Dabco → O-[(2Z)-2-[(Acetyloxy)imino]-2-(2-amino-1,3-thiazol-4-yl)acetyl] O,O-diethyl phosphorothioate

Temperature

-20 °C

To a stirred solution of 134.9 g (Z)-(2-aminothiazol-4-yl)-acetoxyiminoacetic acid dihydrate (508.6 mmol) and 570 mg 1,4-diazabicyclo[2.2.2]octane (DABCO) (5.09 mmol) in 1500 ml dimethylacetamide was added under argon 158 ml tributylamine (661 mmol). The yellowish solution was cooled to -20° C. and over 30 min was added dropwise 104 ml diethyl chlorothiophosphate (661 mmol). Stirring was continued at -20° C. for 3.5 h. The reaction was followed by HPLC. After 3 h, all starting material was consumed. The reaction mixture was allowed to warm up to 0° C. and over 1.0 h was added dropwise 2200 ml water. The precipitated product was filtered, washed with water and dissolved in 800 ml dichloromethane. The aqueous layer was back-extracted with 300 ml dichloromethane. The combined organic layers were dried over 70 g sodium sulfate and concentrated under reduced pressure until the product started to crystallize. The residual solution was cooled to 2° C. and 1200 ml n-hexane was added dropwise over 1 h. The resulting suspension was stirred for 1 h at 2° C. and then filtered. The crystalline product was washed with n-hexane and dried to constant weight. (Z)-(2-aminothiazol-4-yl)-acetoxyiminoacetic acid diethoxythiophosphoryl ester was obtained as a white solid (166.9 g, yield=86%, mp 128°-130° C. and was stored under argon at -20° C. No further purification was necessary and the product was used as isolated for the next step.

1. waitAfter 3 h
2. customall starting material was consumed
3. temperatureto warm up to 0° C. and over 1.0 h
4. additionwas added dropwise 2200 ml water
5. filtrationThe precipitated product was filtered
6. washwashed with water
7. dissolutiondissolved in 800 ml dichloromethane
8. extractionThe aqueous layer was back-extracted with 300 ml dichloromethane
9. dry with materialThe combined organic layers were dried over 70 g sodium sulfate
10. concentrationconcentrated under reduced pressure until the product
11. customto crystallize
12. temperatureThe residual solution was cooled to 2° C.
13. addition1200 ml n-hexane was added dropwise over 1 h
14. stirringThe resulting suspension was stirred for 1 h at 2° C.
15. filtrationfiltered
16. washThe crystalline product was washed with n-hexane
17. customdried to constant weight

ORD record

ord-d32b652af47a4264a7d5026ddda1b741

Source dataset

uspto-grants-1999_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05883247