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

To a solution of 5-chloro-3-fluoropyridine-2-carboxylic acid (23.5 mg, 0.134 mmol, prepared as described in Eur. J. Org. Chem. (24), 4174-4180; 2002) and triethylamine (86.2 uL, 0.618 mmol) in THF (1.1 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (47.0 mg, 0.124 mol). 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 (61 mg, 0.10 mmol; from Example 12, Step 2) was added. The reaction was stirred for two hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed successively with water, 0.1 N 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, and stirred in methanol (1 mL) containing ethylenediamine (0.2 mL) for 1 hour. Preparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH, was used to purify the product (29 mg, 57%). 1H NMR (300 MHz, d6-dmso): δ □12.10 (br s, 1H), 8.81 (s, 1H), 8.61 (s, 1H), 8.55 (dd, 1H), 8.37 (s, 1H), 8.24 (dd, 1H), 7.60 (d, 1H), 6.97 (d, 1H), 4.98 (tt, 1H), 3.65-3.56 (m, 2H), 3.26-3.12 (m, 4H), 2.92-2.77 (m, 2H), 2.64-2.25 (m, 4H); LCMS (M+H)+: 494.2.

1. stirringThe reaction was stirred for two hours
2. customThe reaction mixture was partitioned between water and ethyl acetate
3. washThe organic layer was washed successively with water, 0.1 N 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 methanol (1 mL)
10. additioncontaining ethylenediamine (0.2 mL) for 1 hour
11. washPreparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH
12. customto purify the product (29 mg, 57%)

ORD-Eintrag

ord-d23adb1b38854a57a9337c1382852930

Quelldatensatz

uspto-grants-2016_02

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09249145B2