2-Fluorobenzylamine → HCID 71538329, compound

HRID 1519330Notes

Reaction equation

HRID 1519330 reaction equation
C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[F:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH2:37].O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:25]=[CH:26][C:27]([C:30](=[O:31])[NH:37][CH2:36][C:35]5[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=5[F:33])=[CH:28][CH:29]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]

Participants

7

Reactant 3

HCID 666492-FluorobenzylamineHCID 168937Lithium hydroxide, monohydrate3×HCID 86679835HCID 86679835, compound2×

Product 1

HCID 71538329HCID 71538329, compoundYield 63%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

Using the conditions of General Procedure D for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 2-fluorobenzylamine (available from Aldrich Chemical Company, Inc.; 52 mg, 0.42 mmol) to give the crude amide product. The crude amide was hydrolyzed by adding THF (2 mL), water (0.05 mL), MeOH (1 mL), and lithium hydroxide monohydrate (12.3 mg, 0.29 mmol) and stirring the mixture overnight at room temperature. Tetrahydrofuran (2 mL) was added to dissolve the solid, and lithium hydroxide monohydrate (22 mg, 0.52 mmol) was added. The reaction mixture was stirred overnight, and then another portion of lithium hydroxide monohydrate (22 mg, 0.52 mmol) was added. The reaction mixture was stirred overnight. The reaction mixture was concentrated to dryness under vacuum at 40° C. 1 M HCl (3 mL) was added, and the mixture was stirred, concentrated to dryness, and purified and purified using HPLC Purification Conditions A to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(2-fluoro-benzylcarbamoyl)-biphenyl-2-carboxylic acid (75 mg, 63%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.18 (br s, 1H), 9.10 (t, J=5.8 Hz, 1H), 8.47 (s, 1H), 8.39 (d, J=1.8 Hz, 1H), 8.33 (d, J=2.0 Hz, 1H), 8.24 (dd, J=8.0, 1.8 Hz, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 7.97 (d, J=8.3 Hz, 2H), 7.76 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.40 (t, J=7.7 Hz, 1H), 7.29-7.36 (m, 1H), 7.16-7.23 (m, 2H), 4.56 (d, J=5.8 Hz, 2H).

Workup

  1. customto give the crude amide product
  2. additionwas added
  3. stirringThe reaction mixture was stirred overnight
  4. stirringThe reaction mixture was stirred overnight
  5. concentrationThe reaction mixture was concentrated to dryness under vacuum at 40° C
  6. addition1 M HCl (3 mL) was added
  7. stirringthe mixture was stirred
  8. concentrationconcentrated to dryness
  9. custompurified
  10. custompurified
  11. customHPLC Purification Conditions

Sources & evidence

ORD record
ord-e953866485ff4009bf36cfe9626bc913
Source dataset
uspto-grants-2015_07
Patent number
US09073881B2

Reaction notes

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