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Triethylamine → 4-{4-[4-(difluoromethyl)-2-fluorobenzoyl]piperazin-1-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile

HRID 1772794
Notes
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Reaction equation

HRID 1772794 reaction equation
[F:1][CH:2]([F:13])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([F:12])[CH:4]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.Cl.[N:46]1([CH2:52][CH:53]([N:57]2[CH:61]=[C:60]([C:62]3[C:63]4[CH:70]=[CH:69][N:68](COCC[Si](C)(C)C)[C:64]=4[N:65]=[CH:66][N:67]=3)[CH:59]=[N:58]2)[CH2:54][C:55]#[N:56])[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>C1COCC1.O.C(OCC)(=O)C>[F:13][CH:2]([F:1])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:49]2[CH2:48][CH2:47][N:46]([CH2:52][CH:53]([N:57]3[CH:61]=[C:60]([C:62]4[C:63]5[CH:70]=[CH:69][NH:68][C:64]=5[N:65]=[CH:66][N:67]=4)[CH:59]=[N:58]3)[CH2:54][C:55]#[N:56])[CH2:51][CH2:50]2)=[O:9])=[C:5]([F:12])[CH:4]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

8

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 219534884-(Difluoromethyl)-2-fluorobenzoic acidHCID 670549114-piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride

Product 1

HCID 50995830
4-{4-[4-(difluoromethyl)-2-fluorobenzoyl]piperazin-1-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile
Yield 39.3%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

4-(Difluoromethyl)-2-fluorobenzoic acid (10.1 mg, 0.0532 mmol) was dissolved in THF (0.39 mL). Triethylamine (29.7 uL, 0.213 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (16.2 mg, 0.0426 mmol) were added, followed by 4-piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (21 mg, 0.035 mmol, prepared as in Example 12, step 2). The reaction was stirred for 30 minutes. Ethyl acetate and water were added, shaken, and layers separated. The organic layer was washed successively with water, 0.1N NaOH and brine, dried over sodium sulfate and concentrated. The residue was stirred in a 1:1 mixture of DCM:TFA for 1 hour, concentrated, then stirred in a solution of methanol (1 mL) containing ethylenediamine (0.2 mL) for one hour. Purification via preparative HPLC-MS (eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded product as the free base (7 mg, 39%). 1H NMR (300 MHz, d6-dmso): δ 12.06 (br s, 1H), 8.81 (s, 1H), 8.67 (s, 1H), 8.36 (s, 1H), 7.60 (d, 1H), 7.57-7.43 (m, 3H), 7.07 (t, 1H), 6.97 (d, 1H), 4.98 (tt, 1H), 3.63-3.55 (m, 2H), 3.25-3.18 (m, 2H), 3.317-3.10 (m, 2H), 2.91-2.77 (m, 2H), 2.66-2.26 (m, 4H); LCMS (M+H)+: 509.2.

Workup

  1. stirringshaken
  2. customlayers separated
  3. washThe organic layer was washed successively with water, 0.1N NaOH and brine
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated
  6. stirringThe residue was stirred in a 1:1 mixture of DCM
  7. waitTFA for 1 hour
  8. concentrationconcentrated
  9. stirringstirred in a solution of methanol (1 mL)
  10. additioncontaining ethylenediamine (0.2 mL) for one hour
  11. customPurification via preparative HPLC-MS (
  12. washeluting with a gradient of MeCN/H2O containing 0.15% NH4OH)

Sources & evidence

ORD record
ord-367f802341e447ca86ca894d7d64fccc
Source dataset
uspto-grants-2016_02
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09249145B2

Reaction notes

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