1,8-Diazabicyclo(5.4.0)undec-7-ene → 2-{[5-(3'-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-methyl-amino}-acetamide

HRID 1632084Notes

Reaction equation

HRID 1632084 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH:15]([F:17])[F:16])=[CH:12][CH:11]=[C:10]([CH2:18][C:19]3[CH:20]=[CH:21][C:22](F)=[N:23][CH:24]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:27][NH:28][CH2:29][C:30]([NH2:32])=[O:31].N12CCCN=C1CCCCC2>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH:15]([F:16])[F:17])=[CH:12][CH:11]=[C:10]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([N:28]([CH3:27])[CH2:29][C:30]([NH2:32])=[O:31])=[N:23][CH:24]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 138929562-(Methylamino)acetamide hydrochlorideHCID 577037805-(3'-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine

Product 1

HCID 580199622-{[5-(3'-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-methyl-amino}-acetamideYield 3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
160 °C

Procedure

In an 8 mL vial equipped with a stir bar was placed 5-(3′-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine (I-153, 210 mg, 0.577 mmol), 2-methylamino-acetamide hydrochloride (216 mg, 1.73 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (488 uL, 3.46 mmol). The mixture was heated to 160° C. for 3 hours and then diluted with dichloromethane (5 mL). The organic portion was washed with 0.5M HCl (3 mL) and the aqueous washes were combined and extracted with dichloromethane (2×3 mL). The organic portions were combined, washed with brine (4 mL), dried (MgSO4) and concentrated. The crude material was purified by Teledyne CombiFlash system utilizing a 12 g RediSepRf silica gel cartridge and a gradient elution of 0-30% methanol/dichloromethane, followed by preparative TLC (20×20 cm, 1000 microns) using 5% methanol/dichloromethane as the eluent to produce 8 mg of P-621?? as a dark brown semi-solid in 3% yield. 1H NMR (400 MHz, DMSO-d6) δ 2.98 (s, 3H), 3.83 (s, 2H), 4.03 (s, 2H), 6.53 (d, J=9 Hz, 1H), 7.10 (t, J=74 Hz, 1H), 7.21 (d, J=8 Hz, 1H), 7.30 (dd, J=8, 2 Hz, 1H), 7.36 (d, J=2 Hz, 1H), 7.40-7.50 (m, 5H), 8.01 (d, J=2 Hz, 1H) ppm. MS (APCI+): 432.1 (M+1). LC/MS: 86%.

Workup

  1. customIn an 8 mL vial equipped with a stir bar
  2. washThe organic portion was washed with 0.5M HCl (3 mL)
  3. extractionextracted with dichloromethane (2×3 mL)
  4. washwashed with brine (4 mL)
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated
  7. customThe crude material was purified by Teledyne CombiFlash system
  8. washa gradient elution of 0-30% methanol/dichloromethane
  9. customto produce 8 mg of P-621

Sources & evidence

ORD record
ord-b44a680db6884fc5b815159e0dae6ecf
Source dataset
uspto-grants-2014_07
Patent number
US08791267B2

Reaction notes

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