2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → 6-(5-Chloro-6-methoxy-pyridin-3-yl)-4-methoxy-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

HRID 242312Notes

Reaction equation

HRID 242312 reaction equation
[CH3:1][O:2][C:3]1[C:4]2[CH2:12][NH:11][CH2:10][CH2:9][C:5]=2[N:6]=[CH:7][N:8]=1.Br[C:14]1[CH:15]=[C:16]([Cl:22])[C:17]([O:20][CH3:21])=[N:18][CH:19]=1.CC(C)([O-])C.[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C(O[Pd]OC(=O)C)(=O)C.CCCCCCC.COC(C)(C)C.C1(C)C=CC=CC=1.C(O)(C)(C)C>[Cl:22][C:16]1[CH:15]=[C:14]([N:11]2[CH2:10][CH2:9][C:5]3[N:6]=[CH:7][N:8]=[C:3]([O:2][CH3:1])[C:4]=3[CH2:12]2)[CH:19]=[N:18][C:17]=1[O:20][CH3:21]

Participants

8

Reactant 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 404270045-Bromo-3-chloro-2-methoxypyridineHCID 509892144-methoxy-5H,6H,7H,8H-pyrido[4,3-d]pyrimidine

Product 1

HCID 574953156-(5-Chloro-6-methoxy-pyridin-3-yl)-4-methoxy-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidineYield 19%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 22389680MTBE heptaneSolventHCID 22595558Toluene tert-butyl alcoholSolvent

Conditions

Temperature
110 °C

Procedure

To a glass vial was added 4-methoxy-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (WO 2008/130481, p 47) (0.273 g, 1.65 mmol), 5-bromo-3-chloro-2-methoxypyridine (0.368 g, 1.65 mmol), sodium tert-butoxide (318 mg, 3.31 mmol), diacetoxypalladium (0.037 g, 0.17 mmol), X-Phos (0.079 g, 0.17 mmol) and anhydrous toluene/tert-butanol, 5/1 (6 mL). The vial was flushed with a stream of argon for 15 sec and capped. The mixture was heated with stirring for 2 h at 110° C. then allowed to cool to room temperature and stirred at rt for 5 days. Diluted with CH2Cl2 (10 mL) and water (2 mL), filtered through a celite pad. The organic phase was separated by filtering through a phase separation tube and concentrated in vacuo. Purified by flash chromatography on silica gel with heptane/EtOAc 100/0 to 0/100 to give 6-(5-chloro-6-methoxy-pyridin-3-yl)-4-methoxy-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine as a yellow solid (95 mg, 19% yield) LCMS: [M+H]+=307.0/308.9, Rt(3)=1.62 min.

Workup

  1. customThe vial was flushed with a stream of argon for 15 sec
  2. customcapped
  3. temperatureThe mixture was heated
  4. temperatureto cool to room temperature
  5. stirringstirred at rt for 5 days
  6. additionDiluted with CH2Cl2 (10 mL) and water (2 mL)
  7. filtrationfiltered through a celite pad
  8. customThe organic phase was separated
  9. filtrationby filtering through a phase separation tube
  10. concentrationconcentrated in vacuo
  11. customPurified by flash chromatography on silica gel with heptane/EtOAc 100/0 to 0/100

Sources & evidence

ORD record
ord-86b73652b1214862bf9243744e132c7a
Source dataset
uspto-grants-2014_02
Patent number
US08653092B2

Reaction notes

Loading…