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5-[(2,6-difluoro-4-nitrophenyl)-hydroxymethyl]-3,3-dimethyl-3H-isobenzofuran-1-one

1,2,4 triazole

→

5-[(2,6-difluoro- 4-nitrophenyl)-[1,2,4]triazol-1-yl-methyl]-3,3-dimethyl-3H-isobenzofuran-1-one

수율 67.4%

용매

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후처리

1. 1
   기타equipped with a mechanical stirrer and a nitrogen inlet
2. 2
   온도This rapidly stirred mixture is cooled in an ice bath
3. 3
   기타After 20 min the ice bath is removed
4. 4
   기타The dark solution is transferred to an addition funnel
5. 5
   workup.ADDITIONadded dropwise over 3 hr to 12L of rapidly stirring ice water in a 22L, 4-necked flask, during which time 5-[(2,6-difluoro-4-nitrophenyl)-[1,2,4]triazol-1-yl-methyl]-3,3-dimethyl-3H-isobenzofuran-1-one
6. 6
   기타precipitates as a fine white solid
7. 7
   workup.WAITAfter standing for 2 h at 0° C.
8. 8
   기타the solid product is isolated by vacuum filtration
9. 9
   세척washed with H2O (500 mL), and air
10. 10
    기타dried for 2-12 hr
11. 11
    기타equipped with a reflux condenser, mechanical stirrer
12. 12
    workup.ADDITION1.5 L of MeOH is added
13. 13
    온도the mixture is heated to 55 ° C.
14. 14
    기타to give a dear solution
15. 15
    여과This solution is filtered while hot into a clean 3L 4-necked flask
16. 16
    기타equipped with an addition funnel, and mechanical stirrer
17. 17
    workup.ADDITIONH2O (175 mL) is then added dropwise to this rapidly stirred hot solution
18. 18
    workup.WAITAfter standing at room temperature for about 2 hr to about 12 hr
19. 19
    여과the crystals are collected by filtration, air
20. 20
    기타dried for 3 hr
21. 21
    기타dried under vacuum

실험 절차

The diarylcarbinol (5-[(2,6-difluoro-4-nitrophenyl)-hydroxymethyl]-3,3-dimethyl-3H-isobenzofuran-1-one ((Formula I) as prepared in Example 1; 171.3 g, 0.49 moles) and 1,2,4 triazole (85.7 g, 1.24 moles) are charged into a 3L, 4-necked round bottom flask equipped with a mechanical stirrer and a nitrogen inlet. This rapidly stirred mixture is cooled in an ice bath and 680 mL of ice cold concentrated H2SO4 is added in one portion. After 20 min the ice bath is removed and the resultant solution is stirred at room temperature for 20 hr. The dark solution is transferred to an addition funnel and added dropwise over 3 hr to 12L of rapidly stirring ice water in a 22L, 4-necked flask, during which time 5-[(2,6-difluoro-4-nitrophenyl)-[1,2,4]triazol-1-yl-methyl]-3,3-dimethyl-3H-isobenzofuran-1-one precipitates as a fine white solid. After standing for 2 h at 0° C., the solid product is isolated by vacuum filtration, washed with H2O (500 mL), and air dried for 2-12 hr. The resultant solid is transferred to a clean 3L, 4-necked flask equipped with a reflux condenser, mechanical stirrer, and J-Kem thermocouple. 1.5 L of MeOH is added, and the mixture is heated to 55 ° C. to give a dear solution. This solution is filtered while hot into a clean 3L 4-necked flask, equipped with an addition funnel, and mechanical stirrer. H2O (175 mL) is then added dropwise to this rapidly stirred hot solution. As the solution cools, white crystals of 5-[(2,6-difluoro-4-nitrophenyl)-[1,2,4 ]triazol-1-yl-methyl ]-3,3-dimethyl-3H-isobenzofuran-1 -one form. After standing at room temperature for about 2 hr to about 12 hr, the crystals are collected by filtration, air dried for 3 hr, and then dried under vacuum to afford 132.2 g (67 %) of 5-[(2,6-difluoro- 4-nitrophenyl)-[1,2,4]triazol-1-yl-methyl]-3,3-dimethyl-3H-isobenzofuran-1-one which is >98% pure by HPLC analysis.

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