Reaction #461413

Reaction equation

substituted acylhydrazine

2-(2-[4-nitrophenoxy] tetradecanoyl)-1-(5-methyl 6H-1, 3,4 thiadiazin-2-yl)hydrazine

acetic acid

water

2-(2-[4-nitrophenoxy] tetradecanoyl)-1-(5-methyl 6H-1, 3,4 thiadiazin-2-yl)hydrazine

→

6-methyl-3-(1-[4-nitrophenoxy]tridecyl)- 7H-1,2,4-triazolo-(3,4-b)-1,3,4-thiadiazine

Yield 84.0%

Solvents

water

Conditions

Workup

1. 1
   Otherby collecting the solid
2. 2
   Washwashing with ethyl acetate
3. 3
   Otherdrying
4. 4
   Othercollecting
5. 5
   Otherdrying
6. 6
   Otherto give 54.0 g (90%) with 98 area % by HPLC
7. 7
   workup.ADDITIONis added to the reaction mixture
8. 8
   Temperaturethe mixture is heated
9. 9
   Otherafter which the ring closure reaction
10. 10
    Concentrationthe upper ethyl acetate solution is concentrated under reduced pressure to about 40% of the original volume
11. 11
    TemperatureThe resulting mixture is cooled to 20° C.
12. 12
    workup.STIRRINGstirred at that temperature for 30 min
13. 13
    OtherThe solid is collected
14. 14
    Washwashed with heptane
15. 15
    Otherdried

Procedure

To a solution of 46.8 g (0.122 m) of 2-(4-nitrophenoxy)tetradecanoyl chloride (3b) in 225 ml of ethyl acetate is added 16.6 g (0.244 m) of imidazole. The mixture is stirred at room temperature for 30 min and filtered to remove the precipitated imidazole hydrochloride. The filtrate containing 1-(2-[4-nitrophenoxy]tetradecanoyl)-1H -imidazole (5iib) is added to a mixture of 22.0 g (0.122 m) of (5-methyl-6H-1,3,4-thiadiazin-2-yl)-hydrazine hydrochloride (2b) and 12.3 g (0.122 m) of triethylamine in 200 ml of ethyl acetate. The mixture is stirred at room temperature for an hour. At this point, if it is necessary, the acylhydrazine 1b can be isolated by collecting the solid, washing with ethyl acetate, drying, reslurrying in water, collecting and drying to give 54.0 g (90%) with 98 area % by HPLC. However, the reaction mixture can be used directly in the next ring closure step without isolation of the substituted acylhydrazine 1b. Thus, at the end of reaction, 45 ml of acetic acid is added to the reaction mixture, and the mixture is heated under reflux (approximately 80° C.) for an hour, after which the ring closure reaction is complete. To the reaction mixture is added 400 ml of water and the mixture is stirred at 60° C. for 15 min. After the layers settle, the lower water layer is discarded and the upper ethyl acetate solution is concentrated under reduced pressure to about 40% of the original volume. The resulting mixture is cooled to 20° C. and stirred at that temperature for 30 min. The solid is collected, washed with heptane, and dried to give 48.5 g (84% overall from 2b or 3b) of 6-methyl-3-(1-[4-nitrophenoxy]tridecyl)- 7H-1,2,4-triazolo-(3,4-b)-1,3,4-thiadiazine (4) with 99 area % by HPLC.

Source