Reaction #1797521

Reaction equation

5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid

Intermediate 2

5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid

diisopropylethylamine

tetrahydrofuran

EDC

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

→

5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide

Yield 45.0%

Solvents

dichloromethane

Conditions

Workup

1. 1
   workup.STIRRINGthe reaction mixture was stirred at 70° C. for ˜2 hours
2. 2
   Other(reaction progress monitored by TLC and LCMS)
3. 3
   Washwashed with 1N hydrochloric acid (2×200 mL), and brine (200 mL)
4. 4
   Dryingdried over magnesium sulfate
5. 5
   Filtrationfiltered
6. 6
   Otherevaporated
7. 7
   Otherpurified by column chromatography (eluting with 20% ethyl acetate in heptane)

Procedure

To a solution of 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (Intermediate 2; 5.8 g, 26.1 mmol) in tetrahydrofuran (70 mL) was added 2-adamantamine hydrochloride (available from Aldrich; 6.0 g, 32.0 mmol, 1.2 equivalents) and diisopropylethylamine (5.7 mL, 32.7 mmol, 1.2 equivalents). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC; 7.5 g, 39.1 mmol, 1.5 equivalents) was added portionwise with stirring. Following complete addition of the EDC, the reaction mixture was stirred at 70° C. for ˜2 hours (reaction progress monitored by TLC and LCMS). The reaction mixture was dissolved in dichloromethane (300 mL), washed with 1N hydrochloric acid (2×200 mL), and brine (200 mL), then dried over magnesium sulfate, filtered, evaporated, and purified by column chromatography (eluting with 20% ethyl acetate in heptane) to give 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (4.2 g, 11.8 mmol, 45%), which HPLC analysis indicated was 90% pure. This material was used directly in the next step without further purification.

Source