acetyl isocyanate

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: A solution of (1S,3S,5R,6R) 2,2-dimethyl-6-phenoxyacetamidopenam-3-carboxylic acid-1-oxide p-nitrobenzyl ester (25.18 g, 50.0 mmol), acetyl isocyanate (8.50 ml, 9.53 g, 112 mmol), and dioxane (250 ml) was refluxed under nitrogen for 5 hours, cooled and concentrated in vacuo to a yellow foam. The foam was chromatographed on silica gel (1.7 Kg) with methylene chloride: acetone; 9:1; v:v to give four products; the 3-methyl-Δ3 -cephem; starting sulfoxide, the title penam, and the cepham (in order of elution). The penam fractions were concentrated to a colorless foam in 40.2% yield (11.80 g). Re-chromatography of a portion gave an analytical sample: m.p. 83°-85°; nmr 100 MHz (CDCl3) ppm 8.40 (1, s, ##STR59## 8.20 (2, d, J=8.5, 1/2 aromatic AB pNB), 7.56 (3, d, J=8.5 over m, 1/2 AB, pNB and C6 -NH), 7.5 (2, m) and 6.9 (3, m, O-Ph-H's), 5.7 (2, m's, C5 -C6 -H's), 5.32 (2, br, s, pNB methylene), 4.88 (1, s, C3 -H), 4.56 (2, s, ##STR60## 4.26 and 4.06 (2, d's, J=11.5 AB of C2 -CH2O), 2.22 (3, s, ##STR61## and 1.47 (3, s, C2 -CH3); nmr 13C 4 carbonyls ca 170 ppm, carbamate carbonyl C 157.0, C2 singlet at 67.4, while C2 -CH2O is t at 72.3, and C2 -CH3 is q at 21.7. cooled concentrated in vacuo to a yellow foam The foam was chromatographed on silica gel (1.7 Kg) with methylene chloride v:v to give four products The penam fractions were concentrated to a colorless foam in 40.2% yield (11.80 g) Re-chromatography of a portion gave an analytical sample

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

実験手順: A solution of (1S,3S,5R,6R) 2,2-dimethyl-6-phenoxyacetamidopenam-3-carboxylic acid-1-oxide p-nitrobenzyl ester (25.18 g, 50.0 mmol), acetyl isocyanate (8.50 ml, 9.53 g, 112 mmol), and dioxane (250 ml) was refluxed under nitrogen for 5 hours, cooled and concentrated in vacuo to a yellow foam. The foam was chromatographed on silica gel (1.7 Kg) with methylene chloride: acetone; 9:1; v:v to give four products; the 3-methyl-Δ3 -cephem; starting sulfoxide, the title penam, and the cepham (in order of elution). The penam fractions were concentrated to a colorless foam in 40.2% yield (11.80 g). Re-chromatography of a portion gave an analytical sample: m.p. 83°-85°; nmr 100 MHz (CDCl3) ppm 8.40 (1, s, ##STR59## 8.20 (2, d, J=8.5, 1/2 aromatic AB pNB), 7.56 (3, d, J=8.5 over m, 1/2 AB, pNB and C6 -NH), 7.5 (2, m) and 6.9 (3, m, O-Ph-H's), 5.7 (2, m's, C5 -C6 -H's), 5.32 (2, br, s, pNB methylene), 4.88 (1, s, C3 -H), 4.56 (2, s, ##STR60## 4.26 and 4.06 (2, d's, J=11.5 AB of C2 -CH2O), 2.22 (3, s, ##STR61## and 1.47 (3, s, C2 -CH3); nmr 13C 4 carbonyls ca 170 ppm, carbamate carbonyl C 157.0, C2 singlet at 67.4, while C2 -CH2O is t at 72.3, and C2 -CH3 is q at 21.7. cooled concentrated in vacuo to a yellow foam The foam was chromatographed on silica gel (1.7 Kg) with methylene chloride v:v to give four products The penam fractions were concentrated to a colorless foam in 40.2% yield (11.80 g) Re-chromatography of a portion gave an analytical sample

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

実験手順: 5-(3,5-Dichlorophenylthio)-4-isoproyl-1-(4-pyridylmethyl)-2-hydroxymethyl-1H-imidazole (89) (245 mg, 0.6 mmol) prepared in accordance with the method as described in WO 96/10019 was converted to the carbamate with acetyl isocyanate (5 eq.) in the same manner as the example 66 to give the compound 90 (225 mg, 76%) as crystals. Mp. 135-137° C. Rf 0.32 (10:1 EtOAc - CH3OH).

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

実験手順: A solution of (1S,3S,5R,6R) 2,2-dimethyl-6-phenylacetamidopenam-3-carboxylic acid-1-oxide p-nitrobenzyl ester (4.85 g, 10.0 mmol) and acetyl isocyanate (2.3 ml, 30 mmol) in dioxane (50 ml) was refluxed under nitrogen for 7 hours. The light orange solution was concentrated in vacuo to a foam which was chromatographed on silica gel (500 g) with methylene chloride:acetone; 9:1, v:v. Two major bands were eluted; the first was the Δ3 3-methylcephem (28%, 1.29 g) and the second was the title compound obtained in 45% yield (2.56 g) as an off-white foam: mp 83°-85°; nmr 100 MHz (CDCl3) ppm 8.24 (2, d, J=9 Hz, 1/2 aromatic AB pNB), 7.61 (2, d, J=9, 1/2 pNB AB), 7.28 (5, s, phenyl), 5.54 (2, m's, C6 --C5 --H's), 5.40 (2, br s, pNB methylene), 4.91 (1, s, C3 --H), 4.27 1, d, J=12, 1/2 C2 --CHHO AB), 4.08 (1, d, J=12, 1/2 C2 --methylene AB), 3.12 ##STR73## 2.12 (3, s, acetyl), and 1.41 (3, s, C2 --CH3). The light orange solution was concentrated in vacuo to a foam which was chromatographed on silica gel (500 g) with methylene chloride Two major bands were eluted obtained in 45% yield (2.56 g) as an off-white foam

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

実験手順: A solution of (1S,3S,5R,6R) 2,2-dimethyl-6-phenylacetamidopenam-3-carboxylic acid-1-oxide p-nitrobenzyl ester (4.85 g, 10.0 mmol) and acetyl isocyanate (2.3 ml, 30 mmol) in dioxane (50 ml) was refluxed under nitrogen for 7 hours. The light orange solution was concentrated in vacuo to a foam which was chromatographed on silica gel (500 g) with methylene chloride:acetone; 9:1, v:v. Two major bands were eluted; the first was the Δ3 3-methylcephem (28%, 1.29 g) and the second was the title compound obtained in 45% yield (2.56 g) as an off-white foam: mp 83°-85°; nmr 100 MHz (CDCl3) ppm 8.24 (2, d, J=9 Hz, 1/2 aromatic AB pNB), 7.61 (2, d, J=9, 1/2 pNB AB), 7.28 (5, s, phenyl), 5.54 (2, m's, C6 --C5 --H's), 5.40 (2, br s, pNB methylene), 4.91 (1, s, C3 --H), 4.27 1, d, J=12, 1/2 C2 --CHHO AB), 4.08 (1, d, J=12, 1/2 C2 --methylene AB), 3.12 ##STR73## 2.12 (3, s, acetyl), and 1.41 (3, s, C2 --CH3). The light orange solution was concentrated in vacuo to a foam which was chromatographed on silica gel (500 g) with methylene chloride Two major bands were eluted obtained in 45% yield (2.56 g) as an off-white foam

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

実験手順: A solution of (1S,3S,5R,6R) 2,2-dimethyl-6-phenoxyacetamidopenam-3-carboxylic acid-1-oxide p-nitrobenzyl ester (25.18 g, 50.0 mmol), acetyl isocyanate (8.50 ml, 9.53 g, 112 mmol), and dioxane (250 ml) was refluxed under nitrogen for 5 hours, cooled and concentrated in vacuo to a yellow foam. The foam was chromatographed on silica gel (1.7 Kg) with methylene chloride: acetone; 9:1; v:v to give four products; the 3-methyl-Δ3 -cephem; starting sulfoxide, the title penam, and the cepham (in order of elution). The penam fractions were concentrated to a colorless foam in 40.2% yield (11.80 g). Re-chromatography of a portion gave an analytical sample: m.p. 83°-85°; nmr 100 MHz (CDCl3) ppm 8.40 ##STR60## 8.20 (2, d, J=8.5, 1/2 aromatic AB pNB), 7.56 (3, d, J=8.5 over m, 1/2 AB, pNB and C6 --NH), 7.5 (2, m) and 6.9 (3, m, O--Ph--H's), 5.7 (2, m's, C5 -C6 --H's), 5.32 (2, br s, pNB methylene), 4.88 (1, s, C3 --H), 4.56 ##STR61## 4.26 and 4.06 (2, d's, J=11.5, AB of C2 --CH2O), 2.22 ##STR62## and 1.47 (3, s, C2 --CH3); nmr 13C 4 carbonyls ca 170 ppm, carbamate carbonyl C 157.0, C2 singlet at 67.4, while C2 --CH2O is t at 72.3, and C2 --CH3 is q at 21.7. cooled concentrated in vacuo to a yellow foam The foam was chromatographed on silica gel (1.7 Kg) with methylene chloride v:v to give four products The penam fractions were concentrated to a colorless foam in 40.2% yield (11.80 g) Re-chromatography of a portion gave an analytical sample

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

実験手順: A solution of (1S,3S,5R,6R) 2,2-dimethyl-6-phenoxyacetamidopenam-3-carboxylic acid-1-oxide p-nitrobenzyl ester (25.18 g, 50.0 mmol), acetyl isocyanate (8.50 ml, 9.53 g, 112 mmol), and dioxane (250 ml) was refluxed under nitrogen for 5 hours, cooled and concentrated in vacuo to a yellow foam. The foam was chromatographed on silica gel (1.7 Kg) with methylene chloride: acetone; 9:1; v:v to give four products; the 3-methyl-Δ3 -cephem; starting sulfoxide, the title penam, and the cepham (in order of elution). The penam fractions were concentrated to a colorless foam in 40.2% yield (11.80 g). Re-chromatography of a portion gave an analytical sample: m.p. 83°-85°; nmr 100 MHz (CDCl3) ppm 8.40 ##STR60## 8.20 (2, d, J=8.5, 1/2 aromatic AB pNB), 7.56 (3, d, J=8.5 over m, 1/2 AB, pNB and C6 --NH), 7.5 (2, m) and 6.9 (3, m, O--Ph--H's), 5.7 (2, m's, C5 -C6 --H's), 5.32 (2, br s, pNB methylene), 4.88 (1, s, C3 --H), 4.56 ##STR61## 4.26 and 4.06 (2, d's, J=11.5, AB of C2 --CH2O), 2.22 ##STR62## and 1.47 (3, s, C2 --CH3); nmr 13C 4 carbonyls ca 170 ppm, carbamate carbonyl C 157.0, C2 singlet at 67.4, while C2 --CH2O is t at 72.3, and C2 --CH3 is q at 21.7. cooled concentrated in vacuo to a yellow foam The foam was chromatographed on silica gel (1.7 Kg) with methylene chloride v:v to give four products The penam fractions were concentrated to a colorless foam in 40.2% yield (11.80 g) Re-chromatography of a portion gave an analytical sample

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

実験手順: A solution of (1S,3S,5R,6R) 2,2-dimethyl-6-phenylacetamidopenam-3-carboxylic acid-1-oxide p-nitrobenzyl ester (4.85 g, 10.0 mmol) and acetyl isocyanate (2.3 ml, 30 mmol) in dioxane (50 ml) was refluxed under nitrogen for 7 hours. The light orange solution was concentrated in vacuo to a foam which was chromatographed on silica gel (500 g) with methylene chloride:acetone; 9:1, v:v. Two major bands were eluted; the first was the Δ3 3-methylcephem (28%, 1.29 g) and the second was the title compound obtained in 45% yield (2.56 g) as an off-white foam: mp 83°-85°; nmr 100 MHz (CDCl3) ppm 8.24 (2, d, J=9 Hz, 1/2 aromatic AB pNB), 7.61 (2, d, J=9, 1/2 pNB AB), 7.28 (5, s, phenyl), 5.54 (2, m's C6 --C5 --H's), 5.40 (2, br s, pNB methylene), 4.91 (1, s, C3 --H), 4.27 1, d, J=12, 1/2 C2 --CHHO AB), 4.08 (1, d, J=12, 1/2 C2 -methylene AB), 3.12 (2, s, ##STR72## 2.12 (3, s, acetyl), and 1.41 (3, s, C2 --CH3). The light orange solution was concentrated in vacuo to a foam which was chromatographed on silica gel (500 g) with methylene chloride Two major bands were eluted obtained in 45% yield (2.56 g) as an off-white foam

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

実験手順: A solution of (1S,3S,5R,6R) 2,2-dimethyl-6-phenoxyacetamidopenam-3-carboxylic acid-1-oxide p-nitrobenzyl ester (25.18 g, 50.0 mmol), acetyl isocyanate (8.50 ml, 9.53 g, 112 mmol), and dioxane (250 ml) was refluxed under nitrogen for 5 hours, cooled and concentrated in vacuo to a yellow foam. The foam was chromatographed on silica gel (1.7 Kg) with methylene chloride:acetone; 9:1; v:v to give four products; the 3-methyl-Δ3 -cephem; starting sulfoxide, the title penam, and the cephem (in order of elution). The penam fractions were concentrated to a colorless foam in 40.2% yield (11.80 g). Re-chromatography of a portion gave an analytical sample: m.p. 83°-85°; nmr 100 MHz (CDCl3) ppm 8.40 (1,s, ##STR59## 8.20 (2, d, J=8.5, 1/2 aromatic AB pNB), 7.56 (3, d, J=8.5 over m, 1/2 AB, pNB and C6 --NH), 7.5 (2, m) and 6.9 (3, m, O--Ph--H's), 5.7 (2, m's, C5 --C6 --H's), 5.32 (2, br s, pNB methylene), 4.88 (1, s, C3 --H), 4.56 (2, s, ##STR60## 4.26 and 4.06 (2, d's,J=11.5, AB of C2 --CH2O), 2.22 (3, s, ##STR61## and 1.47 (3, s, C2 --CH3); nmr 13C 4 carbonyls ca 170 ppm, carbamate carbonyl C 157.0, C2 singlet at 67.4, while C2 --CH2O is t at 72.3, and C2 --CH3 is q at 21.7. cooled concentrated in vacuo to a yellow foam The foam was chromatographed on silica gel (1.7 Kg) with methylene chloride v:v to give four products The penam fractions were concentrated to a colorless foam in 40.2% yield (11.80 g) Re-chromatography of a portion gave an analytical sample

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

実験手順: The title compound (13 mg, 51%) was prepared starting from the product of Example 2 and methylformyl isocyanate using the method described in Example 4; MS(ES) m/e 474 [M+H]+.

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

実験手順: A solution of (1S,3S,5R,6R) 2,2-dimethyl-6-phenylacetamidopenam-3-carboxylic acid-1-oxide p-nitrobenzyl ester (4.85 g, 10.0 mmol) and acetyl isocyanate (2.3 ml, 30 mmol) in dioxane (50 ml) was refluxed under nitrogen for 7 hours. The light orange solution was concentrated in vacuo to a foam which was chromatographed on silica gel (500 g) with methylene chloride:acetone; 9:1, v:v. Two major bands were eluted; the first was the Δ3 3-methylcephem (28%, 1.29 g) and the second was the title compound obtained in 45% yield (2.56 g) as an off-white foam: mp 83°-85°; nmr 100 MHz (CDCl3) ppm 8.24 (2, d, J=9 Hz, 1/2 aromatic AB pNB), 7.61 (2, d, J=9, 1/2 pNB AB), 7.28 (5, s, phenyl), 5.54 (2, m's, C6 --C5 --H's), 5.40 (2, br s, pNB methylene), 4.91 (1, s, C3 --H), 4.27 1, d, J=12, 1/2 C2 --CHHO AB), 4.08 (1, d, J=12, 1/2 C2 --methylene AB), 3.12 ##STR73## 2.12 (3, s, acetyl), and 1.41 (3, s, C2 --CH3). The light orange solution was concentrated in vacuo to a foam which was chromatographed on silica gel (500 g) with methylene chloride Two major bands were eluted obtained in 45% yield (2.56 g) as an off-white foam