Boron tribromide → 2-(4-Chloro-7-methylquinazolin-2-yl)-3-fluorophenol

HRID 2062173Notes

Reaction equation

HRID 2062173 reaction equation
[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[C:18]([O:19]C)=[CH:17][CH:16]=[CH:15][C:14]=2[F:21])[N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[C:14]([F:21])=[CH:15][CH:16]=[CH:17][C:18]=2[OH:19])[N:3]=1

Participants

4

Reactant 2

HCID 25134Boron tribromideHCID 586839024-Chloro-2-(2-fluoro-6-methoxyphenyl)-7-methylquinazoline

Product 1

HCID 1361213752-(4-Chloro-7-methylquinazolin-2-yl)-3-fluorophenolYield 66%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
-50 °C

Procedure

Under an N2 atmosphere, 4-chloro-2-(2-fluoro-6-methoxyphenyl)-7-methylquinazolin (7.0 g, 23.12 mmol) was dissolved in CH2Cl2 (110 mL) and cooled to −50° C. internal temperature using a dry ice/acetone bath. A 1.0 M solution of BBr3 in CH2Cl2 (115.6 mL, 115.6 nmol) was added dropwise via an addition funnel while maintaining the internal temperature at −50° C. The reaction mixture was allowed to warm to 0° C., and the reaction was complete after 1.5 h. It was then slowly quenched with saturated aqueous NaHCO3 solution to pH 7. After partitioning between CH2Cl2 and H2O, the mixture was separated and the aqueous layer was twice extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated to a brown solid. Purification via silica gel chromatography using 75% CH2Cl2/25% hexanes gave 2-(4-chloro-7-methylquinazolin-2-yl)-3-fluorophenol as a yellow solid (4.37 g, 66%). LC/MS: m/z 289.1 (M+H)+ at 3.71 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J=8.5 Hz, 1H), 7.95 (s, 1H), 7.60 (dd, J=8.6, 1.5 Hz, 1H), 7.42-7.36 (m, 1H), 6.86-6.82 (m, 2H), 3.81 (s, 3H), 2.64 (s, 3H)

Workup

  1. temperaturewhile maintaining the internal temperature at −50° C
  2. temperatureto warm to 0° C.
  3. customIt was then slowly quenched with saturated aqueous NaHCO3 solution to pH 7
  4. customAfter partitioning between CH2Cl2 and H2O
  5. customthe mixture was separated
  6. extractionthe aqueous layer was twice extracted with CH2Cl2
  7. dry with materialThe combined organic layers were dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated to a brown solid
  10. customPurification via silica gel chromatography

Sources & evidence

ORD record
ord-c3ea569544e4450f8c695b7fb735b7fa
Source dataset
uspto-grants-2012_10
Patent number
US08283354B2

Reaction notes

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