methyl 5-aminofuran-2-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.3 g, 0.52 mmol), was reacted with diisopropylethylamine (0.34 g, 2.6 mmol), diphenylphosphinic chloride (0.25 g, 1 mmol), then reacted with methyl 5-aminofuran-2-carboxylate (Lancaster) (0.11 g, 0.78 mmol) to give rac-5-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-furan-2-carboxylic acid methyl ester as a yellow solid (Yield 5 mg, 2%).

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 5-amino-2-furoate (4 g) by Lancaster was added to a mixed solution of triethyl orthoformate (20 ml) and isopropyl alcohol (20 ml), and then Meldrum acid (4.5 g) was added and the mixture was heated and stirred at 100° C. for 1 hour. After cooling, the precipitated crystals were filtered out and washed with isopropyl alcohol to obtain the title compound (7.8 g). the mixture was heated After cooling the precipitated crystals were filtered out washed with isopropyl alcohol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred solution of methyl 5-amino-2-furoate (1.4 g, 10 mmol) and 1-hexen-3-one (7 mL, 60 mmol) in benzene (50 mL) was heated to reflux for 2 h. The reaction mixture was concentrated under reduced pressure to afford a crude oil. Purification by flash column chromatography (silica, 2:1 hexanes/ethyl acetate) provided methyl 4-amino-5-butyryl-1-hydroxycyclohexa-2,4-diene-1-carboxylate (1.25 g): 1H NMR (300 MHz, CDCl3): δ 6.26–6.23 (m, 1H), 6.09–6.05 (m, 1H), 3.80 (s, 3H), 3.02–2.96 (m, 1H), 2.89–2.84 (m, 1H), 2.42–2.37 (m, 2H) 1.64–1.57 (m, 2H), 0.96–0.88 (m, 3H). to reflux for 2 h The reaction mixture was concentrated under reduced pressure to afford a crude oil Purification by flash column chromatography (silica, 2:1 hexanes/ethyl acetate)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 5-nitro-2-furoate (13 g, 76 mmol) and 10% Pd/C (1.3 g) in ethanol (150 mL) was shaken under an atmosphere of hydrogen at 40 psi for 18 h. The reaction mixture was filtered through diatomaceous earth and concentrated under reduced pressure to afford a crude oil. Purification by flash column chromatography (silica, 1:1 hexanes/ethyl acetate) provided methyl 5-amino-2-furoate (5.6 g): 1H NMR (500 MHz, CDCl3) δ 7.11–7.10 (m, 1H), 5.31–5.29 (m, 1H), 4.31 (br s, 2H), 3.84 (s, 3H). The reaction mixture was filtered through diatomaceous earth concentrated under reduced pressure to afford a crude oil Purification by flash column chromatography (silica, 1:1 hexanes/ethyl acetate)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Beginning with 7.4 mg (0.029 mMol) 3-dimethylamino-1,2,3,4-tetrahydro-9H-carbazole-6-carboxylic acid and 2-amino-5-methoxycarbonylfuran, 1.3 mg (10%) of the title compound were recovered.

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 5-amino-2-furoate (4 g) by Lancaster was added to a mixed solution of triethyl orthoformate (20 ml) and isopropyl alcohol (20 ml), and then Meldrum acid (4.5 g) was added and the mixture was heated and stirred at 100° C. for 1 hour. After cooling, the precipitated crystals were filtered out and washed with isopropyl alcohol to obtain the title compound (7.8 g). the mixture was heated After cooling the precipitated crystals were filtered out washed with isopropyl alcohol

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 5-amino-2-furoate (4 g) by Lancaster was added to a mixed solution of triethyl orthoformate (20 ml) and isopropyl alcohol (20 ml), and then Meldrum acid (4.5 g) was added and the mixture was heated and stirred at 100° C. for 1 hour. After cooling, the precipitated crystals were filtered out and washed with isopropyl alcohol to obtain the title compound (7.8 g). the mixture was heated After cooling the precipitated crystals were filtered out washed with isopropyl alcohol

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of sodium methoxide in methanol (30% w/w, 38 mL, 0.21 mol) was added to a mixture of methyl 5-aminofuran-2-carboxylate (15 g, 0.11 mol) and 2-[(dimethylamino)methylene]-1,3-bis(dimethyliminio)propane bis(tetrafluoroborate)salt (38 g, 0.11 mol) in an oven-dried sealed tube. The resulting mixture was heated at reflux for 1 h, then cooled to 23° C., and diluted carefully with water. The reaction mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 40% ethyl acetate in petroleum ether to give the title compound. 1H NMR (300 MHz, CDCl3): δ 8.50 (d, 1H, J=2.0 Hz), 8.13 (d, 1H, J=2.0 Hz), 7.40 (s, 1H), 5.58 (s, 1H), 3.43 (s, 3H), 3.13 (s, 3H). sealed tube The resulting mixture was heated at reflux for 1 h The reaction mixture was concentrated extracted with ethyl acetate The organic layer was washed with brine dried over sodium sulfate concentrated The residue was purified by flash chromatography on silica gel eluting with 40% ethyl acetate in petroleum ether

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 5-amino-2-furoate (4 g) by Lancaster was added to a mixed solution of triethyl orthoformate (20 ml) and isopropyl alcohol (20 ml), and then Meldrum acid (4.5 g) was added and the mixture was heated and stirred at 100° C. for 1 hour. After cooling, the precipitated crystals were filtered out and washed with isopropyl alcohol to obtain the title compound (7.8 g). the mixture was heated After cooling the precipitated crystals were filtered out washed with isopropyl alcohol

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 5-amino-2-furoate (4 g) by Lancaster was added to a mixed solution of triethyl orthoformate (20 ml) and isopropyl alcohol (20 ml), and then Meldrum acid (4.5 g) was added and the mixture was heated and stirred at 100° C. for 1 hour. After cooling, the precipitated crystals were filtered out and washed with isopropyl alcohol to obtain the title compound (7.8 g). the mixture was heated After cooling the precipitated crystals were filtered out washed with isopropyl alcohol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.3 g, 0.52 mmol), was reacted with diisopropylethylamine (0.34 g, 2.6 mmol), diphenylphosphinic chloride (0.25 g, 1 mmol), then reacted with methyl 5-aminofuran-2-carboxylate (Lancaster) (0.11 g, 0.78 mmol) to give rac-5-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-furan-2-carboxylic acid methyl ester as a yellow solid (Yield 5 mg, 2%).