Triphenylphosphine → HCID 57810118, compound

HRID 2106159Notes

Reaction equation

HRID 2106159 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([OH:34])[CH:32]=5)[N:27]=[CH:26][N:25]=4)=[C:19]([F:37])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N:57]1([CH2:63][CH2:64][CH2:65]O)[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([O:34][CH2:65][CH2:64][CH2:63][N:57]6[CH2:62][CH2:61][O:60][CH2:59][CH2:58]6)[CH:32]=5)[N:27]=[CH:26][N:25]=4)=[C:19]([F:37])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:6][CH:7]=1

Participants

6

Reactant 4

HCID 11776TriphenylphosphineHCID 1995763-Morpholino-1-propanolHCID 5462977Diethyl azodicarboxylateHCID 57810392HCID 57810392, compound

Product 1

HCID 57810118HCID 57810118, compoundYield 10.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Crude cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(6-hydroxy-7-methoxy-quinazolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (333 mg, 0.66 mmol), PS-PPh3 resin, (loading=2.33 mmol/g, 797 mg, 1.86 mmol), 3-morpholin-4-yl-propan-1-ol (0.26 ml, 1.88 mmol), and DEAD (0.31 ml, 1.91 mmol) were combined in CH2Cl2 (10 ml) and stirred at room temperature for 1-2 hrs. The reaction mixture was filtered and the resin thoroughly washed with CH2Cl2. The filtrate was concentrated in vacuo and the resulting residue was dissolved in EtOAc and washed with H2O (4×) and sat'd NaCl (1×) and then extracted with 1N HCl (3×). The combined 1N HCl extractions were washed with EtOAc (2×). The acidic aqueous phase was then basified with 1N NaOH and extracted with EtOAc (3×). The combined EtOAc extractions were washed with H2O (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified by preparative reverse phase HPLC (25 mM NH4OAc/acetonitrile) and the pure fractions were lyophilized to give cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yloxy]-phenyl}-amide (4-fluoro-phenyl)-amide (42.6 mg, 10%). 1H NMR (400 MHz, DMSO-d6): δ 10.37 (br s, 1H), 10.05 (br s, 1H), 8.55 (s, 1H), 7.84 (m, 1H), 7.65 (m, 2H), 7.58 (s, 1H), 7.43 (m, 3H), 7.16 (t, 2H), 4.27 (m, 2H), 4.00 (s, 3H), 3.60 (m, 6H), 2.39 (m, 4H), 1.99 (m, 2H), 1.47 (m, 4H). LC/MS Calcd for [M+H]+ 634.2, found 634.1.

Workup

  1. filtrationThe reaction mixture was filtered
  2. washthe resin thoroughly washed with CH2Cl2
  3. concentrationThe filtrate was concentrated in vacuo
  4. dissolutionthe resulting residue was dissolved in EtOAc
  5. washwashed with H2O (4×) and sat'd NaCl (1×)
  6. extractionextracted with 1N HCl (3×)
  7. extractionThe combined 1N HCl extractions
  8. washwere washed with EtOAc (2×)
  9. extractionextracted with EtOAc (3×)
  10. extractionThe combined EtOAc extractions
  11. washwere washed with H2O (1×), sat'd NaCl (1×)
  12. dry with materialdried (Na2SO4)
  13. concentrationconcentrated in vacuo
  14. customThe resulting residue was purified by preparative reverse phase HPLC (25 mM NH4OAc/acetonitrile)

Sources & evidence

ORD record
ord-138890e157d7435b9d1966d8cd80c69b
Source dataset
uspto-grants-2009_08
Patent number
US07579473B2

Reaction notes

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