p-Toluenesulfonic acid → 4-[4-Fluoro-2-(tetrahydro-2H-pyran-4-yloxy)-phenylamino]-5,8-dihydro-6H-pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester

HRID 450573Notes

Reaction equation

HRID 450573 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][C:11]2[C:12]3[C:17](Cl)=[N:16][CH:15]=[N:14][C:13]=3[S:19][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([O:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][C:11]2[C:12]3[C:17]([NH:27][C:26]4[CH:28]=[CH:29][C:23]([F:22])=[CH:24][C:25]=4[O:30][CH:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[N:16][CH:15]=[N:14][C:13]=3[S:19][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

6

Reactant 3

HCID 6101p-Toluenesulfonic acidHCID 49788563tert-Butyl 4-chloro-5,6-dihydropyrido(4',3':4,5)thieno(2,3-d)pyrimidine-7(8H)-carboxylateHCID 584130794-Fluoro-2-(oxan-4-yloxy)aniline

Product 1

HCID 696691144-[4-Fluoro-2-(tetrahydro-2H-pyran-4-yloxy)-phenylamino]-5,8-dihydro-6H-pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid tert-butyl esterYield 20%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

A solution of 4-chloro-5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (prepared according to WO2007/109279, 0.141 g, 0.43 mmol), 4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)aniline (0.092 g, 0.44 mmol) and para-toluene sulfonic acid (0.08 g, 0.04 mmol) in 1,4-dioxane (2 mL) was purged with nitrogen and then heated at 120° C. for 5 hours. The reaction mixture was diluted with EtOAc, washed with 10% aqueous K2CO3 and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (100% iso-hexane→66% iso-hexane/EtOAc→100% EtOAc) followed by trituration with MeOH afforded the title compound as white solid (0.042 g, 20%).

Workup

  1. washwashed with 10% aqueous K2CO3 and brine
  2. dry with materialThe organic phase was dried (MgSO4)
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. customThe residue was purified by flash column chromatography (100% iso-hexane→66% iso-hexane/EtOAc→100% EtOAc)

Sources & evidence

ORD record
ord-486f5104990040cdbb75b678db0de3aa
Source dataset
uspto-grants-2013_07
Patent number
US08486953B2

Reaction notes

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