4-(4-Fluorophenyl)benzoic acid → 4'-Fluoro-biphenyl-4-carboxylic acid {2-[methyl-(1-methyl-pyrrolidin-3-ylmethyl)-amino]-benzooxazol-5-yl}-amide

HRID 1174928Notes

Reaction equation

HRID 1174928 reaction equation
[CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:6]=2[N:7]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33](O)=[O:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH:12][C:33]([C:30]3[CH:29]=[CH:28][C:27]([C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)=[CH:32][CH:31]=3)=[O:34])=[CH:8][C:6]=2[N:7]=1

Participants

5

Reactant 3

HCID 27826894-(4-Fluorophenyl)benzoic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 57771749Rac-n2-methyl-n2-(1-methyl-pyrrolidin-3-ylmethyl)-benzooxazole-2,5-diamine

Product 1

HCID 115253964'-Fluoro-biphenyl-4-carboxylic acid {2-[methyl-(1-methyl-pyrrolidin-3-ylmethyl)-amino]-benzooxazol-5-yl}-amideYield 30.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Combine rac-N2-methyl-N2-(1-methyl-pyrrolidin-3-ylmethyl)-benzooxazole-2,5-diamine (0.700 g, 2.69 mmol), 4′-fluoro-biphenyl-4-carboxylic acid (0.872 g, 4.03 mmol), HATU (1.43 g, 3.76 mmol), polystyrene-bound diisopropylamine (7.53 g, loading: 2.0 to 3.5 mmol/g), and CH2Cl2 (15 mL). Shake the mixture overnight at room temperature. Filter the mixture and wash the polystyrene resin with 1:1 CH2Cl2/MeOH. Subject the mixture to flash column chromatography on an ISCO Companion (120 g column, eluting with 20% 2M NH3 in MeOH/CH2Cl2) to yield a mixture of products. Subject the mixture to flash column chromatography (3×40 g, eluting with 20% 2M NH3 in MeOH/CH2Cl2) to yield a mixture of products. Concentrate the fractions and suspend the residue in anhydrous diethyl ether. Stir at room temperature for 3 d. Filter the mixture to yield the product as a white solid (0.375 g, 30%). Submit the racemic mixture to chiral chromatography to yield the product (0.187 g) as the second eluting enantiomer; mass spectrum (m/e): 459.2 (M+1), 457.3 (M−1). 1H NMR (400 MHz, DMSO-d6): δ 10.22 (s, 1H), 8.07-8.03 (m, 2H), 7.85-7.79 (m, 4H), 7.73 (d, J=2.0 Hz, 1H), 7.40-7.31 (m, 4H), 3.50 (d, J=7.6 Hz, 2H), 3.13 (s, 3H), 2.65-2.56 (m, 1H), 2.54-2.47 (m, 2H), 2.43-2.36 (m, 1H), 2.29-2.24 (m, 1H), 2.23 (s, 3H), 1.93-1.84 (m, 1H), 1.49-1.40 (m, 1H).

Workup

  1. customthe mixture overnight
  2. customat room temperature
  3. filtrationFilter the mixture
  4. washwash the polystyrene resin with 1:1 CH2Cl2/MeOH
  5. washon an ISCO Companion (120 g column, eluting with 20% 2M NH3 in MeOH/CH2Cl2)
  6. customto yield
  7. additiona mixture of products
  8. washto flash column chromatography (3×40 g, eluting with 20% 2M NH3 in MeOH/CH2Cl2)
  9. customto yield
  10. additiona mixture of products
  11. concentrationConcentrate the fractions
  12. filtrationFilter the mixture

Sources & evidence

ORD record
ord-b70e9eefd8d1404293bed5fb0811e6aa
Source dataset
uspto-grants-2010_11
Patent number
US07838543B2

Reaction notes

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