Hydrochloric Acid → {1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-ethyl}-urea hydrochloride

HRID 1632082Notes

Reaction equation

HRID 1632082 reaction equation
Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([CH:25]([NH2:27])[CH3:26])=[N:23][CH:24]=3)[C:11]=2[F:28])[CH:7]=[CH:8][CH:9]=1.O.[O-:30][C:31]#[N:32].[Na+].Cl>C(OCC)C.C(O)(=O)C>[ClH:3].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([CH:25]([NH:27][C:31]([NH2:32])=[O:30])[CH3:26])=[N:23][CH:24]=3)[C:11]=2[F:28])[CH:7]=[CH:8][CH:9]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 962WaterHCID 517096Sodium CyanateHCID 689999201-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-ethylamine dihydrochloride

Product 1

HCID 68787674{1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-ethyl}-urea hydrochlorideYield 50.1%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 3283Diethyl EtherSolvent2×

Procedure

In an 8 mL vial equipped with a stir bar was placed 1-[5-(3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-ethylamine dihydrochloride (P-606, 55 mg, 0.124 mmol), water (800 uL), glacial acetic acid (400 uL) followed by sodium cyanate (32.2 mg, 0.496 mmol). The mixture was stirred at room temperature for 18 hours and then slowly quenched with a saturated solution of sodium bicarbonate (3 mL) and extracted with dichloromethane (3×4 mL). The organic portions were combined, dried (MgSO4), concentrated and purified by a 10 gram silica gel SNAP cartridge (Biotage SP4 Flash Chromatography instrument) utilizing gradient elution of 2-20% MeOH/dichloromethane to produce 13 mg of P-613 (free base) as an off-white solid in 25% yield. To P-613 (free base) (13 mg, 0.0314 mmol) was added diethyl ether (1 mL) and 2M HCl in diethyl ether (300 uL). The mixture was allowed to stir at room temperature for 10 minutes, concentrated and dried to produce 14 mg of P-613HCl salt as an off-white solid in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ 1.36 (d, J=7 Hz, 3H), 3.73 (s, 3H), 4.06 (s, 2H), 4.82 (m, 1H), 5.53 (br s, 2H), 6.69 (br s, 1H), 6.97 (d, J=9 Hz, 1H), 7.29 (br d, J=6 Hz, 1H), 7.38-7.47 (m, 4H), 7.60 (br d, J=8 Hz, 1H), 8.02 (br d, J=8 Hz, 1H), 8.58 (s, 1H) ppm.

Workup

  1. customIn an 8 mL vial equipped with a stir bar
  2. customslowly quenched with a saturated solution of sodium bicarbonate (3 mL)
  3. extractionextracted with dichloromethane (3×4 mL)
  4. dry with materialdried (MgSO4)
  5. concentrationconcentrated
  6. custompurified by a 10 gram silica gel SNAP cartridge (Biotage SP4 Flash Chromatography instrument)
  7. washelution of 2-20% MeOH/dichloromethane
  8. customto produce 13 mg of P-613 (free base) as an off-white solid in 25% yield
  9. stirringto stir at room temperature for 10 minutes
  10. concentrationconcentrated
  11. customdried

Sources & evidence

ORD record
ord-e0a70f1023de4735a9cd4880280d6164
Source dataset
uspto-grants-2014_07
Patent number
US08791267B2

Reaction notes

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