Methacryloyl chloride → Jak3-IN-6

HRID 882120Notes

Reaction equation

HRID 882120 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:35])[C:32]([CH3:34])=[CH2:33]>C1COCC1>[CH3:34][C:32](=[CH2:33])[C:31]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1)=[O:35]

Participants

5

Reactant 3

HCID 13528Methacryloyl chlorideHCID 81531DiisopropylethylamineHCID 71598790ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate

Product 1

HCID 89629876Jak3-IN-6

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (50 mg, 0.18 mmol) and DIPEA (93 μL, 0.53 mmol) in THF (1.8 mL) at room temperature was added methacryloyl chloride (27.8 mg, 0.266 mmol) and the solution stirred for 1 hour. The reaction was quenched with ethanol (0.1 mL). The desired product was purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. The combined fractions with the desired product were concentrated until only the water layer remained. The water layer was neutralized with 2M aqueous potassium bicarbonate and the mixture was extracted with ethyl acetate (×5). The combined organic fractions were dried over sodium sulfate, filtered and concentrated under reduced pressure to give ethyl 4-{3-[(2-methylacryloyl)amino]phenyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C19H19N4O3 [M+H]+: 351, found 351. 1H NMR (600 MHz, DMSO-D6) δ 13.0 (s, 1H), 9.91 (s, 1H), 8.91 (s, 1H), 8.30 (s, 1H), 8.05 (s, 1H), 7.84 (d, 1H, J=7.04 Hz), 7.40 (t, 1H, J=7.63 Hz), 7.32 (d, 1H, J=7.04 Hz), 5.82 (s, 1H), 5.53 (s, 1H), 3.86 (q, 2H, J=7.04 Hz), 1.95 (s, 3H), 0.85 (t, 3H, J=7.04 Hz).

Workup

  1. customThe reaction was quenched with ethanol (0.1 mL)
  2. customThe desired product was purified by reverse phase HPLC
  3. concentrationThe combined fractions with the desired product were concentrated until only the water layer
  4. extractionthe mixture was extracted with ethyl acetate (×5)
  5. dry with materialThe combined organic fractions were dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-b8203f5ed22c4fb5b8c9daa33a777393
Source dataset
uspto-grants-2015_03
Patent number
US08993756B2

Reaction notes

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