Hydrochloric Acid → 4-Benzyloxy-2-fluoro-benzamidine hydrochloride

HRID 886493Notes

Reaction equation

HRID 886493 reaction equation
[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([F:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-:23][Si](C)(C)C)(C)C.[ClH:28]>C1COCC1>[ClH:28].[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]([NH2:23])=[NH:14])=[C:11]([F:17])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 2733832Lithium HexamethyldisilazideHCID 113336284-(Benzyloxy)-2-fluorobenzonitrile

Product 1

HCID 197001614-Benzyloxy-2-fluoro-benzamidine hydrochlorideYield 72%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of 4-benzyloxy-2-fluoro-benzonitrile (84 g, 0.37 mol) in THF (450 mL) under an atmosphere of nitrogen, was cooled to −70° C. The resultant suspension was treated with a solution of 1M LiHMDS in THF (440 mL, 0.44 mol) over 10 min to reach a maximum temperature of −55° C. The reaction mixture was allowed to warm to RT and stirred for three days. Reaction progress was monitored by TLC analysis. The reaction mixture was poured onto ice/1M HCl mixture, the pH adjusted to ˜1 by addition of 6M HCl and washed with EtOAc (500 mL). The organic layer was extracted with 1M HCl and the combined aqueous extracts washed with EtOAc (500 mL). The acid aqueous extracts were concentrated to low volume in vacuo and the resultant solid filtered off, washed with H2O and dried in vacuo to give 4-Benzyloxy-2-fluoro-benzamidine hydrochloride as a pale cream crystalline solid (74.5 g, 72%). 1H NMR (400 MHz, d6-DMSO): 9.30 (4H, d, J=10.39 Hz), 7.64 (1H, t, J=8.59 Hz), 7.49-7.35 (5H, m), 7.19 (1H, dd, J=12.88, 2.41 Hz), 7.06 (1H, dd, J=8.77, 2.41 Hz), 5.25 (2H, s).

Workup

  1. customa maximum temperature of −55° C
  2. customReaction progress
  3. additionThe reaction mixture was poured onto ice/1M HCl mixture
  4. washwashed with EtOAc (500 mL)
  5. extractionThe organic layer was extracted with 1M HCl
  6. washthe combined aqueous extracts washed with EtOAc (500 mL)
  7. concentrationThe acid aqueous extracts were concentrated to low volume in vacuo
  8. filtrationthe resultant solid filtered off
  9. washwashed with H2O
  10. customdried in vacuo

Sources & evidence

ORD record
ord-4eb19797b4ab4f3cac6fcaa2a1610eaa
Source dataset
uspto-grants-2012_08
Patent number
US08242104B2

Reaction notes

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