1400589-53-8

1174913-80-4

1379338-74-5

1400589-53-8

The general procedure for the synthesis of tert-butyl (R)-2-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)morpholine-4-carboxylate from (R)-2-(aminomethyl)morpholine-4-carboxylic acid tert-butyl ester and 5,7-dichloro pyrido[3,4-b]pyrazine was as follows: Intermediate 22: 1,1-dimethylethyl (2R)-2-{[(7-chloropyrido[3,4-b]pyrazin-5-yl)amino]methyl}-4-morpholinecarboxylate 1. tert-Butyl (R)-2-(aminomethyl)morpholine-4-carboxylate (6 g, 27.7 mmol) was dissolved in N-methyl-2-pyrrolidone (NMP). 2. N,N-diisopropylethylamine (DIPEA, 7.27 mL, 41.6 mmol) and 5,7-dichloropyrido[3,4-b]pyrazine (5.55 g, 27.7 mmol) were added to the above solution. 3. The reaction mixture was homogenized into four large microwave reaction flasks and each flask was heated at 130 °C for 30 min. 4. The progress of the reaction was monitored by liquid chromatography-mass spectrometry (LCMS), and the reaction was continued at 130 °C for 10 min if necessary. 5. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (700 mL) and dilute aqueous ammonium chloride solution (1 L). 6. The aqueous layer was re-extracted with ethyl acetate (300 mL) and the organic phases were combined. 7. The combined organic phases were washed with aqueous ammonium chloride (500mL), dried over anhydrous sodium sulfate and concentrated in vacuum to give the crude product as a brown oil. 8. The crude product was dissolved in dichloromethane (DCM) and purified by silica gel column (70g). 9. Eluted sequentially with the following eluents: pure DCM (6 x 40mL), 5% ethyl acetate in DCM (2 x 40mL), 10% ethyl acetate in DCM (5 x 40mL), 15% ethyl acetate in DCM (appropriate amount), 20% ethyl acetate in DCM (2 x 40mL). 10. The suitable elution grades were collected, combined and concentrated in vacuum to give the target product N8231-100-2 as an orange-yellow, slightly gelatinous solid in a yield of 7.7 g. The product was then concentrated in vacuo. 11. LCMS (Method B) analysis: retention time (Rt) = 1.17 min, molecular ion peak (MH+) = 380.