Acetic Acid → HCID 22624939, compound

HRID 1384567Notes

Reaction equation

HRID 1384567 reaction equation
N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([OH:37])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1.C(P(CCCC)CCCC)CCC.O[CH2:55][CH2:56][CH2:57][C:58]1[CH:63]=[CH:62][N:61]=[CH:60][CH:59]=1.C(O)(=O)C>C(Cl)Cl>[ClH:19].[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH2:55][CH2:56][CH2:57][C:58]4[CH:63]=[CH:62][N:61]=[CH:60][CH:59]=4)=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 13831TributylphosphineHCID 729234-PyridinepropanolHCID 730421,1'-(Azodicarbonyl)dipiperidineHCID 1355137204-(4-Chloro-2-fluorophenylamino)-7-hydroxy-6-methoxyquinazoline

Product 1

HCID 22624939HCID 22624939, compoundYield 156.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

1,1′-(Azodicarbonyl)dipiperidine (1.06 g, 4.2 mmol) in methylene chloride (15 ml) was added dropwise to a solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (448 mg, 1.4 mmol), (prepared as described for the starting material in Example 24), tributylphosphine (848 mg, 4.2 mmol) and 4-(3-hydroxypropyl)pyridine (322 mg, 2.4 mmol) in methylene chloride (15 ml) and the mixture stirred for 3 hours at ambient temperature. Acetic acid (126 mg, 2.1 mmol) was added and the solvent was removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5). The purified product was triturated with ether, the resulting solid collected and dissolved in methylene chloride (20 ml). 5M Hydrogen chloride in isopropanol solution (0.7 ml) was added, the solution was diluted with isopropanol (5 ml) and concentrated by evaporation to a total volume of 4 ml. Ether was added and the resulting solid was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(4-pyridyl)propoxy)quinazoline hydrochloride (520 mg, 73%). 1H NMR Spectrum: (DMSOd6) 2.30(m, 2H); 3.09(t, 2H); 3.97(s, 3H); 4.27(t, 2H); 7.42(s, 1H); 7.44(d, 1H); 7.59(t, 1H); 7.67(dd, 1H); 7.95(d, 2H); 8.34(s, 1H); 8.8(s, 1H); 8.82(d, 2H) MS-ESI: 439 [MH]+

Workup

  1. custom(prepared
  2. customthe solvent was removed by evaporation
  3. customThe residue was purified by column chromatography
  4. washeluting with methylene chloride/methanol (95/5)
  5. customThe purified product was triturated with ether
  6. customthe resulting solid collected
  7. dissolutiondissolved in methylene chloride (20 ml)
  8. addition5M Hydrogen chloride in isopropanol solution (0.7 ml) was added
  9. additionthe solution was diluted with isopropanol (5 ml)
  10. concentrationconcentrated by evaporation to a total volume of 4 ml
  11. additionEther was added
  12. filtrationthe resulting solid was collected by filtration
  13. washwashed with ether
  14. customdried under vacuum

Sources & evidence

ORD record
ord-ff8275a17e694d07ac65f92f26d8d488
Source dataset
uspto-grants-2001_07
Patent number
US06258951B1

Reaction notes

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