Sodium Hydroxide → (R)-2-(1-(biphenyl-4-yl)-3-carboxypropan-2-ylcarbamoyl)isonicotinic acid

HRID 70855Notes

Reaction equation

HRID 70855 reaction equation
Cl.[NH2:2][C@H:3]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][C:5]([O:7]CC)=[O:6].O.[N:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][C:25]=1[C:33]([OH:35])=[O:34].CCN=C=NCCCN(C)C.ON1C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[OH-].[Na+]>CN(C=O)C.O.C1COCC1.CO>[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:13]=[CH:12][C:11]([CH2:10][C@@H:3]([NH:2][C:30]([C:27]2[CH:28]=[CH:29][N:24]=[C:25]([C:33]([OH:35])=[O:34])[CH:26]=2)=[O:31])[CH2:4][C:5]([OH:7])=[O:6])=[CH:16][CH:15]=1.[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:13]=[CH:12][C:11]([CH2:10][C@@H:3]([NH:2][C:33]([C:25]2[CH:26]=[C:27]([CH:28]=[CH:29][N:24]=2)[C:30]([OH:32])=[O:31])=[O:34])[CH2:4][C:5]([OH:7])=[O:6])=[CH:16][CH:15]=1

Participants

12

Reactant 6

HCID 14798Sodium HydroxideHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 81531DiisopropylethylamineHCID 181649HOAtHCID 162198812,4-Pyridinedicarboxylic acid monohydrateHCID 68424075(R)-ethyl 3-amino-4-(biphenyl-4-yl)butanoate hydrochloride

Product 2

HCID 59607803(R)-2-(1-(biphenyl-4-yl)-3-carboxypropan-2-ylcarbamoyl)isonicotinic acidHCID 59607919(R)-4-(1-(biphenyl-4-yl)-3-carboxypropan-2-ylcarbamoyl)picolinic acid

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (R)-ethyl 3-amino-4-(biphenyl-4-yl)butanoate hydrochloride (200 mg, 0.625 mmol), 2,4-pyridinedicarboxylic acid hydrate (151 mg, 0.813 mmol), EDCI (132 mg, 0.688 mmol) and 1-hydroxy-7-azabenzotriazole (94 mg, 0.688 mmol) in DMF (6 ml), DIPEA (0.164 ml, 0.938 mmol) is added. The reaction mixture is allowed to stir for 3 hours. Then, the reaction mixture is diluted with H2O. The precipitated solid is collected on a funnel and dried under reduced pressure. To a solution of the crude in THF (8 ml) and MeOH (1 ml), 1 M aqueous NaOH (2.5 ml, 2.5 mmol) is added. After stirring for 1 hour, the reaction is quenched with 5% citric acid and brine, and the products are extracted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1% TFA) to 100% MeCN to give (R)-4-(1-(biphenyl-4-yl)-3-carboxypropan-2-ylcarbamoyl)picolinic acid and (R)-2-(1-(biphenyl-4-yl)-3-carboxypropan-2-ylcarbamoyl)isonicotinic acid as white solids, respectively (Example 13-1: 33 mg; Example 13-2: 36 mg). Example 13-1, HPLC retention time=1.50 minutes (condition D); MS (m+1)=405.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.53-2.62 (m, 2 H) 2.88-2.97 (m, 2 H) 4.50-4.59 (m, 1 H) 7.31-7.35 (m, 3 H) 7.42-7.45 (m, 2 H) 7.57-7.64 (m, 4 H) 7.89 (dd, J=5, 1.6 Hz, 1 H) 8.83 (dd, J=5, 0.8 Hz, 1 H) 8.37 (dd, J=1.6, 0.8 Hz) 8.89 (d, J=8.3 Hz, 1 H). Example 13-2, HPLC retention time=1.24 minutes (condition A); MS (m+1)=405.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.52-2.68 (m, 2 H) 2.91 (A of ABX, Jab=13.6 Hz, Jax=6.1 Hz, 1 H) 3.01 (B of ABX, Jab=13.6 Hz, Jbx=8.1 Hz, 1 H) 4.56-4.65 (m, 1 H) 7.29-7.34 (m, 3 H) 7.41-7.45 (m, 2 H) 7.55-7.64 (m, 4 H) 7.99 (dd, J=5, 1.6 Hz, 1 H) 8.34 (dd, J=1.6, 0.8 Hz, 1 H) 8.84 (dd, J=5, 0.8 Hz, 1 H) 8.90 (d, J=9.1 Hz, 1 H) 12.26 (br s, 1 H) 13.87 (br s, 1 H).

Workup

  1. customThe precipitated solid is collected on a funnel
  2. customdried under reduced pressure
  3. stirringAfter stirring for 1 hour
  4. customthe reaction is quenched with 5% citric acid and brine
  5. extractionthe products are extracted with EtOAc
  6. washThe organic layer is washed with brine
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe resulting residue is purified by preparative HPLC

Sources & evidence

ORD record
ord-bfed4498c3a848f4a6e642cbd3a21727
Source dataset
uspto-grants-2014_09
Patent number
US08822534B2

Reaction notes

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