Sodium Hydroxide → 3-(N-methyl-6-((3-methyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)butyl)amino)nicotinamido)propanoic acid

HRID 2173844Notes

Reaction equation

HRID 2173844 reaction equation
[CH3:1][N:2]([CH2:33][CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:6][CH:5]=1.C(=O)=O.CO.FC(F)(F)C1C=CC(C2N=CC(C=O)=CN=2)=CC=1.C(O)(C(F)(F)F)=O.C(Cl)Cl.[OH-].[Na+]>O>[CH3:1][N:2]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:6][CH:5]=1

Participants

7

Reactant 5

HCID 14798Sodium HydroxideHCID 21863450Trifluoroacetic acid methylene chlorideHCID 219363042-(4-Trifluoromethyl-phenyl)-pyrimidine-5-carbaldehydeHCID 21973728Carbon dioxide methanolHCID 67980840tert-butyl 3-(N-methyl-6-((3-methyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)butyl)amino)nicotinamido)propanoate

Product 1

HCID 573888523-(N-methyl-6-((3-methyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)butyl)amino)nicotinamido)propanoic acidYield 88.2%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

The title compound is obtained by a method analogous to the one described for example 1.23 except tert-butyl 3-(N-methyl-6-((3-methyl-1-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)butyl)amino)nicotinamido)propanoate used in the synthesis was resolved by chiral chromatography; Column: Chiralpak AD-H. Dimensions: 10 mm×250 cm. Mobile Phase: 65/35 CO2/methanol. Flow Rate: 10 mL/min. Modifier: none. Retention time: 4.23 min (peak 1), 6.81 min. (peak 2; >99% ee). Peak 2 (1.15 g, 2.02 mmol) was then deprotected under the TFA/DCM previously reported. Concentration of the reaction mixture under reduced pressure provide a crude orange gum. Water (150 mL) added to the gum and NaOH 1M aq. added slowly until reaching pH 11 to obtain a clear solution of the crude. Acidification to pH4 with 1N HCl followed by filtration of the solid formed (washed with plenty of water) provide 3-(N-methyl-6-((3-methyl-1-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)butyl)amino)nicotinamido)propanoic acid (915 mg, 88.2%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 0.91 (d, 3H) 0.95 (d, J=6.46 Hz, 3H) 1.49-1.59 (m, 1H) 1.61-1.71 (m, 1H) 1.71-1.82 (m, 1H) 2.52-2.55 (m, 2H) 2.92 (s, 3H) 3.53 (t, J=7.24 Hz, 2H) 5.09 (br. s., 1H) 6.56 (d, J=1.17 Hz, 1H) 7.44 (d, J=9.39 Hz, 1H) 7.50 (d, J=8.22 Hz, 2H) 7.54-7.65 (m, 1H) 7.67 (d, J=8.02 Hz, 2H) 7.75-7.82 (m, 2H) 7.83-7.89 (m, 2H) 8.00 (d, J=2.15 Hz, 1H) 12.27 (br. s., 1H); MS (M+1): 514.4.

Workup

  1. customRetention time: 4.23 min (peak 1), 6.81 min. (peak 2; >99% ee)
  2. customConcentration of the reaction mixture under reduced pressure provide a crude orange gum
  3. additionaq. added slowly
  4. customto obtain a clear solution of the crude
  5. filtrationAcidification to pH4 with 1N HCl followed by filtration of the solid
  6. customformed
  7. wash(washed with plenty of water)

Sources & evidence

ORD record
ord-40238b98d82442468f8d0a945c15a82e
Source dataset
uspto-grants-2015_06
Patent number
US09056834B2

Reaction notes

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