Dichloromethane → (E)-4-(4-bromo2-fluoroanilino)-6-methoxy-7-(4-pyrrolidin-1-ylbut-2-en-1-yloxy)quinazoline hydrochloride

HRID 547205Notes

Reaction equation

HRID 547205 reaction equation
N(C(OCC)=O)=NC(OCC)=O.[Br:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.[N:35]1([CH2:40]/[CH:41]=[CH:42]/[CH2:43]O)[CH2:39][CH2:38][CH2:37][CH2:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)[Cl:65]>>[ClH:65].[Br:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:43]/[CH:42]=[CH:41]/[CH2:40][N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1

Participants

6

Reactant 5

HCID 6344Dichloromethane3×HCID 11776Triphenylphosphine2×HCID 220568ethyl N-ethoxycarbonyliminocarbamate2×HCID 22030876(E)-4-(pyrrolidin-1-yl)but-2-en-1-ol2×HCID 1355038524-[(4-Bromo-2-fluorophenyl)amino]-6-methoxy-7-quinazolinol

Product 1

HCID 22478260(E)-4-(4-bromo2-fluoroanilino)-6-methoxy-7-(4-pyrrolidin-1-ylbut-2-en-1-yloxy)quinazoline hydrochlorideYield 32%

Conditions

Temperature
5 °C

Procedure

Diethyl azodicarboxylate (1.55 ml, 9.89 mmol), 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (1.2g, 3.3 mmol), (prepared as described for the starting material in Example 48), and a solution of (E)-4-(pyrrolidin-1-yl)but-2-en-1-ol (697 mg, 4.9 mmol), (prepared as described for the starting material in Example 17), in methylene chloride (5 ml) were added successively to a solution of triphenylphosphine (2.59 g, 9.89 mmol) in methylene chloride (150 ml) cooled at 5° C. The mixture was stirred at ambient temperature for 10 minutes then methylene chloride (100 ml) was added followed successively by triphenylphosphine (432 mg, 1.6 mmol), (E)-4-(pyrrolidin-1-yl)but-2-en-1-ol (232 mg, 1.6 mmol) and diethyl azodicarboxylate (246 μl, 1.6 mmol). The mixture was stirred at ambient temperature for 30 minutes and then the solvent was removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (8/2 followed by 7/3 and 6/4). The semi-purified product was repurified by column chromatography eluting with methylene chloride/methanol (8/2 followed by 7.5/2.5). The purified product was dissolved in methylene chloride, 3.7M ethereal hydrogen chloride (3 ml) was added and the volatiles were removed by evaporation. The residue was triturated with ether, collected by filtration and dried under vacuum to give (E)-4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(4-pyrrolidin-1-ylbut-2-en-1-yloxy)quinazoline hydrochloride (600 mg, 32%).

Workup

  1. custom(prepared
  2. stirringThe mixture was stirred at ambient temperature for 30 minutes
  3. customthe solvent was removed by evaporation
  4. customThe residue was purified by column chromatography
  5. washeluting with methylene chloride/methanol (8/2 followed by 7/3 and 6/4)
  6. customThe semi-purified product was repurified by column chromatography
  7. washeluting with methylene chloride/methanol (8/2 followed by 7.5/2.5)
  8. dissolutionThe purified product was dissolved in methylene chloride
  9. addition3.7M ethereal hydrogen chloride (3 ml) was added
  10. customthe volatiles were removed by evaporation
  11. customThe residue was triturated with ether
  12. filtrationcollected by filtration
  13. customdried under vacuum

Sources & evidence

ORD record
ord-02f958f724cc4144b95583c492ebe03e
Source dataset
uspto-grants-2011_05
Patent number
USRE042353E1

Reaction notes

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