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

HRID 45020Notes

Reaction equation

HRID 45020 reaction equation
C(O)(C(F)(F)F)=O.C[Si](C)(C)CCOC[N:14]1[C:18]2[N:19]=[CH:20][N:21]=[C:22]([C:23]3[CH:24]=[N:25][N:26]([CH:28]4[CH2:33][CH2:32][C:31](=[CH:34][C:35]#[N:36])[CH2:30][CH2:29]4)[CH:27]=3)[C:17]=2[CH:16]=[CH:15]1.[OH-].[NH4+]>CC#N.O>[N:19]1[C:18]2[NH:14][CH:15]=[CH:16][C:17]=2[C:22]([C:23]2[CH:24]=[N:25][N:26]([CH:28]3[CH2:29][CH2:30][C:31](=[CH:34][C:35]#[N:36])[CH2:32][CH2:33]3)[CH:27]=2)=[N:21][CH:20]=1

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acidHCID 14923Ammonium HydroxideHCID 57477975HCID 57477975, compound

Product 1

HCID 578812994-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylideneacetonitrile

Reagents, catalysts & solvents 1

HCID 18373917Acetonitrile--water (1/1)Solvent

Procedure

A solution of TFA (0.5 mL, 0.006 mol) and 4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylideneacetonitrile (22.7 mg, 0.0000522 mol), was stirred for 1.5 h. The solution was then concentrated using a rotary evaporator to remove TFA. LCMS analysis showed conversion to the hydroxymethyl intermediate, M+H 335. Methanol was added; and the methanol mixture was concentrated again using a rotary evaporator. The resulting residue was dissolved in methanol (1 mL) and ammonium hydroxide (0.25 mL, 0.0064 mol) was added. The resulting solution was stirred for 16 h. LCMS analysis showed complete de-protection. The solution was then concentrated using a rotary evaporator. The product was isolated by prep HPLC using a 30 mm×100 mm C18 column; 18% CH3CN—H2O (0.1% TFA), 1 min, to 35% at 6 min; 60 mL/min; detector set at 254 nm; retention time, 4.4 min. The eluate was freeze dried. yield 7.6 mg of a white solid (TFA salt; racemic; 34.6%). 1H NMR (d6 DMSO) δ 12.9 (br s, 1H, NH); 8.9 (s, 2H); 8.5 (s, 1H); 7.8 (m, 1H); 7.3 (m, 1H); 5.6 (s, 1H, olefin); 4.6 (m, 1H, NCH); 2.8 (m, 1H); 2.6 (m, 1H); 2.5 (m, 2H); 2.3 (m, 2H) 2.0 (m, 2H). MS(ES) 305 (M+1).

Workup

  1. concentrationThe solution was then concentrated
  2. customa rotary evaporator
  3. customto remove TFA
  4. additionMethanol was added
  5. concentrationand the methanol mixture was concentrated again
  6. customa rotary evaporator
  7. dissolutionThe resulting residue was dissolved in methanol (1 mL)
  8. concentrationThe solution was then concentrated
  9. customa rotary evaporator
  10. customThe product was isolated by prep HPLC
  11. customretention time, 4.4 min
  12. customdried

Sources & evidence

ORD record
ord-198f96927b0442bfbc9ffaef1852d5f7
Source dataset
uspto-grants-2013_09
Patent number
US08541425B2

Reaction notes

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