Triethylamine → 3-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-5-[(dimethylamino)methyl]benzonitrile

Temperature

120 °C

To a solution of 3-bromo-5-[(dimethylamino)methyl]benzoic acid (31.4 mg, 0.122 mmol, from Step B) in tetrahydrofuran (1.0 mL) was added triethylamine (0.045 mL, 0.32 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (43.2 mg, 0.114 mmol). The mixture was pre-stirred for 15 minutes, followed by the addition of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (40. mg, 0.081 mmol, prepared as described in Example 1, Step H, except worked up to provide the free base). After stirring for two hours, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with water, 0.1N NaOH and sat. NaCl, dried over sodium sulfate and concentrated. The residue was dissolved in N,N-dimethylformamide (1.50 mL) and zinc cyanide (57 mg, 0.49 mmol) was added. The solution was degassed via a stream of nitrogen through the mixture for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.016 mmol) was added, and the reaction was heated to 120° C. in the microwave for 30 minutes. The reaction mixture was worked up by partition between water and ethyl acetate. The ethyl acetate layer was washed twice with water, once with brine, dried over sodium sulfate and concentrated. The residue was stirred in a 1:1 mixture of DCM:TFA for one hour, then concentrated. The residue was redissolved in methanol (1 mL), and ethylenediamine (0.2 mL) was added. Upon complete deprotection, the product was isolated via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: 11.7 mg (26%); LC-MS: 549.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.15 (br s, 1H), 8.82 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 7.85 (s, 1H), 7.82 (s, 1H), 7.66 (s, 1H), 7.61 (dd, 1H), 7.07 (dd, 1H), 4.14-4.03 (m, 1H), 3.80-3.28 (m, 9H), 3.22-3.02 (m, 2H), 2.59-2.51 (m, 1H), 1.83-1.71 (m, 1H), 1.69-1.58 (m, 1H), 1.35-1.15 (m, 2H).

1. custommg, 0.081 mmol, prepared
2. customto provide the free base)
3. stirringAfter stirring for two hours
4. customthe reaction mixture was partitioned between ethyl acetate and water
5. washThe organic layer was washed successively with water, 0.1N NaOH and sat. NaCl
6. dry with materialdried over sodium sulfate
7. concentrationconcentrated
8. dissolutionThe residue was dissolved in N,N-dimethylformamide (1.50 mL)
9. customThe solution was degassed via a stream of nitrogen through the mixture for 10 minutes
10. customby partition between water and ethyl acetate
11. washThe ethyl acetate layer was washed twice with water, once with brine
12. dry with materialdried over sodium sulfate
13. concentrationconcentrated
14. stirringThe residue was stirred in a 1:1 mixture of DCM
15. waitTFA for one hour
16. concentrationconcentrated
17. dissolutionThe residue was redissolved in methanol (1 mL)
18. additionethylenediamine (0.2 mL) was added
19. customUpon complete deprotection, the product was isolated via preparative HPLC-MS (C18
20. washeluting with a gradient of MeCN/H2O containing 0.15% NH4OH)

ORD record

ord-21a29fa59b3c48bc8c7f3b657506a523

Source dataset

uspto-grants-2014_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08765734B2