Reaction #88183

Reaction equation

HOBT

methyl 3-(aminomethyl)benzoate hydrochloride

N-Methyl morpholine

(R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid

EDCl

→

(R)-methyl 3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)benzoate

Yield 74.5%

Solvents

DMSO

THF

Conditions

Workup

1. 1
   Temperaturemaintaining the temperature at 15° C
2. 2
   TemperatureThe reaction mixture was warmed to 20-25° C.
3. 3
   ConcentrationThe reaction mixture was concentrated under reduced pressure
4. 4
   Otherthe residue was partitioned between water (200 mL) and pentane-ethyl acetate (1:2, 300 mL)
5. 5
   ExtractionThe aqueous phase was further extracted with ethyl acetate (2 times with 100 mL)
6. 6
   WashThe combined organic extracts were rinsed sequentially with water (200 mL), saturated aqueous sodium bicarbonate solution (2 times with 100 mL), and brine (2 times with 25 mL)
7. 7
   DryingThe organic layer was then dried over sodium sulfate
8. 8
   Filtrationfiltered
9. 9
   Concentrationconcentrated

Procedure

To a 500-mL 3-neck flask was added methyl 3-(aminomethyl)benzoate hydrochloride (12.9 g, 64.1 mmol) followed by DMSO (26 mL). The solution was cooled to 15° C. N-Methyl morpholine (27 mL, 240 mmol) was added followed by EDCl (13 g, 68 mmol) and HOBT (4.09 g, 30 mmol), maintaining the temperature at 15° C. A solution of (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (20.94 g, 60.98 mmol) in THF (100 mL) was added dropwise over 10 min. The reaction mixture was warmed to 20-25° C. and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between water (200 mL) and pentane-ethyl acetate (1:2, 300 mL). The aqueous phase was further extracted with ethyl acetate (2 times with 100 mL). The combined organic extracts were rinsed sequentially with water (200 mL), saturated aqueous sodium bicarbonate solution (2 times with 100 mL), and brine (2 times with 25 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated to afford (R)-methyl 3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)benzoate (22.3 g). MS (ES+) 491.3 (M+H).

Source