Triphenylphosphine → 4-(4-Chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline hydrochloride

HRID 577374Notes

Reaction equation

HRID 577374 reaction equation
C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][CH2:33][CH:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1.[Cl:41][C:42]1[CH:61]=[CH:60][C:45]([NH:46][C:47]2[C:56]3[C:51](=[CH:52][C:53](O)=[C:54]([O:57][CH3:58])[CH:55]=3)[N:50]=[CH:49][N:48]=2)=[C:44]([F:62])[CH:43]=1>C(Cl)Cl>[ClH:41].[Cl:41][C:42]1[CH:61]=[CH:60][C:45]([NH:46][C:47]2[C:56]3[C:51](=[CH:52][C:53]([O:32][CH2:33][CH:34]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]4)=[C:54]([O:57][CH3:58])[CH:55]=3)[N:50]=[CH:49][N:48]=2)=[C:44]([F:62])[CH:43]=1

Participants

6

Reactant 4

HCID 11776Triphenylphosphine2×HCID 220568ethyl N-ethoxycarbonyliminocarbamate2×HCID 2719711-Methyl-4-piperidinemethanol2×HCID 1355137204-(4-Chloro-2-fluorophenylamino)-7-hydroxy-6-methoxyquinazoline

Product 1

HCID 231333204-(4-Chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline hydrochlorideYield 8.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Triphenylphosphine (615 mg, 2.3 mmol) followed by diethyl azodicarboxylate (369 μl, 2.3 mmol) were added to a solution of 4-hydroxymethyl-1-methylpiperidine (151 mg, 1.1 mmol), (J. Med. Chem. 1973, 16, 156), and 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (250 mg, 0.78 mmol), (prepared as described for the starting material in Example 7), in methylene chloride (5 ml). After stirring for 30 minutes at ambient temperature, 4-hydroxymethyl-1-methylpiperidine (51 mg, 0.39 mmol), triphenylphosphine (102 mg, 0.39 mmol) and diethyl azodicarboxylate (61 μl, 0.39 mmol) were added. After stirring for 15 minutes, the volatiles were removed under vacuum and the residue was purified by column chromatography eluting with methylene chloride/acetonitrile/methanol (70/10/20 followed by 75/5/20 and 80/0/20). The fractions containing the expected product were combined and the volatiles were removed by evaporation. The residue was dissolved in a mixture of methylene chloride and methanol and 5M hydrogen chloride in isopropanol was added. The suspension was concentrated and the solid was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline hydrochloride (16 mg, 4%).

Workup

  1. custom(prepared
  2. stirringAfter stirring for 15 minutes
  3. customthe volatiles were removed under vacuum
  4. customthe residue was purified by column chromatography
  5. washeluting with methylene chloride/acetonitrile/methanol (70/10/20 followed by 75/5/20 and 80/0/20)
  6. additionThe fractions containing the expected product
  7. customthe volatiles were removed by evaporation
  8. dissolutionThe residue was dissolved in a mixture of methylene chloride and methanol and 5M hydrogen chloride in isopropanol
  9. additionwas added
  10. concentrationThe suspension was concentrated
  11. filtrationthe solid was collected by filtration
  12. washwashed with ether
  13. customdried under vacuum

Sources & evidence

ORD record
ord-018227f29e6540f9acb1920c84888081
Source dataset
uspto-grants-2015_05
Patent number
US09040548B2

Reaction notes

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