Diisopropylethylamine → (S)-tert-butyl 1-(((2-(7-(4-(3-(2,4-difluorophenyl)ureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-5-yl)methyl)(2-methoxyethyl)amino)-3-methyl-1-oxobutan-2-ylcarbamate

HRID 409981Notes

Reaction equation

HRID 409981 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[CH:26]=[C:27]([C:29]4[N:30]([CH3:40])[C:31]([CH2:34][NH:35][CH2:36][CH2:37][O:38][CH3:39])=[CH:32][N:33]=4)[S:28][C:21]=23)=[C:15]([F:41])[CH:14]=1)=[O:11].[C:42]([O:46][C:47]([NH:49][C@@H:50]([CH:54]([CH3:56])[CH3:55])[C:51](O)=[O:52])=[O:48])([CH3:45])([CH3:44])[CH3:43].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>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:11])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[CH:26]=[C:27]([C:29]4[N:30]([CH3:40])[C:31]([CH2:34][N:35]([CH2:36][CH2:37][O:38][CH3:39])[C:51](=[O:52])[C@@H:50]([NH:49][C:47](=[O:48])[O:46][C:42]([CH3:45])([CH3:44])[CH3:43])[CH:54]([CH3:56])[CH3:55])=[CH:32][N:33]=4)[S:28][C:21]=23)=[C:15]([F:41])[CH:14]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 83693Boc-L-ValineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 579194881-(2,4-difluorophenyl)-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea

Product 1

HCID 67048306(S)-tert-butyl 1-(((2-(7-(4-(3-(2,4-difluorophenyl)ureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-5-yl)methyl)(2-methoxyethyl)amino)-3-methyl-1-oxobutan-2-ylcarbamateYield 53.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of the compound 351 (280 mg, 0.481 mmol) in DMF (10 ml) was added (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (209 mg, 2 eq, 0.961 mmol), iPr2NEt (0.252 ml, 3 eq, 0.1.442 mmol) and HATU (365 mg, 2 eq, 0.961 mmol) and the reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc and washed with water, saturated NAHCO3 solution then brine. The organic phase was collected, dried over Na2SO4, filtered then concentrated. Purification of the residue by column chromatography (eluent 20% MeOH in EtOAc) afforded the desired compound 352 as an off-white solid (200 mg, 53% yield). MS (m/z)=782.7 (M+H).

Workup

  1. washwashed with water
  2. customThe organic phase was collected
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationthen concentrated
  6. customPurification of the residue by column chromatography (eluent 20% MeOH in EtOAc)

Sources & evidence

ORD record
ord-e834a0164fb346b781d4273e09cb5a93
Source dataset
uspto-grants-2014_06
Patent number
US08759522B2

Reaction notes

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