methyl 2-[bis(methylsulfanyl)methylideneamino]acetate

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of N-[Bis(methylthio)methylene]glycine methyl ester (1 mmole) in anhydrous THF (2 mL) was added to a solution of t-BuOK (1.4 mmole) in anhydrous THF (10 mL) at −78° C. and the mixture was stirred for 30 min. Then a solution of ethyl isothiocyanate (1 mmole) in anhydrous THF (2 mL) was added and the reaction was stirred at −78° C. for 30 min and at room temperature for 2 h. The reaction was quenched with water. Extraction and chromatography gave 2-methylthio-5-(N-ethylamino)-4-methoxycarbonylthiazole as a yellow solid, which was subjected to Step B and C of Example 18 followed by Step C of Example 3 to give 2-methylthio-5-(N-ethylamino)-4-phosphonomethoxycarbonylthiazole (18.4) as a solid. Mp>200° C. (decomp). Anal. Calcd. for C8H13N2O5PS2+0.1 HBr: C: 29.99; H: 4.12; N: 8.74. Found: C: 29.71; H: 4.10; N: 8.60. the reaction was stirred at −78° C. for 30 min and at room temperature for 2 h The reaction was quenched with water Extraction and chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of N-[Bis(methylthio)methylene]glycine methyl ester (1 mmole) in anhydrous THF (2 mL) was added to a solution of t-BuOK (1.4 mmole) in anhydrous THF (10 mL) at −78° C. and the mixture was stirred for 30 min. Then a solution of ethyl isothiocyanate (1 mmole) in anhydrous THF (2 mL) was added and the reaction was stirred at −78° C. for 30 min and at room temperature for 2 h. The reaction was quenched with water. Extraction and chromatography gave 2-methylthio-5-(N-ethylamino)-4-methoxycarbonylthiazole as a yellow solid, which was subjected to Step B and C of Example 18 followed by Step C of Example 3 to give 2-methylthio-5-(N-ethylamino)-4-phosphonomethoxycarbonylthiazole (18.4) as a solid. Mp>200° C. (decomp). Anal. calcd. for C8H13N2O5PS2+0.1HBr: C: 29.99; H: 4.12; N: 8.74. Found: C: 29.71; H: 4.10; N: 8.60. the reaction was stirred at −78° C. for 30 min and at room temperature for 2 h The reaction was quenched with water Extraction and chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of N-[Bis(methylthio)methylene]glycine methyl ester (1 mmole) in anhydrous THF (2 mL) was added to a solution of t-BuOK (1.4 mmole) in anhydrous TKF (10 mL) at −78° C. and the mixture was stirred for 30 min. Then a solution of ethyl isothiocyanate (1 mmole) in anhydrous THF (2 mL) was added and the reaction was stirred at −78° C. for 30 min and at room temperature for 2 h. The reaction was quenched with water. Extraction and chromatography gave 2-methylthio-5-(N-ethylamino)-4-methoxycarbonylthiazole as a yellow solid, which was subjected to Step B and C of Example 18 followed by Step C of Example 3 to give 2-methylthio-5-(N-ethylamino)-4-phosphonomethoxycarbonylthiazole (18.4) as a solid. Mp>200° C. (decomp). Anal. Calcd. for C8H13N2O5PS2+0.1 HBr: C, 29.99; H, 4.12; N, 8.74. Found: C, 29.71; H, 4.10; N, 8.60. the reaction was stirred at −78° C. for 30 min and at room temperature for 2 h The reaction was quenched with water Extraction and chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of N-[Bis(methylthio)methylene]glycine methyl ester (1 mmole) in anhydrous THF (2 mL) was added to a solution of t-BuOK (1.4 mmole) in anhydrous THF (10 mL) at −78° C. and the mixture was stirred for 30 min. Then a solution of ethyl isothiocyanate (1 mmole) in anhydrous THF (2 mL) was added and the reaction was stirred at −78° C. for 30 min and at room temperature for 2 h. The reaction was quenched with water. Extraction and chromatography gave 2-methylthio-5-(N-ethylamino)-4-methoxycarbonylthiazole as a yellow solid, which was subjected to Step B and C of Example 18 followed by Step C of Example 3 to give 2-methylthio-5-(N-ethylamino)-4-phosphonomethoxycarbonylthiazole (18.4) as a solid. Mp>200° C. (decomp). Anal. Calcd. for C8H13N2O5PS2+0.1 HBr: C: 29.99; H: 4.12; N: 8.74. Found: C: 29.71; H: 4.10; N: 8.60. the reaction was stirred at −78° C. for 30 min and at room temperature for 2 h The reaction was quenched with water Extraction and chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of N-[Bis(methylthio)methylene]glycine methyl ester (1 mmole) in anhydrous THF (2 mL) was added to a solution of t-BuOK (1.4 mmole) in anhydrous THF (10 mL) at −78° C. and the mixture was stirred for 30 min. Then a solution of ethyl isothiocyanate (1 mmole) in anhydrous THF (2 mL) was added and the reaction was stirred at −78° C. for 30 min and at room temperature for 2 h. The reaction was quenched with water. Extraction and chromatography gave 2-methylthio-5-(N-ethylamino)-4-methoxycarbonylthiazole as a yellow solid, which was subjected to Step B and C of Example 18 followed by Step C of Example 3 to give 2-methylthio-5-(N-ethylamino)-4-phosphonomethoxycarbonylthiazole (18.4) as a solid. Mp>200° C. (decomp). Anal. Calcd. for C8H13N2O5PS2+0.1 HBr: C: 29.99; H: 4.12; N: 8.74. Found: C: 29.71; H: 4.10; N: 8.60. the reaction was stirred at −78° C. for 30 min and at room temperature for 2 h The reaction was quenched with water Extraction and chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of N-[Bis(methylthio)methylene]glycine methyl ester (1 mmole) in anhydrous THF (2 mL) was added to a solution of t-BuOK (1.4 mmole) in anhydrous THF (10 mL) at −78° C. and the mixture was stirred for 30 min. Then a solution of ethyl isothiocyanate (1 mmole) in anhydrous THF (2 mL) was added and the reaction was stirred at −78° C. for 30 min and at room temperature for 2 h. The reaction was quenched with water. Extraction and chromatography gave 2-methylthio-5-(N-ethylamino)-4-methoxycarbonylthiazole as a yellow solid, which was subjected to Step B and C of Example 18 followed by Step C of Example 3 to give 2-methylthio-5-(N-ethylamino)-4-phosphonomethoxycarbonylthiazole (18.4) as a solid. Mp>200° C. (decomp). Anal. Calcd. for C8H13N2O5PS2+0.1 HBr: C: 29.99; H: 4.12; N: 8.74. Found: C: 29.71; H: 4.10; N: 8.60. the reaction was stirred at −78° C. for 30 min and at room temperature for 2 h The reaction was quenched with water Extraction and chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of potassium tert-butoxide (1.18 g; 10.52 mmol) in dry tetrahydrofuran (20 ml), cooled at -78 C., under argon, is treated with a solution of N-[bis(methylthio)methylene] glycine methyl ester (1.02 g; 5.26 mmol) in dry tetrahydrofuran (7 ml). After stirring for 45 minutes, it is added a solution of 4-fluorobenzoyl chloride (0.75 g; 6.31 mmol) in tetrahydrofuran (7 ml). After stirring at -78 C. for 20 minutes, it is brought to room temperature and stirred an additional 16 hours. The reaction mixture is diluted with water (30 ml) and extracted with ethyl acetate (70 ml). The aqueous phase is washed with ethyl acetate (20 ml). The combined organic phases are washed with saturated brine (20 ml), dried over sodium sulfate and concentrated to dryness. Purification by radial chromatography on silica gel using an ethyl acetate/hexane gradient (10%-70%) affords the product as a white solid (0.23 g; 16%). HNMR (CDCl3): 8.07 (m, 2H), 7.16 (t, 2H, J=8.9 Hz), 3.93 (s, 3H), 2.73 (s, 3H). Mass spectrum: m/e calculated (MH+)=268.3; observed (MH+)=268.1. cooled at -78 C After stirring at -78 C for 20 minutes is brought to room temperature stirred an additional 16 hours extracted with ethyl acetate (70 ml) The aqueous phase is washed with ethyl acetate (20 ml) The combined organic phases are washed with saturated brine (20 ml) dried over sodium sulfate concentrated to dryness Purification by radial chromatography on silica gel using an ethyl acetate/hexane gradient (10%-70%)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of potassium tert-butoxide (1.18 g; 10.52 mmol) in dry tetrahydrofuran (20 ml), cooled at -78 C., under argon, is treated with a solution of N-[bis(methylthio)methylene] glycine methyl ester (1.02 g; 5.26 mmol) in dry tetrahydrofuran (7 ml). After stirring for 45 minutes, it is added a solution of 4-fluorobenzoyl chloride (0.75 g; 6.31 mmol) in tetrahydrofuran (7 ml). After stirring at -78 C. for 20 minutes, it is brought to room temperature and stirred an additional 16 hours. The reaction mixture is diluted with water (30 ml) and extracted with ethyl acetate (70 ml). The aqueous phase is washed with ethyl acetate (20 ml). The combined organic phases are washed with saturated brine (20 ml), dried over sodium sulfate and concentrated to dryness. Purification by radial chromatography on silica gel using an ethyl acetate/hexane gradient (10%-70%) affords the product as a white solid (0.23 g; 16%). HNMR (CDCl3): 8.07 (m, 2H), 7.16 (t, 2H, J=8.9 Hz), 3.93 (s, 3H), 2.73 (s, 3H). Mass spectrum: m/e calculated (MH+)=268.3; observed (MH+)=268.1. cooled at -78 C After stirring at -78 C for 20 minutes is brought to room temperature stirred an additional 16 hours extracted with ethyl acetate (70 ml) The aqueous phase is washed with ethyl acetate (20 ml) The combined organic phases are washed with saturated brine (20 ml) dried over sodium sulfate concentrated to dryness Purification by radial chromatography on silica gel using an ethyl acetate/hexane gradient (10%-70%)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Commercially available N-[Bis(methylthio)methylene]glycine methyl ester (5.06 g, 26.18 mmol) and N,N-Dimethylformamide dimethyl acetal (4.03 g, 31.41 mmol) were dissolved in N,N-dimethylformamide (10 mL) and heated to reflux under nitrogen for 4.5 h. The solvent was removed under reduced pressure and the product solidified (6.44 g, 99%) after storage at room temperature under high vacuum over night. 1H NMR (CDCl3, 400 MHz): δ 6.96 (s, 1H); 3.68 (s, 3H); 2.95 (s, 6H); 2.53 (s, 3H); 2.49 (s, 3H). heated to reflux under nitrogen for 4.5 h The solvent was removed under reduced pressure at room temperature

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of N-[Bis(methylthio)methylene]glycine methyl ester (1 mmole) in anhydrous THF (2 mL) was added to a solution of t-BuOK (1.4 mmole) in anhydrous THF (10 mL) at −78° C. and the mixture was stirred for 30 min. Then a solution of ethyl isothiocyanate (1 mmole) in anhydrous THF (2 mL) was added and the reaction was stirred at −78° C. for 30 min and at room temperature for 2 h. The reaction was quenched with water. Extraction and chromatography gave 2-methylthio-5-(N-ethylamino)-4-methoxycarbonylthiazole as a yellow solid, which was subjected to Step B and C of Example 18 followed by Step C of Example 3 to give 2-methylthio-5-(N-ethylamino)-4-phosphonomethoxycarbonylthiazole (18.4) as a solid. Mp>200° C. (decomp). Anal. calcd. for C8H13N2O5PS2+0.1HBr: C: 29.99; H: 4.12; N: 8.74. Found: C: 29.71; H: 4.10; N: 8.60. the reaction was stirred at −78° C. for 30 min and at room temperature for 2 h The reaction was quenched with water Extraction and chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of N-[Bis(methylthio)methylene]glycine methyl ester (1 mmole) in anhydrous THF (2 mL) was added to a solution of t-BuOK (1.4 mmole) in anhydrous TKF (10 mL) at −78° C. and the mixture was stirred for 30 min. Then a solution of ethyl isothiocyanate (1 mmole) in anhydrous THF (2 mL) was added and the reaction was stirred at −78° C. for 30 min and at room temperature for 2 h. The reaction was quenched with water. Extraction and chromatography gave 2-methylthio-5-(N-ethylamino)-4-methoxycarbonylthiazole as a yellow solid, which was subjected to Step B and C of Example 18 followed by Step C of Example 3 to give 2-methylthio-5-(N-ethylamino)-4-phosphonomethoxycarbonylthiazole (18.4) as a solid. Mp>200° C. (decomp). Anal. Calcd. for C8H13N2O5PS2+0.1 HBr: C, 29.99; H, 4.12; N, 8.74. Found: C, 29.71; H, 4.10; N, 8.60. the reaction was stirred at −78° C. for 30 min and at room temperature for 2 h The reaction was quenched with water Extraction and chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of N-[Bis(methylthio)methylene]glycine methyl ester (1 mmole) in anhydrous THF (2 mL) was added to a solution of t-BuOK (1.4 mmole) in anhydrous THF (10 mL) at −78° C. and the mixture was stirred for 30 min. Then a solution of ethyl isothiocyanate (1 mmole) in anhydrous THF (2 mL) was added and the reaction was stirred at −78° C. for 30 min and at room temperature for 2 h. The reaction was quenched with water. Extraction and chromatography gave 2-methylthio-5-(N-ethylamino)-4-methoxycarbonylthiazole as a yellow solid, which was subjected to Step B and C of Example 18 followed by Step C of Example 3 to give 2-methylthio-5-(N-ethylamino)-4-phosphonomethoxycarbonylthiazole (18.4) as a solid. Mp>200° C. (decomp). Anal. Calcd. for C8H13N2O5PS2+0.1 HBr: C: 29.99; H: 4.12; N: 8.74. Found: C: 29.71; H: 4.10; N: 8.60. the reaction was stirred at −78° C. for 30 min and at room temperature for 2 h The reaction was quenched with water Extraction and chromatography