were dried over anhydrous sodium carbonate
  9. concentrationconcentrated to dryness
  10. customThe title compound crystallized upon trituration of the residue with diethyl ether (50 mL)
  11. washThe crystals were washed with diethyl ether
  12. customdried
  13. customto give 17.20 g (64% of th.)

Sources & evidence

ORD record
ord-c680494fb04846838e4f5661daf9e112
Source dataset
uspto-grants-2015_05
Patent number
US09040691B2

Reaction notes

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