Reaction #44284

Reaction equation

1-hydroxybenzotriazole hydrate

N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride

N-methyl morpholine

ammonia

1-[1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]pyrrolidine-3-carboxylic acid

1-hydroxybenzotriazole hydrate

N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride

ammonia

N-methyl morpholine

→

title compound

(3R)—N-methyl-1-[1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]pyrrolidin-3-amine

Solvents

DMF

methyl tert-butyl ether

Conditions

Workup

1. 1
   workup.STIRRINGthe reaction was stirred overnight
2. 2
   workup.STIRRINGthe solution was stirred for 1 hour at room temperature
3. 3
   workup.WAITAfter 6 hours
4. 4
   Washthe organic solution was washed with saturated sodium bicarbonate (2×20 mL) and brine (20 mL)
5. 5
   Filtrationchloroform, filtered
6. 6
   Concentrationthe filtrate was concentrated
7. 7
   OtherThe crude product was purified by flash chromatography
8. 8
   Othera Horizon purification system on a 40S column
9. 9
   Washeluting with chloroform/7 N methanolic ammonia (0.1-6%)

Procedure

To a solution of 1-[1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]pyrrolidine-3-carboxylic acid (143 mg, 0.328 mmol) and 1-hydroxybenzotriazole hydrate (93 mg, 0.69 mmol) in DMF (4.0 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (132 mg, 0.690 mmol) followed by N-methyl morpholine (159 μL, 1.31 mmol). The resulting solution was stirred for 4 hours at room temperature then ammonia (7 N in methanol, 234 μL, 1.64 mmol) was added and the reaction was stirred overnight. To the reaction was added more 1-hydroxybenzotriazole hydrate, N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, and N-methyl morpholine and the solution was stirred for 1 hour at room temperature then ammonia (0.5 N in dioxane) was added. After 6 hours, the solution was diluted with methyl tert-butyl ether (100 mL) and the organic solution was washed with saturated sodium bicarbonate (2×20 mL) and brine (20 mL). The combined aqueous layers were combined and lyophilized. The resulting solids were slurried in 1:1 methanol:chloroform, filtered and the filtrate was concentrated. The crude product was purified by flash chromatography using a Horizon purification system on a 40S column eluting with chloroform/7 N methanolic ammonia (0.1-6%) to afford the title compound as the racemic mixture (86 mg, 70%). The mixture was separated by SCF chromatography to afford pure the enantiomers in 100% ee (peak 1, 37%; peak 2, 42%).

Source