Sodium hydride → 1,8-Dioxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (2'-fluoro-3-nitro-biphenyl-4-yl)-amide

HRID 1518145Notes

Reaction equation

HRID 1518145 reaction equation
[O:1]1[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:4][C:3]([C:11]([OH:13])=O)=[N:2]1.C(Cl)(=O)C(Cl)=O.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[C:29]([N+:34]([O-:36])=[O:35])[CH:28]=1.[H-].[Na+]>ClCl.CN(C=O)C.C1COCC1>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:11]([C:3]2[CH2:4][C:5]3([CH2:6][CH2:7][O:8][CH2:9][CH2:10]3)[O:1][N:2]=2)=[O:13])=[C:29]([N+:34]([O-:36])=[O:35])[CH:28]=1

Participants

8

Reactant 4

HCID 24758Sodium hydrideHCID 65578Oxalyl chlorideHCID 224778582'-Fluoro-3-nitro-[1,1'-biphenyl]-4-amineHCID 509941151,8-Dioxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid

Product 1

HCID 592800831,8-Dioxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (2'-fluoro-3-nitro-biphenyl-4-yl)-amideYield 76%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 8028TetrahydrofuranSolventHCID 24526ChlorineSolvent

Procedure

A solution of 1,8-dioxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (87.7 mg, 0.474 mmol, as prepared in the previous step) in CH2 Cl2 (10 mL) was treated with oxalyl chloride (41.3 μL, 0.474 mmol) and DMF (1 drop) at rt for 1 h. Simultaneously, a solution of 2′-fluoro-3-nitro-biphenyl-4-ylamine (100 mg, 0.431 mmol, as prepared in step A of this Example) in dry THF (10 mL) was treated with NaH (51.7 mg, 1.29 mmol, 60% dispersion in oil) at rt for 1 h. The acid chloride solution was concentrated in vacuo, taken up in dry THF (10 mL), and slowly added to the 2′-fluoro-3-nitro-biphenyl-4-ylamine solution. The mixture was allowed to stir for 20 min at rt, quenched with satd aq NH4Cl, diluted with water, and extracted with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 40-g Sepra Si 50 SPE column (Isco system: Flow rate=20 mL/min; Eluent=EtOAc/hexanes, 1:9 v/v for 10 min, then 1:9 to 2:3 v/v over 40 min) to afford the title compound (131 mg, 76%) as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ: 11.58 (s, 1H), 8.87 (d, J=8.8 Hz, 1H), 8.47 (d, J=2.0 Hz, 1H), 7.89 (dt, J=8.8, 1.6 Hz, 1H), 7.47 (td, J=7.7, 1.8 Hz, 1H), 7.35-7.44 (m, 1H), 7.24-7.31 (m, 1H), 7.20 (ddd, J=10.9, 8.3, 1.0 Hz, 1H), 3.92 (ddd, J=11.8, 8.8, 3.2 Hz, 2H), 3.71-3.82 (m, 2H), 3.10 (s, 2H), 1.94-2.03 (m, 2H), 1.83-1.93 (m, 2H). Mass Spectrum (LCMS, APCI pos.): Calcd. for C20H18FN3O5: 400.1 (M+H). found: 400.1.

Workup

  1. concentrationThe acid chloride solution was concentrated in vacuo
  2. additionslowly added to the 2′-fluoro-3-nitro-biphenyl-4-ylamine solution
  3. customquenched with satd aq NH4Cl
  4. additiondiluted with water
  5. extractionextracted with EtOAc
  6. dry with materialThe combined organic extracts were dried over MgSO4
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified on a 40-g Sepra Si 50 SPE column (Isco system
  9. waitEluent=EtOAc/hexanes, 1:9 v/v for 10 min

Sources & evidence

ORD record
ord-3dfb009c56b54630b6ffd29f721e81ac
Source dataset
uspto-grants-2012_07
Patent number
US08232409B2

Reaction notes

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