Dimethylphosphinic acid → [6-({3-(Aminocarbonyl)-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-thienyl}amino)pyridin-2-yl]methyl dimethylphosphinate

HRID 386035Notes

Reaction equation

HRID 386035 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:12]1[S:16][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][OH:25])[N:19]=2)=[C:14]([C:26]([NH2:28])=[O:27])[CH:13]=1.[CH3:29][P:30]([CH3:33])(=O)[OH:31].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:29][P:30]([CH3:33])(=[O:31])[O:25][CH2:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([NH:17][C:15]2[S:16][C:12]([C:3]3[CH:4]=[CH:5][C:6]([C:8]([OH:11])([CH3:9])[CH3:10])=[CH:7][C:2]=3[F:1])=[CH:13][C:14]=2[C:26]([NH2:28])=[O:27])[N:19]=1

Participants

7

Reactant 5

HCID 76777Dimethylphosphinic acid2×HCID 81531Diisopropylethylamine2×HCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate2×HCID 516892Sodium BicarbonateHCID 251234855-(2-Fluoro-4-(1-hydroxy-1-methylethyl)phenyl)-2-((6-(hydroxymethyl)-2-pyridinyl)amino)-3-thiophenecarboxamide

Product 1

HCID 59526131[6-({3-(Aminocarbonyl)-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-thienyl}amino)pyridin-2-yl]methyl dimethylphosphinate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

5-[2-Fluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-{[6-(hydroxymethyl)pyridin-2-yl]amino}thiophene-3-carboxamide (Example 43) (125 mg, 0.31 mmol), dimethylphosphinic acid (32.2 mg, 0.34 mmol), BOP (207 mg, 0.47 mmol) and DIPEA (48.3 mg, 0.37 mmol) were stirred in DMF (1 mL) at room temperature for 6 hours. Additional dimethylphosphinic acid (11.71 mg, 0.13 mmol), BOP (68.9 mg, 0.16 mmol) and DIPEA (0.033 mL, 0.19 mmol) were added and the reaction mixture was maintained at room temperature overnight. Saturated sodium bicarbonate was added and the mixture was extracted with EtOAc (×5). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by silica gel column chromatography (0-10% MeOH-EtOAc) gave the title compound as a pale yellow solid.

Workup

  1. extractionthe mixture was extracted with EtOAc (×5)
  2. washThe combined organic extracts were washed with brine
  3. dry with materialdried over MgSO4
  4. concentrationconcentrated in vacuo
  5. customPurification of the residue by silica gel column chromatography (0-10% MeOH-EtOAc)

Sources & evidence

ORD record
ord-e16c62da5f6a4451b55e85ad9b0be557
Source dataset
uspto-grants-2013_02
Patent number
US08367706B2

Reaction notes

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