Pyrrolidine → 5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-pyrrolidin-1-yl-pyridine

HRID 1632076Notes

Reaction equation

HRID 1632076 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20](F)=[N:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.N12CCCN=C1CCCCC2>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[N:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 31268PyrrolidineHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 577037115-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine

Product 1

HCID 687909895-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-pyrrolidin-1-yl-pyridineYield 69%

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-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine (P-456,100 mg, 0.289 mmol), pyrrolidine (60.3 uL, 0.723 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (204 uL, 1.45 mmol). The mixture was heated to 160° C. for 30 minutes and then cooled to room temperature. The reaction mixture was diluted with dichloromethane (25 mL) and washed with 0.5M HCl (3×10 mL). The combined aqueous portions were extracted with dichloromethane (15 mL), the organic portions were combined, washed with brine (15 mL), dried (MgSO4) and concentrated. The crude material was purified by silica gel column chromatography utilizing 10% acetone/dichloromethane as the eluent to produce 79 mg of P-582 as a pale orange semisolid in 69% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.89-1.93 (m, 4H), 3.31-3.34 (m, 4H), 3.71 (s, 3H), 3.77 (s, 2H), 6.37 (d, J=9 Hz, 1H), 6.91 (d, J=9 Hz, 1H), 7.23-7.28 (m, 2H), 7.32 (dd, J=9, 2 Hz, 1H), 7.36 (s, 1H), 7.41-7.47 (m, 2H), 7.95 (d, J=2 Hz, 1H) ppm. MS (APCI+): 397.1 (M+1) LC-MS: 98%

Workup

  1. customIn an 8 mL vial equipped with a stir bar
  2. temperaturecooled to room temperature
  3. washwashed with 0.5M HCl (3×10 mL)
  4. extractionThe combined aqueous portions were extracted with dichloromethane (15 mL)
  5. washwashed with brine (15 mL)
  6. dry with materialdried (MgSO4)
  7. concentrationconcentrated
  8. customThe crude material was purified by silica gel column chromatography
  9. customto produce 79 mg of P-582 as a pale orange semisolid in 69% yield

Sources & evidence

ORD record
ord-1569bee632344ffd9b886815744bdb11
Source dataset
uspto-grants-2014_07
Patent number
US08791267B2

Reaction notes

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