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

HRID 1802553Notes

Reaction equation

HRID 1802553 reaction equation
[CH2:1]1[C:5]2([CH2:10][CH2:9][CH2:8][N:7]([C:11](OC(C)(C)C)=O)[CH2:6]2)[CH2:4][CH2:3][NH:2]1.CCN(CC)CC.[CH3:25][C:26](OC(C)=O)=[O:27].C(OC(=O)[NH:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[S:46][CH:47]=[CH:48][CH:49]=2)=[CH:41][C:40]=1[NH:50][C:51]([C:53]1[CH:54]=[N:55]C(Cl)=[CH:57][CH:58]=1)=[O:52])(C)(C)C>CN(C=O)C>[C:26]([N:2]1[CH2:3][CH2:4][C:5]2([CH2:10][CH2:9][CH2:8][N:7]([C:11]3[CH:57]=[CH:58][C:53]([C:51]([NH:50][C:40]4[CH:41]=[C:42]([C:45]5[S:46][CH:47]=[CH:48][CH:49]=5)[CH:43]=[CH:44][C:39]=4[NH2:38])=[O:52])=[CH:54][N:55]=3)[CH2:6]2)[CH2:1]1)(=[O:27])[CH3:25]

Participants

6

Reactant 4

HCID 7918Acetic AnhydrideHCID 8471Triethylamine2×HCID 23282891tert-Butyl 2,7-diazaspiro(4.5)decane-7-carboxylateHCID 57717453tert-Butyl 2-(6-chloronicotinamido)-4-(thiophen-2-yl)phenylcarbamate

Product 1

HCID 247464376-(2-Acetyl-2,7-diazaspiro[4.5]dec-7-yl)-N-[2-amino-5-(2-thienyl)phenyl]-nicotinamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

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.

Workup

  1. customThe reaction mixture was partitioned between EtOAc and saturated NaHCO3
  2. dry with materialthe organic layer was dried (Na2SO4)
  3. filtrationfiltered
  4. concentrationconcentrated
  5. additionThe mixture was treated with 1:1 TFA/CH2Cl2
  6. stirringstirred for 1 h
  7. concentrationconcentrated
  8. customThe oily residue was azeotroped with methanol
  9. customplaced under high vacuum overnight
  10. dissolutionThe resulting thick residue was then dissolved in 2 mL of DMSO
  11. stirringstirred at 90° C. for 12 h
  12. customThe reaction mixture was partitioned between EtOAc and saturated NaHCO3
  13. dry with materialthe organic layer was dried (Na2SO4)
  14. filtrationfiltered
  15. concentrationconcentrated
  16. dissolutionFinally, the residue was dissolved in 1:1 TFA/CH2Cl2
  17. stirringstirred for 1 h
  18. concentrationconcentrated
  19. customReverse-phase chromatography (10-100% MeCN/water with 0.05% TFA) followed by TFA removal by EtOAc/saturated extraction
  20. dry with materialdrying (Na2SO4)

Sources & evidence

ORD record
ord-3dab9ad655a34bb7971cb5f81dd7dd89
Source dataset
uspto-grants-2013_01
Patent number
US08349825B2

Reaction notes

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