Diisopropylethylamine → Ethyl 5-(4-((6-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl)piperazin-1-yl)pentanoate

HRID 1400950Notes

Reaction equation

HRID 1400950 reaction equation
[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][N:31]6[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]6)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Br[CH:48]([CH3:56])[CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52]>CS(C)=O.CCOC(C)=O.CO.C(Cl)Cl>[OH-:6].[NH4+:4].[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][C:27]([CH2:30][N:31]6[CH2:32][CH2:33][N:34]([CH2:56][CH2:48][CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH2:35][CH2:36]6)=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)[CH2:3][CH2:2]1

Participants

8

Reactant 3

HCID 81531DiisopropylethylamineHCID 316888Ethyl 4-bromopentanoateHCID 674423881-Cyclopropyl-3-(3-fluoro-4-(2-(5-(piperazin-1-ylmethyl)pyridin-2-yl)thieno[3,2-b]-pyridin-7-yloxy)phenyl)urea

Product 2

HCID 14923Ammonium HydroxideYield 2%HCID 67443956Ethyl 5-(4-((6-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl)piperazin-1-yl)pentanoateYield 74.4%

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 8857Ethyl AcetateSolventHCID 21226129Dichloromethane methanolSolvent

Conditions

Temperature
52.5 °C

Procedure

To a stirred solution of 49 (200 mg, 0.39 mmol, scheme 15) and DIPEA (202 μl, 1.16 mmol) in DMSO (5 ml) at rt under nitrogen was added ethyl 4-bromovalerate (85 μl, 0.58 mmol), and the reaction mixture was heated at 50-55° C. for 1 h, then at rt. The reaction mixture was diluted with AcOEt, and successively washed with water, a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified twice by Biotage (SiliaFlash 25 g cartridge: 2% of ammonium hydroxide in MeOH/DCM: 1/99 to 10/90 over 20 CV, then 10/90 to 15/85 over 10 CV; Snap 25 g cartridge: 2% of ammonium hydroxide in MeOH/DCM: 1/99 to 15/85 over 30 CV) to afford the desired product 517 (94 mg, 0.145 mmol, 37% yield) as a colorless sticky solid. MS (m/z): 647.75 (M+H).

Workup

  1. customat rt
  2. washsuccessively washed with water
  3. dry with materiala saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe residue was purified twice by Biotage (SiliaFlash 25 g cartridge

Sources & evidence

ORD record
ord-867b3d0933624afab5e0627a0e6c4f4c
Source dataset
uspto-grants-2014_12
Patent number
US08906852B2

Reaction notes

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