تفاعل #2045115

معادلة التفاعل

2-chloro-5-((3,5-dibromo-1H-1,2,4-triazol-1-yl)methyl)-4-methylnicotinonitrile

methyl 2-(cyclopropylamino)-5-hydroxy-3-methylbenzoate

Cs2CO3

→

product

المردود 75.9%

methyl 5-(3-cyano-5-((3,5-dibromo-1H-1,2,4-triazol-1-yl)methyl)-4-methylpyridin-2-yloxy)-2-(cyclopropylamino)-3-methylbenzoate

المردود 75.9%

المذيبات

DMF

DMF

ظروف التفاعل

المعالجة

1. 1
   workup.ADDITIONthe mixture is added into the 250 ml flask over 30 min
2. 2
   درجة الحرارةThen, the reaction mixture is cooled to 20° C.
3. 3
   أخرىthe reaction is quenched with EtOAc (50 mL) and water (50 mL)
4. 4
   أخرىThe bottom aqueous layer is then removed
5. 5
   غسيلthe organic layer is washed with two times of 10% NaCl (40 mL each)
6. 6
   workup.DISTILLATIONThe solvent of the organic layer is distilled under vacuum with internal temperature of the solvent as between 30˜45° C.
7. 7
   workup.DISTILLATIONThe resulting solvent is then distilled under vacuum with internal temperature of the solvent as between 30˜45° C.
8. 8
   workup.ADDITIONThen MeOH (70 mL) is added into the solvent
9. 9
   workup.DISTILLATIONthe resulting solvent is distilled under vacuum with internal temperature of the solvent as between 30˜45° C.
10. 10
    workup.ADDITIONAnother 70 ml of MeOH is added into the solvent
11. 11
    workup.DISTILLATIONthe resulting solvent is distilled under vacuum with internal temperature of the solvent as between 30˜45° C.
12. 12
    workup.ADDITIONAn additional 70 ml of MeOH is added into the solvent
13. 13
    درجة الحرارةthe resulting solvent is heated to 60° C.
14. 14
    درجة الحرارةis cooled down to 20° C. in 2 h
15. 15
    workup.STIRRINGstirred at 20° C. for 2 h
16. 16
    ترشيحThe resulting mixture is filtered
17. 17
    غسيلthe filter cake is washed with MeOH (15 mL)
18. 18
    أخرىThe filter cake is then dried under vacuum at 20° C.

الإجراء التجريبي

Cs2CO3 (14.9 g, 45.8 mmol) and DMF (25 mL) are added into a 250 mL flask, and the reaction mixture is heated to 80° C. 2-chloro-5-((3,5-dibromo-1H-1,2,4-triazol-1-yl)methyl)-4-methylnicotinonitrile (7.2 g, 18.3 mmol) and hydrochloride salt of methyl 2-(cyclopropylamino)-5-hydroxy-3-methylbenzoate (4.2 g, 18.3 mmol) is dissolved by DMF (25 mL) in a 100 mL flask, and the mixture is added into the 250 ml flask over 30 min. The resulting mixture is stirred at 80° C. for 30 min. A sample of the mixture is taken for HPLC analysis. The reaction mixture is kept stifling until the conversion to product is at least 99%. Then, the reaction mixture is cooled to 20° C., and the reaction is quenched with EtOAc (50 mL) and water (50 mL). The bottom aqueous layer is then removed, and the organic layer is washed with two times of 10% NaCl (40 mL each). The solvent of the organic layer is distilled under vacuum with internal temperature of the solvent as between 30˜45° C. to ⅙ of original volume. Then the resulting solvent is passed through a pad of silica gel (15 g) by 4:1 hexanes/EtOAc (100 mL). The resulting solvent is then distilled under vacuum with internal temperature of the solvent as between 30˜45° C. to ⅛ of original volume. Then MeOH (70 mL) is added into the solvent, and the resulting solvent is distilled under vacuum with internal temperature of the solvent as between 30˜45° C. to ⅛ of original volume. Another 70 ml of MeOH is added into the solvent, and the resulting solvent is distilled under vacuum with internal temperature of the solvent as between 30˜45° C. to ⅛ of original volume. An additional 70 ml of MeOH is added into the solvent, and the resulting solvent is heated to 60° C., then is cooled down to 20° C. in 2 h and stirred at 20° C. for 2 h. The resulting mixture is filtered, and the filter cake is washed with MeOH (15 mL). The filter cake is then dried under vacuum at 20° C. to afford 8 g product with more than 97% purity.

المصدر