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

HRID 473209Notes

Reaction equation

HRID 473209 reaction equation
[F:1][C:2]([F:24])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:3]1[N:12]=[C:11]([OH:13])[C:10]2[C:5](=[C:6]([C:14]([OH:16])=[O:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.Cl.[CH3:26]COCC>CO>[F:24][C:2]([F:1])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[C:6]([C:14]([O:16][CH3:26])=[O:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1

Participants

4

Reactant 2

HCID 10953452Ether hydrochlorideHCID 178524224HCID 178524224, compound

Product 1

HCID 136340599Methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylateYield 51%

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. temperaturewas heated
  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-6732e2b053904dbf9566a7a61b9e7b73
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

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