Hydrochloric Acid → (2E)-3-{4-[({1-[({3-cyclohexyl-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2-phenyl-1H-indol-6-yl}carbonyl)amino]cyclopentyl}carbonyl)amino]phenyl}acrylic acid

HRID 1713951Notes

Reaction equation

HRID 1713951 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]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)=[O:21])[C:8]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=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.[NH2:68][C:69]1([C:74]([NH:76][C:77]2[CH:82]=[CH:81][C:80](/[CH:83]=[CH:84]/[C:85]([O:87]CC)=[O:86])=[CH:79][CH:78]=2)=[O:75])[CH2:73][CH2:72][CH2:71][CH2:70]1.Cl>CN(C=O)C.CCOC(C)=O.C1COCC1.CO.O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([NH:68][C:69]4([C:74]([NH:76][C:77]5[CH:78]=[CH:79][C:80](/[CH:83]=[CH:84]/[C:85]([OH:87])=[O:86])=[CH:81][CH:82]=5)=[O:75])[CH2:70][CH2:71][CH2:72][CH2:73]4)=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:19][C:20]([N:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]3)=[O:21])[C:8]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 64808913-Cyclohexyl-1-[2-(4-methylpiperazin-1-yl)-2-oxo-ethyl]-2-phenyl-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 11614623(2E)-3-{4-[({1-[({3-cyclohexyl-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2-phenyl-1H-indol-6-yl}carbonyl)amino]cyclopentyl}carbonyl)amino]phenyl}acrylic acidYield 20%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolventHCID 21892291Methanol tetrahydrofuran waterSolvent

Conditions

Temperature
25 °C

Procedure

A solution of 3-cyclohexyl-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2-phenyl-1H-indole-6-carboxylic acid (from Step 4) in DMF (0.1 M) was treated with DIPEA (4 eq.), HATU (1.5 eq.) and ethyl (2E)-3-(4-{[(1-aminocyclopentyl)carbonyl]amino}phenyl)acrylate (1.1 eq, prepared as described in Example 1, Step 7). The solution was stirred at 25° C. overnight. The mixture was diluted with EtOAc, and then washed sequentially with HCl (2×, 1N), saturated aqueous NaHCO3 (2×) and brine. The organic layer was dried over Na2SO4 and concentrated to afford an oil, which was dissolved in a mixture of THF/MeOH/H2O (0.05 M, 4:1:1, v/v/v). LiOH monohydrate (1.3 eq.) was added and the resultant mixture stirred at 40° C. for 5 h. The reaction mixture was acidified with HCl (1N) and purified by RP-HPLC (column: Waters X-terra C18, 19×150 mm, 5 micron; flow 17 mL/min) to give the title compound (20%) as a white powder after lyophilization.

Workup

  1. washwashed sequentially with HCl (2×, 1N), saturated aqueous NaHCO3 (2×) and brine
  2. dry with materialThe organic layer was dried over Na2SO4
  3. concentrationconcentrated
  4. customto afford an oil, which
  5. custompurified by RP-HPLC (column: Waters X-terra C18, 19×150 mm, 5 micron; flow 17 mL/min)

Sources & evidence

ORD record
ord-5e50ec2cbfef48d4afbfe9342836f96a
Source dataset
uspto-grants-2010_09
Patent number
US07795250B2

Reaction notes

Loading…