p-Toluenesulfonic acid → [4-Fluoro-2-(tetrahydro-2H-pyran-4-yloxy)-phenyl]-(5,7-dihydro-1H-pyrrolo[3',4':4,5]thieno[2,3-d]pyrimidin-4-yl)-amine

HRID 450576Notes

Reaction equation

HRID 450576 reaction equation
C(OC([N:11]1[CH2:23][C:14]2[S:15][C:16]3[NH:17][CH2:18][N:19]=[C:20](Cl)[C:21]=3[C:13]=2[CH2:12]1)=O)C1C=CC=CC=1.C(OC(N1CCC2C3C(Cl)=NC=NC=3SC=2C1)=O)(C)(C)C.[F:45][C:46]1[CH:52]=[CH:51][C:49]([NH2:50])=[C:48]([O:53][CH:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)[CH:47]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[F:45][C:46]1[CH:52]=[CH:51][C:49]([NH:50][C:20]2[C:21]3[C:13]4[CH2:12][NH:11][CH2:23][C:14]=4[S:15][C:16]=3[NH:17][CH2:18][N:19]=2)=[C:48]([O:53][CH:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)[CH:47]=1

Participants

6

Reactant 4

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)anilineHCID 1363723404-chloro-5,7-dihydro-1H-pyrolo[3',4':4,5]thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester

Product 1

HCID 136372339[4-Fluoro-2-(tetrahydro-2H-pyran-4-yloxy)-phenyl]-(5,7-dihydro-1H-pyrrolo[3',4':4,5]thieno[2,3-d]pyrimidin-4-yl)-amineYield 10%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

A solution of 4-chloro-5,7-dihydro-1H-pyrolo[3′,4′:4,5]thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester (prepared in an analogous fashion to 4-chloro-5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester, WO2007/109279, 0.135 g, 0.39 mmol), 4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)aniline (0.090 g, 0.39 mmol) and para-toluene sulfonic acid (0.08 g, 0.04 mmol) in 1,4-dioxane (2 mL) was purged with nitrogen and heated at 120° C. for 21 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→100% DCM→3% MeOH/DCM→200:10:1 DCM/MeOH/NH4OH) to afford the title compound as white solid (0.015 g, 10%).

Workup

  1. customwas purged with nitrogen
  2. additionThe reaction mixture was diluted with EtOAc
  3. washwashed with 10% aqueous K2CO3 and brine
  4. dry with materialThe organic phase was dried (MgSO4)
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified by flash column chromatography (100% iso-hexane→100% DCM→3% MeOH/DCM→200:10:1 DCM/MeOH/NH4OH)

Sources & evidence

ORD record
ord-d6695b8adf754af196f41b52559bc87b
Source dataset
uspto-grants-2013_07
Patent number
US08486953B2

Reaction notes

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