Triethylamine → 4-[4-(1H-indazol-5-ylsulfonyl)piperazin-1-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile

HRID 1772804Notes

Reaction equation

HRID 1772804 reaction equation
[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10](Cl)(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[N:15]1([CH2:21][CH:22]([N:26]2[CH:30]=[C:29]([C:31]3[C:32]4[CH:39]=[CH:38][N:37](COCC[Si](C)(C)C)[C:33]=4[N:34]=[CH:35][N:36]=3)[CH:28]=[N:27]2)[CH2:23][C:24]#[N:25])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(#N)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10]([N:18]3[CH2:17][CH2:16][N:15]([CH2:21][CH:22]([N:26]4[CH:30]=[C:29]([C:31]5[C:32]6[CH:39]=[CH:38][NH:37][C:33]=6[N:34]=[CH:35][N:36]=5)[CH:28]=[N:27]4)[CH2:23][C:24]#[N:25])[CH2:20][CH2:19]3)(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 225671441H-Indazole-5-sulfonyl chlorideHCID 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 581809974-[4-(1H-indazol-5-ylsulfonyl)piperazin-1-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

1H-Indazole-5-sulfonyl chloride (26 mg, 0.12 mmol; from Step 1) was added to a solution of 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 (24 mg, 0.041 mmol; from Example 12, Step 2) and triethylamine (57 uL, 0.40 mmol) in acetonitrile (0.30 mL). The mixture was stirred for 16 hours, then solvent was removed in vacuo. The residue was stirred in a 1:1 mixture of DCM:TFA for 1 hour, concentrated, and 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 (5 mg, 24%). 1H NMR (300 MHz, d6-dmso): δ 12.08 (br s, 1H), 8.70 (s, 1H), 8.60 (s, 1H), 8.31-8.30 (m, 2H), 8.26-8.23 (m, 1H), 7.72 (d, 1H), 7.61 (dd, 1H), 7.52 (d, 1H), 6.87 (d, 1H), 4.93-4.81 (m, 1H), 3.39-2.41 (m, 12H); LCMS (M+H)+: 517.1.

Workup

  1. customsolvent was removed in vacuo
  2. stirringThe residue was stirred in a 1:1 mixture of DCM
  3. waitTFA for 1 hour
  4. concentrationconcentrated
  5. stirringstirred in a solution of methanol (1 mL)
  6. additioncontaining ethylenediamine (0.2 mL) for one hour
  7. customPurification via preparative HPLC-MS
  8. washeluting with a gradient of MeCN/H2O containing 0.15% NH4OH afforded product as the free base (5 mg, 24%)

Sources & evidence

ORD record
ord-a6d442bee52b457697da4caf3f44c2a9
Source dataset
uspto-grants-2016_02
Patent number
US09249145B2

Reaction notes

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