Triethylamine → 4-(4-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]carbonyl}piperazin-1-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile

HRID 1772800Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1772800
[F:1][C:2]1[C:3]([C:12]([OH:14])=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(N(CC)CC)C.Cl.[N:23]1([CH2:29][CH:30]([N:34]2[CH:38]=[C:37]([C:39]3[C:40]4[CH:47]=[CH:46][N:45](COCC[Si](C)(C)C)[C:41]=4[N:42]=[CH:43][N:44]=3)[CH:36]=[N:35]2)[CH2:31][C:32]#[N:33])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C1COCC1>[F:1][C:2]1[C:3]([C:12]([N:26]2[CH2:25][CH2:24][N:23]([CH2:29][CH:30]([N:34]3[CH:38]=[C:37]([C:39]4[C:40]5[CH:47]=[CH:46][NH:45][C:41]=5[N:42]=[CH:43][N:44]=4)[CH:36]=[N:35]3)[CH2:31][C:32]#[N:33])[CH2:28][CH2:27]2)=[O:14])=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1

Komponenten

5

Edukt 3

HCID 8471TriethylamineHCID 130018353-Fluoro-5-(trifluoromethyl)pyridine-2-carboxylic 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

Produkt 1

HCID 509960024-(4-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]carbonyl}piperazin-1-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel

Versuchsvorschrift

N,N,N′,N-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (16.2 mg, 0.0000426 mol) was added to a solution of 3-fluoro-5-(trifluoromethyl)pyridine-2-carboxylic acid (11 mg, 0.053 mmol) and triethylamine (30 microL, 0.21 mmol) in THF (0.4 mL). After stirring for 15 minutes, 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; from Example 12, Step 2) was added and the reaction was stirred for two hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with water, 0.1N NaOH and brine, dried over sodium sulfate and concentrated. The residue was dissolved and stirred in a 1:1 mixture of DCM:TFA for 1 hour, concentrated, then stirred in methanol (1 mL) containing ethylenediamine (0.2 mL) for one hour. Preparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH, was used to purify the product (9 mg, 48%). 1H NMR (300 MHz, d6-dmso): δ □8.88 (s, 1H), 8.81 (s, 1H), 8.67 (s, 1H), 8.48 (dd, 1H), 8.37 (s, 1H), 7.60 (d, 1H), 6.97 (d, 1H), 4.99 (tt, 1H), 3.67-3.56 (m, 2H), 3.25-3.12 (m, 4H), 2.92-2.79 (m, 2H), 2.66-2.55 (m, 1H), 2.55-2.38 (m 2H), 2.38-2.25 (m, 1H); LCMS (M+H)+: 528.3.

Aufarbeitung

  1. stirringthe reaction was stirred for two hours
  2. customThe reaction mixture was partitioned between ethyl acetate and water
  3. washThe organic layer was washed successively with water, 0.1N NaOH and brine
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated
  6. dissolutionThe residue was dissolved
  7. stirringstirred in a 1:1 mixture of DCM
  8. waitTFA for 1 hour
  9. concentrationconcentrated
  10. stirringstirred in methanol (1 mL)
  11. additioncontaining ethylenediamine (0.2 mL) for one hour
  12. washPreparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH
  13. customto purify the product (9 mg, 48%)

Quellen und Nachweise

ORD-Eintrag
ord-26a6efd50df04cc2bf77e07c2e819726
Quelldatensatz
uspto-grants-2016_02
Patentnummer
US09249145B2

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