Trifluoroacetic acid → 4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]piperidin-4-ylacetonitrile

HRID 1426650Notes

Reaction equation

HRID 1426650 reaction equation
[C:1]([CH2:3][C:4]1([N:17]2[CH:21]=[C:20]([C:22]3[C:23]4[CH:30]=[CH:29][N:28](COCC[Si](C)(C)C)[C:24]=4[N:25]=[CH:26][N:27]=3)[CH:19]=[N:18]2)[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)#[N:2].C(O)(C(F)(F)F)=O>>[N:25]1[C:24]2[NH:28][CH:29]=[CH:30][C:23]=2[C:22]([C:20]2[CH:19]=[N:18][N:17]([C:4]3([CH2:3][C:1]#[N:2])[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]3)[CH:21]=2)=[N:27][CH:26]=1

Participants

3

Reactant 2

HCID 6422Trifluoroacetic acidHCID 57478052tert-Butyl 4-(cyanomethyl)-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate

Product 1

HCID 574780534-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]piperidin-4-ylacetonitrileYield 3.6%

Procedure

tert-Butyl 4-(cyanomethyl)-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (0.670 g, 1.24 mmol) was dissolved in TFA (5.0 mL, 65 mmol) and was stirred for 1.3 h. LCMS showed conversion to the hydroxymethyl intermediate, M+H 338. The solution was concentrated to remove the TFA. Methanol was added to the resulting residue, and the resulting mixture was concentrated. The resulting residue was dissolved in methanol (10 mL) and 15.0 M ammonium hydroxide in water (1.66 mL) was added. The resulting solution was stirred for 2 h. LCMS and HPLC analyses showed complete deprotection. The mixture was concentrated. Toluene was added to the resulting residue and the resulting mixture was concentrated to provide a white semisolid. Most of this intermediate product was used for the next step. The rest was purified by prep HPLC using a 30 mm×100 mm C18 column; 8% ACN—H2O (0.1% NH4OH), 1.0 min, to 27% at 6 min; 60 mL/min; detector set at m/z 308; retention time, 5.4 min. Tubes containing pure product were combined and freeze dried to give 13.6 mg of the product.

Workup

  1. concentrationThe solution was concentrated
  2. customto remove the TFA
  3. additionMethanol was added to the resulting residue
  4. concentrationthe resulting mixture was concentrated
  5. dissolutionThe resulting residue was dissolved in methanol (10 mL)
  6. addition15.0 M ammonium hydroxide in water (1.66 mL) was added
  7. stirringThe resulting solution was stirred for 2 h
  8. concentrationThe mixture was concentrated
  9. additionToluene was added to the resulting residue
  10. concentrationthe resulting mixture was concentrated
  11. customto provide a white semisolid
  12. customThe rest was purified by prep HPLC
  13. wait8% ACN—H2O (0.1% NH4OH), 1.0 min, to 27% at 6 min
  14. customretention time, 5.4 min
  15. additionTubes containing pure product
  16. customfreeze dried

Sources & evidence

ORD record
ord-64ad325062e443048061cc8b39f6a495
Source dataset
uspto-grants-2015_01
Patent number
US08933086B2

Reaction notes

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