methyl 4-oxooxane-3-carboxylate

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

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

Procedure: Methyl 4-oxo-tetrahydro-2H-pyran-3-carboxylate and methyl 4-hydroxy-5,6-dihydro-2H-pyran-3-carboxylate (13.5 g, 85.5 mmol) were dissolved in DMF (70 mL). Sodium hydride (60%, 3.6 g, 1.05 eq) was added at 0° C. After 10 min, iodomethane (6.7 mL, 1.25 eq) was added. The reaction was stirred overnight, diluted with ethyl acetate (200 mL), and washed with water (5×100 mL). The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel eluting with 20% ethyl acetate/hexane to yield 8.2 g (61%) of methyl 3-methyl-4-oxo-tetrahydro-2H-pyran-3-carboxylate. washed with water (5×100 mL) The aqueous layer was re-extracted with ethyl acetate The combined organic layers were washed with brine dried over MgSO4 concentrated The residue was purified by chromatography on silica gel eluting with 20% ethyl acetate/hexane

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

Procedure: Methyl 4-oxo-tetrahydro-2H-pyran-3-carboxylate and methyl 4-hydroxy-5,6-dihydro-2H-pyran-3-carboxylate (13.5 g, 85.5 mmol) were dissolved in DMF (70 mL). Sodium hydride (60%, 3.6 g, 1.05 eq) was added at 0° C. After 10 min, iodomethane (6.7 mL, 1.25 eq) was added. The reaction was stirred overnight, diluted with ethyl acetate (200 mL), and washed with water (5×100 mL). The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel eluting with 20% ethyl acetate/hexane to yield 8.2 g (61%) of methyl 3-methyl-4-oxo-tetrahydro-2H-pyran-3-carboxylate. washed with water (5×100 mL) The aqueous layer was re-extracted with ethyl acetate The combined organic layers were washed with brine dried over MgSO4 concentrated The residue was purified by chromatography on silica gel eluting with 20% ethyl acetate/hexane

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

Procedure: A mixture of methyl 4-oxotetrahydro-2H-pyran-3-carboxylate (1.0 g, 6.3 mmol), 2-chloropropanimidamide hydrochloride (0.9 g, 6.3 mmol), and triethylamine (3.52 mL, 25.4 mmol) was stirred at ambient temperature for 24 h. The mixture was concentrated in vacuo to give the title compound (1.4 g), which was used directly to the next step without further purification. MS m/z 215.2 (M+1), retention time=1.27 min. The mixture was concentrated in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of crude 4-oxo-tetrahydro-pyran-3-carboxylic acid methyl ester (1780 g, 11 mol) and NEt3 (830 g, 8.2 mol) in MeOH (3560 mL) was cooled to 0° C. under N2. A solution of 2-chloro-acetamidine (567 g, 4.4 mol) in 890 mL of MeOH was added dropwise over 50 minutes. The reaction mixture was stirred at 0° C. for 30 minutes and then at about 20° C. for 16 hours. LCMS at 215 nm and TLC (DCM:MeOH=10:1) analysis showed that most of 4-oxo-tetrahydro-pyran-3-carboxylic acid methyl ester was consumed. The mixture was then filtered and concentrated to give black oil, which was subsequently purified by flash column chromatography on silica gel and eluted with DCM to give yellow solid/oil mixture, which was further triturated with MTBE (1200 mL) and H2O: CH3CN: EA=1:1:2 (˜600 mL) to give the title compound as a white solid (318 g). MS m/z 201.2 (M+H). CHN analysis: calculated (results). C, 47.89 (47.95), H, 4.52 (4.401), N, 13.96 (13.76). at about 20° C. for 16 hours was consumed The mixture was then filtered concentrated to give black oil, which was subsequently purified by flash column chromatography on silica gel eluted with DCM to give yellow solid/oil mixture, which was further triturated with MTBE (1200 mL) and H2O

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

Procedure: To benzyl 2-amino-2-iminoethylcarbamate (1.77 g, 8.54 mmol) in methanol (67.5 mL) was added methyl 4-oxotetrahydro-2H-pyran-3-carboxylate (1.35 g, 8.54 mmol) and potassium carbonate (3.54 g, 25.6 mmol). The reaction mixture was stirred 15 h at room temperature. The solution was filtered and concentrated under vacuum. Purification was accomplished on a 100 g Isco column with 0% to 10% methanol in dichloromethane over 20 column volumes to give title compound (1.63 g, 59% yield). Exact mass calculated for C16H17N3O4 315.3. found 316.2 (ESI, M+H); 1H NMR (400 MHz, MeOD) 8 ppm 7.17-7.46 (m, 5H) 5.11 (s, 2H) 4.47 (br. s., 2H) 4.22 (s, 2H) 3.92 (t, J=5.31 Hz, 2H) 2.65 (br. s., 2H). The solution was filtered concentrated under vacuum Purification

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

Procedure: To a solution of methyl 4-oxotetrahydro-2H-pyran-3-carboxylate (51.1 g, 323 mmol) and benzyl 2-amino-2-iminoethylcarbamate hydrochloride (78.8 g, 323 mmol) in anhydrous ethanol was added sodium ethoxide (122 mL, 323 mmol, 21% in ethanol). The mixture was mechanically stirred, heated at reflux for 24 h, cooled down to ambient temperature, and filtered to give the title compound (55.6 g, 55% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.40 (br. s., 1H), 7.69 (t, J=5.8 Hz, 1H), 7.15-7.44 (m, 5H), 4.99-5.08 (m, 2H), 4.35 (s, 2H), 4.04-4.11 (m, 2H), 3.84 (t, J=5.3 Hz, 2H), 2.48-2.57 (m, 2H). MS m/z 316.2 (M+1), retention time=1.10 min. heated at reflux for 24 h filtered

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

Procedure: To a solution of tetrahydro-pyran-4-one (1.3 kg, 12.98 mol) and carbonic acid dimethyl ester (11.69 kg, 129.8 mol) was added solid potassium tert-butoxide (1.89 kg, 16.08 mol) in portions at −10° C. over 2 h under nitrogen protection. The suspension was stirred at room temperature 10 h after the addition. LCMS (215 nm) indicated that tetrahydro-pyran-4-one had been completely consumed. The reaction was acidified by HCl (2 N) to pH 6˜7 and then the phases were separated. The organic phase was washed with water (3 L×2) and the combined aqueous phases were extracted with MTBE (2.5 L×2). The combined organic phase was concentrated under reduced pressure at 25° C. to remove most of MTBE. The residue was distilled out by oil pump (˜200 Pa) at 74° C. to give the title compound as colorless oil (545 g, 26.3%). CHN analysis: calculated (results). C, 53.16 (53.10), H, 6.37 (6.245), N, 0.00 (0.00). after the addition had been completely consumed the phases were separated The organic phase was washed with water (3 L×2) the combined aqueous phases were extracted with MTBE (2.5 L×2) The combined organic phase was concentrated under reduced pressure at 25° C. to remove most of MTBE The residue was distilled out by oil pump (˜200 Pa) at 74° C.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of crude 4-oxo-tetrahydro-pyran-3-carboxylic acid methyl ester (1780 g, 11 mol) and NEt3 (830 g, 8.2 mol) in MeOH (3560 mL) was cooled to 0° C. under N2. A solution of 2-chloro-acetamidine (567 g, 4.4 mol) in 890 mL of MeOH was added dropwise over 50 minutes. The reaction mixture was stirred at 0° C. for 30 minutes and then at about 20° C. for 16 hours. LCMS at 215 nm and TLC (DCM:MeOH=10:1) analysis showed that most of 4-oxo-tetrahydro-pyran-3-carboxylic acid methyl ester was consumed. The mixture was then filtered and concentrated to give black oil, which was subsequently purified by flash column chromatography on silica gel and eluted with DCM to give yellow solid/oil mixture, which was further triturated with MTBE (˜1200 mL) and H2O: CH3CN: EA=1:1:2 (˜600 mL) to give the title compound as a white solid (318 g). MS m/z 201.2 (M+H). CHN analysis: calculated (results). C, 47.89; (47.95), H, 4.52; (4.401), N, 13.96; (13.76). at about 20° C. for 16 hours was consumed The mixture was then filtered concentrated to give black oil, which was subsequently purified by flash column chromatography on silica gel eluted with DCM to give yellow solid/oil mixture, which was further triturated with MTBE (˜1200 mL) and H2O

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of crude 4-oxo-tetrahydro-pyran-3-carboxylic acid methyl ester (1780 g, 11 mol) and NEt3 (830 g, 8.2 mol) in MeOH (3560 mL) was cooled to 0° C. under N2. A solution of 2-chloro-acetamidine (567 g, 4.4 mol) in 890 mL of MeOH was added dropwise over 50 minutes. The reaction mixture was stirred at 0° C. for 30 minutes and then at about 20° C. for 16 hours. LCMS at 215 nm and TLC (DCM:MeOH=10:1) analysis showed that most of 4-oxo-tetrahydro-pyran-3-carboxylic acid methyl ester was consumed. The mixture was then filtered and concentrated to give black oil, which was subsequently purified by flash column chromatography on silica gel and eluted with DCM to give yellow solid/oil mixture, which was further triturated with MTBE (˜1200 mL) and H2O: CH3CN: EA=1:1:2 (˜600 mL) to give the title compound as a white solid (318 g). MS m/z 201.2 (M+H). CHN analysis: calculated (results). C, 47.89; (47.95), H, 4.52; (4.401), N, 13.96; (13.76). at about 20° C. for 16 hours was consumed The mixture was then filtered concentrated to give black oil, which was subsequently purified by flash column chromatography on silica gel eluted with DCM to give yellow solid/oil mixture, which was further triturated with MTBE (˜1200 mL) and H2O

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

Procedure: To benzyl 2-amino-2-iminoethylcarbamate (1.77 g, 8.54 mmol) in methanol (67.5 mL) was added methyl 4-oxotetrahydro-2H-pyran-3-carboxylate (1.35 g, 8.54 mmol) and potassium carbonate (3.54 g, 25.6 mmol). The reaction mixture was stirred 15 h at room temperature. The solution was filtered and concentrated under vacuum. Purification was accomplished on a 100 g Isco column with 0% to 10% methanol in dichloromethane over 20 column volumes to give title compound (1.63 g, 59% yield). Exact mass calculated for C16H17N3O4 315.3. found 316.2 (ESI, M+H); 1H NMR (400 MHz, MeOD) δ ppm 7.17-7.46 (m, 5H) 5.11 (s, 2H) 4.47 (br. s., 2H) 4.22 (s, 2H) 3.92 (t, J=5.31 Hz, 2H) 2.65 (br. s., 2H). The solution was filtered concentrated under vacuum Purification

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

Procedure: To a solution of methyl 4-oxotetrahydro-2H-pyran-3-carboxylate (51.1 g, 323 mmol) and benzyl 2-amino-2-iminoethylcarbamate hydrochloride (78.8 g, 323 mmol) in anhydrous ethanol was added sodium ethoxide (122 mL, 323 mmol, 21% in ethanol). The mixture was mechanically stirred, heated at reflux for 24 h, cooled down to ambient temperature, and filtered to give the title compound (55.6 g, 55% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.40 (br. s., 1H), 7.69 (t, J=5.8 Hz, 1H), 7.15-7.44 (m, 5H), 4.99-5.08 (m, 2H), 4.35 (s, 2H), 4.04-4.11 (m, 2H), 3.84 (t, J=5.3 Hz, 2H), 2.48-2.57 (m, 2H). MS m/z 316.2 (M+1), retention time=1.10 min. heated at reflux for 24 h filtered