Hydrochloric Acid → HCID 10064565, compound

Temperature

60 °C

A mixture of 5-methyl-2-thiophenecarboxaldehyde (108 μL, 1.00 mmol), (4-amino-2-nitro-phenyl)-carbamic acid ethyl ester (225 mg, 1.00 mmol) and Amberlite IRC-84 (10 mg) in o-xylene (4 mL) was heated at reflux under Ar for 5 hours. Volatiles were removed by evaporation in vacuo, and the residue was dissolved in acetonitrile (5 mL). To the resulting solution was added NaBH3CN (0.25 g, 4.0 mmol) followed by HOAc (5 drops). After stirring for 5 minutes, the solution became dark red. Formaldehyde (37% solution in water, 0.89 mL, 12 mmol) was added, and stiring was continued for 30 minutes with occasional addition of HOAc. The reaction mixture was evaporated to dryness in vacuo and the residue was partitioned between saturated aqueous sodium bicarbonate (50 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (50 mL) and the combined organic layers were dried (Na2SO4) and the solvents evaporated in vacuo. The residue was then dissolved in ethanol (10 mL). 6 N aqueous HCl (2.0 mL, 12 mmol) and iron powder (0.34 g, 6.0 mmol) were added, and the red mixture was heated at 60° C. until the red color had faded to yellow, ca. 15 minutes. The mixture was poured into saturated aqueous sodium bicarbonate (50 mL) and EtOAc (50 mL), the resulting mixture was filtered, the phases were separated, and the aqueous phase was further extracted with EtOAc (2×50 mL). The combined organic layers were dried (Na2SO4) and the solvents evaporated in vacuo. The product was purified by chromatography on silica gel on a FlashMaster system using as eluent heptane/ethyl acetate (linear gradient elution, typically from 8:2 to 1:1). The fractions containing the product were pooled and evaporated in vacuo to yield the title compound as a pale yellow solid (145 mg, 45% overall). LC-MS: (m/z)=319.9 (M+H+), calcd for C16H22N3O2S: 320.1427, tR=1.80 min, UV purity=98.4%, ELS purity=97.2%. 1H NMR (CDCl3): 1.29 (t, J=7.1, 3 H), 2.41 (s, 3 H), 2.91 (s, 3 H), 3.76 (b, 2 H), 4.19 (q, J=7.1 Hz, 2 H), 4.52 (s, 2 H), 6.02 (b, 1 H), 6.17 (d, J=2.8 Hz, 1 H), 6.25 (dd, J=2.8, 8.5 Hz, 1 H), 6.53-6.58 (m, 1 H), 6.66 (d, J=3.3 Hz, 1 H), 6.98 (d, J=8.5 Hz, 1 H).

1. temperaturewas heated
2. temperatureat reflux under Ar for 5 hours
3. customVolatiles were removed by evaporation in vacuo
4. dissolutionthe residue was dissolved in acetonitrile (5 mL)
5. customThe reaction mixture was evaporated to dryness in vacuo
6. customthe residue was partitioned between saturated aqueous sodium bicarbonate (50 mL) and EtOAc (50 mL)
7. extractionThe aqueous phase was extracted with EtOAc (50 mL)
8. dry with materialthe combined organic layers were dried (Na2SO4)
9. customthe solvents evaporated in vacuo
10. dissolutionThe residue was then dissolved in ethanol (10 mL)
11. customca. 15 minutes
12. filtrationthe resulting mixture was filtered
13. customthe phases were separated
14. extractionthe aqueous phase was further extracted with EtOAc (2×50 mL)
15. dry with materialThe combined organic layers were dried (Na2SO4)
16. customthe solvents evaporated in vacuo
17. customThe product was purified by chromatography on silica gel on a FlashMaster system
18. washlinear gradient elution
19. additionThe fractions containing the product
20. customevaporated in vacuo

ORD record

ord-551ba680e63645e190437d6127f810d4

Source dataset

uspto-grants-2008_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07368472B2