Potassium Phosphate, Tribasic → methyl[6-({1-[4-(2-tert-butoxy-2-oxoethoxy)phenyl]-2-methylindolizin-3-yl}carbonyl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl]acetate

HRID 1502213Notes

Reaction equation

HRID 1502213 reaction equation
Br[C:2]1[C:3]([CH3:30])=[C:4]([C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[N:17]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:16]3=[O:29])=[O:12])[N:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.[C:31]([O:35][C:36](=[O:54])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42](B2OC(C)(C)C(C)(C)O2)=[CH:41][CH:40]=1)([CH3:34])([CH3:33])[CH3:32].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[CH3:28][O:27][C:25](=[O:26])[CH2:24][N:17]1[C:16](=[O:29])[C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:11]([C:4]3[N:5]4[C:10]([CH:9]=[CH:8][CH:7]=[CH:6]4)=[C:2]([C:42]4[CH:41]=[CH:40][C:39]([O:38][CH2:37][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:54])=[CH:44][CH:43]=4)[C:3]=3[CH3:30])=[O:12])[CH:14]=2)[NH:19][C:18]1=[O:23]

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 59852411Tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetateHCID 89618502methyl {6-[(1-bromo-2-methylindolizin-3-yl)carbonyl]-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl}acetate

Product 1

HCID 131734304methyl[6-({1-[4-(2-tert-butoxy-2-oxoethoxy)phenyl]-2-methylindolizin-3-yl}carbonyl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl]acetateYield 42.5%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 80711,2-DimethoxyethaneSolvent

Procedure

Methyl {6-[(1-bromo-2-methylindolizin-3-yl)carbonyl]-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl}acetate [described in Step 1.5.] (0.85 g; 1.81 mmol), tert-butyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenoxy]acetate [CAS 769968-17-4; D. Fan et al, Journal of Organic Chemistry, 2007, 72(14), 5350-5357] (0.91 g; 2.71 mmol), 5.4 mL of a molar solution of potassium phosphate, 17 mL of 1,2-dimethoxyethane and the catalyst PdCl2(dppf) (198 mg; 0.27 mmol) are successively introduced into a reactor, under argon. The mixture is heated at reflux for 2 hours under argon. The reaction medium is filtered through Celite. The filtrate is diluted with ethyl acetate and the solution is washed with a saturated solution of potassium hydrogen carbonate and with a saturated solution of sodium chloride, and then dried over sodium sulphate and concentrated to dryness. The residue obtained is purified by flash chromatography on silica (DCM/EtOH: 100/0 to 80/10). 0.46 g (42%) of a yellow-red powder is obtained.

Workup

  1. temperatureThe mixture is heated
  2. temperatureat reflux for 2 hours under argon
  3. filtrationThe reaction medium is filtered through Celite
  4. additionThe filtrate is diluted with ethyl acetate
  5. washthe solution is washed with a saturated solution of potassium hydrogen carbonate and with a saturated solution of sodium chloride
  6. dry with materialdried over sodium sulphate
  7. concentrationconcentrated to dryness
  8. customThe residue obtained
  9. customis purified by flash chromatography on silica (DCM/EtOH: 100/0 to 80/10)

Sources & evidence

ORD record
ord-d193d874763a4088a77a5d5a2330b0f9
Source dataset
uspto-grants-2015_12
Patent number
US09206177B2

Reaction notes

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