Reaktion #2071957

Reaktionsgleichung

tert-butyl [2-{[(6-chloropyridin-3-yl)carbonyl]amino}-4-(2-thienyl)phenyl]carbamate

tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate

NEt3

Ac2O

NEt3

→

title compound

6-(2-Acetyl-2,7-diazaspiro[4.5]dec-7-yl)-N-[2-amino-5-(2-thienyl)phenyl]-nicotinamide

Lösungsmittel

DMF

Reaktionsbedingungen

Aufarbeitung

1. 1
   SonstigeThe reaction mixture was partitioned between EtOAc and saturated NaHCO3
2. 2
   Trocknenthe organic layer was dried (Na2SO4)
3. 3
   Filtrationfiltered
4. 4
   Einengenconcentrated
5. 5
   workup.ADDITIONThe mixture was treated with 1:1 TFA/CH2Cl2
6. 6
   workup.STIRRINGstirred for 1 h
7. 7
   Einengenconcentrated
8. 8
   SonstigeThe oily residue was azeotroped with methanol
9. 9
   Sonstigeplaced under high vacuum overnight
10. 10
    workup.DISSOLUTIONThe resulting thick residue was then dissolved in 2 mL of DMSO
11. 11
    workup.STIRRINGstirred at 90° C. for 12 h
12. 12
    SonstigeThe reaction mixture was partitioned between EtOAc and saturated NaHCO3
13. 13
    Trocknenthe organic layer was dried (Na2SO4)
14. 14
    Filtrationfiltered
15. 15
    Einengenconcentrated
16. 16
    workup.DISSOLUTIONFinally, the residue was dissolved in 1:1 TFA/CH2Cl2
17. 17
    workup.STIRRINGstirred for 1 h
18. 18
    Einengenconcentrated
19. 19
    SonstigeReverse-phase chromatography (10-100% MeCN/water with 0.05% TFA) followed by TFA removal by EtOAc/saturated extraction
20. 20
    Trocknendrying (Na2SO4)

Vorschrift

A mixture of tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate (200 mg, 0.833 mmol), NEt3 (0.200 mL, 1.44 mmol) and Ac2O (0.100 mL, 1.06 mmol) in 1 mL of DMF was stirred for 5 h. The reaction mixture was partitioned between EtOAc and saturated NaHCO3, the organic layer was dried (Na2SO4), filtered and concentrated. The mixture was treated with 1:1 TFA/CH2Cl2, stirred for 1 h and concentrated. The oily residue was azeotroped with methanol and placed under high vacuum overnight. The resulting thick residue was then dissolved in 2 mL of DMSO containing tert-butyl [2-{[(6-chloropyridin-3-yl)carbonyl]amino}-4-(2-thienyl)phenyl]carbamate (100 mg, 0.233 mmol), treated with NEt3 (0.50 mL) and stirred at 90° C. for 12 h. The reaction mixture was partitioned between EtOAc and saturated NaHCO3, the organic layer was dried (Na2SO4), filtered and concentrated. Finally, the residue was dissolved in 1:1 TFA/CH2Cl2, stirred for 1 h and concentrated. Reverse-phase chromatography (10-100% MeCN/water with 0.05% TFA) followed by TFA removal by EtOAc/saturated extraction and drying (Na2SO4) gave the title compound: 1H NMR (600 MHz, CD3OD): δ 8.69 and 8.71 (2s, 1H), 8.05 and 8.07 (2d, J=9.1 Hz, 1H), 7.47 (s, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.23 (d, J=5.0 Hz, 1H), 7.20 (d, J=3.5 Hz, 1H), 7.01 (dd, J=5.0, 3.5 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.82 (dd, J=9.1, 6.2 Hz, 1H), 3.75 (m, 2H), 3.65 (m, 1H), 3.52 (m, 3H), 3.03 and 3.19 (2d, J=12.3 Hz, 1H), 2.00 and 2.04 (2s, 3H), 1.6-1.9 (m, 6H); MS (ESI+): cal'd [M+H]+ 476.2, obs'd 476.2.

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