Cesium carbonate → 2-(1-((5-(2-ethyl-1H-benzo[d]imidazol-1-yl)-7-morpholinothiazolo[4,5-d]pyrimidin-2-yl)methyl)piperidin-4-yl)propan-2-ol

HRID 1945950Notes

Reaction equation

HRID 1945950 reaction equation
Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[N:8][C:6]=2[N:7]=1.[CH2:28]([C:30]1[NH:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[N:31]=1)[CH3:29].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:28]([C:30]1[N:31]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]4)=[N:8][C:6]=3[N:7]=2)[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1)[CH3:29]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 158072-EthylbenzimidazoleHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 596053572-[1-(5-Chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidin-2-ylmethyl)piperidin-4-yl]propan-2-ol

Product 1

HCID 596056722-(1-((5-(2-ethyl-1H-benzo[d]imidazol-1-yl)-7-morpholinothiazolo[4,5-d]pyrimidin-2-yl)methyl)piperidin-4-yl)propan-2-olYield 37.1%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Procedure

A mixture of 2-[1-(5-chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidin-2-ylmethyl)piperidin-4-yl]propan-2-ol (100 mg, 0.243 mmol), 2-ethyl-1H-benzoimidazole (39 mg, 0.267 mmol), Pd2(dba)3 (11 mg, 0.0122 mmol), XPhos (23 mg, 0.049 mmol) and cesium carbonate (158 mg, 0.486 mmol) in 1,4-dioxane (1.5 mL) was purged with argon gas for 15 min. The resulting reaction mixture was irradiated with microwaves at 150° C. for 30 min. The crude residue was loaded on an Isolute® SCX-2 cartridge (5 g). The cartridge was washed with DCM/MeOH and the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM. The resulting residue was further purified by column chromatography (Si—PCC, 2 M NH3 in MeOH:DCM: gradient 0:100 to 5:95) to afford 420 as a brown solid (47 mg, 37%) LCMS (Method I): RT 2.53 min, [M+H]+ 522. 1H NMR (400 MHz, CDCl3): δ 8.11 (1 H, m), 7.77-7.70 (1 H, m), 7.23 (2 H, m), 4.01-3.99 (6 H, m), 3.87 (5 H, m), 3.42-3.39 (2 H, m), 3.10 (2 H, m), 2.27 (2 H, m), 1.79 (2 H, m), 1.50 (2 H, d, m), 1.46-1.40 (3 H, m), 1.32 (1 H, m), 1.20 (6 H, s)

Workup

  1. customwas purged with argon gas for 15 min
  2. customThe resulting reaction mixture
  3. customwas irradiated with microwaves at 150° C. for 30 min
  4. washThe cartridge was washed with DCM/MeOH
  5. washthe desired product was subsequently eluted
  6. additiona mixture of 2M NH3 in MeOH and DCM
  7. customThe resulting residue was further purified by column chromatography (Si—PCC, 2 M NH3 in MeOH:DCM: gradient 0:100 to 5:95)

Sources & evidence

ORD record
ord-f685adf755574cd494b8c72229bad645
Source dataset
uspto-grants-2013_03
Patent number
US08394796B2

Reaction notes

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