Benzyl Bromide → HCID 21899041, compound

HRID 719558Notes

Reaction equation

HRID 719558 reaction equation
[CH:1]([Li])([CH2:3]C)[CH3:2].[CH2:6]([C:10]1[N:14](CC2C=CC(C3C=CC=CC=3C3NN=NN=3)=CC=2)[N:13]=[C:12]([CH2:33][C:34](=O)[CH2:35][CH2:36][CH3:37])[N:11]=1)[CH2:7][CH2:8][CH3:9].C(Br)C1C=CC=CC=1.C1C[O:50]CC1>>[CH2:6]([C:10]1[NH:14][N:13]=[C:12]([C:33](=[O:50])[CH2:34][C:35]2[CH:36]=[CH:37][CH:3]=[CH:1][CH:2]=2)[N:11]=1)[CH2:7][CH2:8][CH3:9]

Participants

5

Reactant 4

HCID 7498Benzyl BromideHCID 8028TetrahydrofuranHCID 178418400CID 53628100HCID 178441655HCID 178441655, compound

Product 1

HCID 21899041HCID 21899041, compoundYield 31%

Procedure

Under nitrogen, 7.3 mmol of sec-butyl lithium was added dropwise to 2.0 g (6.1 mmol) of the Sem-protected 5-butyl-3-(dimethoxymethyl)-1H-1,2,4-triazole from Example 30 in 100 ml of anhydrous THF at −78° C. The reaction was stirred for 1 h and then quenched with 0.87 ml (7.3 mmol) of benzyl bromide. The reaction was allowed to warm to ambient temperature and stir overnight. The THF was removed in vacuo; the residue dissolved in methylene chloride, washed with water and dried (MgSO4). The methylene chloride was removed in vacuo. The residue was dissolved in 10 ml of ethanol and 10 ml of 3M HCl and stirred at reflux for 2.5 h. The solvents were removed in vacuo. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution, and dried (MgSO4). Silica gel chromatography (Waters Prep 500A) using ethyl acetate/hexane (35:65) gave 460 mg (31%) of 5-butyl-3-(phenylacetyl)-1H-1,2,4-triazole: NMR (CDCl3) δ 0.92 (t, J=8 Hz, 3H), 1.31–1.55 (m, 2H), 1.70–1.83 (m, 2H), 2.88 (t, J=8 Hz, 2H), 4.39 (s, 2H), 7.21–7.38 (m, 5H). Following General Procedure A, 440 mg (1.8 mmol) of this material was reacted with 1.8 mmol of the alkylating reagent prepared in step 1 of Example 3. The crude product was dissolved in 10 ml of acetic acid/water (9:1) and stirred at ambient temperature for 4 days. The solvent was removed in vacuo; the residue dissolved in dilute base and washed with toluene. The water was acidified and extracted with ethyl acetate. Purification by reverse phase chromatography (Waters Delta Prep 3000) using acetonitrile/water (45:55) gave 50 mg (5%) of 5-[4′-[[5-butyl-3-(phenylacetyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole as the colorless TFA salt: NMR (DMSO-d6) δ 0.86 (t, J=8 Hz, 3H), 1.23–1.38 (m, 2H), 1.52–1.65 (m, 2H), 2.80 (t, J=8 Hz, 2H), 4.32 (s, 2H), 5.52 (s, 2H), 7.11 (d, J=8 Hz, 2H), 7.19 (d, J=8 Hz, 2H), 7.23–7.35 (m, 5H), 7.52–7.63 (m, 2H), 7.65–7.74 (m, 2H); MS (FAB) m/e (rel intensity) 478 (100), 244 (8), 235 (8), 207 (34), 192 (12); HRMS. Calc'd for M+H: 478.2355. Found: 478.2414.

Workup

  1. stirringstir overnight
  2. customThe THF was removed in vacuo
  3. dissolutionthe residue dissolved in methylene chloride
  4. washwashed with water
  5. dry with materialdried (MgSO4)
  6. customThe methylene chloride was removed in vacuo
  7. dissolutionThe residue was dissolved in 10 ml of ethanol
  8. stirring10 ml of 3M HCl and stirred
  9. temperatureat reflux for 2.5 h
  10. customThe solvents were removed in vacuo
  11. dissolutionThe residue was dissolved in ethyl acetate
  12. washwashed with saturated sodium bicarbonate solution
  13. dry with materialdried (MgSO4)

Sources & evidence

ORD record
ord-deff24c0156342e2aad47eec57ea70b2
Source dataset
uspto-grants-2006_11
Patent number
US07132437B2

Reaction notes

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