Diisopropylethylamine → N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-5-({[(2-{[2-(methyloxy)ethyl]oxy}ethyl)oxy]acetyl}amino)-1H-indole-2-carboxamide

HRID 1875021Notes

Reaction equation

HRID 1875021 reaction equation
F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl-].FC(F)(F)C(O)=O.[NH2:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41]([C:46]([NH:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[C:52]([O:57][C:58]3[CH:63]=[C:62]([C:64]#[N:65])[CH:61]=[C:60]([Cl:66])[CH:59]=3)[C:51]=1[F:67])=[O:47])=[CH:40]2.[CH3:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][O:75][CH2:76][C:77](O)=[O:78].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C.O>[Cl:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][NH:48][C:46]([C:41]2[NH:42][C:43]3[C:39]([CH:40]=2)=[CH:38][C:37]([NH:36][C:77](=[O:78])[CH2:76][O:75][CH2:74][CH2:73][O:72][CH2:71][CH2:70][O:69][CH3:68])=[CH:45][CH:44]=3)=[O:47])=[C:51]([F:67])[C:52]=1[O:57][C:58]1[CH:63]=[C:62]([C:64]#[N:65])[CH:61]=[C:60]([Cl:66])[CH:59]=1

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 85241(2-(2-Methoxyethoxy)ethoxy)acetic acidHCID 866448845-amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetateHCID 131720136BOP chloride

Product 1

HCID 59451587N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-5-({[(2-{[2-(methyloxy)ethyl]oxy}ethyl)oxy]acetyl}amino)-1H-indole-2-carboxamideYield 42%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

BOP chloride (0.079 g, 0.309 mmol) was added to a solution of 5-amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.060 g, 0.103 mmol), [(2-{[2-(methyloxy)ethyl]oxy}ethyl)oxy]acetic acid (0.016 mL, 0.103 mmol) and diisopropylethylamine (0.090 mL, 0.514 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was purified by reverse phase HPLC (acetonitrile:water with 0.1% trifluoroacetic acid) to give the title compound (0.027 g, 42%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H), 9.39 (s, 1H), 8.97 (t, 1H), 7.92 (s, 1H), 7.78 (s, 1H), 7.49 (d, 1H), 7.46 (s, 1H), 7.42-7.45 (m, 1H), 7.33-7.40 (m, 1H), 7.31 (s, 2H), 7.09 (d, 1H), 4.53 (d, 2H), 4.02 (s, 2H), 3.61-3.66 (m, 2H), 3.56-3.60 (m, 2H), 3.53 (dd, 2H), 3.38-3.44 (m, 2H), 3.19 (s, 3H). ES MS: m/z 629 (M+1).

Workup

  1. washThe organic layer was washed with water
  2. dry with materialdried over sodium sulfate
  3. concentrationconcentrated
  4. customThe residue was purified by reverse phase HPLC (acetonitrile:water with 0.1% trifluoroacetic acid)

Sources & evidence

ORD record
ord-1251b6307d7a4a32bfed2a79575ad550
Source dataset
uspto-grants-2012_11
Patent number
US08304419B2

Reaction notes

Loading…