Triethylamine → HCID 53380753, compound

HRID 1617413Notes

Reaction equation

HRID 1617413 reaction equation
[F:1][CH:2]([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:11]=1)[C:6]([OH:8])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH:48]1[CH2:53][CH2:52][CH:51]([N:54]2[CH2:57][C:56]([CH2:80][C:81]#[N:82])([N:58]3[CH:62]=[C:61]([C:63]4[C:64]5[CH:71]=[CH:70][N:69](COCC[Si](C)(C)C)[C:65]=5[N:66]=[CH:67][N:68]=4)[CH:60]=[N:59]3)[CH2:55]2)[CH2:50][CH2:49]1>O1CCCC1>[F:16][CH:2]([F:1])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:11]=1)[C:6]([N:48]1[CH2:49][CH2:50][CH:51]([N:54]2[CH2:55][C:56]([CH2:80][C:81]#[N:82])([N:58]3[CH:62]=[C:61]([C:63]4[C:64]5[CH:71]=[CH:70][NH:69][C:65]=5[N:66]=[CH:67][N:68]=4)[CH:60]=[N:59]3)[CH2:57]2)[CH2:52][CH2:53]1)=[O:8]

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 58431368HCID 58431368, compoundHCID 67391103{1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile

Product 1

HCID 53380753HCID 53380753, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A mixture of 3-(difluoromethyl)-5-[(dimethylamino)methyl]benzoic acid (14.0 mg, 0.0609 mmol, from Step D), Triethylamine (28.3 μL, 0.203 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (21.2 mg, 0.0558 mmol) in tetrahydrofuran (0.56 mL) was stirred for 15 minutes. {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (25.0 mg, 0.0507 mmol, prepared as described in Example 1, Step H, except worked up to provide the free base) was added and the reaction was stirred for two hours. The reaction mixture was partitioned between ethyl acetate and water. The organic portion was washed with water, 0.1N NaOH and sat. NaCl, dried over sodium sulfate, filtered and concentrated. The residue was stirred in 1:1 DCM:TFA for 1 hour, solvents were removed in vacuo, and the resulting residue stirred in methanol (1 mL) containing ethylenediamine (0.2 mL) until deprotection was complete. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded product as a white powder. Yield: 0.012 g (40%); LC-MS: 574.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.09 (br s, 1H), 8.82 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 7.61 (d, 1H), 7.56 (s, 1H), 7.46-7.41 (m, 2H), 7.07 (t, 1H), 7.07 (d, 1H), 4.17-4.03 (m, 1H), 3.75 (d, 2H), 3.62-3.25 (m, 7H), 3.22-3.03 (m, 2H), 2.58-2.51 (m, 1H), 2.15 (s, 6H), 1.85-1.55 (m, 2H), 1.33-1.12 (m, 2H).

Workup

  1. customto provide the free base)
  2. additionwas added
  3. stirringthe reaction was stirred for two hours
  4. customThe reaction mixture was partitioned between ethyl acetate and water
  5. washThe organic portion was washed with water, 0.1N NaOH and sat. NaCl
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. stirringThe residue was stirred in 1:1 DCM
  10. waitTFA for 1 hour
  11. customsolvents were removed in vacuo
  12. stirringthe resulting residue stirred in methanol (1 mL)
  13. additioncontaining ethylenediamine (0.2 mL) until deprotection
  14. customPurification via preparative HPLC-MS (C18
  15. washeluting with a gradient of MeCN/H2O containing 0.15% NH4OH)
  16. customafforded product as a white powder

Sources & evidence

ORD record
ord-b29241a19da34a608766fc0186328a89
Source dataset
uspto-grants-2014_07
Patent number
US08765734B2

Reaction notes

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