Diisopropylethylamine → (2e)-3-[4-({[1-({[3-Cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-(4-methoxyphenyl)-1h-indol-6-yl]carbonyl}amino)cyclopentyl]carbonyl}amino)-phenyl]acrylic acid

HRID 1713932Notes

Reaction equation

HRID 1713932 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][C:28]([O:31][CH3:32])=[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.[NH2:66][C:67]1([C:72]([NH:74][C:75]2[CH:80]=[CH:79][C:78](/[CH:81]=[CH:82]/[C:83]([O:85]CC)=[O:84])=[CH:77][CH:76]=2)=[O:73])[CH2:71][CH2:70][CH2:69][CH2:68]1>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([NH:66][C:67]4([C:72]([NH:74][C:75]5[CH:76]=[CH:77][C:78](/[CH:81]=[CH:82]/[C:83]([OH:85])=[O:84])=[CH:79][CH:80]=5)=[O:73])[CH2:68][CH2:69][CH2:70][CH2:71]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][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 52754503-Cyclohexyl-1-dimethylcarbamoylmethyl-2-(4-methoxy-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 11498502(2e)-3-[4-({[1-({[3-Cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-(4-methoxyphenyl)-1h-indol-6-yl]carbonyl}amino)cyclopentyl]carbonyl}amino)-phenyl]acrylic acidYield 11%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
25 °C

Procedure

A solution (0.04 M) of 3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-(4 methoxyphenyl)-1H-indole-6-carboxylic acid (from Step 4) in DMF was treated with DIPEA (3 eq.), HATU (2 eq.) and ethyl (2E)-3-(4-{[(1-aminocyclopentyl)carbonyl]amino}phenyl)acrylate (1.1 eq.). The solution was stirred at 25° C. for 12 h. The mixture was diluted with EtOAc then washed sequentially with aqueous HCl (1N), NaOH (2 N) and brine. The dried organic layer was concentrated and the residue dissolved in a solution 1:1 of THF/H2O. The resulting solution was treated with LiOH monohydrate (3 eq.) and stirred at 50° C. for 5 h. The mixture was concentrated under reduced pressure and the residue was treated with aqueous HCl (1 N). Purification by HPLC (stationary phase: Water Symmetry C18 19×300 mm) gave the title compound (11%) as a solid. 1H NMR (400 MHz, DMSO-d6, 300K) δ 1.11-1.40 (m, 3H), 1.62-1.91 (m, 11H), 2.05-2.16 (m, 2H), 2.28-2.44 (m, 2H), 2.50-2.62 (m, 1H), 2.80 (s, 3H), 2.92 (s, 3H), 3.85 (s, 3H), 4.83 (s, 2H), 6.40 (d, J 16.0, 1H), 7.08 (d, J 8.6, 2H), 7.24 (d, J 8.6, 2H), 7.52 (d, J 16.0, 1H), 7.60 (d, J 8.3, 2H), 7.66 (d, J 8.3, 2H), 7.71 (d, J 8.3, 1H), 7.78 (d, J 8.3, 1H), 7.83 (s, 1H), 8.26 (s, 1H), 9.67 (s, 1H), 12.40 (br s, 1H); MS (ES+) m/z 691 (M+H)+.

Workup

  1. washthen washed sequentially with aqueous HCl (1N), NaOH (2 N) and brine
  2. concentrationThe dried organic layer was concentrated
  3. dissolutionthe residue dissolved in a solution 1:1 of THF/H2O
  4. stirringstirred at 50° C. for 5 h
  5. concentrationThe mixture was concentrated under reduced pressure
  6. additionthe residue was treated with aqueous HCl (1 N)
  7. customPurification by HPLC (stationary phase: Water Symmetry C18 19×300 mm)

Sources & evidence

ORD record
ord-7a1a3c57f3a54fe4b2433a4625625bf8
Source dataset
uspto-grants-2010_09
Patent number
US07795250B2

Reaction notes

Loading…