Sodium Hydroxide → (2E)-3-{4-[({1-[({3-Cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-phenyl-1H-indol-6-yl}carbonyl)amino]cyclopentyl}carbonyl)amino]phenyl}-acrylic acid

HRID 1713927Notes

Reaction equation

HRID 1713927 reaction equation
[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16](O)=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:19][C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[C:8]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:64][C:65]1([C:70]([NH:72][C:73]2[CH:78]=[CH:77][C:76](/[CH:79]=[CH:80]/[C:81]([O:83]CC)=[O:82])=[CH:75][CH:74]=2)=[O:71])[CH2:69][CH2:68][CH2:67][CH2:66]1.[OH-].[Na+]>CN(C=O)C.CCOC(C)=O.C1COCC1.CO>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([NH:64][C:65]4([C:70]([NH:72][C:73]5[CH:74]=[CH:75][C:76](/[CH:79]=[CH:80]/[C:81]([OH:83])=[O:82])=[CH:77][CH:78]=5)=[O:71])[CH2:69][CH2:68][CH2:67][CH2:66]4)=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:19][C:20]([N:22]([CH3:23])[CH3:24])=[O:21])[C:8]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

10

Reactant 5

HCID 14798Sodium HydroxideHCID 81531DiisopropylethylamineHCID 52754443-Cyclohexyl-1-dimethylcarbamoylmethyl-2-phenyl-1H-indole-6-carboxylic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 58745796Ethyl (2E)-3-(4-{[(1-aminocyclopentyl)carbonyl]amino}phenyl)acrylate

Product 1

HCID 11679112(2E)-3-{4-[({1-[({3-Cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-phenyl-1H-indol-6-yl}carbonyl)amino]cyclopentyl}carbonyl)amino]phenyl}-acrylic acidYield 45%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
25 °C

Procedure

A solution of 3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-phenyl-1H-indole-6-carboxylic acid (from Step 6) in DMF (0.1 M) was treated with DIPEA (2 eq.), HATU (1.1 eq.) and ethyl (2E)-3-(4-{[(1-aminocyclopentyl)carbonyl]amino}phenyl)acrylate (from Step 7, 1.1 eq.). The solution was stirred at 25° C. for 12 h, then for 24 h at 50° C. The mixture was diluted with EtOAc, and then washed sequentially with HCl (2×, 1 N), NaOH (2×, 1N) and brine. The organic layer was dried over Na2SO4 and concentrated to afford an oil, which was dissolved in a mixture of THF and MeOH (0.5M, 2:1, v/v). NaOH (2 eq., 1 N) was added and the resultant mixture stirred at 50° C. for 1 h. The reaction mixture was diluted with EtOAc, and then washed with HCl (2×, 1 N), brine, and dried over Na2SO4. Evaporation gave an off-white foam, which was purified by RP-HPLC (column: Waters X-terra C18, 19×150 mm, 5 micron; flow 20 mL/min) to give the title compound (45%) as a white powder after lyophilization. 1H NMR (400 MHz, DMSO-d6, 300 K) δ 1.11-1.39 (m, 3H), 1.60-1.96 (m, 11H), 2.03-2.17 (m, 2H), 2.28-2.40 (m, 2H), 2.61 (m, 1H), 2.81 (s, 3H), 2.88 (s, 3H), 4.84 (s, 2H), 6.40 (d, J 16.0, 1H), 7.32 (d, J 6.4, 2H), 7.46-7.55 (m, 4H), 7.59 (d, J 8.4, 2H), 7.65 (d, J 8.4, 2H), 7.71 (d, J 8.2, 1H), 7.80 (d, J 8.2, 1H), 7.86 (s, 1H), 8.27 (s, 1H), 9.67 (s, 1H), 12.1 (bs, 1H). MS (ES+) m/z 661 (M+H)+.

Workup

  1. waitfor 24 h at 50° C
  2. washwashed sequentially with HCl (2×, 1 N), NaOH (2×, 1N) and brine
  3. dry with materialThe organic layer was dried over Na2SO4
  4. concentrationconcentrated
  5. customto afford an oil, which
  6. washwashed with HCl (2×, 1 N), brine
  7. dry with materialdried over Na2SO4
  8. customEvaporation
  9. customgave an off-white foam, which
  10. customwas purified by RP-HPLC (column: Waters X-terra C18, 19×150 mm, 5 micron; flow 20 mL/min)

Sources & evidence

ORD record
ord-5a8b03495c3a476f8a3262ceada90f38
Source dataset
uspto-grants-2010_09
Patent number
US07795250B2

Reaction notes

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