Dimethylamine, hydrochloride → 3-Cyclohexyl-1-dimethylcarbamoylmethyl-2-(4-methoxy-phenyl)-1H-indole-6-carboxylic acid

HRID 1713931Notes

Reaction equation

HRID 1713931 reaction equation
[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18]C)=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][C:21]([OH:23])=O)[C:8]=2[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[CH2:33][N:34](C(C)C)[CH:35](C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CNC.[OH-].[K+]>C(Cl)Cl.CCOC(C)=O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][C:21]([N:34]([CH3:35])[CH3:33])=[O:23])[C:8]=2[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1

Participants

8

Reactant 5

HCID 10473Dimethylamine, hydrochlorideHCID 14797Potassium HydroxideHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 11189363[3-cyclohexyl-6-(methoxycarbonyl)-2-(4-methoxyphenyl)-1H-indol-1-yl]acetic acid

Product 1

HCID 52754503-Cyclohexyl-1-dimethylcarbamoylmethyl-2-(4-methoxy-phenyl)-1H-indole-6-carboxylic acidYield 91%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
25 °C

Procedure

A solution (0.04 M) of [3-cyclohexyl-6-(methoxycarbonyl)-2-(4-methoxyphenyl)-1H-indol-1-yl]acetic acid (from Step 3) in CH2Cl2 was treated with DIPEA (4 eq.), HATU (2 eq.) and dimethylamine hydrochloride (1.5 eq.). The solution was stirred at 25° C. for 12 h. The mixture was diluted with EtOAc and then washed sequentially with aqueous HCl (1 N), NaOH (2 N) and brine. The dried organic layer was concentrated and the residue dissolved in a 1:1 mixture of THF/H2O. The resulting solution (0.05 M) was treated with aqueous KOH (1 N, 4 eq.), then stirred at 70° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was treated with aqueous HCl (1 N) and extracted with EtOAc. The dried organic phase was washed with brine, dried and then concentrated to give the title compound (91%) as a solid. 1H NMR (300 MHz, DMSO-d6, 300K) δ 1.14-1.35 (m, 3H), 1.63-1.98 (m, 7H), 2.54-2.65 (m, 1H), 2.83 (s, 3H), 2.94 (s, 3H), 3.85 (s, 3H), 4.86 (s, 2H), 7.09 (d, J 8.6, 2H), 7.25 (d, J 8.6, 2H), 7.66 (d, J 8.4, 1H), 7.82 (d, J 8.4, 1H), 7.92 (s, 1H), 12.45 (br s, 1H); MS (ES+) m/z 435 (M+H)+.

Workup

  1. washwashed sequentially with aqueous HCl (1 N), NaOH (2 N) and brine
  2. concentrationThe dried organic layer was concentrated
  3. dissolutionthe residue dissolved in a 1:1 mixture of THF/H2O
  4. stirringstirred at 70° C. for 16 h
  5. concentrationThe mixture was concentrated under reduced pressure
  6. additionthe residue was treated with aqueous HCl (1 N)
  7. extractionextracted with EtOAc
  8. washThe dried organic phase was washed with brine
  9. customdried
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-bcf698f3a5094a0692f7f33c04d71829
Source dataset
uspto-grants-2010_09
Patent number
US07795250B2

Reaction notes

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