Water → HCID 86652142, compound

HRID 1923928Notes

Reaction equation

HRID 1923928 reaction equation
[ClH:1].[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:14]([Br:15])=[CH:13][N:12]=[C:11]3[NH:16][CH:17]=[C:18]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])[C:10]=23)[CH2:4]1.Br[CH2:26][CH2:27][F:28].CCN(C(C)C)C(C)C.O>CN(C=O)C>[ClH:1].[Br:15][C:14]1[C:9]([N:5]2[CH2:6][CH2:7][CH2:8][C@@H:3]([NH:2][CH2:26][CH2:27][F:28])[CH2:4]2)=[C:10]2[C:18]([NH:19][C:20]([CH:22]3[CH2:23][CH2:24]3)=[O:21])=[CH:17][NH:16][C:11]2=[N:12][CH:13]=1

Participants

6

Reactant 4

HCID 962WaterHCID 129822-Fluoroethyl bromideHCID 81531DiisopropylethylamineHCID 670451631657014-42-0

Product 1

HCID 86652142HCID 86652142, compoundYield 15.8%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

(R)-N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide hydrochloride (0.112 g, 0.248 mmol; Example 29, Step C), 1-bromo-2-fluoroethane (0.0222 mL, 0.298 mmol) and DIEA (0.173 mL, 0.993 mmol, d 0.742) were placed in DMF (2 mL) and heated to 80° C. for 36 hours. The reaction was then cooled to room temperature, poured into water, and extracted with EtOAc. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by reverse phase chromatography (Biotage SP4, C-18 40M+, 5-50% water:ACN). The product was next dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (R)-N-(5-bromo-4-(3-(2-fluoroethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide hydrochloride (0.018 g, 15% yield) as a solid. 1H NMR (400 MHz, D2O) δ 8.23 (s, 1H), 7.26 (s, 1H), 4.69-4.67 (m, 1H), 4.56-4.55 (m, 1H), 3.84-3.81 (m, 1H), 3.57-3.54 (m, 1H), 3.42-3.16 (m, 5H), 2.22-2.19 (m, 1H), 1.80-1.73 (m, 3H), 1.57-1.55 (m, 1H), 0.90-0.80 (m, 4H). LCMS (APCI+) m/z 424, 426 (M+H)+.

Workup

  1. temperatureThe reaction was then cooled to room temperature
  2. extractionextracted with EtOAc
  3. dry with materialThe combined organic fractions were dried (MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customto give the crude product, which
  7. customwas purified by reverse phase chromatography (Biotage SP4
  8. dissolutionThe product was next dissolved in minimal DCM (with MeOH to aid solubility)
  9. additionadded to a stirring solution of 1M HCl in ether
  10. filtrationThe resulting solid was filtered
  11. washwashed with ether
  12. customdried

Sources & evidence

ORD record
ord-9c1cec7c4d474f59b5ba4d9d0b53d898
Source dataset
uspto-grants-2012_05
Patent number
US08178131B2

Reaction notes

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