Ethylenediamine → HCID 69675055, compound

HRID 575505Notes

Reaction equation

HRID 575505 reaction equation
[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[C:9]([F:11])[CH:10]=1)[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.O[CH:49]1[CH2:54][CH2:53][N:52]([CH2:55][CH:56]([N:60]2[CH:64]=[C:63]([C:65]3[C:66]4[CH:73]=[CH:72][N:71](COCC[Si](C)(C)C)[C:67]=4[N:68]=[CH:69][N:70]=3)[CH:62]=[N:61]2)[CH2:57][C:58]#[N:59])[CH2:51][CH2:50]1.FC(F)(F)C(O)=O.C(N)CN>C(Cl)Cl.CO>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([F:11])[CH:10]=1)[O:12][CH:49]1[CH2:50][CH2:51][N:52]([CH2:55][CH:56]([N:60]2[CH:64]=[C:63]([C:65]3[C:66]4[CH:73]=[CH:72][NH:71][C:67]=4[N:68]=[CH:69][N:70]=3)[CH:62]=[N:61]2)[CH2:57][C:58]#[N:59])[CH2:53][CH2:54]1)[CH3:1]

Participants

9

Reactant 6

HCID 3301EthylenediamineHCID 6422Trifluoroacetic acidHCID 11776Triphenylphosphine2×HCID 97268Di-tert-butyl azodicarboxylate2×HCID 67956408HCID 67956408, compoundHCID 69671898HCID 69671898, compound

Product 1

HCID 69675055HCID 69675055, compound

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent4×

Procedure

To a mixture of 3-[(dimethylamino)methyl]-5-fluorophenol (158 mg, 0.934 mmol) in methylene chloride (9 mL) was added Resin of triphenylphosphine (578 mg, 1.37 mmol) and di-tert-butyl azodicarboxylate (229 mg, 0.996 mmol). The mixture was stirred for 20 minutes before adding a solution of 4-(4-hydroxypiperidin-1-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile (300 mg, 0.6 mmol) in methylene chloride (2 mL). The reaction was stirred at room temperature overnight. Additional resin of triphenylphosphine (0.5 g), di-tert-butyl azodicarboxylate (0.23 g), and DCM (8 mL) were added and stirred for additional 2 hours. The vial and resin were washed with DCM and filtered. The filtrates were washed with 10% aq. NaOH solution. The organic layer was dried over MgSO4, filtered, and concentrated. The crude was purified by silica gel column (eluted with 0-15% methanol/DCM) to give the SEM protected product. LCMS (M+H)+: 633.5. To the purified product was added methylene chloride (1.5 mL) and trifluoroacetic acid (1.5 mL, 19 mmol) and stirred for 2 hours. The solvents were evaporated before adding methanol (3.5 mL) and ethylenediamine (0.70 mL, 10 mmol). The resulting mixture was stirred for 1 hour then concentrated. The concentrate was taken up in DCM and washed with water, dried over Na2SO4, filtered, and concentrated to give the crude product which was purified by chiral prep-HPLC (Chiralcel OJ-H column, 4.6×250 mm, 5 μ, 60% ethanol/Hex, 0.5 ml/min) to afford 2 enantiomers.

Workup

  1. stirringThe reaction was stirred at room temperature overnight
  2. stirringstirred for additional 2 hours
  3. washThe vial and resin were washed with DCM
  4. filtrationfiltered
  5. washThe filtrates were washed with 10% aq. NaOH solution
  6. dry with materialThe organic layer was dried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe crude was purified by silica gel column (eluted with 0-15% methanol/DCM)
  10. customto give the SEM
  11. stirringstirred for 2 hours
  12. customThe solvents were evaporated
  13. stirringThe resulting mixture was stirred for 1 hour
  14. concentrationthen concentrated
  15. washwashed with water
  16. dry with materialdried over Na2SO4
  17. filtrationfiltered
  18. concentrationconcentrated

Sources & evidence

ORD record
ord-1d4e5e2936c742129105375a0b8be34f
Source dataset
uspto-grants-2015_05
Patent number
US09034884B2

Reaction notes

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