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CAS No. : | 13435-12-6 | MDL No. : | MFCD00008671 |
Formula : | C5H13NOSi | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | LWFWUJCJKPUZLV-UHFFFAOYSA-N |
M.W : | 131.25 | Pubchem ID : | 25989 |
Synonyms : |
|
Signal Word: | Danger | Class: | 4.1 |
Precautionary Statements: | P210-P240-P241-P280 | UN#: | 1325 |
Hazard Statements: | H228 | Packing Group: | Ⅲ |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With saccharin at 130℃; for 0.583333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In tetrahydrofuran at -78℃; for 0.666667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In Petroleum ether for 3h; Heating / reflux; | 13 Preparation Example 13: 1 -benzyl-(3-chloro-2-trimethyIsiIyl-propyl)-aminel-Benzylamino-3-chloropropane-2-ol; (42.2 g, 0.21 mol) prepared in Preparation Example 1 was dissolved in petroleum ether (700 mi). N-(trimethylsilyl)acetamide (30.5 g, 0.23 mol) was added thereto, and refluxed with stirring for 3 hours. After removing solid precipitates by filtration, the filtrate was concentrated under a reduced pressure to obtain 54 g (yield: 95 %) of the title compound..H NMR (200 MHz, CDC13): 5 0.51 (s, 9H), 3.08 (m, 2H), 3.78 (s, 2H), 3.80 (m,2H), 7.33 (m,5H). |
In Petroleum ether for 2h; Heating; | ||
In Petroleum ether for 3h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With n-butyllithium; lithium diisopropyl amide In tetrahydrofuran 8 h, 0 deg C, 8 h, 25 deg C; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With n-butyllithium; lithium diisopropyl amide In tetrahydrofuran at 0℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With triethylamine In ligroin; acetonitrile | P.18.b b b 1-(p-Fluorobenzyl)-3-trimethylsilyloxyazetidine STR57 To a solution of 3-chloro-1-(p-fluorobenzylamino)-2-propanol (50.0 g, 0.230 mol) in acetonitrile (200 ml) were added triethylamine (96 ml, 0.69 mol) and N-trimethylsilylacetamide (30.2 g, 0.230 mol) and the mixture was heated under reflux for 20 hours. After the so separated substance was filtered off, the filtrate was distilled off under reduced pressure. After ligroin (500 ml) was added thereto, insolubles were further filtered off. The filtrate was distilled off under reduced pressure to give a yellow oily substance, which was then distilled under reduced pressure (125°-130° C./4-5 mmHg) to give 51.4 g of the title compound as a main fraction as a colorless oily substance. Purity=65%. Reduced yield=33%. This compound was used for the subsequent reaction without purification. 1 H-NMR(CDCl3)δ0.09(s,9H), 2.86(ddd,J=2 Hz,6 Hz,6 Hz,2H), 3.57(s,2H), 3.60(ddd,J=2 Hz,6 Hz,6 Hz,2H), 4.41(quint,J=6 Hz, 1H), 6.99(t,J=9 Hz,2H), 7.22(dd,J=6 Hz,9 Hz,2H) |
With triethylamine acetonitrile, refux, 3 days; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium In N,N,N,N,N,N-hexamethylphosphoric triamide at 40 - 50℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In N,N-dimethyl-formamide at 50℃; for 72h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In N,N-dimethyl-formamide at 50℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In N,N-dimethyl-formamide at 50℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With thianthrene-5-oxide; trifluoromethylsulfonic anhydride; N,N-diethylaniline In dichloromethane; chloroform at 23℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With thianthrene-5-oxide; trifluoromethylsulfonic anhydride; N,N-diethylaniline In dichloromethane; chloroform at 23℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Stage #1: 3,4,6-tri-O-benzyl-D-glucal; N-Trimethylsilylacetamide With thianthrene-5-oxide; trifluoromethylsulfonic anhydride; N,N-diethylaniline In dichloromethane; chloroform at 23℃; for 2h; Stage #2: benzyl alcohol With Amberlyst-15 acidic resin In dichloromethane; chloroform | |
69% | Stage #1: 3,4,6-tri-O-benzyl-D-glucal With thianthrene-5-oxide; trifluoromethanesulfonic acid anhydride In dichloromethane; chloroform at -78℃; Stage #2: N-Trimethylsilylacetamide With N,N-diethylaniline In dichloromethane; chloroform at 23℃; Stage #3: benzyl alcohol With Amberlyst-15 acidic resin In dichloromethane; chloroform for 30h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: 3-O-benzyl-4,6-O-isopropylidene-D-arabino-hex-1-enitol; N-Trimethylsilylacetamide With thianthrene-5-oxide; trifluoromethylsulfonic anhydride; N,N-diethylaniline In dichloromethane; chloroform at 23℃; for 2h; Stage #2: benzyl alcohol With Amberlyst-15 acidic resin In dichloromethane; chloroform |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage #1: 3,4,6-tri-O-benzyl-D-glucal; N-Trimethylsilylacetamide With thianthrene-5-oxide; trifluoromethylsulfonic anhydride; N,N-diethylaniline In dichloromethane; chloroform at 23℃; for 2h; Stage #2: isopropyl alcohol With Amberlyst-15 acidic resin In dichloromethane; chloroform | |
73% | Stage #1: 3,4,6-tri-O-benzyl-D-glucal With thianthrene-5-oxide; trifluoromethanesulfonic acid anhydride In dichloromethane; chloroform at -78℃; Stage #2: N-Trimethylsilylacetamide With N,N-diethylaniline In dichloromethane; chloroform at -78 - 23℃; Stage #3: isopropyl alcohol With Amberlyst-15 acidic resin In dichloromethane; chloroform for 30h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Stage #1: 3-O-benzyl-4,6-O-isopropylidene-D-arabino-hex-1-enitol; N-Trimethylsilylacetamide With thianthrene-5-oxide; trifluoromethylsulfonic anhydride; N,N-diethylaniline In dichloromethane; chloroform at 23℃; for 2h; Stage #2: Cholestanol With Amberlyst-15 acidic resin In dichloromethane; chloroform |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Stage #1: N-Trimethylsilylacetamide; 6-O-allyl-3,4-di-O-benzyl-α-D-glucal With thianthrene-5-oxide; trifluoromethylsulfonic anhydride; N,N-diethylaniline In dichloromethane; chloroform at 23℃; for 2h; Stage #2: methyl 2,3,4-tri-O-benzyl-D-glucopyranoside With Amberlyst-15 acidic resin In dichloromethane; chloroform | |
55% | Stage #1: 6-O-allyl-3,4-di-O-benzyl-α-D-glucal With thianthrene-5-oxide; trifluoromethanesulfonic acid anhydride In dichloromethane; chloroform at -78℃; Stage #2: N-Trimethylsilylacetamide With N,N-diethylaniline In dichloromethane; chloroform at 23℃; Stage #3: methyl 2,3,4-tri-O-benzyl-D-glucopyranoside With Amberlyst-15 acidic resin In dichloromethane; chloroform for 30h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Stage #1: 3,4,6-tri-O-benzyl-D-glucal With thianthrene-5-oxide; trifluoromethanesulfonic acid anhydride In dichloromethane; chloroform at -78℃; Stage #2: N-Trimethylsilylacetamide With N,N-diethylaniline In dichloromethane; chloroform at 23℃; for 0.666667h; Stage #3: methyl 2,3,4-tri-O-benzyl-D-glucopyranoside With camphor-10-sulfonic acid In dichloromethane; chloroform for 40h; Further stages.; | |
60% | Stage #1: 3,4,6-tri-O-benzyl-D-glucal; N-Trimethylsilylacetamide With thianthrene-5-oxide; trifluoromethylsulfonic anhydride; N,N-diethylaniline In dichloromethane; chloroform at 23℃; for 2h; Stage #2: methyl 2,3,4-tri-O-benzyl-D-glucopyranoside With Amberlyst-15 acidic resin In dichloromethane; chloroform |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 3,4,6-tri-O-benzyl-D-glucal; N-Trimethylsilylacetamide With thianthrene-5-oxide; trifluoromethylsulfonic anhydride; N,N-diethylaniline In dichloromethane; chloroform at 23℃; for 2h; Stage #2: Cholestanol With Amberlyst-15 acidic resin In dichloromethane; chloroform at 23℃; for 17h; | |
70% | Stage #1: 3,4,6-tri-O-benzyl-D-glucal With thianthrene-5-oxide; trifluoromethanesulfonic acid anhydride In dichloromethane; chloroform at -78℃; Stage #2: N-Trimethylsilylacetamide With N,N-diethylaniline In dichloromethane; chloroform at 23℃; Stage #3: Cholestanol With Amberlyst-15 acidic resin In dichloromethane; chloroform for 30h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With triethylamine In diethyl ether at 15℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-O-acetyl-2,3-O-isopropylidene-L-rhamnopyranose With 2,4,6-tri-tertbutylpyridine; dimethylsulfide; trifluoromethylsulfonic anhydride In dichloromethane at -45 - 23℃; for 1.5h; Stage #2: N-Trimethylsilylacetamide In dichloromethane at 23℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: 3,4,6-tri-O-benzyl-D-glucal; trifluoromethylsulfonic anhydride; 1,1'-sulfinylbisbenzene In dichloromethane; chloroform at -78℃; Stage #2: N-Trimethylsilylacetamide With N-ethyl-N,N-diisopropylamine In dichloromethane; chloroform at -78 - 23℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: 3,4,6-tri-O-benzyl-D-glucal With thianthrene-5-oxide; trifluoromethanesulfonic acid anhydride In dichloromethane; chloroform at -78℃; for 0.2h; Stage #2: N-Trimethylsilylacetamide With N,N-diethylaniline In dichloromethane; chloroform for 0.666667h; Stage #3: benzyl 2,3-O-cyclohexylidene-α-L-rhamnopyranoside With camphor-10-sulfonic acid In dichloromethane; chloroform for 40h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 71% 2: 6% | Stage #1: 3,4,6-tri-O-benzyl-D-glucal With thianthrene-5-oxide; trifluoromethanesulfonic acid anhydride In dichloromethane; chloroform at -78℃; for 0.2h; Stage #2: N-Trimethylsilylacetamide With N,N-diethylaniline In dichloromethane; chloroform at 23℃; for 1h; Stage #3: With sodium azide; copper(II) bis(trifluoromethanesulfonate) In N,N-dimethyl-formamide for 48h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | Stage #1: 3,4,6-tri-O-benzyl-D-galactal With thianthrene-5-oxide; trifluoromethylsulfonic anhydride In dichloromethane; chloroform at -78℃; Stage #2: N-Trimethylsilylacetamide With N,N-diethylaniline In dichloromethane; chloroform at 23℃; Stage #3: Cholestanol With Amberlyst-15 acidic resin In dichloromethane; chloroform for 30h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage #1: 3,4-di-O-benzyl-6-O-dimethylpropanoyl-D-glucal With thianthrene-5-oxide; trifluoromethanesulfonic acid anhydride In dichloromethane; chloroform at -78℃; for 0.183333h; Stage #2: N-Trimethylsilylacetamide With N,N-diethylaniline In dichloromethane; chloroform at 23℃; for 0.5h; Stage #3: Cholestanol With Amberlyst-15 acidic resin In dichloromethane; chloroform for 30h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Stage #1: 3,4,6-tri-O-benzyl-D-galactal With thianthrene-5-oxide; trifluoromethanesulfonic acid anhydride In dichloromethane; chloroform at -78℃; Stage #2: N-Trimethylsilylacetamide With N,N-diethylaniline In dichloromethane; chloroform at 23℃; Stage #3: With sodium azide; copper(II) bis(trifluoromethanesulfonate) In N,N-dimethyl-formamide for 48h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: 3-O-benzyl-4,6-di-O-tert-butylsilylidene-D-glucal With thianthrene-5-oxide; trifluoromethanesulfonic acid anhydride In dichloromethane; chloroform at -78℃; Stage #2: N-Trimethylsilylacetamide With N,N-diethylaniline In dichloromethane; chloroform at 23℃; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Stage #1: 3,4,6-tri-O-benzyl-D-glucal With 2,4,6-tri-tertbutylpyridine; 2,8-dimethyldibenzo[b,d]thiophene 5-oxide; trifluoromethanesulfonic acid anhydride In dichloromethane at -78℃; for 1h; Stage #2: N-Trimethylsilylacetamide With N,N-diethylaniline In dichloromethane at -78℃; Stage #3: With sodium azide; camphor-10-sulfonic acid; copper(II) bis(trifluoromethanesulfonate) In dichloromethane at 23℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | Stage #1: 6-O-allyl-3,4-di-O-benzyl-α-D-glucal With 2,4,6-tri-tertbutylpyridine; 2,8-dimethyldibenzo[b,d]thiophene 5-oxide; trifluoromethanesulfonic acid anhydride In dichloromethane at -78℃; for 1h; Stage #2: N-Trimethylsilylacetamide With N,N-diethylaniline In dichloromethane at -78℃; Stage #3: cholestanol With camphor-10-sulfonic acid In dichloromethane at 23℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Stage #1: 3,4,6-tri-O-benzyl-D-glucal With 2,4,6-tri-tertbutylpyridine; 2,8-dimethyldibenzo[b,d]thiophene 5-oxide; trifluoromethanesulfonic acid anhydride In dichloromethane at -78℃; for 1h; Stage #2: N-Trimethylsilylacetamide With N,N-diethylaniline In dichloromethane at -78℃; Stage #3: benzyl alcohol With camphor-10-sulfonic acid In dichloromethane at 23℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | Stage #1: Benzoic acid (2R,3S,4R)-3,4-bis-benzyloxy-3,4-dihydro-2H-pyran-2-ylmethyl ester With 2,4,6-tri-tertbutylpyridine; 2,8-dimethyldibenzo[b,d]thiophene 5-oxide; trifluoromethanesulfonic acid anhydride In dichloromethane at -78℃; for 1h; Stage #2: N-Trimethylsilylacetamide With N,N-diethylaniline In dichloromethane at -78℃; Stage #3: With sodium azide; camphor-10-sulfonic acid; copper(II) bis(trifluoromethanesulfonate) In dichloromethane at 23℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 1,8-Dimethoxy-3-methoxycarbonylmethyl-naphthalene-2-carboxylic acid methyl ester With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.333333h; Stage #2: N-Trimethylsilylacetamide With n-butyllithium In tetrahydrofuran; hexane at 0 - 20℃; for 14h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.77 g | With trimethylsilyl trifluoromethanesulfonate In toluene at 80℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 42% 2: 17% 3: 15% | Stage #1: 3,4,6-tri-O-benzyl-D-glucal; trifluoromethylsulfonic anhydride; 1,1'-sulfinylbisbenzene In dichloromethane; chloroform at -78℃; Stage #2: N-Trimethylsilylacetamide With N-ethyl-N,N-diisopropylamine In dichloromethane; chloroform at -78 - 23℃; Stage #3: isopropyl alcohol With Amberlyst-15 acidic resin In dichloromethane; chloroform Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3,4,6-tri-O-benzyl-D-glucal With thianthrene-5-oxide; trifluoromethanesulfonic acid anhydride In dichloromethane; chloroform at -78℃; Stage #2: N-Trimethylsilylacetamide With N,N-diethylaniline In dichloromethane; chloroform at -78 - 23℃; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 3,4-di-O-benzyl-6-O-dimethylpropanoyl-D-glucal With thianthrene-5-oxide; trifluoromethanesulfonic acid anhydride In dichloromethane; chloroform at -78℃; for 0.2h; Stage #2: N-Trimethylsilylacetamide With N,N-diethylaniline In dichloromethane; chloroform at 23℃; Stage #3: With sodium azide; copper(II) bis(trifluoromethanesulfonate) In N,N-dimethyl-formamide for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.3% | at 175℃; 30-theoretical-plates distillation column of Old-ershaw type; | |
198.6 g | at 150 - 180℃; 20-theoretical-plates distillation column of Old-ershaw type; | |
118.9 g | at 100 - 121℃; 30-theoretical-plates distillation column of Old-ershaw type; |
154.2 g | at 130 - 162℃; 20-theoretical-plates distillation column of Old-ershaw type; | |
at 175℃; 20-theoretical-plates distillation column of Old-ershaw type; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21.9% | With sodium chloride; N-ethyl-N,N-diisopropylamine In methoxyoxalyl chloride; water; ethyl acetate; N,N-dimethyl-formamide; acetonitrile | 25 EXAMPLE 25 EXAMPLE 25 To a mixture of N-[(3R)-1-{3-(1-tert-butoxycarbonyl-4piperidyl)-propionyl}-3-piperidylcarbonyl]-2(S)-amino-β-alanine (200 mg) and N-trimethylsilylacetamide (595 mg) in N,N-dimethylformamide (2 mL) was added in turn with methoxyoxalyl chloride (81 μL) and diisopropylethylamine (76.6 μL) under nitrogenatmosphere at 5° C., and the mire was stirred overnight. The reaction mixture was partitioned between diethyl ether and an aqueous sodium hydrogencarbonate solution. The separated aqueous layer was acidified with 20% aqueous potassium hydrogensulfate solution, added saturated sodium chloride in water and extracted with a mixture of tetrahydrofluran and ethyl acetate. The separated organic layer was washed three times with brine and dried over sodium sulfate. The organic layer was evaporated and the residue was treated with 4 N-HCl in ethyl acetate. The resulting insoluble material was collected by filtration, dried and dissolved in water. Thus obtained solution was neutralized with an aqueous saturated sodium hydrogencarbonate solution, purified by ODS column chromatography (Daisogel-120sp) eluding with 2, 4, 6 and 8 and 10% CH3CN/H2O and lyophilized to give N-[(3R)-1-{3-(4-piperidyl)-propionyl}-3-piperidylcarbonyl]-2(S)-methoxyoxalylamino-β-alanine as an amorphous powder (42.6 mg, 21.9%). IR (KBr) 3430, 1751, 1693, 1612, 1552, 1533 cm-1; 1H-NMR (D2O, δ): 1.30-2.10 (11H, m), 2.30-2.60 (3H, m), 2.80-3.10 (3H, m), 3.15-4.00 (6H, m), 3.93 (3H, s), 4.10-4.50 (2H, m); (+)-APCI/MS (m/z): 441 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42.4% | In tetrahydrofuran; dichloromethane; water; ethyl acetate; N-ethyl-N,N-diisopropylamine; N,N-dimethyl-formamide; acetonitrile; | EXAMPLE 23 To a solution of 2-(4-methoxyphenyl)propionic acid (159 mg) and N,N-dimethylformaniide (68.1 muL) in dichloromethane (5 mL) was added oxalyl chrolide (76.8 muL) under nitrogen atmosphere at 5 C. and the mixture was stirred for 30 minutes. To a stirred mixture of N-[(3R)-1-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-amino-beta-alanine (400 mg) and N-trimethylsilylacetamide (1.16 g) in N,N-dimethylformamide (8 mL) was added the resulting solution in the previous paragraph and diisopropylethylamine (153 muL) under nitrogen atmosphere at 5 C., and the mixture was then stirred overnight. The reaction mixture was partitioned between diethyl ether and an aqueous sodium hydrogencarbonate solution. The separated aqueous layer was acidified with 20% aqueous potassium hydrogensulfate solution, added with an aqueous saturated sodium chloride solution and extracted with a mixture of tetrahydrofuran and ethyl acetate. The separated organic layer was washed three times with brine and dried over sodium sulfate. The organic layer was evaporated and the residue was purified by a silica-gel column chromatography (Wakogel C-200) eluding with CHCl3-MeOH 100:1, 50:1, 40:1, 30:1 and 20:1. The obtained product was dissolved in ethyl acetate (4 mL) and the solution was added 4 N-HCl in ethyl acetate (820 muL) under nitrogen atmosphere at 5 C. The reaction mixture was allowed to warm to ambient temperature and stirred for 5 hours. The resulting insoluble material was collected by filtration, dried and dissolved in water. The solution was neutralized with an aqueous saturated sodium hydrogencarbonate solution, purified by ODS column chromatography (Daisogel-120sp) eluding with 5, 10, 15 and 20% CH3CN/H2O and lyophilized to give N-[(3R)-1-{3-(4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-(2-(4-methoxyphenyl)propionyl)amino-beta-alanine (169 mg, 42.4%) as an amorphous powder. IR (KBr) 3410, 1635, 1612, 1552, 1514 cm-1; 1H-NMR (D2O, delta): 1.20-2.10 (11H, m), 2.15-2.65 (5H, m), 2.70-3.65 (10H, m), 3.81 (3H, s), 3.80-3.95 (1H, m), 4.10-4.45 (2H, m), 6.81 (2H, dd, J=8.7, 2.4 Hz), 7.24 (2H, d, J=8.1 Hz); (+)-APCI/MS (m/z): 517 (M++1); Anal. Calcd for C27H40N4O6.1.2H2O: C, 60.25; H, 7.94; N, 10.41. Found: C, 60.11; H, 8.24; N, 10.36. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.6% | In water; ethyl acetate; acetonitrile | 35 EXAMPLE 35 EXAMPLE 35 To a stirred solution of N-[(3R)-1-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-(2-aminoacetyl)amino-β-alanine (600 mg) and N-trimethylsilylacetoamide (770 mg) in acetonitrile (10 mL) was added terephtalic acid monomethyl ester chloride (233 mg) at 4° C. After stirring for 3 hours, the reaction mixture was acidified with 5% aqueous potassium hydrogensulfate solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The organic layer was evaporated and the residue was treated with 4 N-HCl in ethyl acetate. The resulting insoluble material was collected by filtration, dried and dissolved in water. The solution was neutralized with an aqueous saturated sodium hydrogencarbonate solution, purified by ODS column chromatography (Daisogel-120sp) eluding with 5, 10, 15 and 20% CH3CN/H2O and lyophilized to give N-[(3R)-1-{3-(4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-(2-((4-methoxycarbonylbenzoyl)amino)acetyl)amino-β-alanine (500.5 mg, 74.6%) as an amorphous powder. IR (KBr) 3555-3280, 1720, 1655, 1639, 1625, 1552, 1500 cm-1; 1H-NMR (D2O, δ): 1.20-2.05 (11H, m), 2.20-2.50 (3H, m), 2.50-2.70 (3H, m), 2.85-3.10 (3H, m), 3.35-3.55 (3H, m), 3.60-3.85 (2H, m), 3.97 (3H, s), 4.05-4.25 (1H, m), 4.16 (2H, s), 4.35-4.45 (1H, m), 7.97 (2H, d, J=8.2 Hz), 8.10-8.20 (2H, m); (+)-APCI/MS (m/z): 547 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In methanol; dimethyl sulfoxide | Preparation of 1(R)-(3-Chloro-phenyl)-2-[1,1-dimethyl-2-(4-nitro-phenyl)-ethylamino]-ethanol (I-1a); Preparation of 1(R)-(3-Chloro-phenyl)-2-[1,1-dimethyl-2-(4-nitro-phenyl)-ethylamino]-ethanol (I-1a); A solution of 2.2 g of 2-amino-2-methyl-1-(4-nitrophenyl)propane (prepared by the procedures described in J. Milecki, et al. J. Med. Chem., 30, 1563 (1987)) and N-trimethylsilylacetamide (1.6 g) in 2.2 mL DMSO was stirred for 30 min, then (R)-3-chlorostyrene oxide (1.8 g) was added and the resulting solution was stirred at 95° C. for 22 h. The reaction solution was allowed to cool, poured over a mixture of ice (30 g) and 6 N aqueous hydrochloric acid (10 mL). A small portion of MeOH was added to produce a homogenous solution, which was stirred for 30 min. The resulting solution was basified with saturated aqueous sodium carbonate, extracted with ethyl acetate, the organic phase dried (Na2SO4) and concentrated in vacuo to afford 4.3 g of the title compound (I-1a) as an orange oil. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium bicarbonate; trichlorophosphate In tetrahydrofuran; water; ethyl acetate; N,N-dimethyl-formamide | 52 EXAMPLE 52 EXAMPLE 52 Phosphorus oxychloride (473 μl) was added dropwise to a mixture of N,N-dimethylformamide (388 μl) and ethyl acetate (1 ml) under ice-cooling. After being stirred for 10 minutes at the same temperature, the mixture was cooled until a precipitate appeared. To the suspension was added tetrahydrofuran (17 ml). The suspension was stirred at the same temperature for 30 minutes. To the suspension was added 2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)acetic acid (1.0 g). The mixture was stirred at the same temperature for 30 minutes to give an activated acid solution. On the other hand, to a suspension of 7β-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thio-3-cephem-4-carboxylic acid (1.16 g) in tetrahydrofuran (17 ml) was added N-trimethylsilylacetamide (3.7 g). The suspension was stirred at 20-40° C. for 40 minutes to give a clear solution. To the solution was added the activated acid solution prepared above at -20° C. The mixture was stirred at -20~5° C. for 40 minutes. The reaction mixture was added to a mixture of ethyl acetate (100 ml), sodium hydrogen carbonate (1.59 g) and water (100 ml). To the separated aqueous solution was added ethyl acetate (100 ml). The mixture was adjusted to pH 2 with 1N-hydrochloric acid. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether to give 7β-[2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thio-3-cephem-4-carboxylic acid (1.17 g). NMR (DMSO-d6, δ): 1.50 (9H, s), 2.72 (3H, s), 3.54 and 3.86 (2H, ABq, J=17 Hz), 3.70 and 3.79 (2H, ABq, J=15 Hz), 5.24 (1H, d, J=5 Hz), 5.80 (1H, dd, J=5 and 8 Hz), 9.22 (1H, d, J=8 Hz), 12.29 (1H, br s). |
Yield | Reaction Conditions | Operation in experiment |
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With sodium chloride In tetrahydrofuran; water; ethyl acetate | 97 EXAMPLE 97 EXAMPLE 97 To a solution of benzhydryl 7β-amino-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (500 mg) in tetrahydrofuran (12.5 ml) was added N-trimethylsilylacetamide (550 mg), and stirred at room temperature for 20 minutes. To the solution was added dropwise a solution of phenyl acetyl chloride (146 μl) above at -20° C. for 2 minutes. The mixture was stirred at -20~-15° C. for 50 minutes. To the reaction mixture were added water (50 ml), ethyl acetate (50 ml) and tetrahydrofuran (15 ml). The organic layer was separated, washed with water and saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate to give benzhydryl 7β-(2-phenylacetamido)-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (532 mg). NMR (DMSO-d6, δ): 3.50 and 3.59 (2H, ABq, J=14 Hz), 3.82 and 4.10 (2H, ABq, J=18 Hz), 5.21 (1H, d, J=5 Hz), 5.78 (1H, dd, J=5 and 8 Hz), 6.76 (1H, d, J=11 Hz), 6.81 (1H, d, J=11 Hz), 6.94 (1H, s), 7.2-7.5 (16H, m), 7.7-7.8 (1H, m), 8.4-8.5 (1H, m), 8.59 (1H, m), 9.22 (1H, d, J=8 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium chloride In tetrahydrofuran; water; ethyl acetate | 98 EXAMPLE 98 EXAMPLE 98 To a solution of benzhydryl 7β-amino-3-[(E)-2-(4-pyrazolyl)vinylthio]-3-cephem-4-carboxylate (515 mg) in tetrahydrofuran (12.5 ml) was added N-trimethylsilylacetamide (550 mg), and stirred at room temperature for 15 minutes. To the solution was added dropwise a solution of phenylacetyl chloride (146 μl) above at -20° C. for 2 minutes. The mixture was stirred at -20~-15° C. for 1 hour. To the reaction mixture were added water (100 ml) and ethyl acetate (100 ml). The organic layer was separated, washed with buffer solution (pH 7) and saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was subjected to column chromatography on silica gel (eluent: dichloromethane:ethyl acetate=9:1) to give benzhydryl 7β-(2-phenylacetamido)-3-[(E)-2-(1-benzylcarbonylpyrazol-4-yl)vinylthio]-3-cephem-4-carboxylate (93.4 mg). NMR (DMSO-d6, δ): 3.51 and 3.60 (2H, ABq, J=14 Hz), 3.80 and 3.99 (2H, ABq, J=18 Hz), 4.45 (2H, s), 5.21 (1H, d, J=5 Hz), 5.72 (1H, dd, J=5 and 8 Hz), 6.74 (1H, d, J=15 Hz), 6.90 (1H, s), 7.18 (1H, d, J=15 Hz), 7.2-7.6 (15H, m), 8.20 (1H, s), 8.55 (1H, s), 9.19 (1H, d, J=8 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With hydrogenchloride; aq. sodium hydroxide | 3.B B. B. (2S)-1-[[1-(3,4-Dimethoxyphenyl)-2-phenylethyl]-amino]-3-(4-fluorophenoxy)-2-propanol, trifluoroacetate (1:1) salt To 1-(3,4-dimethoxyphenyl)-2-phenylethylamine (m.w. 257,500 mg, 1.9 mmol, 1.9 equiv.) at room temperature under argon was added N-(trimethylsilyl)acetamide (m.w. 131, 275 mg, 2.1 mmol, 2.1 equiv.). The mixture was stirred as a melt at 60° C. for two hours. To the mixture was then added the title A compound (m.w. 168, 168 mg, 1.0 mmol). The resulting solution was heated for three days at 100° C. The mixture was cooled to room temperature and diluted with ethyl acetate (~10 mL). About 10 mL of chipped ice and 4 mL conc. hydrochloric acid were added. This mixture was stirred for four hours, allowing the ice to melt. The mixture was basified to pH 12 by addition of 1M aq. sodium hydroxide. The ethyl acetate layer was removed, and the aqueous layer was then extracted four times with methylene chloride (100 mL). The various organic extracts were combined, dried over sodium sulfate, and then concentrated to a thick oil, which was purified by silica gel chromatography eluding with 5% (10% conc. aq. ammonium hydroxide/methanol)/methylene chloride. The chromatographed product was dissolved in ether (~30 mL) and then trifiuoroacetic acid (m.w. 114, d 1.5, 0.230 mL, 0.34 g, 3.0 mmol, 3.0 equiv.) was added. The solution was then coevaporated several times with toluene, then with methylene chloride, and finally with ether. This produced 340 mg of the title compound as a white powder (63% yield). MS: (M+H)+ at 426. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34 mg (11%) | With hydrogenchloride In dimethyl sulfoxide | 11.E 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-3H-benzofuran-2,2-dicarboxylic acid diethyl ester E. 5-{2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-3H-benzofuran-2,2-dicarboxylic acid diethyl ester (11e): A solution of 205 mg (0.0.64 mmol) of 5-(2-amino-propyl)-3H-benzofuran-2,2-dicarboxylic acid diethyl ester in 1.1 mL of anhydrous DMSO was treated with 109 mg (0.832 mmol) of N-(trimethylsilyl)acetamide, and the mixture was stirred for about 0.5 hour. (R)-3-Chlorostyrene oxide (108 mg, 0.704 mmol) was then added with stirring to produce a yellow solution which was heated to about 60° C. for about 48 hours, then cooled and stirred at room temperature for about 64 hours. The reaction mixture then was poured into 3 mL of cold 1N HCl, stirred for about 0.5 hour, adjusted to pH 11 with cold 6N NaOH, and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (Na2 SO4), and concentrated to 55 mg (18%) of the crude product as a beige oil. This was chromatographed on silica gel (5:95 methanol-CHCl3) to give 34 mg (11%) of 11e. 1 H NMR (CDCl3): d=7.30 (s, 1H); 7.14-7.2 (m, 3H); 6.76-6.96 (m, 3H); 6.52-6.56 (br, 1 H); 4.50-4.56 (m, 1H); 4.24-4.30 (m, 4H); 3.73 (s, 2H); 2.82-2.88 (m, 2H); 2.54-2.65 (m, 4H); 1.28 (t, 6H); 1.02 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With magnesium sulfate In tetrahydrofuran; dichloromethane; ethyl acetate | p-Methoxybenzyl 7β-[2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetamido]-3-[(Z)-3-chloro-1-propen-1-yl]-3-cephem-4-carboxylate STR199 p-Methoxybenzyl 7β-[2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-2-fluoromethoxyiminoacetamido]-3-[(Z)-3-chloro-1-propen-1-yl]-3-cephem-4-carboxylate STR199 To a mixture of ethyl acetate (37 ml), tetrahydrofuran (5 ml), and dichloromethane (15.7 ml) were added N-(trimethylsilyl)acetamide (8.17 g) and p-methoxybenzyl 7β-amino-3-[(Z)-3-chloro-1-propen-1-yl]-3-cephem-4-carboxylate hydrochloride (3.33 g) to dissolve the latter materials. The solution was cooled to -20° C., then the compound of Experiment 11 (3.80 g) was added thereto, and agitated at 10° C. for 1 hour. After the addition of ethyl acetate (500 ml) to the reaction solution, the mixture was washed successively with water, a saturated aqueous sodium bicarbonate solution, 1N hydrochloric acid, and a saturated brine solution, and then anhydrous magnesium sulfate was added thereto to dry the same. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain the objective product (4.33 g). The infrared absorption spectrum and the NMR spectrum of the resultant product coincided with those of Experiment 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trichlorophosphate In tetrahydrofuran; <i>N</i>-methyl-acetamide; ethyl acetate | p-Methoxybenzyl 7β-[2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-2-cyanomethoxyiminoacetamido]-3-[(Z)-3-chloro-1-propen-1-yl]-3-cephem-4-carboxylate STR175 p-Methoxybenzyl 7β-[2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-2-cyanomethoxyiminoacetamido]-3-[(Z)-3-chloro-1-propen-1-yl]-3-cephem-4-carboxylate STR175 1.51 ml of dimethylformamide and 18 ml of tetrahydrofuran were cooled to -10° C. and 1.81 ml of phosphoryl chloride was added thereto. The resulting mixture was stirred for 40 minutes under ice-cooling. Then a solution of 7.64 g of the compound of Experiment 8 in 24 ml of tetrahydrofuran was added thereto and the resulting mixture was stirred at the same temperature for additional one hour. A solution comprising 6.00 g of p-methoxybenzyl 7β-amino-3-[(Z)-3-chloro-1-propen-1-yl]-3-cephem-4-carboxylate hydrochloride, 12.8 g of N-trimethylsilylacetamide and 60 ml of ethyl acetate was cooled to -25° C. Then the above-mentioned reaction mixture was added thereto and the resulting mixture was stirred for 40 minutes while raising the temperature to 0° C. This reaction mixture was extracted with ethyl acetate and the organic layer was washed with a saturated brine solution and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified with silica gel column chromatography. Thus 7.80 g of the objective compound was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trichlorophosphate In tetrahydrofuran; <i>N</i>-methyl-acetamide; ethyl acetate | p-methoxybenzyl 7β-[2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-2-(2,2,2-trifluoroethyl)oxyiminoacetamido]-3-[(Z)-3-chloro-1-propen-1-yl]3-cephem-4-carboxylate STR146 p-methoxybenzyl 7β-[2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-2-(2,2,2-trifluoroethyl)oxyiminoacetamido]-3-[(Z)-3-chloro-1-propen-1-yl]3-cephem-4-carboxylate STR146 A mixture solution comprising dimethylformamide (0.247 ml) and tetrahydrofuran (3 ml) was cooled to -10° C., and phosphorus oxychloride (0.297 ml) was added thereto and stirred for 40 minutes with ice-cooling. To the resulting solution was added the tetrahydrofuran solution (4 ml) of 2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-2-(2,2,2-trifluoroethyl)oxyiminoacetic acid (1.36 g), followed by stirring for further one hour at the said temperature. The resulting reaction solution was added to a mixture solution comprising p-methoxybenzyl 7β-amino-3-[(Z)-3-chloro-1-propen-1-yl]-3-cephem-4-carboxylate hydrochloride (1.145 g), N-(trimethylsilyl)acetamide (2.09 g) and ethyl acetate (10 ml), with cooling at -20° C., followed by elevating the temperature up to 0° C. with stirring for one hour. After ethyl acetate was added to the reaction solution, this was washed with water and dried with anhydrous sodium sulfate. The solvent was evaporated out and the residue was purified by silicagel column chromatography to obtain the desired product (1.43 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In tetrahydrofuran; water | 15 EXAMPLE 15 EXAMPLE 15 To 25 ml. of dry THF were added 252 mg. (0.5 mmole) of 7-(α-amino)phenylacetamido-3-(4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazin-3-ylthio)methyl-3-cephem-4-carboxylic acid and 650 mg (5 mmole) of N-trimethylsilylacetamide. The mixture was stirred for about 3 hours after which time solution occurred. The solution then was cooled to 0° C., and 76 mg. (0.5 mmole) of N,N'-dimethyl-N-(chloroformyl)urea were added. The resulting mixture was stirred for one hour at room temperature, and the mixture was evaporated in vacuo to an oil. Water (20 ml.) was added to the oil, and the pH of the resulting mixture was raised to 8.0 by addition of aqueous sodium bicarbonate. The resulting mixture was washed with ethyl acetate, and the pH of the aqueous layer was lowered to 2.0 by addition of 1 N hydrochloric acid. The resulting precipitate was filtered and dried to obtain 118 mg. of 7-α-[3-(N-methylcarbonylamino)-3-methyl-1-ureido]phenylacetamido-3-(4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazin-3-ylthio)methyl-3-cephem-4-carboxylic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | In N-Bromosuccinimide; dichloromethane | 56 EXAMPLE 56 EXAMPLE 56 208 mg of N-trimethylsilylacetamide (1.59 mmoles) were added to a suspension of 383 mg (1.14 mmoles) of 7-benzamido-3-methyl-3-cephem-4-carboxylic acid-1-oxide in 25 ml of dichloromethane, and after stirring for 11/2 hours at room temperature, a clear solution was obtained, which was diluted with dichloromethane to 50 ml. 200 mg of amidosulfonic acid (1.04 mmoles) were added thereto and the mixture was cooled in an ice-bath. Bromination was carried out in half an hour using 310 mg (1.74 mmoles) of N-bromosuccinimide as the brominating agent to obtain a 48% yield of trimethylsilyl 7-benzamido-3-bromomethyl-3-cephem-4-carboxylate-1-oxide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | In N-Bromosuccinimide; dichloromethane | 25 EXAMPLE 25 EXAMPLE 25 To a refluxing suspension of 329 mg (0.95 mmole) of 3-methyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide in 25 ml of dichloromethane, 298 mg (2.27 mmoles) of N-trimethylsilylacetamide were added and a clear, colorless solution was obtained after 15 minutes. Refluxing was continued for another 30 minutes after which 300 mg (3.06 mmoles) of amidosulfonic acid were added. The mixture was diluted with dichloromethane to 40 ml and cooled in an ice-bath. Bromination was carried out in one hour using 280 mg (1.57 mmoles) of N-bromosuccinimide as the brominating agent to obtain a yield of 50% of trimethylsilyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | In N-Bromosuccinimide; dichloromethane | 24 EXAMPLE 24 EXAMPLE 24 342 mg (0.98 mmole) of 3-methyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide were suspended in 25 ml of dichloromethane and the mixture was heated to refluxed 157 mg of N-trimethylsilylacetamide (1.20 mmoles) were added thereto and refluxing was continued for 3/4 hour. To the clear, colorless solution obtained, 50 mg of amidosulfonic acid (0.51 mmoles) were added and the mixture was diluted to 40 ml with dichloromethane. The ice-cooled solution was brominated in half an hour using 280 mg (1.57 mmoles) of N-bromosuccinimide as the brominating agent to obtain a yield of 49% of trimethylsilyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trichlorophosphate In tetrahydrofuran; <i>N</i>-methyl-acetamide; water; ethyl acetate | 2 EXAMPLE 2 EXAMPLE 2 Vilsmeier reagent was prepared from phosphorus oxychloride (2.0 g) and dimethylformamide (0.95 g) in ethyl acetate (3.8 ml) in usual manner. 2-(5-chloro-2-formamidothiazol-4-yl)-2-t-butoxycarbonylmethoxyiminoacetic acid (syn isomer) (4.0 g) was added to the stirred suspension of Vilsmeier reagent in tetrahydrofuran (50 ml) under ice cooling and stirred for 20 minutes at same temperature to produce an activated solution. N-(trimethylsilyl)acetamide (9.2 g) was added to the stirred suspension of p-nitrobenzyl-7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride (4.1 g) in tetrahydrofuran (80 ml) and stirred for 20 minutes at 35° C. to 40° C. To the solution was added the above activated solution at -10° C. and stirred at same temperature for 30 minutes. Water and ethyl acetate were added to the reaction mixture. The separated organic layer was washed with saturated aqueous sodium bicarbonate, aqueous sodium chloride and dried over magnesium sulfate. The solvent was evaporated to give p-nitrobenzyl 7-[2-(5-chloro-2-formamidothiazol-4-yl)-2-t-butoxycarbonylmethoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer) (6.3 g). IR (Nujol): 1780, 1720, 1675, 1600 cm-1. NMR (DMSO-d6, δ): 1.43 (9H, s), 3.91 (2H, q, J=18.0 Hz), 4.62 (2H, s), 5.31 (1H, d, J=5.0 Hz), 5.45 (2H, s), 5.94 (1H, d-d, J=5.0 Hz 8.0 Hz), 7.68 (2H, d, J=8.0 Hz), 8.23 (2H, d, J=8.0 Hz), 8.51 (1H, s), 9.67 (1H, d, J=8.0 Hz), 12.82 (1H, broad s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In tetrahydrofuran; water | 16 EXAMPLE 16 EXAMPLE 16 To 25 ml. of dry THF were added 554 mg. (1.1 mmole) of 7-(α-amino)phenylacetamido-3-(4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazin-3-ylthio)methyl-3-cephem-4-carboxylic acid and 650 mg. (5 mmole) of N-trimethylsilylacetamide. The mixture was stirred for three hours until solution occurred. The solution then was cooled to 0° C., and 650 mg. (5 mmole) of 1-chloroformylimidazolidine-2-one were added. The resulting mixture was stirred for 30 minutes at 0° C. and then for 1 hour at room temperature. Water (2 ml.) then was added to the mixture. The mixture then was evaporated in vacuo to an oil. Water (25 ml.) was added to the oil, and the pH was raised to 7.5 with sodium bicarbonate. The solution was washed with ethyl acetate, and the aqueous layer then was acidified to pH 1.8 by addition of 1 N hydrochloric acid. The resulting solid was filtered and triturated with methanol, and the methanol insolubles were filtered. The resulting methanol solution was slowly evaporated in vacuo to an oil. Water (25 ml.) was added to the oil, and the pH was raised to 7.5 with sodium bicarbonate. The solution was washed with ethyl acetate, and the aqueous layer then was acidified to pH 1.8 by addition of 1 N hydrochloric acid. The resulting solid was filtered and triturated with methanol, and the methanol insolubles were filtered. The resulting methanol solution was slowly evaporated in vacuo until precipitation resulted. The precipitate was filtered and dried to obtain 92 mg. of 7-α-(imidazolidine-2-one-1-yl-carbonylamino)phenylacetamido-3-(4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazin-3-ylthio)methyl-3-cephem-4-carboxylic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium hydrogencarbonate; In tetrahydrofuran; water; | EXAMPLE 17 To 20 ml. of dry THF were added 554 mg. (1.1 mmole) of 7-(alpha-amino)phenylacetamido-3-(4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazin-3-ylthio)methyl-3-cephem-4-carboxylic acid and 650 mg. (5 mmole) of N-trimethylsilylacetamide. The mixture was stirred for about three hours after which solution was complete. The solution then was cooled to 9 C., and 339 mg. (1.5 mmole) of 1-chloroformyl-3-methanesulfonylimidazolidine-2-one were added. The reaction mixture was stirred for about 30 minutes at 0 C. and then for about 1.5 hours at room temperature. Water (2 ml.) was added to the mixture. The solution then was evaporated in vacuo to an oil. Water (25 ml.) then was added, and the pH of the mixture was raised to 7.5 by addition of sodium bicarbonate. The solution then was washed with ethyl acetate, and the aqueous layer was separated and acidified to pH 1.8 by addition of 1 N hydrochloric acid. The solid which precipitated was filtered and dried to obtain 416 mg. of 7-alpha-(3-methanesulfonylimidazolidine-2-one-1-ylcarbonylamino)phenylacetamido-3-(4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazin-3-ylthio)methyl-3-cephem-4-carboxylic acid. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium chloride; sodium hydrogencarbonate; trichlorophosphate In tetrahydrofuran; dichloromethane; di-isopropyl ether; water; ethyl acetate; N,N-dimethyl-formamide | 4 EXAMPLE 4 EXAMPLE 4 Vilsmeier reagent prepared from N,N-dimethylformamide (0.46 ml) and phosphorous oxychloride (0.55 ml) was suspended in dry tetrahydrofuran (20 ml). To the suspension was added 2-(2-formamido-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetic acid (syn isomer) (1.8 g) under ice-cooling with stirring and then the solution was stirred at the same temperature for an hour to prepare the activated acid solution. To the solution of 7-amino-3-cephem-4-carboxylic acid (1.1 g) and N-trimethylsilylacetamide (6.5 g) in methylene chloride (20 ml) was added the activated acid solution obtained above all at once at -20° C., and the solution was stirred at -20° C. to -10° C. for an hour. After water and ethyl acetate were added to the resultant solution, the mixed solution was adjusted to pH 7.3 with a saturated aqueous solution of sodium bicarbonate. Then the aqueous layer was adjusted to pH 2.0 with conc. hydrochloric acid, extracted with mixed solvent of ethyl acetate (100 ml) and tetrahydrofuran (50 ml). The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After removing the solvent, diisopropyl ether was added to the residue. The insoluble residue was collected by filtration to give 7-[2-(2-formamido-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) (2.35 g), mp 145° to 149° C. (dec.). IR (Nujol): 3200, 1775, 1720, 1670 cm-1. NMR (DMSO-d6, δ): 1.45 (9H, s), 3.60 (2H, m), 4.60 (2H, s), 5.09 (1H, d, J=5 Hz), 5.87 (1H, dd, J=5 Hz, 8 Hz), 6.47 (1H, m), 8.50 (1H, s), 9.50 (1H, d, J=8 Hz). |
Yield | Reaction Conditions | Operation in experiment |
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With sodium chloride; sodium hydrogencarbonate; trichlorophosphate In tetrahydrofuran; water; ethyl acetate; N,N-dimethyl-formamide | 3 EXAMPLE 3 EXAMPLE 3 Vilsmeier reagent was prepared from phosphorus oxychloride (1.2 g) and N,N-dimethylformamide (0.6 g) in ethyl acetate (2.4 ml) in a usual manner. 2-(2-Formamido-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetic acid (syn isomer) (2.4 g) was added to the stirred suspension of Vilsmeier reagent in dry tetrahydrofuran (24 ml) under ice-cooling and stirred for 20 minutes at same temperature [Solution A]. N-Trimethylsilylacetamide (6.4 g) was added to the stirred suspension of 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (2.0 g) in tetrahydrofuran (40 ml), and the mixture was stirred for 30 minutes at 35° to 40° C. To the solution was added the solution [Solution A] at -10° C., and the resulting solution was stirred at same temperature for 30 minutes. Water and ethyl acetate were added to the reaction mixture at -10° C. The organic layer was separated and added to water. The mixture was adjusted to pH 7.5 with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was separated and adjusted to pH 2.0 with 10% aqueous hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give 7-[2-(2-formamido-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (3.72 g). IR (Nujol): 1775, 1710, 1670 cm-1. NMR (DMSO-d6, δ): 1.44 (9H, s), 3.71 (2H, m), 4.45 (2H, q, J=14.0 Hz), 4.64 (2H, s), 5.17 (1H, d, J=5.0 Hz), 5.87 (1H, dd, J=5.0 Hz, 8.0 Hz), 8.56 (1H, s), 9.56 (1H, s), 9.60 (1H, d, J=8.0 Hz), 12.90 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
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With sodium chloride; sodium hydrogencarbonate; trichlorophosphate In tetrahydrofuran; water; ethyl acetate; N,N-dimethyl-formamide | 1 EXAMPLE 1 EXAMPLE 1 Dry tetrahydrofuran (20 ml) and 2-(tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer, 2.1 g) were added to a Vilsmeier reagent, which was prepared from dry N,N-dimethylformamide (0.6 g), dry ethyl acetate (2.4 ml) and phosphorus oxychloride (1.4 g) in an usual manner, and the resulting mixture was stirred at -3° to 3° C. for 30 minutes to give a solution containing the activated acid. Dry ethyl acetate (50 ml) and N-(trimethylsilyl)acetamide (5.4 g) were added to 4-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride (2.5 g), and stirred at 40° C. for 20 minutes. To the solution was added the solution containing the activated acid at -10° C. and stirred at -10° to -5° C. for 30 minutes. Water (40 ml) was added to the resultant solution and allowed to stand at room temperature. The organic layer was separated, washed with a saturated solution of sodium bicarbonate twice and saturated solution of sodium chloride subsequently, and dried over magnesium sulfate. The solution was concentrated to dryness and triturated with diisopropyl ether. The precipitates were collected by filtration and dried to give 4-nitrobenzyl 7-[2-(tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 3.9 g). IR (Nujol): 1780, 1730, 1680, 1640 cm-1. NMR (DMSO-d6, δ): 1.45 (9H, s), 3.93 (2H, q, J=16.0 Hz), 4.63 (2H, s), 5.26 (1H, d, J=5.0 Hz), 5.48 (2H, s), 5.96 (1H, dd, J=5.0 Hz, 8.0 Hz), 7.45 (1H, s), 7.72 (2H, d, J=9.0 Hz), 8.28 (2H, d, J=9.0 Hz), 8.55 (1H, s), 9.72 (1H, d, J=8.0 Hz). |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide; phosphorus pentachloride; triethylamine In tetrahydrofuran; dichloromethane; water; ethyl acetate | 1 EXAMPLE 1 EXAMPLE 1 2-Ethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (2.2 g) was added to a solution of phosphorus pentachloride (2.0 g) in dichloromethane (40 ml) at -10° C., and stirred at -5° C. to -10° C. for 1 hour. After the addition of triethylamine (2.0 g), the resulting mixture was stirred at -5° C. for 5 minutes [Solution A]. N-trimethylsilylacetamide (9.8 g) was added to a stirred suspension of 1-[(7-amino-4-carboxy-3-cephem-3-yl)methyl]pyridinium chloride hydrochloride dihydrate (3.0 g) in dry tetrahydrofuran (60 ml), and the mixture was stirred for 20 minutes at 35° C. to 40° C. To the solution was added the solution A at -10° C. and the resulting solution was stirred at the same temperature for 40 minutes. Water and ethyl acetate were added to the reaction mixture at -10° C. and the separated aqueous layer was washed with ethyl acetate and adjusted to pH 4.0 with 10% aqueous solution of sodium hydroxide. The resulting solution was subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" (Trademark: Prepared by Mitsubishi Chemical Industries) and eluted with 10% aqueous solution of isopropyl alcohol. The fractions containing the object compound were collected and concentrated and lyophilized to give 7-[2-ethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (1.52 g). |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide; trichlorophosphate In tetrahydrofuran; water; ethyl acetate; N,N-dimethyl-formamide | 2 EXAMPLE 2 EXAMPLE 2 Phosphorus oxychloride (1.7 g) was added to a stirred suspension of 2-propoxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer) (2.0 g) in dry tetrahydrofuran (20 ml) and water (0.114 g) at 0° to 3° C. and the resulting mixture was stirred for 30 minutes and thereto was added N-trimethylsilylacetamide (1.2 g) at the same temperature. The resulting mixture was stirred for 15 minutes and thereto was added phosphorus oxychloride (1.7 g) at the same temperature and then stirred for 15 minutes. To the resulting mixture was added dry N,N-dimethylformamide (0.9 g) at the same temperature and then stirred for 30 minutes [Solution A]. N-trimethylsilylacetamide (11.4 g) was added to a stirred suspension of 1-[(7-amino-4-carboxy-3-cephem-3-yl)methyl]pyridinium chloride hydrochloride dihydrate (3.5 g) in tetrahydrofuran (70 ml). To the resulting solution was dropwise added the Solution A at -5° C. and stirred at 0° to -5° C. for 40 minutes. To the reaction mixture was added water and ethyl acetate at -5° C. The aqueous layer was separated, washed with ethyl acetate and then adjusted to pH 4.0 with 10% aqueous solution of sodium hydroxide under ice-cooling. The solution was subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" (Trademark: Prepared by Mitsubishi Chemical Industries) and eluted with 20% aqueous solution of isopropyl alcohol. The fractions containing the object compound were collected, concentrated and lyophilized to give 7-[2-propoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer). I.R. (Nujol): 3300, 3170, 1750, 1610 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
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46% | In N-Bromosuccinimide; dichloromethane | 23 EXAMPLE 23 EXAMPLE 23 To a refluxing suspension of 359 mg (1.03 mmoles) of 3-methyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide in 25 ml of dichloromethane, 189 mg of N-trimethylsilylacetamide (1.45 mmoles) were added and the clear solution that was obtained after refluxing for 3/4 hours was cooled in an ice-bath and diluted to 40 ml with dichloromethane. Bromination was carried out in half an hour using 287 mg (1.61 mmoles) of N-bromosuccinimide as the brominating agent to obtain a yield of 46% of trimethylsilyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide. |
Yield | Reaction Conditions | Operation in experiment |
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With trichlorophosphate In <i>N</i>-methyl-acetamide; water; ethyl acetate | 1 EXAMPLE 1 EXAMPLE 1 Vilsmeier reagent was prepared from phosphorus oxychloride (1.3 g) and dimethylformamide (0.6 g) in ethyl acetate (2.4 ml) in a usual manner. 2-(t-Butoxycarbonylmethoxyimino)-2-(4-thiazolyl)acetic acid (syn isomer) (2.0 g) was added to the stirred suspension of Vilsmeier reagent in ethyl acetate (20 ml) under ice cooling and stirred for 20 minutes at same temperature to produced an activated solution. N-(trimethylsilyl)acetamide (5.8 g) was added to the stirred suspension of benzhydryl 7-amino-3-methylthio-3-cephem-4-carboxylate hydrochloride (2.9 g) in ethyl acetate (30 ml) and stirred for 10 minutes at 40° C. To the solution was added the above activated solution at -10° C. and stirred for 30 minutes at same temperature. Water was added to the reaction mixture and separated organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and then dried over magnesium sulfate. The solvent was evaporated to give benzyhydryl 7-[2-(t-butoxycarbonylmethoxyimino)-2-(4-thiazolyl)acetamido]-3-methylthio-3 -cephem-4-carboxylate (syn isomer) (3.62 g). IR (Nujol): 3270, 1780, 1720, 1655 cm-1. NMR (DMSO-d6, δ): 1.43 (9H, s), 2.33 (3H, s), 3.80 (2H, s), 4.63 (2H, s), 5.21 (1H, d, J=5.0 Hz), 5.82 (1H, dd, J=5.0 Hz, 8.0 Hz), 6.83 (1H, s), 7.07-7.70 (10H, m), 7.94 (1H, d, J=2.0 Hz), 9.12 (1H, d, J=2.0 Hz), 9.57 (1H, d, J=8.0 Hz). |
Yield | Reaction Conditions | Operation in experiment |
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With 4-methyl-morpholine; methanesulfonic acid In tetrahydrofuran; <i>N</i>-methyl-acetamide; methanol; chloroform; ethyl acetate; Petroleum ether | 7.a (a) (a) 7β-[D-2-(4-tert-Butoxycarbonylmethoxyphenyl)-2-(p-methoxybenzyloxycarbonylamino)acetamido]-3-(1-carboxymethyl-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid: A dimethylformamide solution (45 ml) of D-2-(4-tert-butoxycarbonylmethoxphenyl)-2-(p-methoxybenzyloxycarbonylamino)acetic acid (11.65 g) was stirred at -40° to 45° C., to which ethyl chloroformate (2.57 ml) and N-methylmorpholine (2.97 ml) were successively added dropwise. The resulting mixture was stirred at the same temperature for further 30 minutes to obtain a cloudy solution. 7β-Amino-3-(1-carboxymethyl-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid (10.05 g) was added to a dimethylformamide solution (80 ml) of N-trimethylsilylacetamide (20.20 g) and methanesulfonic acid (0.622 g). The resulting mixture was stirred at room temperature for 30 minutes. The thus-obtained solution was cooled to -40° C. and then added with stirring to the above-prepared cloudy solution. The thus-obtained solution was stirred for 1 hour at -45° to -20° C. After adding methanol (2 ml) to the liquid reaction mixture, 0.5N-hydrochloric acid (300 ml) and ethyl acetate (200 ml) which had been ice-cooled were added and the resulting mixture was stirred. The ethyl acetate layer was separated, while the water layer was extracted further with ethyl acetate. Both ethyl acetate layers were combined together and, after being washed twice with ice water (200 ml in total), dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure and the thus-formed residue was purified by silica gel chromatography. The residue was charged using chloroform and the column was eluted successively with a 975:25:2 mixed solvent of chloroform, methanol and formic acid, a 970:30:2 mixed solvent of the same solvents and a 960:40:2 mixed solvent of the same solvents. Fractions containing the desired product were combined together and then concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 ml) and then filtered. The filtrate was added dropwise with stirring to a 1:2 mixture of ethyl ether and petroleum ether (300 ml). The resulting precipitate was collected by filtration, washed with petroleum ether, and then dried under reduced pressure to obtain the desired product as yellowish white powder (6.02 g). Infrared absorption spectrum[(cm-1, Nujol(trade mark)]: 1770, 1700, 1600. NMR spectrum(δ, DMSO-d6): 1.40(9H, s), 3.72(3H, s), 4.16(1H, d, J=13 Hz), 4.38(1H, d, J=13 Hz), 4.60(2H, s), 4.93(2H, s), 4.94(1H, d, J=5 Hz), 5.22(2H, s), 5.30(1H, d, J=8 Hz), 5.64(1H, dd, J=8 Hz, 5 Hz), 6.80(2H, d, J=8 Hz), 6.87(2H, d, J=8 Hz), 7.26(2H, d, J=8 Hz), 7.32(2H, d, J=8 Hz), 7.88(1H, d, J=8 Hz), 9.11(1H, d, J=8 Hz). |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydrogencarbonate; bis-(trimethylsilyl)acetamide; trichlorophosphate In tetrahydrofuran; N,N-dimethyl-formamide | 71 EXAMPLE 71 EXAMPLE 71 Phosphorus oxychloride (0.53 ml) was dropwise added to N,N-dimethylformamide (0.42 ml) under ice-cooling. After stirring for 10 minutes at the same temperature, the mixture was cooled until a precipitate appeared. To the suspension was added 2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (1.12 g). The mixture was stirred at the same temperature for 30 minutes to give an activated acid solution. On the other hand, a mixture of 7β-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (1.5 g), N-trimethylsilylacetamide (1.4 g) and bis(trimethylsilyl)acetamide (2.2 g) in tetrahydrofuran (26 ml) was stirred at 30° C. for 30 minutes to give a clear solution. To the clear solution was added the activated acid solution prepared above at -30° C. The mixture was stirred for 30 minutes at -20° C. to -15° C. The mixture was poured into ice-water, adjusted to pH 7.2 with saturated aqueous solution of sodium bicarbonate, and washed with ethyl acetate. The aqueous solution was adjusted to pH 2.5 with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diisopropyl ether to give 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (2.1 g). |
Yield | Reaction Conditions | Operation in experiment |
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With trichlorophosphate In water; ethyl acetate; N,N-dimethyl-formamide | 1 Example 1 Example 1 Vilsmeier reagent was prepared from N,N-dimethylformamide (0.31 g) and phosphorus oxychloride (0.64 g) in a usual manner. 2-tert-butoxycarbonylmethoxyimino-2-(1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (1.0 g) was added to a stirred suspension of the Vilsmeier reagent prepared above in ethyl acetate (11 ml) under ice-cooling, and the stirring was continued for 30 minutes at the same temperature to produce an activated acid solution. N-Trimethylsilylacetamide (3.2 g) was added to a stirred suspension of 7-amino-3-cephem-4-carboxylic acid (0.7 g) in ethyl acetate (20 ml), and the stirring was continued at 40° to 43° C. for 30 minutes. To this solution was added the above activated acid solution at -10° C., followed by stirring at the same temperature for 30 minutes. Water (10 ml) was added to the resultant solution, and the separated organic layer was washed with water, dried over magnesium sulfate and then evaporated to give 7-[2-tert-butoxycarbonylmethoxyimino-2-(1,2,4-thiadiazol-3 -yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer) (1.4 g). IR (Nujol): 3220, 1780, 1680, 1640, 1540 cm-1 NMR (DMSO-d6, δ): 1.40 (9H, s), 3.57 (2H, m), 4.67 (2H, s), 5.07 (1H, d, J=5 Hz), 5.87 (1H, dd, J=5 Hz, 8 Hz), 6.43 (1H, m), 9.58 (1H, d, J=8 Hz), 10.25 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trichlorophosphate In tetrahydrofuran; water; ethyl acetate; N,N-dimethyl-formamide | 45 EXAMPLE 45 EXAMPLE 45 Vilsmeir reagent was prepared from phosphorus oxychloride (0.97 g) and N,N-dimethylformamide (0.46 g) in ethyl acetate (1.84 ml) in a usual manner. 2-tert-Butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (1.8 g) was added to a stirred suspension of the Vilsmeir reagent in dry tetrahydrofuran (20 ml) under ice-cooling, followed by stirring at the same temperature for 20 minutes to give the activated acid solution. On the other hand, N-(trimethylsilyl)acetamide (4.5 g) was added to a stirred suspension of p-toluenesulfonic acid salt of tert-butyl 7-amino-3-methoxymethyl-3-cephem-4-carboxylate (2.3 g) in tetrahydrofuran (40 ml), and the mixture was stirred at 40° C. for 30 minutes. To the resultant solution was added the activated acid solution prepared above at -10° C., and the mixture was stirred at -10° to -5° C. for 30 minutes. To the reaction mixture was added water, and the separated organic layer was washed with a saturated aqueous sodium bicarbonate and water. After drying over magnesium sulfate, the solution was evaporated to give tert-butyl 7-[2-tert-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-methoxymethyl-3-cephem-4-carboxylate (syn isomer) (2.69 g). IR (Nujol): 3230, 3170, 1780, 1720 1680 cm-1. NMR δppm (DMSO-d6): 1.46 (9H, s), 1.49 (9H, s), 3.23 (3H, s), 3.53 (2H, m), 4.14 (2H, s), 4.62 (2H, s), 5.20 (1H, d, J=5.0 Hz), 5.84 (1H dd, J=5.0, 9.0 Hz), 7.43 (1H, s), 8.53 (1H, s), 9.58 (1H, d, J=8.0 Hz), 12.50 (1H,broad s). |
Yield | Reaction Conditions | Operation in experiment |
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With thionyl chloride In <i>N</i>-methyl-acetamide; ice-water; dichloromethane; water | 20 EXAMPLE 20 EXAMPLE 20 A mixture of dimethylformamide (0.88 g.) and thionyl chloride (20 ml.) was heated at 50° C on an oil bath for an hour, and then the excess of thionyl chloride was distilled off under reduced pressure. Ether was added to the residue and the mixture was allowed to stand for a while and then the solvent was distilled off, which were repeated twice. And then the similar operations were repeated twice by using methylene chloride instead of ether. The residue was suspended in methylene chloride (30 ml.), and to the suspension was added hydrochloric acid salt (2.93 g.) of DL-2-phenyl-2-picolinoyloxyacetic acid under ice-cooling, and then the mixture was stirred for 2 hours at room temperature. On the other hand, to methylene chloride (30 ml.) were added 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (3.38 g.) and a solution (13 ml.) of N-trimethylsilylacetamide in methylene chloride (1 mole/372 ml.), and the mixtures was stirred for 4 hours at room temperature. To the solution was added the solution obtained above all at once under cooling with dry ice and acetone, and the reaction mixture was stirred for 3.25 hours. The reacting mixture was concentrated and to the residue was added ice-water. The powder preciptitated by scrubbing the wall of a vessel was collected by filtration, washed with water and suspended in water. The suspension was adjusted to pH 6 with a dilute sodium bicarbonate aqueous solution and dissolved into the solution. After removal of an insoluble substance by filtration, the filtrate was adjusted to ph 3.5 with 1N-hydrochloric acid. The appearing precipitate was collected by filtration and washed with water to give 7-(DL-2-phenyl-2-picolinoyloxyacetamido)-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (4.7 g.). This substance was suspended in water and dissolved into the solution by addition of a sodium bicarbonate aqueous solution, and an insoluble material was filtered off. |
Yield | Reaction Conditions | Operation in experiment |
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With thionyl chloride In <i>N</i>-methyl-acetamide; ice-water; dichloromethane | 19 EXAMPLE 19 EXAMPLE 19 A mixture of dimethylformamide (0.44 g.) and thionyl chloride (2.5 ml.) was stirred for 30 minutes at 50° C, and then the excess of thionyl chloride was distilled off under reduced pressure. Ether was added to the residue, and the mixture was allowed to stand for a while and then the solvent was distille off, which were repeated twice. And then the similar operations were repeated twice by using methylene chloride instead of ether. Thus obtained white substance was suspended in methylene chloride (25 ml.), and to the suspension was added hydrochloric acid salt (1.47 g.) of DL-2-phenyl-2-isonicotinoyloxyacetic acid under ice-cooling, and then the mixture was stirred for 2.5 hours at room temperature. On the other hand, to methylene chloride (30 ml.) were added 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.65 g.) and a solution (6.4 ml.) of N-trimethylsilylacetamide in methylene chloride (1 mole/ 372 ml.), and then the mixture was stirred for 3 hours at room temperature. To the solution was added the solution obtained above all at once under cooling, and the reaction mixture was stirred for 1.5 hours at the same temperature. The reaction mixture was concentrated, ice-water was added to the residue, the wall of vessel was scrubbed and the mixture was decanted. This operation was repeated several times, and thus obtained powder was collected by filtration, washed with water and dried to give 7-(D-2-phenyl-2-isonicotinoyloxyacetamido)-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.1 g.), m.p. 145° to 150° C (dec.). |
Yield | Reaction Conditions | Operation in experiment |
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With thionyl chloride In <i>N</i>-methyl-acetamide; ice-water; dichloromethane | 3 EXAMPLE 3 EXAMPLE 3 A mixture of dimethylformamide (0.42 g.) and thionyl chloride (2.5 ml.) was heated for 30 minutes at 50° C, and the excess of thionyl chloride was distilled off under reduced pressure. Ether was added to the residue, and the mixture was allowed to stand for a while and then the solvent was distilled off, which were repeated twice. And then the similar operations were repeated twice by using methylene chloride instead of ether. Thus obtained white residue was suspended in methylene chloride (20 ml.), and to the suspension was added hydrochloric acid salt of D-2-phenyl-2-isonicotinoyloxyacetic acid (1.7 g.) under ice-cooling, and then the mixture was stirred for 2.5 hours at room temperature. On the other hand, to methylene chloride (15 ml.) were added 7-amino-3-methyl-3-cephem-4-carboxylic acid (1.1 g.) and a solution of N-trimethylsilylacetamide (6.5 ml.) in methylene chloride (1 mole/372 ml.), and the mixture was stirred for 4 hours at room temperature. To the solution was added the solution obtained above all at once under ice-cooling, and then the mixture was stirred for 1.5 hours at the same temperature. The reaction mixture was concentrated. To the residue was added ice-water followed by operations of scrubbing the wall of a vessel and decantation which were repeated several times. Thus obtained powder was collected by filtration, washed with water and dried to give 7-(D-phenyl-2-isonicotinoyloxyacetamido)-3-methyl-3-cephem-4-carboxylic acid (1.4 g.), m.p. 140° to 150° C (dec.). |
Yield | Reaction Conditions | Operation in experiment |
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With thionyl chloride In <i>N</i>-methyl-acetamide; ice-water; dichloromethane; ethyl acetate | 2 EXAMPLE 2 EXAMPLE 2 A mixture of dimethylformamide (0.88 g.) and thionyl chloride (2.0 ml.) was heated for 30 minutes at 50° C, and then the excess of thionyl chloride was distilled off under reduced pressure. Ether was added to the residue and the mixture was allowed to stand for a while and then the solvent was distilled off, which were repeated three times. Thus obtained residue was suspended in methylene chloride (30 ml.), and to the suspension was added hydrochloric acid salt of D-2-phenyl-2-nicotinoyloxyacetic acid (2.4 g.) under ice-cooling, and then the mixture was stirred for 3 hours at room temperature. On the other hand, to methylene chloride (30 ml.) were added 7-amino-3-methyl-3-cephem-4-carboxylic acid (2.14 g.) and a solution of N-trimethylsilylacetamide in methylene chloride (1 mole/372 ml.) (13 ml.), and then the mixture was stirred for 4 hours at room temperature. To the solution was added the solution obtained above all at once under ice-water cooling, and then the mixture was stirred for 3.25 hours at the same temperature. The reaction mixture was allowed to stand for overnight in a freezer and then concentrated. To the residue were added ice-water and ethyl acetate in turn, and then insoluble material was collected by filtration and washed with ethyl acetate to give 7-(D-2-phenyl-2-nicotinoyloxyacetamido)-3-methyl-3-cephem-4-carboxylic acid (2.5 g.), m.p. 200° to 201° C (dec.). | |
With thionyl chloride In <i>N</i>-methyl-acetamide; ice-water; dichloromethane; ethyl acetate | 2 EXAMPLE 2 EXAMPLE 2 A mixture of dimethylformamide (0.88 g.) and thionyl chloride (2.0 ml.) was heated for 30 minutes at 50° C, and then the excess of thionyl chloride was distilled off under reduced pressure. Ether was added to the residue and the mixture was allowed to stand for a while and then the solvent was distilled off, which were repeated three times. Thus obtained residue was suspended in methylene chloride (30 ml.), and to the suspension was added hydrochloric acid salt of D-2-phenyl-2-nicotinoyloxyacetic acid (2.4 g.) under ice-cooling, and then the mixture was stirred for 3 hours at room temperaure. On the other hand, to methylene chloride (30 ml.) were added 7-amino-3-methyl-3-cephem-4-carboxylic acid (2.14 g.) and a solution of N-trimethylsilylacetamide in methylene chloride (1 mole/372 ml.) (13 ml.), and then the mixture was stirred for 4 hours at room temperature. To the solution was added the solution obtained above all at once under ice-water cooling, and then the mixture was stirred for 3.25 hours at the same temperature. The reaction mixture was allowed to stand for overnight in a freezer and then concentrated. To the residue were added ice-water and ethyl acetate in turn, and then insoluble material was collected by filtration and washed with ethyl acetate to give 7-(D-2-phenyl-2-nicotinoyloxyacetamido)-3-methyl-3-cephem-4-carboxylic acid (2.5g.), m.p. 200° to 201° (dec.). |
Yield | Reaction Conditions | Operation in experiment |
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With thionyl chloride In <i>N</i>-methyl-acetamide; dichloromethane; water | 4 EXAMPLE 4 EXAMPLE 4 A mixture of dimethylformamide (0.9 g.) and thionyl chloride (1.4 g.) was stirred for 30 minutes at 50° C, and then the excess of thionyl chloride was distilled off under reduced pressure. Ether was added to the residue, and the mixture was allowed to stand for a while and then the solvent was distilled off, which were repeated twice. And then the similar operations were repeated three times by using methylene chloride instead of ether. Thus obtained white powder was suspended in methylene chloride (40 ml.), and to the suspension was added hydrochloric acid salt of DL-2-(2-thienyl)-2-isonicotinoyloxyacetic acid (3.0 g.) under ice-cooling, and then the mixture was stirred for 2 hours at room temperature. On the other hand, to methylene chloride (30 ml.) were added 7-amino-3-methyl-3-cephem-4-carboxylic acid (2.14 g.) and a solution (16 ml.) of N-trimethylsilylacetamide in methylene chloride (1 mole/372 ml.), and the mixture was stirred for 4 hours at room temperature. To the solution was added the solution obtained above all at once under ice-cooling, and the reaction mixture was stirred for 3 hours at the same temperature. The reacting mixture was concentrated and to the residue was added water. The powder precipitated by scrubbing the wall of a vessel was collected by filtration, washed with water and dried to give 7-{DL-2-(2-thienyl)-2-isonicotinoyloxyacetamido}-3-methyl-3-cephem-4-carboxylic acid (3.7 g.), m.p. 160° C (dec.). |
Yield | Reaction Conditions | Operation in experiment |
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With thionyl chloride In <i>N</i>-methyl-acetamide; dichloromethane; water | 5 EXAMPLE 5 EXAMPLE 5 A mixture of dimethylformamide (0.7 g.) and thionyl chloride (1.24 g.) was stirred for 30 minutes at 50° C, and then the excess of thionyl chloride was distilled off under reduced pressure. Ether was added to the residue, and the mixture was allowed to stand for a while and then the solvent was distilled off, which were repeated twice. And then the similar operations were repeated twice by using methylene chloride instead of ether. Thus obtained white substance was suspended in methylene chloride (30 ml.), and to the suspension was added hydrochloric acid salt of DL-2-(2-thienyl)-2-nicotinoyloxyacetic acid (2.4 g.) under ice-cooling, and then the mixture was stirred for 2.5 hours at room temperature. On the other hand, to methylene chloride (24 ml.) were added 7-amino-3-methyl-3-cephem-4-carboxylic acid (1.7 g.) and a solution (13 ml.) of N-trimethylsilylacetamide in methylene chloride (1 mole/372 ml.), and then the mixture was stirred. To the solution was added the solution obtained above all at once under cooling, and the reaction mixture was stirred for 2.75 hours at the same temperature. The reaction mixture was concentrated, and to the residue was added water. The powder precipitated by scrubbing the wall of a vessel was collected by filtration and washed with water to give 7-{DL-2-(2-thienyl)-2-nicotinoyloxyacetamido}-3-methyl-3-cephem-4-carboxylic acid (2.8 g.). |
Yield | Reaction Conditions | Operation in experiment |
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With thionyl chloride; triethylamine In dichloromethane; water; N,N-dimethyl-formamide | 8 EXAMPLE 8 EXAMPLE 8 A solution of DL-2-(2-thienyl)-2cinnamoyloxyacetic acid (1.4 g.), N,N-dimethylformamide (0.4 g.) and thionyl chloride (1.18 g.) in methylene chloride (20 ml.) was cooled at -60° C. To the solution was added dried triethylamine (0.79 ml.) under stirring and then the mixture was stirred for 30 minutes. To the mixture was added all at once a solution of 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.7 g.) and a solution (2.28 ml.) of N-trimethylsilylacetamide in methylene chloride (containing 2.0 * 10-2 mole) in methylene chloride (15 ml.). The reaction mixture was stirred for 30 minutes at -40~- 50° C, and for 3 hours at -10~- 20° C, and then the reaction temperature was elevated at room temperature. The reaction solvent was distilled off from the reaction mixture under reduced pressure. To the residue was added water (50 ml.), and extracted three times with ethyl acetate (100 ml. + 50 ml. + 50 ml.). The extract was washed with water and dried, and then the solvent was distilled off under reduced pressure to give oily substance. The substance was crystalized with ether (180 ml.) to give 7-[DL-2-(2-thienyl)-2-cinnamoyloxyacetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (0.9 g.), m.p. 115° to 120° C (dec.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride In <i>N</i>-methyl-acetamide; dichloromethane; water | 5 EXAMPLE 5 EXAMPLE 5 A mixture of dimethylformamide (0.7 g.) and thionyl chloride (1.24 g.) was stirred for 30 minutes at 50° C, and then the excess of thionyl chloride was distilled off under reduced pressure. Ether was added to the residue, and the mixture was allowed to stand for a while and then the solvent was distilled off, which were repeated twice. And then the similar operations were repeated twice by using methylene chloride instead of ether. Thus, obtained white substance was suspended in methylene chloride (30 ml.), and to the suspension was added hydrochloric acid salt of DL-2-(2-thienyl)-2-nicotinoyloxyacetic acid (2.4 g.) under ice-cooling, and then the mixture was stirred for 2.5 hours at room temperature. On the other hand, to methylene chloride (24 ml.) were added 7-amino-3-methyl-3-cephem-4-carboxylic acid (1.7 g.) and a solution (13 ml.) of N-trimethylsilylacetamide in methylene chloride (1 mole/372 ml.), and then the mixture was stirred. To the solution was added the solution obtained above all at once under cooling, and the reaction mixture was stirred for 2.75 hours at the same temperature. The reaction mixture was concentrated, and to the residue was added water. The powder precipitiated by scrubbing the wall of a vessel was collected by filtraion and washed with water to give 7-{DL-2-(2-thienyl)-2-nicotinoyloxyacetamido}-3-methyl-3-cephem-4-carboxylic acid (2.8 g.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1H-tetrazole In water; ethyl acetate | 6 Bis-Trimethylsilyl Cefamandole via Silylated Tetrazole Nucleus EXAMPLE 6 Bis-Trimethylsilyl Cefamandole via Silylated Tetrazole Nucleus In this example the tetrazole nucleus is first silylated and then added to the acylating agent. Eight grams (24.4 mmoles) of tetrazole nucleus, 7-amino-3-(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, were reacted with 12.8 g (97.6 mmoles) of N-trimethylsilylacetamide in 45 ml of ethyl acetate at 60° C until solution occurred. The mixture was allowed to cool to room temperature. The solution of silylated nucleus was added to 2.82 g (15.8 mmoles) of D-anhydro O-carboxymandelic acid in 35 ml of ethyl acetate at ambient temperature and stirred for 2 hours. The insoluble product was filtered and dried in vacuo. The silyl product was washed in 300 ml of water to remove acetamide. The material was dried to yield 7.4 g of trimethylsilyl 7-[D-(O-trimethylsilyl)mandelamido]3-(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride In dichloromethane; water | 5 EXAMPLE 5 EXAMPLE 5 A mixture of 1-aminocyclohexane-1-acetic acid hydrochloride (3.87 g.) and thionyl chloride (2.3 ml.) in dichloromethane (50 ml.) was heated under reflux for 3 hours and then filtered. The filtrate was concentrated under reduced pressure and the residual pale yellow crystals were washed with dry ether and dissolved in dry dichloromethane (30 ml.). This solution was added dropwise to a mixed solution of 7-amino-3-methyl-3-cephem-4-carboxylic acid (4.28 g.), a dichloromethane solution (20 ml.) containing N-(trimethylsilyl)acetamide (433 mg./ml.) and dichloromethane (80 ml.) at -50° to -60° C with stirring over 15 minutes. The resultant mixture was stirred at -50° to -60° C for 2 hours and furthermore at room temperature for 2 hours. To the reaction mixture was added water and an insoluble substance was filtered off. The filtrate was washed with dichloromethane and then the aqueous layer was separated, adjusted to about pH 3.5 with sodium hydrogen carbonate, treated with activated charcoal and then concentrated under reduced pressure. The precipitate in the concentrate was filtered and then the filtrate was passed through an ion-exchange resin (IR-45, IRC-50). The precipitate was filtered to give 7-[2-(1-aminocyclohexan-1-yl) acetamido]-3-methyl-3-cephem-4-carboxylic acid (2.2 g.), m.p. 210° to 211° C (dec.). The mother liquid was concentrated under reduced pressure and then the precipitate in the concentrate was filtered off. The filtrate gave the same object product (1.3 g.) by scratching the inner wall of the reaction vessel. Total yield is 3.5 g. UV (Phosphate buffer, pH 6.4): λmax 262 mμ, E = 212. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 7-MPCA; N-Trimethylsilylacetamide In dichloromethane at -25 - 25℃; for 1h; Stage #2: 4-bromo-2-methoxyimino-3-oxo butyric acid chloride In dichloromethane at -25 - -20℃; for 1.16667h; Stage #3: With water In dichloromethane at 2 - 5℃; for 1h; | 1.I.A; 1.I.C To a suspension of 7-amino-3-[(1-methyl-1-pyrrolidinium)methyl]-3-cephem-4-carboxylate hydrochloride (10 g, 0.03 mol) in methylene chloride (100 ml) at 20-25° C., N-trimethylsilylacetamide solution (containing 26.72 g N-trimethylsilylacetamide, 0.20 mol) was added and stirred for 1 hour to obtain a clear solution. This solution was cooled to -25° C. to -20° C. until use.; Solution B was added to solution A, while maintaining the temperature between -25° C. and -20° C. over a period of about 10 minutes and the reaction mass was stirred for 1 hour at this temperature. Thereafter cold water (50 ml, 5° C.) was added and the reaction mass was stirred at 2-5° C. for 1 hour. The product thus obtained was filtered, washed with methylene chloride (20 ml) and dried to obtain the bromo intermediate as its hydrochloride salt (13.2 g). The structure of this compound was confirmed by spectroscopic data. [0034] 1H NMR (300 MHz) (DMSO-d6) δ: 2.11 (m, 4H), 2.94 (s, 3H), 3.45 (m, 1H), 3.59 (m, 3H), 3.66 & 4.05 (2d, each 1H), 4.05 (s, 3H), 4.30 & 4.61 (2d, each 1H), 4.86 (s, 2H), 5.33 (s, 1H), 5.91 (dd, 1H),9.55 (d, 1H). [0035] IR (KBr) cm-1: 1785, 1714, 1678, 1610 [0036] MASS (Positive ion Mode) : 503, 505 [M+1]; 525, 527 [M+Na] corresponding to 79Br and 81Br isotopes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 7-MPCA; N-Trimethylsilylacetamide In dichloromethane at -25 - 25℃; for 1h; Stage #2: 4-chloro-2-methoxyimino-3-oxobutyrylchloride Stage #3: With water In dichloromethane at 2 - 5℃; for 1h; | 1.I.A; 2.I. To a suspension of 7-amino-3-[(1-methyl-1-pyrrolidinium)methyl]-3-cephem-4-carboxylate hydrochloride (10 g, 0.03 mol) in methylene chloride (100 ml) at 20-25° C., N-trimethylsilylacetamide solution (containing 26.72 g N-trimethylsilylacetamide, 0.20 mol) was added and stirred for 1 hour to obtain a clear solution. This solution was cooled to -25° C. to -20° C. until use.; Solution B was added to solution A, while maintaining the temperature between -25° C. and -20° C. over a period of about 10 minutes and the reaction mass was stirred for 1 hour at this temperature. Thereafter cold water (50 ml, 5° C.) was added and the reaction mass was stirred at 2-5° C. for 1 hour. The product thus obtained was filtered, washed with methylene chloride (20 ml) and dried to obtain the bromo intermediate as its hydrochloride salt (13.2 g). The structure of this compound was confirmed by spectroscopic data. [0034] 1H NMR (300 MHz) (DMSO-d6) δ: 2.11 (m, 4H), 2.94 (s, 3H), 3.45 (m, 1H), 3.59 (m, 3H), 3.66 & 4.05 (2d, each 1H), 4.05 (s, 3H), 4.30 & 4.61 (2d, each 1H), 4.86 (s, 2H), 5.33 (s, 1H), 5.91 (dd, 1H),9.55 (d, 1H). [0035] IR (KBr) cm-1: 1785, 1714, 1678, 1610 [0036] MASS (Positive ion Mode) : 503, 505 [M+1]; 525, 527 [M+Na] corresponding to 79Br and 81Br isotopes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran at -78℃; for 2h; Inert atmosphere; | 4.3 Organocatalytic enantioselective deprotonation of prochiral cyclohexanones 4.3.1 General procedure II General procedure: To a solution of cyclohexanone 2a-f (0.25mmol) and QN+1, 4-MeOC6H4O- (0.0125mmol, 7mg) in THF (0.25mL) at -78°C was added BSA (0.375mmol, 92μL) as a solution in THF (0.25mL). The reaction mixture was stirred at the same temperature for 2h. The conversion was measured by GC-FID. Next, 100μL of a saturated solution of NaHCO3 was added at -78°C. The reaction mixture was dried over Na2SO4, filtered and concentrated. The crude product 3a-f was purified on silica gel by using petroleum ether/Et2O (95:5) as eluent and then subjected to GC-FID analysis using chiral column in order to determine the enantiomeric excess. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.85 g | In toluene at 50℃; for 1h; | 1 (Synthesis Example 1) Synthesis of 5- (trimethylsilyloxy) -1,4-naphthoquinone In a 100 mL three-necked flask equipped with a thermometer and a stirrer, 1.74 g (10 mmol) of 5-hydroxy-1,4-naphthoquinone,2.4 g (12 mmol) of trimethylsilylacetamide,12 g of toluene was charged to make an orange slurry and heated at 50 ° C. for 1 hour.Thereafter, 15 g of n-hexane was added, the filtrate was concentrated,Red oily crystal of 5-trimethylsilyloxy-1,4-naphthoquinone1.85 g (7.5 mmol) was obtained.The isolated yield based on 5-hydroxy-1,4-naphthoquinone as a raw material was 75 mol%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.83 g | In toluene at 50℃; for 5h; | 1 Synthesis Example 1 Synthesis of 1- (trimethylsilyloxy) -9,10-anthraquinone In a 100 mL three-necked flask equipped with a thermometer and a stirrer, 1.12 g (5 mmol) of 1-hydroxy-9,10-anthraquinone,1.2 g (6 mmol) of trimethylsilylacetamide,And 8 g of toluene were charged to form an orange slurry and heated at 50 ° C. for 5 hours.Thereafter, 15 g of n-hexane was added, and the filtrate was concentrated.As yellow crystals precipitate, it is subjected to suction filtration and drying,Yellow crystal of 1-trimethylsilyloxy-9,10-anthraquinone0.83 g (3.05 mmol) was obtained.The isolated yield based on 1-hydroxy-9,10-anthraquinone as a raw material was 61 mol%. |
Tags: 13435-12-6 synthesis path| 13435-12-6 SDS| 13435-12-6 COA| 13435-12-6 purity| 13435-12-6 application| 13435-12-6 NMR| 13435-12-6 COA| 13435-12-6 structure
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