Hydrochloric Acid → 3-(Adamantan-1-yl)-1-p-tolyl-1H-pyrazol-5-amine

To a solution of acetonitrile (200 μL, 160 mg, 1.60 mmol) in THF (10 mL) at RT was added a solution of potassium 2-methylbutan-2-olate in toluene (1.7 M, 6.7 mL, 11 mmol) followed by the dropwise addition of ethyl adamantane-1-carboxylate (798 mg, 3.8 mmol) and the reaction mixture maintained at RT for 16 hr. The resulting mixture was concentrated in vacuo to a volume of ˜10 mL and was then diluted with EtOH (10 mL), treated with p-tolylhydrazine hydrochloride (607 mg, 3.83 mmol) and was acidified to pH 1 by the addition of conc hydrochloric acid. The resulting heterogeneous mixture was heated to 70° C. for 2 hr, was cooled to RT and concentrated in vacuo to a volume of ˜10 mL. The mixture was diluted with water (30 mL) and was adjusted to pH 12 by the addition of 2M aq NaOH and was then extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (30 mL), dried, and then evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, EtOAc in isohexane, 0-50%, gradient elution) and the impure product so obtained was triturated with isohexane (20 mL) to afford the title compound, Intermediate A29, as an impure beige solid (730 mg, 65% purity, 40%) containing approximately 35% w/w 3-(adamantan-1-yl)-3-oxopropanenitrile; Rt 4.92 min (Method 1 basic); m/z 308 (M+H)+, (ES+). This material was used in subsequent steps without further purification.

1. concentrationThe resulting mixture was concentrated in vacuo to a volume of ˜10 mL
2. additionwas then diluted with EtOH (10 mL)
3. temperatureThe resulting heterogeneous mixture was heated to 70° C. for 2 hr
4. temperaturewas cooled to RT
5. concentrationconcentrated in vacuo to a volume of ˜10 mL
6. additionThe mixture was diluted with water (30 mL)
7. additionwas adjusted to pH 12 by the addition of 2M aq NaOH
8. extractionwas then extracted with EtOAc (2×20 mL)
9. washThe combined organic extracts were washed with brine (30 mL)
10. customdried
11. customevaporated in vacuo
12. customThe residue was purified by flash column chromatography (SiO2, EtOAc in isohexane, 0-50%, gradient elution)
13. customthe impure product so obtained
14. customwas triturated with isohexane (20 mL)

ORD record

ord-91457a1b938f4d7fa2ba5858643aee6a

Source dataset

uspto-grants-2015_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09024041B2