Ether hydrochloride → Methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate

HRID 473208Notes

Reaction equation

HRID 473208 reaction equation
[F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]([NH:5][C:6]1[C:14]([C:15](=[O:17])[NH2:16])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=O.Cl.[CH3:27]COCC>CO>[F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[NH:16][C:15](=[O:17])[C:14]2[C:6](=[C:7]([C:8]([O:10][CH3:27])=[O:9])[CH:11]=[CH:12][CH:13]=2)[N:5]=1

Participants

4

Reactant 2

HCID 10953452Ether hydrochlorideHCID 666098362-(2,2-Difluoro-2-(5-fluoropyridin-2-yl)acetamido)-3-carbamoylbenzoic acid

Product 1

HCID 136340599Methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylateYield 62%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

2-(2,2-difluoro-2-(5-fluoropyridin-2-yl)acetamido)-3-carbamoylbenzoic acid (28.5 g, 81 mmol) in MeOH (1000 mL) was treated with 2M HCl/ether (4 mL) and then heated at reflux overnight. The mixture was concentrated to 10% of the original volume and the resulting precipitate was collected by filtration and washed with a small amount of MeOH to afford methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate (17.5 g, 62%). Separately, 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-hydroxyquinazoline-8-carboxylic acid (10.5 g, 31 mmol) in MeOH (200 mL) was treated with 2M HCl/ether (1 mL) and was heated at reflux overnight. The mixture was concentrated to 10% of the original volume and the resulting precipitate was collected by filtration and washed with a small amount of MeOH to afford methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate (5.5 g, 51%). The filtrates from the two procedures above were concentrated at 65° C. and allowed to cool. The solid was collected by filtration to afford additional methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate (3 g). Purification of the filtrate by silica gel chromatography eluting with EtOAc/hexanes afforded additional methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate (4 g). The isolated solids were combined to afford methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate as a solid (30 g). LC-MS (ESI) m/z 350 (M+H+).

Workup

  1. temperatureheated
  2. temperatureat reflux overnight
  3. concentrationThe mixture was concentrated to 10% of the original volume
  4. filtrationthe resulting precipitate was collected by filtration
  5. washwashed with a small amount of MeOH

Sources & evidence

ORD record
ord-8ef9114c59c847dfb9754e72ebbe5023
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

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