Cesium carbonate → 3-{2-[2-((S)-1-Hydroxyethyl)benzoimidazol-1-yl]-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene}azetidine-1-carboxylic acid tert-butyl ester

HRID 1945687Notes

Reaction equation

HRID 1945687 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]2[N:14]([CH3:29])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17](Cl)[N:16]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[C@@H:39]([OH:41])[CH3:40].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+]>C1(C)C=CC=CC=1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]2[N:14]([CH3:29])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:30]2[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[N:32]=[C:31]2[C@@H:39]([OH:41])[CH3:40])[N:16]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 7293911-(1H-Benzimidazol-2-yl)ethanol, (S)-HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl2×HCID 59605709tert-butyl 3-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methylene)azetidine-1-carboxylate

Product 1

HCID 596056333-{2-[2-((S)-1-Hydroxyethyl)benzoimidazol-1-yl]-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene}azetidine-1-carboxylic acid tert-butyl esterYield 55%

Reagents, catalysts & solvents 2

HCID 9832798Tris(dibenzylideneacetone) dipalladiumCatalyst2×HCID 1140TolueneSolvent

Conditions

Temperature
140 °C

Procedure

A mixture of 3-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene)azetidine-1-carboxylic acid tert-butyl ester (180 mg, 0.43 mmol), (S)-1-(1H-benzoimidazol-2-yl)ethanol (84 mg, 0.52 mmol), tris(dibenzylideneacetone) dipalladium (40 mg, 0.04 mmol), XPhos (82 mg, 0.17 mmol) and Cs2CO3 (279 mg, 0.86 mmol) in toluene (3 mL) was purged with argon then heated at 140° C. for 1 h in a microwave reactor. Further tris(dibenzylideneacetone) dipalladium (40 mg, 0.04 mmol) and XPhos (82 mg, 0.17 mmol) were added and the mixture heated at 140° C. for a further 1 h. The reaction mixture was filtered through Celite®, washing with EtOAc and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-15%) affording the title compound (127 mg, 55%). LCMS (method A): RT 3.27 min [M+H]+ 547.4

Workup

  1. customwas purged with argon
  2. temperaturethe mixture heated at 140° C. for a further 1 h
  3. filtrationThe reaction mixture was filtered through Celite®
  4. washwashing with EtOAc
  5. concentrationthe filtrate concentrated in vacuo
  6. customThe resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-15%)

Sources & evidence

ORD record
ord-0d21206a9f994c8eb79013164cadd8ae
Source dataset
uspto-grants-2013_03
Patent number
US08394796B2

Reaction notes

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