2-(Ethoxymethylene)propanedinitrile → 5-amino-1-cyclobutyl-1H-pyrazole-4-carbonitrile

A suspension of cyclobutylhydrazine dihydrochloride (11.63 g, 73.12 mmol) in EtOH (110 mL) was cooled in an ice bath and treated portion-wise with solid sodium ethoxide (9.95 g, 146 mmol) over 45 mins, while keeping the internal temp of the reaction mixture at approximately 0° C. The mixture was stirred in the ice bath for an additional hour, and then a solution of (ethoxymethylene)malononitrile (8.93 g, 73.1 mmol) in EtOH (70 mL) was added drop-wise over about 1.5 h, at a rate which maintained the internal temperature of the reaction mixture between 0° C. and 5° C. The reaction was then allowed to warm to room temp over about 18 h, after which it was heated at reflux for 1.5 h. After cooling to room temp, solvents were removed in vacuo, and the residue was partitioned between EtOAc and water. The aqueous layer was extracted twice with additional EtOAc, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to provide crude C14, which was used in the next step without purification. Yield: 14.1 g, >100% mass recovery. 1H NMR (300 MHz, CDCl3) δ 1.9 (m, 2H), 2.4 (m, 2H), 2.65 (m, 2H), 4.25 (br s, 2H), 4.45 (m, 1H), 7.5 (s, 1H).

1. temperaturewas cooled in an ice bath
2. customat approximately 0° C
3. temperatureat a rate which maintained the internal temperature of the reaction mixture between 0° C. and 5° C
4. temperatureafter which it was heated
5. temperatureat reflux for 1.5 h
6. temperatureAfter cooling to room temp
7. customsolvents were removed in vacuo
8. customthe residue was partitioned between EtOAc and water
9. extractionThe aqueous layer was extracted twice with additional EtOAc
10. washthe combined organic layers were washed with saturated aqueous sodium chloride solution
11. dry with materialdried over sodium sulfate
12. filtrationfiltered
13. concentrationThe filtrate was concentrated under reduced pressure
14. customto provide crude C14, which
15. customwas used in the next step without purification

ORD record

ord-7483e3a2ca334781b6017af31b2fb710

Source dataset

uspto-grants-2013_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08618117B2