Acetic Acid → Diethyl 3-methyl-1h-pyrrole-2,4-dicarboxylate

Temperature

55 °C

To a solution of ethyl isocyanoacetate (38.1 mL, 0.34 mol) and DBU (50.8 mL, 0.34 mol) in THF (400 mL) at 50° C. was added a solution of acetaldehyde (9.5 mL, 0.17 mol) in THF (100 mL) over 25 min. The reaction mixture was stirred at 55° C. for 17 h, cooled to 25° C. and acetic acid (20 mL) was slowly added. The resulting mixture was concentrated in vacuo and the resulting residue was dissolved in ethyl acetate (800 mL) and washed with HCl (1 N, 3×300 mL). The combined aqueous washes were extracted with ethyl acetate (3×200 mL) and the combined organic layers were washed with NaHCO3 (sat. aq., 3×200 mL), water (100 mL) and brine (100 mL) and then concentrated in vacuo to afford a dark brown oil. Elution of this oil through a silica pad using ethyl acetate/hexanes (1:1) and the concentration in vacuo provided compound 1A (16 g, 42% yield) as a yellow solid. HPLC: 100% at 3.536 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 226.0 [M+H]+. B. Preparation of 1-Amino-3-methyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester (1B)

1. temperaturecooled to 25° C.
2. concentrationThe resulting mixture was concentrated in vacuo
3. dissolutionthe resulting residue was dissolved in ethyl acetate (800 mL)
4. washwashed with HCl (1 N, 3×300 mL)
5. extractionThe combined aqueous washes were extracted with ethyl acetate (3×200 mL)
6. washthe combined organic layers were washed with NaHCO3 (sat. aq., 3×200 mL), water (100 mL) and brine (100 mL)
7. concentrationconcentrated in vacuo
8. customto afford a dark brown oil
9. washElution of this oil through a silica pad
10. concentrationthe concentration in vacuo

ORD record

ord-d26271c2df324aaa8754f775606c7775

Source dataset

uspto-grants-2005_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06900208B2