Hydrochloric Acid → 5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-((2S,5S)-2,5-dimethyl-pyrrolidin-1-yl)-pyridine

HRID 1632075Notes

Reaction equation

HRID 1632075 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.[CH3:25][C@H:26]1[CH2:30][CH2:29][C@H:28]([CH3:31])[NH:27]1.N12CCCN=C1CCCCC2.Cl>O>[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:27]4[C@@H:28]([CH3:31])[CH2:29][CH2:30][C@@H:26]4[CH3:25])=[N:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 69940992,5-Dimethylpyrrolidine, (2S,5S)-HCID 577037115-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine

Product 1

HCID 687877865-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-((2S,5S)-2,5-dimethyl-pyrrolidin-1-yl)-pyridine

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

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), (2S,5S)-2,5-dimethyl-pyrrolidine (176 mg, 1.30 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (367 uL, 2.60 mmol). The mixture was heated to 160° C. for 3 hours and then cooled to room temperature. The reaction mixture was treated with water (4 mL) and 1M HCl (6 mL). The aqueous portion was extracted with dichloromethane (2×30 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 5% acetone/dichloromethane as the eluent to produce 10 mg of P-577 as a pale viscous oil. 1H NMR (400 MHz, DMSO-d6) δ 1.05 (d, J=6 Hz, 6H), 1.56-1.61 (m, 4H), 3.72 (s, 3H), 3.75 (s, 2H), 4.07-4.12 (m, 2H), 6.38 (d, J=9 Hz, 1H), 6.92 (d, J=8 Hz, 1H), 7.27-7.32 (m, 3H), 7.37 (s, 1H), 7.41-7.47 (m, 2H), 7.95 (d, J=2 Hz, 1H) ppm. MS (APCI+): 425.1 (M+1) LC-MS: 92%

Workup

  1. customIn an 8 mL vial equipped with a stir bar
  2. temperaturecooled to room temperature
  3. extractionThe aqueous portion was extracted with dichloromethane (2×30 mL)
  4. washwashed with brine (15 mL)
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated
  7. customThe crude material was purified by silica gel column chromatography
  8. customto produce 10 mg of P-577 as a pale viscous oil

Sources & evidence

ORD record
ord-1137f2f527934147bb6dc9349a4e445d
Source dataset
uspto-grants-2014_07
Patent number
US08791267B2

Reaction notes

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