2-Acetoxypropionylchloride synthesis

Yield: 94%

Reaction Conditions:

with oxalyl dichloride in dichloromethane;N,N-dimethyl-formamide at 20; for 0.5 h;

Steps:

91.2
Step 2: Preparation of l-(7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-1- oxopropan-2-yl acetate. [0617] In a separate vial, to a solution of 2-acetoxypropanoic acid (245 mg, 1.86 mmol) in DCM (2 mL), DMF (17 mg, 0.23 mmol) was added oxalyl chloride (0.2 mL, 2.33 mmol). The reaction mixture was stirred at 20 °C for 0.5 hour. A light yellow solution was formed. The mixture was concentrated to give yellow oil. To a solution of 7-bromo-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazine (100 mg, 0.465 mmol) in DCM (5 mL) was added TEA (0.3 mL, 2.33 mmol). The reaction mixture was cooled to 0 °C and then added l-chloro-1-oxopropan- 2-yl acetate in DCM (2 mL) dropwise. The reaction mixture was then warmed to 20 °C, stirred at 20 °C for 2 h under N2 atmosphere. The colorless solution turned to dark red gradually. LCMS showed the purity of the desired product (Rt = 0.583 min; MS Calc'd: 328.0; MS Found: 329.3 [M+H]⁺). The reaction mixture was concentrated. The residue was purified by Combi Flash (1% TEA in DCM) to afford 1-(7-bromo-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-1-yl)-1-oxopropan-2-yl acetate (180 mg, yield: 94%). 'H NMR (400 MHz, CDCh) d 1.51 (3H, d, J = 6.4 Hz), 2.13 (3H, s), 3.73-3.84 (1H, m), 4.00-4.10 (1H, m), 4.40- 4.52 (2H, m), 5.43 (1H, q, J= 6.8 Hz), 8.08 (1H, d, J= 2.0 Hz), 8.45 (1H, br s).

References:

PETRA PHARMA CORPORATION;LINDSTRÖM, Johan;PERSSON, Lars Boukharta;VIKLUND, Jenny;KESICKI, Edward A.;HICKEY, Eugene R.;DAHLGREN, Markus K.;GERASYUTO, Aleksey I. WO2019/126731, 2019, A1 Location in patent:Paragraph 0617