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

4-Cyano-2,6-difluorobenzoic acid (82 mg, 0.32 mmol), Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (110 mg, 0.00025 mol) and triethylamine (180 uL, 0.0013 mol) were stirred together in DMF (0.5 mL) 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 (125 mg, 0.211 mmol; from Example 12, Step 2) was added and the reaction stirred for 16 hours. To push the reaction to completion, additional 4-cyano-2,6-difluorobenzoic acid (82 mg, 0.32 mol) and triethylamine (58.9 uL, 0.000422 mol) were mixed, in a separate vial, in N,N-Dimethylformamide (1.6 mL) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (110 mg, 0.25 mmol) was added. This mixture was stirred separately for 15 minutes, and then was added to the incomplete original reaction mixture. The reaction was continued for 1.5 hours, then was diluted with a large quantity of ethyl acetate. The solution was washed with three portions of water, once with brine, dried over sodium sulfate and concentrated. The residue was stirred in a mixture of 1:1 dichloromethane (DCM):TFA for one hour, was concentrated, then was stirred in methanol (3 mL) containing ethylenediamine (0.5 mL) until deprotection was complete as evidenced by LCMS. Two successive purifications vial HPLC-MS (eluting first with a gradient of MeCN/H2O containing 0.1% TFA, then repurification eluting with a gradient of MeCN/H2O containing 0.15% NH4OH afforded clean product (46 mg, 43%). 1H NMR (400 MHz, d6-dmso): δ 12.11 (br s, 1H), 8.81 (s, 1H), 8.67 (s, 1H), 8.37 (s, 1H), 7.98-7.91 (m, 2H), 7.60 (d, 1H), 6.97 (d, 1H), 5.02-4.93 (tt, 1H), 3.66-3.54 (m, 2H), 3.25-3.16 (m, 4H), 2.91-2.78 (m, 2H), 2.63-2.54 (m, 1H), 2.52-2.38 (m, 2H), 2.37-2.28 (m, 1H); LCMS (M+H)+: 502.1.

1. additionwere mixed
2. stirringThis mixture was stirred separately for 15 minutes
3. additionwas added to the incomplete original reaction mixture
4. waitThe reaction was continued for 1.5 hours
5. washThe solution was washed with three portions of water, once with brine
6. dry with materialdried over sodium sulfate
7. concentrationconcentrated
8. stirringThe residue was stirred in a mixture of 1:1 dichloromethane (DCM)
9. waitTFA for one hour
10. concentrationwas concentrated
11. stirringwas stirred in methanol (3 mL)
12. additioncontaining ethylenediamine (0.5 mL) until deprotection
13. washTwo successive purifications vial HPLC-MS (eluting first with a gradient of MeCN/H2O containing 0.1% TFA
14. customrepurification
15. washeluting with a gradient of MeCN/H2O containing 0.15% NH4OH afforded clean product (46 mg, 43%)

ORD record

ord-70dcd285c31b408481310f222ea7ad7c

Source dataset

uspto-grants-2016_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09249145B2