Sodium hydride → 8-bromo-3-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-chloro-quinazolin-4(3H)-one

HRID 1056386Notes

Reaction equation

HRID 1056386 reaction equation
[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[N:8]=[C:7]2[OH:13].[H-].[Na+].[Br-].[Li+].Br[CH2:19][CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>COCCOC.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[N:8]([CH2:19][CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:27])([CH3:29])[CH3:28])([CH3:24])[CH3:25])[C:7]2=[O:13]

Participants

7

Reactant 4

HCID 24758Sodium hydrideHCID 82050Lithium BromideHCID 607486(3-Bromopropoxy)(tert-butyl)dimethylsilaneHCID 178517813HCID 178517813, compound

Product 1

HCID 897821118-bromo-3-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-chloro-quinazolin-4(3H)-oneYield 43.6%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 80711,2-DimethoxyethaneSolvent

Procedure

To a solution of 8-bromo-2-chloroquinazolin-4(3H)-one (407c; 0.110 g, 0.424 mmol) in 2 mL DME and 0.5 mL DMF in an ice/water bath was added sodium hydride (60% in mineral oil; Aldrich; 0.019 g, 0.466 mmol). After 10 min, lithium bromide (Aldrich; 0.074 g, 0.848 mmol) was added and the reaction was warmed to RT. After 15 min, (3-bromopropoxy)-tert-butyldimethylsilane (0.108 mL, 0.466 mmol) was added. After 30 min, the reaction was placed in a 60° C. oil bath and heated over the weekend. The reaction was partitioned between water and EtOAc. The aq layer was extracted 2× EtOAc and The combined organic layers were washed with water 2 times, satd aq NaCl once, and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography using 0-20% EtOAc/hexane. The product-containing fractions were concentrated to afford 8-bromo-3-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-chloroquinazolin-4(3H)-one (0.080 g, 0.185 mmol, 43% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.21 (1H, dd, J=7.9, 1.3 Hz), 8.02 (1H, dd, J=7.8, 1.4 Hz), 7.34 (1H, t, J=7.8 Hz), 4.38-4.50 (2H, m), 3.78 (2H, t, J=5.8 Hz), 1.96-2.05 (2H, m), 0.89 (9H, s), 0.03-0.08 (6H, m). m/z (ESI, +ve ion) 431.0/433.0/435.0 (M+H)+.

Workup

  1. waitAfter 15 min
  2. waitAfter 30 min
  3. customwas placed in a 60° C.
  4. temperatureheated over the weekend
  5. customThe reaction was partitioned between water and EtOAc
  6. extractionThe aq layer was extracted 2× EtOAc
  7. washThe combined organic layers were washed with water 2 times
  8. dry with materialthe organics were dried over anhydrous Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. additionThe material was treated with DCM
  12. custompurified by silica gel chromatography
  13. concentrationThe product-containing fractions were concentrated

Sources & evidence

ORD record
ord-331683879d6642bc86c4f9876fc758af
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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