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 1026799Notes

Reaction equation

HRID 1026799 reaction equation
[NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.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>[CH3:54][P:52]([C:55]1[CH:56]=[C:57]([NH:58][C:39](=[O:40])[NH:1][C:2]2[CH:36]=[CH:35][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:13]=[C:14]([C:16]5[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][CH:17]=5)[S:15][C:8]=34)=[C:4]([F:37])[CH:3]=2)[CH:59]=[CH:60][CH:61]=1)([CH3:51])=[O:53]

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-5435340f91604c6fb08131c5639f81df
Source dataset
uspto-grants-2014_05
Patent number
US08729268B2

Reaction notes

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