Ammonia → Methyl 4'-({[(1-{[amino(oxo)acetyl]amino}cyclopropyl)carbonyl]amino}methyl)-3,3'-difluoro-1,1'-biphenyl-2-carboxylate

HRID 10075Notes

Reaction equation

HRID 10075 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16]([C:18]3([NH:21][C:22](=[O:27])[C:23]([O:25]C)=O)[CH2:20][CH2:19]3)=[O:17])=[C:10]([F:28])[CH:9]=2)[C:3]=1[C:29]([O:31][CH3:32])=[O:30].[NH3:33]>C(Cl)Cl.CO>[NH2:33][C:23](=[O:25])[C:22]([NH:21][C:18]1([C:16]([NH:15][CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:4]3[C:3]([C:29]([O:31][CH3:32])=[O:30])=[C:2]([F:1])[CH:7]=[CH:6][CH:5]=3)=[CH:9][C:10]=2[F:28])=[O:17])[CH2:20][CH2:19]1)=[O:27]

Participants

5

Reactant 2

HCID 222AmmoniaHCID 21988941Methyl 3,3'-difluoro-4'-({[(1-{[methoxy(oxo)acetyl]amino}cyclopropyl)-carbonyl]amino}methyl)-1,1'-biphenyl-2-carboxylate

Product 1

HCID 21988956Methyl 4'-({[(1-{[amino(oxo)acetyl]amino}cyclopropyl)carbonyl]amino}methyl)-3,3'-difluoro-1,1'-biphenyl-2-carboxylate

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of methyl 3,3′-difluoro-4′-({[(1-{[methoxy(oxo)acetyl]-amino}cyclopropyl)carbonyl]amino}methyl)-1,1′-biphenyl-2-carboxylate (0.02 g, 0.045 mmol, Example 5) in methylene chloride (2 mL) at room temperature was added ammonia (0.224 mL of a 2M solution in methanol, 0.45 mmol). The reaction mixture was stirred at room temperature for 4 hrs and then concentrated to obtain the crude product. This crude product was purified by reverse phase HPLC (Vydac column #218TP1022, gradient elution 5–95% acetonitrile:water containing 0.1% TFA). The pure fractions were lyophilized to afford the title compound as a solid. Purity was determined by LCMS (ES MS, M++H found:432) and proton NMR (400 MHz, CDCl3: δ 7.86 (1H,s), 7.45(1H,dt, J=5.7 and 8.1 Hz), 7.35 (1H, t, J=7.8 Hz), 7.20–7.00 (4H,m), 6.59 (1H, m), 5.61(1H, s), 4.54 (2H, d,J=6.0 Hz), 3.74(3H,s), 1.68(2H,m), 1.12 (2H,m) ppm.

Workup

  1. concentrationconcentrated
  2. customto obtain the crude product
  3. customThis crude product was purified by reverse phase HPLC (Vydac column #218TP1022, gradient elution 5–95% acetonitrile:water containing 0.1% TFA)

Sources & evidence

ORD record
ord-816f4cc57baa49938806dfe8822092c7
Source dataset
uspto-grants-2006_08
Patent number
US07091380B2

Reaction notes

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