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

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.

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)

ORDレコード

ord-367f802341e447ca86ca894d7d64fccc

出典データセット

uspto-grants-2016_02

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US09249145B2