1-Bromo-3-chloropropane → 3-[(3-Chloropropyl)thio]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole

HRID 2384553Notes

Reaction equation

HRID 2384553 reaction equation
CC[O-].[Na+].[CH3:5][N:6]1[C:10]([C:11]2[O:15][CH:14]=[N:13][C:12]=2[CH3:16])=[N:9][NH:8][C:7]1=[S:17].Br[CH2:19][CH2:20][CH2:21][Cl:22]>CCO>[Cl:22][CH2:21][CH2:20][CH2:19][S:17][C:7]1[N:6]([CH3:5])[C:10]([C:11]2[O:15][CH:14]=[N:13][C:12]=2[CH3:16])=[N:9][N:8]=1

Participants

5

Reactant 3

HCID 80061-Bromo-3-chloropropaneHCID 2723922Sodium ethoxideHCID 104202044-Methyl-3-(4-methyloxazol-5-yl)-1H-1,2,4-triazole-5(4H)-thione

Product 1

HCID 446279943-[(3-Chloropropyl)thio]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
25 °C

Procedure

This material (498 g, 1 wt) was dissolved in dry tetrahydrofuran (5 vol), under nitrogen, cooled to 0° C. DCC (1.62 wt, 1 eq) was added portionwise followed by HOBt (1.07 wt, 1 eq). The mixture was warmed to 25±2° C. and stirred for 30 min. 4-Methyl-3-thiosemicarbazide (0.83 wt, 1 eq) was then added and the mixture further stirred for 2 h at 25±2° C. The mixture was filtered and the cake was washed with fresh tetrahydrofuran (1 vol) and dried on the filter for a few hours. The cake was suspended in 1 M aqueous NaOH (13 vol) and heated to 70° C. for 30 min. After this time, the mixture was cooled to 25±2° C. and a solid was removed by filtration. The cake was washed with 1 M aqueous NaOH (10 vol). The combined mother liquors were cooled to 0° C. and acidified to ca. pH 5 with HCl (aqueous, 16%; NOTE: keep temperature while adding HCl below +10° C.). The suspended product was isolated by filtration washing with water (2×3 vol). The cake was dried at 40° C. for 18 h in high vacuum to obtain 4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (respectively a tautomeric form thereof; 290 g, 37%). NaOEt (21% solution in EtOH, 2.08 vol, 1.1 eq) was added to EtOH (20 vol) under nitrogen atmosphere. 4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (respectively a tautomeric form thereof; 290 g, 1 wt) was added in one portion and the resulting mixture stirred at 25±2° C. until a clear solution was obtained. Then 1-bromo-3-chloropropane (0.54 vol, 1.1 eq) was added and the solution stirred at 40° C. for 24 h then cooled to 25° C. After filtration water (20 vol) was added and the ethanolic phase was removed by vacuum distillation (internal temperature ˜40° C.). The mixture was extracted with EtOAc (41 vol). The aqueous layer was removed and the organic phase was evaporated to dryness. Dichloromethane (4 vol) was added. The organic solution is purified through a short silica gel column (18 wt of silica), eluting with EtOAc (200 vol) to give the title compound as a solid foam (267.64 g, 66%).

Workup

  1. addition290 g, 1 wt) was added in one portion
  2. customwas obtained
  3. stirringthe solution stirred at 40° C. for 24 h
  4. temperaturethen cooled to 25° C
  5. filtrationAfter filtration water (20 vol)
  6. additionwas added
  7. customthe ethanolic phase was removed by vacuum distillation (internal temperature ˜40° C.)
  8. extractionThe mixture was extracted with EtOAc (41 vol)
  9. customThe aqueous layer was removed
  10. customthe organic phase was evaporated to dryness
  11. additionDichloromethane (4 vol) was added
  12. customThe organic solution is purified through a short silica gel column (18 wt of silica)
  13. washeluting with EtOAc (200 vol)

Sources & evidence

ORD record
ord-4549d039c275425fbbd55b6028f68392
Source dataset
uspto-grants-2012_09
Patent number
US08263782B2

Reaction notes

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