Diisopropylethylamine → Tert-butyl(6-(7-(4-(3-(3-(dimethylphosphoryl)phenyl)ureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate

HRID 409958Notes

Reaction equation

HRID 409958 reaction equation
[C:1]([O:5][C:6](=[O:37])[N:7]([CH2:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[S:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][C:25]=3[O:28][C:29]3[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:30]=3[F:36])[CH:20]=2)=[CH:17][CH:18]=1)[CH2:8][CH2:9][O:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].Cl[C:39](OC1C=CC([N+]([O-])=O)=CC=1)=[O:40].[CH3:51][P:52]([C:55]1[CH:56]=[C:57]([CH:59]=[CH:60][CH:61]=1)[NH2:58])([CH3:54])=[O:53].CCN(C(C)C)C(C)C>O1CCCC1.CN(C=O)C>[C:1]([O:5][C:6](=[O:37])[N:7]([CH2:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[S:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][C:25]=3[O:28][C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:39]([NH:58][C:57]4[CH:59]=[CH:60][CH:61]=[C:55]([P:52]([CH3:51])([CH3:54])=[O:53])[CH:56]=4)=[O:40])=[CH:31][C:30]=3[F:36])[CH:20]=2)=[CH:17][CH:18]=1)[CH2:8][CH2:9][O:10][CH3:11])([CH3:4])([CH3:2])[CH3:3]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 821294-Nitrophenyl chloroformateHCID 579194724-[[2-[5-[[Boc(2-methoxyethyl)amino]methyl]-2-pyridyl]-7-thieno[3,2-b]pyridyl]oxy]-3-fluoroanilineHCID 582077813-(Dimethylphosphoryl)aniline

Product 1

HCID 67049417Tert-butyl(6-(7-(4-(3-(3-(dimethylphosphoryl)phenyl)ureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamateYield 84%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-20 °C

Procedure

To a solution of compound 126 (schemes 6 or 9) (200 mg, 0.381 mmol) in dry tetrahydrofuran (8 mL) under nitrogen at −20° C. was added 4-nitrophenyl chloroformate (115 mg, 0.572 mmol). The reaction mixture was stirred at −20° C. for 2 h. A solution of 3-(dimethylphosphoryl)aniline 287 (97 mg, 0.57 mmol) and N,N′-diisopropylethylamine (0.200 mL, 1.14 mmol) in a mixture of dry tetrahydrofuran (2 mL) and dry N,N′-dimethylformamide (2 mL) were added at −20° C., the reaction mixture was allowed to warm to room temperature slowly, and the stirring was continued for an additional 16 h. The solvent was removed under reduced pressure; the residue was diluted with ethyl acetate, washed with a saturated aqueous solution of ammonium chloride, dried over anhydrous sodium sulfate and concentrated. Purification via Biotage (linear gradient 0-20%, methanol/dichloromethane; 25M column) afforded compound 288 (230 mg, 0.32 mmol, 84%). MS (m/z): 720.4 (M+H).

Workup

  1. additionwere added at −20° C.
  2. temperatureto warm to room temperature slowly
  3. waitthe stirring was continued for an additional 16 h
  4. customThe solvent was removed under reduced pressure
  5. additionthe residue was diluted with ethyl acetate
  6. washwashed with a saturated aqueous solution of ammonium chloride
  7. dry with materialdried over anhydrous sodium sulfate
  8. concentrationconcentrated
  9. customPurification via Biotage (linear gradient 0-20%, methanol/dichloromethane; 25M column)

Sources & evidence

ORD record
ord-ab0208f84b7c4d02ab14fcb6ff49c08d
Source dataset
uspto-grants-2014_06
Patent number
US08759522B2

Reaction notes

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