Hydrochloric Acid → 2-Fluoro-6-hydroxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid

HRID 401116Notes

Reaction equation

HRID 401116 reaction equation
[F:1][C:2]1[CH:11]=[C:10]([CH:12]=O)[CH:9]=[C:8]([OH:14])[C:3]=1[C:4]([O:6]C)=[O:5].[C:15]1([C:21](=O)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH2:30][C:31]([NH2:33])=[O:32].Cl>C(O)C>[F:1][C:2]1[CH:11]=[C:10]([CH:12]2[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:33][C:31](=[O:32])[NH:30]2)[CH:9]=[C:8]([OH:14])[C:3]=1[C:4]([OH:6])=[O:5]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 1176UreaHCID 99482-PhenylacetophenoneHCID 86669343Methyl 2-fluoro-4-formyl-6-hydroxybenzoate2×

Product 1

HCID 513470392-Fluoro-6-hydroxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acidYield 13.3%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
40 °C

Procedure

To a solution of methyl 2-fluoro-4-formyl-6-hydroxybenzoate (Intermediate 83) (150 mg, 0.76 mmol), 1,2-diphenylethanone (150 mg, 0.76 mmol) and urea (144 mg, 2.4 mmol) in ethanol (5 mL) was added conc. HCl (0.2 mL) and the reaction mixture was refluxed under N2 overnight. Removed solvent in vacuo and the residue (320 mg) was used without further purification. A mixture of this intermediate compound (320 mg) and aqueous NaOH (2 M, 10 mL) in MeOH (10 mL) was stirred at 40° C. for 3 hours. The resulting mixture was cooled and acidified with aqueous HCl (2 M, 12 mL) and a standard aqueous/EtOAc workup was followed. Purification by prep-HPLC (0.1% TFA as additive) gave Compound 158 as a yellow solid (41 mg, two step yield 13%). 1H NMR (CD3OD 400 MHz): δ 7.30-7.20 (m, 5H), 7.10-7.05 (m, 3H), 6.91-6.88 (m, 2H), 6.75 (s, 1H), 6.65 (d, J=11.6 Hz, 1H), 5.29 (s, 1H). MS (ESI): m/z 405.0 [M+1]+.

Workup

  1. temperaturethe reaction mixture was refluxed under N2 overnight
  2. customRemoved solvent in vacuo and the residue (320 mg) was used without further purification
  3. additionA mixture of this intermediate compound (320 mg) and aqueous NaOH (2 M, 10 mL) in MeOH (10 mL)
  4. temperatureThe resulting mixture was cooled
  5. customPurification by prep-HPLC (0.1% TFA as additive)

Sources & evidence

ORD record
ord-d687446315e448e29309d05b5f6c67a7
Source dataset
uspto-grants-2014_06
Patent number
US08741915B2

Reaction notes

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