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CAS No. : | 24589-78-4 | MDL No. : | MFCD00000411 |
Formula : | C6H12F3NOSi | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MSPCIZMDDUQPGJ-UHFFFAOYSA-N |
M.W : | 199.25 | Pubchem ID : | 32510 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.83 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 42.11 |
TPSA : | 20.31 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.91 cm/s |
Log Po/w (iLOGP) : | 2.16 |
Log Po/w (XLOGP3) : | 2.26 |
Log Po/w (WLOGP) : | 3.1 |
Log Po/w (MLOGP) : | 1.39 |
Log Po/w (SILICOS-IT) : | -0.17 |
Consensus Log Po/w : | 1.75 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.3 |
Solubility : | 0.996 mg/ml ; 0.005 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.32 |
Solubility : | 0.947 mg/ml ; 0.00475 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.71 |
Solubility : | 3.88 mg/ml ; 0.0195 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.48 |
Signal Word: | Danger | Class: | 3 |
Precautionary Statements: | P210-P233-P240-P241-P242-P243-P261-P264-P271-P280-P303+P361+P353-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P370+P378-P403+P233-P403+P235-P405-P501 | UN#: | 1993 |
Hazard Statements: | H225-H315-H319-H335 | 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 |
---|---|---|
91% | With dmap In acetonitrile |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-(Trimethylsilyl)imidazole at 60℃; for 0.166667h; | ||
With ammonium iodide; 2-hydroxyethanethiol at 60℃; for 0.333333h; | 2.2.4 Fraction collection and solvolysis General procedure: For metabolite characterisation, a LC fractionation of urine samples was performed. Sample preparation described above in Section 2.2.3. was applied to 20 replicates of 5 mL of urine. Prior to evaporation, the organic phases of all the replicates were combined, evaporated, reconstituted and injected in a single injection. Fractions corresponding to the expected retention time (RT ± 0.2 min) of the peaks of each metabolite were manually collected in pre- and post-administration samples. LC fractions were evaporated, and a solvolysis was performed using a procedure described elsewhere [17,26]. Briefly, fractions were reconstituted with 4 mL of ethyl acetate/methanol/sulphuric acid (80:20:0.06, v/v/v) and incubated at 55 °C for 2 h. Extracts were neutralized with 60 μL of 1 M NaOH and evaporated to dryness. The residues were reconstituted in 1 mL of sodium phosphate buffer (0.2 M, pH 7) and 250 μL of 5% K2CO3 solution were added. The extraction was performed with 6 mL of TBME by shacking at 40 mpm for 20 min. After centrifugation (3000g, 5 min), the organic layers were separated and evaporated. The dry extracts were derivatized by adding 50 μL of a mixture of MSTFA/NH4I/2-mercaptoethanol (1000:2:6, v/w/v) and incubating at 60 °C for 20 min. After incubation, the derivatized extracts were transferred to injection vials and 1 μL was analysed by GC-MS. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-(Trimethylsilyl)imidazole at 60℃; for 0.166667h; | ||
With ammonium iodide; 2-hydroxyethanethiol at 60℃; for 0.333333h; | 2.2.4 Fraction collection and solvolysis General procedure: For metabolite characterisation, a LC fractionation of urine samples was performed. Sample preparation described above in Section 2.2.3. was applied to 20 replicates of 5 mL of urine. Prior to evaporation, the organic phases of all the replicates were combined, evaporated, reconstituted and injected in a single injection. Fractions corresponding to the expected retention time (RT ± 0.2 min) of the peaks of each metabolite were manually collected in pre- and post-administration samples. LC fractions were evaporated, and a solvolysis was performed using a procedure described elsewhere [17,26]. Briefly, fractions were reconstituted with 4 mL of ethyl acetate/methanol/sulphuric acid (80:20:0.06, v/v/v) and incubated at 55 °C for 2 h. Extracts were neutralized with 60 μL of 1 M NaOH and evaporated to dryness. The residues were reconstituted in 1 mL of sodium phosphate buffer (0.2 M, pH 7) and 250 μL of 5% K2CO3 solution were added. The extraction was performed with 6 mL of TBME by shacking at 40 mpm for 20 min. After centrifugation (3000g, 5 min), the organic layers were separated and evaporated. The dry extracts were derivatized by adding 50 μL of a mixture of MSTFA/NH4I/2-mercaptoethanol (1000:2:6, v/w/v) and incubating at 60 °C for 20 min. After incubation, the derivatized extracts were transferred to injection vials and 1 μL was analysed by GC-MS. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In benzene at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In tetrahydrofuran at 55℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With 1,4-diaza-bicyclo[2.2.2]octane; dmap In acetonitrile at 110℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | at 25℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 43% 2: 33% | Stage #1: Acetic acid (1R,2R,4S,5R,6S,8S,11S)-11-allyl-5-benzyloxy-8-(tert-butyl-dimethyl-silanyloxymethyl)-2-methyl-10-oxo-12-oxa-tricyclo[6.3.1.01,6]dodec-4-yl ester; lithium phenylacetylide With lithium bromide In tetrahydrofuran at -78℃; Stage #2: N-methyl-N-trimethylsilyl-2,2,2-trifluoroacetamide In tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In acetonitrile at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In acetonitrile at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Stage #1: N-methyl-N-trimethylsilyl-2,2,2-trifluoroacetamide; DL-serine amide; hydrochloride In acetonitrile at 20℃; for 1h; Stage #2: With triethylamine at 0℃; Stage #3: With sulfur dioxide In acetonitrile at 0 - 20℃; Further stages.; | |
With sulfur dioxide; triethylamine In tetrahydrofuran; chloroform; water; acetone; acetonitrile | 21.A A. A. Preparation of 3-Hydroxymethyl-4-hydroxy-1,2,5-thiadiazole A solution of 2-amino-3-hydroxypropanamide hydrochloride (20.25g) in acetonitrile (270 ml) was treated with N-methyl-N-(trimethylsilyl)trifluoroacetamide (172 g). After one hour, this solution was cooled to 0° C. and treated with triethylamine (20 ml). After about five minutes, the resulting solution was treated with a solution of condensed sulfur dioxide (30.75 ml) in acetonitrile (113.25 ml). After addition of the sulfur dioxide solution was complete, the ice-bath was removed and the reaction mixture allowed to warm to room temperature. After three hours, the reaction mixture was placed in a refrigerator overnight. After an additional two hours at room temperature, the reaction mixture was treated with water (8.55 ml). After fifteen minutes, the resulting mixture was concentrated in vacuo. The residue was treated with water (400 ml) and extracted with methylene chloride. The organic extracts were discarded and the aqueous phase concentrated in vacuo. The residue was treated with THF (250 ml), sonicated in an ultrasonic bath, and filtered. The THF filtrate was concentrated in vacuo. This residue was dissolved in hot acetone (36 ml), and the resulting solution treated with chloroform (165 ml). This mixture was concentrated on a steam bath to a volume of about 165 ml, then filtered. The filtrate was concentrated to about 150 ml, cooled, sonicated in an ultrasonic bath, and refrigerated, to give 5.9 g of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 80℃; for 1h; | Probenvorbereitung Fig. 1 gibt ein Gaschromatogramm des Tridecanols (als Trimethylsilylether) wieder, das unter folgenden Bedingungen gemessen wurde: Probenvorbereitung: 3 Tropfen Tridecanol wurden mit 1,5 ml N-Methyltrimethylsilyltrifluoracetamid 60 min bei 80 °C umgesetzt. Das Injektionsvolumen betrug 1 µl. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In hexane; dichloromethane; ethyl acetate; 1,2-dichloro-ethane; | The 6-(1-pyrrolyl)-9-(2,3,5-tri-O-benzoyl-beta-L-ribofuranosyl)purine used as a starting material was prepared as follows: To a suspension of 1.0 g of 6-(1-pyrrolyl)purine (prepared according to K. G. Estep et al, J.Med.Chem., 1995, 38, 2582) and 0.97 g of 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-L-ribofuranose in 30 ml of 1,2-dichloroethane was added dropwise 2.30 g of N-methyl-N-trimethylsilyl trifluoroacetamide, and the mixture heated to 80 C. Following addition of 0.635 g of trimethylsilyl trifluoromethane sulphonate dropwise, the mixture was stirred at 80 C. overnight. After cooling to room temperature, the mixture was diluted with 60 ml of dichloromethane and washed four times with a saturated solution of aqueous sodium hydrogen carbonate. The organic extract was dried over sodium sulphate, filtered and evaporated and the residue purified by flash column chromatography on silica gel using ethyl acetate/hexane (10:90) for the elution to give 0.56 g of 6-(1-pyrrolyl)-9-(2,3,5-tri-O-benzoyl-beta-L-ribofuranosyl)purine as a white solid; mass spectrum (ESI) 630 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine In dichloromethane | 120 2-Methylsulfonylamino-4-morpholin-4-yl-benzoic acid EXAMPLE 120 2-Methylsulfonylamino-4-morpholin-4-yl-benzoic acid To a suspension of 2-amino-4-morpholin-4-ylbenzoic acid (230 mg; 1.04 mmol) in CH2Cl2 (3 mL) was added N-methyl-N-(trimethylsilyl)trifluoro-acetamide (0.4 mL; 2.1 mmol) via syringe at room temperature under a nitrogen atmosphere. The resulting mixture was heated to reflux for 10 minutes, then allowed to cool to room temperature. Methanesulfonyl chloride (1.2 eq.) and triethylamine (1.2 eq.) were added, and the resulting mixture allowed to stir for 2 hours. The reaction was diluted with CH2Cl2 (30 mL) and washed with water (2*10 mL) and brine, then dried (MgSO4), filtered, and concentrated in vacuo to provide the sulfonamide as a white solid (280 mg; 90%). 1H NMR (d6-DMSO, 400 MHz): δ10.88 (s, 1H), 7.80 (d, 1H), 6.92 (d, 1H), 6.71 (dd, 1H), 3.71 (t, 4H), 3.25 (t, 4H), 3.16 (s, 3H). LRMS (Electrospray, negative): Da/e 299.0 (m-1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trimethylsilyl iodide In tetrahydrofuran; methanol; dichloromethane; acetonitrile | 1 Preparation of [6R-trans]-4-[3-carboxy-1-(2-fluoroethyl)-6,8-difluoro-1,4-dihydro-4-oxoquinolin-7-yl]-1-[[2-carboxy-8-oxo-7-[(phenoxyacetyl)amino]-5-thia-1-azabicyclo-[4.2.0]oct-2-en-3-yl]methyl]-1-methylpiperazinium iodide STR32 EXAMPLE 1 Preparation of [6R-trans]-4-[3-carboxy-1-(2-fluoroethyl)-6,8-difluoro-1,4-dihydro-4-oxoquinolin-7-yl]-1-[[2-carboxy-8-oxo-7-[(phenoxyacetyl)amino]-5-thia-1-azabicyclo-[4.2.0]oct-2-en-3-yl]methyl]-1-methylpiperazinium iodide STR32 Under an argon atmosphere, a mixture of 406 mg (1 mmol) of [6R-trans]-3-(acetyloxy)methyl]-8-oxo-7-[(phenoxyacetyl)amino]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-2-carboxylic acid, 2 mL of dry methylene chloride, a nd 0.60 mL (3 mmol) of N-methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA) was stirred for one hour: 0.28 mL (2 mmol) of iodotrimethylsilane was then added, and the mixture stirred for 2 hours. The solution was then concentrated to dryness under reduced pressure, and the residual oil dissolved in 2 mL of acetonitrile. Five drops of anhydrous THF were added, and the mixture was stirred for 5-10 minutes. A solution prepared from 111 mg (0.3 mmol) of 6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, 0.11 mL (0.6 mmol) of MSTFA and 1 mL of acetonitrile was added, and stirring was continued for 2 hours. The mixture was chilled in ice, and approximately 100 mg of methanol were added. The solid which precipitated was filtered, washed with acetonitrile, and dried under reduced pressure to obtain the title compound: NMR (Me2 SO-d6) δ 3.15 (s, 3H, NCH3), 3.45-3.85 (m, 9H, 4 x NCH2 and CH of SCH2), 3.95 (d, 1H, J gem=16.5 Hz, CH of SCH2), 4.39 and 4.77 (AB, 2H, J gem=13 Hz, NCH2). 4.61 and 4.64 (AB, 2H, J gem=15 Hz, OCH2 CO), 4.83-5.07 (m, 4H, NCH2 CH2 F), 5.24 (d, 1H, J=5Hz, CH), 5.82 (dd, 1H, J=5 and 7 Hz, CH), 6.95 (d, 2H, J=8 Hz, Ar), 6.97 (t, 1H, J=8 Hz, Ar), 7.29 (t, 2H, J=8 Hz), 7.96 (d, 1 H, J=12 Hz, Ar), 8.91 (s, 1H, =CH--), 9.18 (d, 1H, J=7 Hz, NH); IR (KBr) 3400, 1788, 1728, 1700, 1612, cm-1; mass spectrum m/z 716 (cation). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trimethylsilyl iodide In tetrahydrofuran; methanol; acetonitrile | 8 Preparation of [6R-[6α,7β(Z)]]-1-[[7-[[(2-amino-4-thiazolyl)[[1,1-dimethyl-2-(1,1-dimethylethoxy)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-4-[3-carboxy-(2-fluoroethyl)-6,8-difluoro-1,4-dihydro-4-oxoquinolin-7-yl]-1-methylpiperazinium iodide STR39 EXAMPLE 8 Preparation of [6R-[6α,7β(Z)]]-1-[[7-[[(2-amino-4-thiazolyl)[[1,1-dimethyl-2-(1,1-dimethylethoxy)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-4-[3-carboxy-(2-fluoroethyl)-6,8-difluoro-1,4-dihydro-4-oxoquinolin-7-yl]-1-methylpiperazinium iodide STR39 Under an argon atmosphere, a mixture of 272 mg (1 mmol) of 7-aminocephalosporanic acid, 0.67 mL (3.6 mmol) of MSTFA and 3 mL of dry acetonitrile was stirred for 30 minutes; 0.25 mL (1.75 mmol) of iodotrimethylsilane was then added and stirring was continued for another 30 minutes. The mixture was cooled momentarily, and 0.14 mL (1.75 mmol) of anhydrous THF was added. After 10 minutes, a solution prepared from 277 mg (0.75 mmol) of 6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, 0.17 mL (0.9 mmol) of MSTFA and 3 mL of dry acetonitrile was added. Stirring at room temperature was continued for 2.5 hours: 478 mg (1 mmol) of 2-[[[1-(2-amino-4-thiazolyl)-2-[(2-benzothiazolyl)thio]-2-oxoethylidene]amino]oxy]methylpropanoic acid 1,1-dimethylethyl ester and 4 mL of dry acetonitrile were added, and the mixture was stirred overnight. After filtration to remove a small amount of insoluble solid, the mixture was concentrated to dryness under reduced pressure. The residual oil was redissolved in 4 mL of acetonitrile, and with ice cooling, 0.16 mL of methanol was added. After stirring for one minute and standing for 3 minutes, the precipitated solid was filtered. After washing with three 3-mL portions of acetonitrile, and drying under pressure, 530 mg of the title compound was obtained: NMR (Me2 SO-d6), δ 1.36 (s, 12H, t-Bu and CH3), 1.40 (s, 3H, CH3), 3.12 (s, 3H, NCH3), 3.40-3.86 (m, 9H, 4 x NCH2 and CH of SCH2), 3.96 (d, 1H, J gem=16 Hz, CH of SCH2), 4.40-4.66 (AB, 2H, J gem=13 Hz, NCH2), 4.62-5.06 (m, 4H, NCH2 CH2 F), 5.26 (d, 1H, J=5 Hz, CH), 5.93 (dd, 1H, J=5 and 7 Hz, CH), 6.68 (s, 1H, Ar), 7.25 (s, 2H, NH2), 7.92 (d, 1H, J=12 Hz, Ar), 8.88 (s, 1H, =CH--), 9.44 (d, 1H, J=7 Hz, NH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trimethylsilyl iodide In tetrahydrofuran; methanol; dichloromethane; acetonitrile | 3 Preparation of [6R-[6α,7β(Z)]]-1-[[7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-8-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methyl]-4-(3-carboxy-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-quinolinyl)-1-methylpiperazinium iodide STR34 EXAMPLE 3 Preparation of [6R-[6α,7β(Z)]]-1-[[7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-8-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methyl]-4-(3-carboxy-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-quinolinyl)-1-methylpiperazinium iodide STR34 Under an argon atmosphere, a mixture of 273 mg (0.6 mmol) of [6R-[6α,7β(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 2 mL of dry methylene chloride, and 0.45 mL (2.4 retool) of MSTFA was stirred for 2 hours; 0.17 mL (1.2 mmol) of iodotrimethylsilane was added, and stirring was continued for another 2 hours. The mixture was concentrated under reduced pressure, and the residual oil was dissolved in 2 mL of dry acetonitrile. A few drops of dry THF were added, and the mixture stirred for 15 minutes. A solution prepared from 60 mg (0.18 mmol) of 1-ethyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, 1 mL of dry acetonitrile, and 0.07 mL (0.36 mmol) of MSTFA was added, and stirring was continued for 2 hours. Dropwise addition of 125 mg of methanol caused the product to precipitate. The solid was filtered, washed with four 1-mL portions of acetonitrile, and dried under reduced pressure. After trituration with methanol and drying under reduced pressure, the title compound was obtained: NMR (Me2 SO-d6) δ 1.45 (brt, 3H, CH3 of NEt), 3.15 (s, 3H, NCH3), 3.50-3.95 (m, 9H, 4 x NCH2 and CH of SCH2), 3.85 (s, 3H, OCH3), 3.99 (d, 1H, J gem=16.5 Hz, CH of SCH2), 4.43 and 4.70 (AB, 2H, J gem=14 Hz, NCH2), 4.61 (brq, 2H, CH2 of NEt), 5.31 (d, 1H, J=5 Hz, CH), 5.94 (dd, 1H, J=5 and 8 Hz, CH), 6.76 (s, 1H, Ar), 7.30 (br, 2H, NH2), 7.31 (d, 1H, J=6.5 Hz, Ar), 8.03 (d, 1H, J=12.5 Hz, Ar), 9.03 (s, 1H, =CH--), 9.68 (d, 1H, J=8 Hz, NH); IR (KBr) 1785, 1720, 1680, 1628, cm-1; mass spectrum m/z=729 (cation). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate In dichloromethane; water | 58.a (a) (a) (1aS,3aR,6bR)-2-Acetyl-5-carbamoyloxymethyl-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diazacyclobut[cd]indene-6-carboxylic acid sodium salt (1aS,3aR,6bR)-5-Carbamoyloxymethyl-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diazacyclobut[cd]indene-6-carboxylic acid trifluoroacetate (148 mg; 0.4 mmol) was suspended in methylene chloride (5 ml) and treated with N-methyl-N-trimethylsilyltrifluoroacetamide (0.171 ml; 0.88 mmol). After 10 minutes at room temperature sodium bicarbonate (41 mg; 0.48 mmol) and acetyl chloride (0.035 ml; 0.48 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours and subsequently concentrated. The residue obtained was taken up in water (1 ml) and the pH value was adjusted to 7 with saturated aqueous sodium bicarbonate solution. The solution was chromatographed over a polymeric hydrophobic gel with water/acetonitrile and lyophilized. Yield: 72 mg (54%) as a yellowish powder. IR (KBr): 1755, 1710, 1640, 1609, 1402 cm-1 MS (ISP): (M+H)+ 332.4 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane | 2 Preparation of beta-anomer enriched 1-(2'-deoxy-2',2'-difluoro-3',5'-di-O-benzoyl-D-ribofuranosyl)-4-aminopyrimidin-2-one with 20 equivalents of bis-trimethylsilylcytosine EXAMPLE 2 Preparation of beta-anomer enriched 1-(2'-deoxy-2',2'-difluoro-3',5'-di-O-benzoyl-D-ribofuranosyl)-4-aminopyrimidin-2-one with 20 equivalents of bis-trimethylsilylcytosine A bis-trimethylsilylcytosine solution was prepared by suspending 5.78 g of cytosine in 75 ml of dichloromethane and adding 20.57 ml of N-methyl-N-trimethylsilyltrifluoroacetamide and cooling the resulting solution to -30° C. To 1 g of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoate was added 10 ml of dichloromethane and 0.55 ml of triethylamine. | |
With triethylamine In dichloromethane | 4 Preparation of beta-anomer enriched 1-(2'-deoxy-2',2'-difluoro-3',5'-di-O-benzoyl-D-ribofuranosyl)-4-aminopyrimidin-2-one with 20 equivalents of bis-trimethylsilylcytosine EXAMPLE 4 Preparation of beta-anomer enriched 1-(2'-deoxy-2',2'-difluoro-3',5'-di-O-benzoyl-D-ribofuranosyl)-4-aminopyrimidin-2-one with 20 equivalents of bis-trimethylsilylcytosine A bis-trimethylsilylcytosine solution was prepared by suspending 5.78 g of cytosine in 20 ml of dichloromethane and adding 20.57 ml of N-methyl-N-trimethylsilyltrifluoroacetamide in 10 ml of dichloromethane and cooling the resulting solution to 0° C. To 1 g of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoate was added 10 ml of dichloromethane and 0.55 ml of triethylamine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In dichloromethane | 11 (a) (1 aS,3aR,6bR)-2-(3-Carbamoyl-pyridin-1-ylioacetyl)-5-methylsulphonyloxy-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diazacyclobut[cd]indene-6-carboxylate (1aS,3aR,6bR)-5-Methylsulphonyloxy-1-oxo-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diazacyclobut[cd]indene-6-carboxylic acid trifluoroacetate (500 mg; 1.24 mmol; from Example 8(a)) was suspended in abs. methylene chloride (10 ml) and treated with N-methyl-N-trimethylsilyltrifluoroacetamide (0.53 ml). After 10 minutes at room temperature the solution obtained was cooled to -20° C., treated with pyridine (0.18 ml; 2.2 mmol) and subsequently with bromoacetyl bromide (0.14 ml; 1.6 mmol). The reaction mixture was stirred at 0° C. for an additional 1 hour, diluted with water (25 ml) and extracted with ethyl acetate (3*100 ml). The combined organic phases were washed with saturated aqueous sodium chloride solution (25 ml), dried over magnesium sulphate and concentrated. The residue was triturated with n-hexane (20 ml) and filtered off under suction. There were obtained 390 mg (66%) of (1aS,3aR,6bR)-2-bromoacetyl-5-methylsulphonyloxy-1-oxo-1 a,2,3,3a,4,6a-hexahydro-1H-2,6a -diazacyclobut[cd]indene-6-carboxylic acid as a colourless solid. IR (KBr): 2800, 1778, 1727, 1657, 1350, 1230, 1156 cm-1 MS (ISN): M-H)- 407 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane | 11 Preparation of beta-anomer enriched 1-(2'-deoxy-2',2'-difluoro-3',5'-di-O-benzoyl-D-ribofuranosyl)-4-aminopyrimidin-2-one with 20 equivalents of bis-trimethylsilylcytosine EXAMPLE 11 Preparation of beta-anomer enriched 1-(2'-deoxy-2',2'-difluoro-3',5'-di-O-benzoyl-D-ribofuranosyl)-4-aminopyrimidin-2-one with 20 equivalents of bis-trimethylsilylcytosine To 5.78 g of cytosine were added 5 ml of dichloromethane, 20.6 ml of N-methyl-N-trimethylsilyltrifluoroacetamide and 5 ml of dichloromethane to form a homogenous bis-trimethylsilylcytosine solution. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium bicarbonate In dichloromethane | 3.j (aj) (aj) (1aS,3aR,6bR)-2-Methylsulphonyl-1-oxo-5-(pyridin-4-ylsulphanyl)-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diazacyclobut[cd]indene-6-carboxylic acid sodium salt N-methyl-N-trimethylsilyltrifluoroacetamid (300 ml; 1.6 mmol) was added to a suspension of (1aS,3aR,6bR)-1-oxo-5-(pyridin-4-ylsulphanyl)-1a,2,3,3a,4,6b-hexahydro-1H-2,6a-diazacyclobut[cd]indene-6-carboxylic acid trifluoroacetate (120 mg; 0.24 mmol; from Example 2(d)) in methylene chloride (5 ml). The suspension was stirred at room temperature for 0.5 hour, with all solid material passing into solution. This solution was treated with sodium hydrogen carbonate (28 mg; 0.33 mmol) and mesyl chloride (21 ml; 0.27 mmol), stirred for 23 hours and then poured into water (5 ml). The pH of the aqueous phase was adjusted to 7 by the addition of sodium hydrogen carbonate. The solvent was removed. The residue was dissolved in a small amount of water and chromatographed over a hydrophobic polymer (eluent: water/acetonitrile). 17 mg(17%) of a yellowish powder were obtained. IR (KBr): 1756, 1616, 1577, 1398, 1333, 1153 cm-1 MS (ISN): (M-Na)- 380.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methoxybenzene | 3 Preparation of beta-anomer enriched 1-(2'-deoxy-2',2'-difluoro-3',5'-di-O-benzoyl-D-ribofuranosyl)-4-aminopyrimidin-2-one hydrochloride salt with 15 equivalents of bis-trimethylsilylcytosine EXAMPLE 3 Preparation of beta-anomer enriched 1-(2'-deoxy-2',2'-difluoro-3',5'-di-O-benzoyl-D-ribofuranosyl)-4-aminopyrimidin-2-one hydrochloride salt with 15 equivalents of bis-trimethylsilylcytosine Bis-trimethylsilylcytosine was prepared by combining 18.33 g of cytosine and 10 ml of anisole with 64.3 ml of N-methyl-N-(trimethylsilyl)-trifluoroacetamide and heating the solution at 80° C. for 30 minutes. 5.0 g of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-α-methanesulfonate, dissolved in 10 ml anisole, were reacted with the bis-trimethylsilylcytosine solution at 105° C. for 5 hours. HPLC analysis confirmed completion of the reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trimethylsilyl iodide In tetrahydrofuran; acetonitrile | 18 [3S-[3α(Z).4β]]-[[3-[[(2-Amino 4-thiazolyl)-(methoxyimino)acetyl]amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid, sodium salt EXAMPLE 18 [3S-[3α(Z).4β]]-[[3-[[(2-Amino 4-thiazolyl)-(methoxyimino)acetyl]amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid, sodium salt MSTFA (0.43 ml, 2.2 mmol) was added to a solution of (3S-trans)-[[3-[(benzyloxycarbonyl)-amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid, 1.1-dimethylethyl ester (0.73 g. 2.0 mmol) (see example 6) in 20 ml of dry acetonitrile at 0° C. Iodotrimethylsilane (0.56 ml, 4.4 mmol) was added 30 minutes later at 0° C. and stirring was continued for 30 minutes at room temperature. After evaporation in vacuo the residue was dissolved in 15 ml of dry tetrahydrofuran, (Z)-2-amino-α-(methoxyimino)-4-thiazoleacetic acid, 1-hydroxybenzotriazole ester (0.64 g: 2.0 mmol) was added and the mixture was stirred overnight at room temperature. The solvent was removed in vacuo. After adding ether and ice-cold water the pH was adjusted to 6.5 with NaHCO3. The organic layer was separated and the aqueous phase freeze-dried. chromatography on HP-20 with 8:2 water/acetone as eluent yielded the title compound (260 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoroacetic acid In methanol; methoxybenzene; acetonitrile | 35 (3S-trans)-[(3-Amino-4-methyl-2-oxo-1-azetidinyl)-oxy]acetic acid, 1,1-dimethylethyl ester EXAMPLE 35 (3S-trans)-[(3-Amino-4-methyl-2-oxo-1-azetidinyl)-oxy]acetic acid, 1,1-dimethylethyl ester (3S-trans)-[[3-[(t-Butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid 1,1-dimethylethyl ester (1.44 g, 4.4 mmol) (see example 34) was dissolved in a mixture of 8.8 ml of trifluoroacetic acid and 0.88 ml of anisole at -10° C. The solution was evaporated in vacuo 10 minutes later at 0° C., and the residue was stirred with ether, filtered off and dried over P2 O5 to give colorless crystals of the trifluoroacetate salt of the title compound; yield 0.61 g, melting point 111°-112° C., dec. The salt (1.38 g. 4.0 mmol) was suspended in dry acetonitrile at 0° C. N-Methyl-N-trimethylsilyltrifluoroacetamide (1.56 m 8.0 mmol) was added and stirring was continued for 30 minutes at room temperature. After addition of methanol (0.32 ml, 8.0 mmol) at 0° C. the precipitation of the title compound was completed by adding dry ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; acetonitrile | 13.C (C) (C) [1-[[1,4-Dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]carbonyl]-2-[(phenylmethoxy)carbonyl]hydrazino]acetic acid, 1,1-dimethylethyl ester 15.6 ml (80.0 mmol) of N-Methyl-N-trimethylsilyltrifluoroacetamide was added to a solution of 11.2 g (40.0 mmol) of [2-[(phenylmethoxy)carbonyl]hydrazino]acetic acid, 1,1-dimethylethyl ester in 60 ml of dry acetonitrile. After stirring for 30 minutes at room temperature, the clear solution was evaporated in vacuo and the residue was dissolved in 45 ml of dry dichloromethane. This solution was dropped into a suspension of 15.61 g of N,O-dibenzyl-comenamyl chloride, hydrochloride in 60 ml of dry dichloromethane at room temperature. After stirring overnight, the reaction mixture was evaporated in vacuo to leave a residue which was stirred with 10 ml of methanol, evaporated in vacuo again and then chromatographed on silica gel eluding with ethyl acetate and ethyl acetate/methanol (10:1). After evaporation in vacuo, the appropriate fractions yielded a solid foam which became crystalline by stirring with ether. Yield: 12.7 g; melting point 177°-178° C., dec. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; triethylamine In dichloromethane; water; ethyl acetate; Petroleum ether | F (F) (F) (3S)-[1-[[[[3-[[(1,4-Dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester To a suspension of 13.8 g of (S)-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone in 500 ml of ethyl acetate was added 5.63 ml (0.0626 mol) of chlorosulfonyl isocyanate. The mixture was stirred for 1 hour at room temperature to form a solution of (S)-1-[[(chlorosulfonyl)amino]carbonyl]-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone. The solution was cooled to 0° C., at which temperature a solution of silylated 1,4-dihydro-5-hydroxy-4-oxo-N-(2-oxo-1-imidazolidinyl)2-pyridinecarboxamide (prepared from a suspension of 14.9 g (0.0626 mol) of 1,4-dihydro-5-hydroxy-4-oxo-N-(2-oxo-1-imidazolidinyl)-2-pyridinecarboxamide in 500 ml of ethyl acetate by the addition of 46.4 ml of N-methyl-N-(trimethylsilyl)trifluoroacetamide (0.25 mol) and stirring for 30 minutes) was added slowly. Then 150 ml of dichloromethane was added, and the mixture was stirred at room temperature overnight. To the clear solution was added 26.2 ml of triethylamine (0.188 mol), followed by 300 g of ice and 200 ml of water. The pH was 6.5. After stirring for 11/2hours, the two phases were separated and the aqueous phase was washed with three 200 ml portions of ethyl acetate. After removal of residual ethyl acetate in vacuo, the pH of the aqueous phase was adjusted to 2 by the slow addition of 2N hydrochloric acid (47 ml) with cooling. The crystals were filtered off, suspended in 200 ml of ethyl acetate and stirred for one hour. Then the crystals were filtered off, washed twice with 30 ml of ethyl acetate and twice with 50 ml of petroleum ether and dried in vacuo, to yield 28.6 g of the title compound, melting point 190°-200° C., dec. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In <i>N</i>-methyl-acetamide; acetonitrile-water; ethyl acetate; acetone | 24.F (F) (F) (3S)-1-[[[[[(1,4-Dihydro-5-hydroxy-4-oxo-2pyridinyl)methyl]amino]sulfonyl]amino]carbonyl]2-oxo-3-[[(phenylmethoxy)carbonyl]amino]azetidine To a stirred suspension of 2-(aminomethyl)-4-oxo-5-(phenylmethoxy)pyridine (2.330 g, 10.13 mmole) in 60 ml of ethyl acetate was added N-methyl-N(trimethylsilyl)trifluoroacetamide (3.76 ml, 20.26 mmole). The resulting solution was stirred for 30 minutes at room temperature and then cooled to 0° C. Concurrently, to a stirred suspension of (S)-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone (2.228 g, 10.13 mmole) in 60 ml of ethyl acetate was added chlorosulfonyl isocyanate (882 μ1, 10.13 mmol). The resulting solution was stirred for 30 minutes at room temperature then cooled to 0° C. and treated with triethylamine (4.23 ml, 30.39 mmole) followed by the solution of silylated 2-(aminomethyl)-4-oxo-5-(phenylmethoxy)pyridine described above. The mixture was stirred for two days at room temperature. The mixture was concentrated in vacuo, the residue dissolved in acetonitrile-water (40-60) and the pH lowered to 2.9 whereupon a thick oil separated. Upon cooling to 5° C., the oil solidified. The solid was separated, washed four times with water, and dried in vacuo to afford 3.4 g of crude title compound. The crude was dissolved in a minimum volume of dimethylformamide and loaded on a column (1L) of macroreticular styrene-divinylbenzene copolymer. The column was eluted with a stepwise acetone-water gradient. Desired material eluted with ca. 65% acetone. The relevant fractions were combined and lyophilized to afford 2.69 g of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In <i>N</i>-methyl-acetamide; water; ethyl acetate; acetone | 4 (E) (3S)-[1-[[[[[[1,4-Dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]methyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester (E) (3S)-[1-[[[[[[1,4-Dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]methyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester To a stirred suspension of 2-(aminomethyl)-5-(phenylmethoxy)-4(1H)-pyridinone (2.330 g, 10.13 mmole) in 60 ml ethyl acetate was added N-methyl-N-(trimethylsilyl)trifluoroacetamide (3.76 ml, 20.26 mmole). The resulting solution was stirred for 30 minutes at room temperature and then cooled to 0° C. Concurrently, to a stirred suspension of (S)-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone (2.228 g, 10.13 mmole) in 60 ml ethyl acetate was added chlorosulfonyl isocyanate (882 μl, 10.13 mmol). The resulting solution was stirred for 30 minutes at room temperature, cooled to 0° C., and finally treated with triethylamine (4.23 ml, 30.39 mmole) followed by the solution of silylated 2-(aminomethyl)-5-(phenylmethoxy)-4(1H)-pyridinone described above. The mixture was stirred for two days at room temperature. The mixture was concentrated in vacuo, the residue dissolved in CH3 CN-water (40-60) and the pH lowered to 2.9 whereupon a thick oil separated. Upon cooling to 5° C., the oil solidified. The solid was separated, washed four times with water, and dried in vacuo to afford 3.4 g crude product. The crude product was dissolved in a minimum volume of dimethylformamide and loaded on a column (1 1) of HP-20 resin. The column was eluted with a stepwide acetone-water gradient Desired material eluted with ca. 65% acetone. The relevant fractions were combined and lyophilized to afford 2.69 g of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid In ethyl acetate; isopropyl alcohol | 18.A (A) (A) (2S-trans)-[1-[[[[3-[[[1,4-Dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-methyl4-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester (3S-trans)-(4-methyl-2-oxo-3-azetidinyl)carbamic acid, phenylmethyl ester (2.35 g) and 1.41 g of chlorosulfonyl isocyanate were stirred for 1 hour at 0°-5° C. in 50 ml of ethyl acetate. A clear solution was obtained (solution A). 1,4-Dihydro-4-oxo-N-(2-oxo-1-imidazolidinyl)-5-(phenylmethoxy)-2-pyridinecarboxamide (3.28 g) and 6 g of N-methyl-N-(trimethylsilyl)trifluoroacetamide were stirred in 50 ml of ethyl acetate for 1 hour at 40° C. (solution B). To the cooled (0° C.) solution A was added solution B during 30 minutes of stirring. After continuous stirring overnight, the solvent was evaporated and the residue (oily) stirred with 50 ml of isopropanol and 1 drop of acetic acid. The title compound was formed as a beige precipitate; melting point 163° C., dec.; 4.3 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane; ethyl acetate | 9.F (F) (F) (S)-[1-[[[[4-[[1,4-Dihydro-4-oxo-5-(phenylmethoxy)-1-(phenylmethyl)-2-pyridinyl]methyl]-2,3-dioxo-1-piperazinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester To a solution of (S)-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone (0.44 g, 2.0 mmol) in 25 ml of dry ethyl acetate was added 0.28 g (2.0 mmol) of chlorosulfonyl isocyanate and the solution was stirred for 30 minutes at room temperature. To this were added 12 ml of dichloromethane, 0.61 g (6 mmol) of triethylamine and a prestirred (three hours) mixture of 1-[[1,4-dihydro-4-oxo-5-(phenylmethoxy)-1-(phenylmethyl)-2-pyridinyl]methyl]-2,3-piperazinedione (0.83 g, 2.0 mmol) and N-methyl-N-(trimethylsilyl)trifluoroacetamide (1.59 g, 8.0 mmol) in 25 ml of dry ethyl acetate. After stirring for three days at room temperature, ice water was added and the pH was adjusted to one with hydrochloric acid. The insoluble residue was filtered off and dried in vacuo yielding 1.15 g of the title compound of 72% purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; water; ethyl acetate; acetone | 11.C (C) (C) (S)-[1-[[[[4-[[[4,5-Bis(phenylmethoxy)-2-pyridinyl]carbonyl]amino]-2,3-dioxo-1-piperazinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester To a suspension of (S)-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone (2.02 g, 9.18 mmol) in 130 ml of ethyl acetate, chlorosulfonyl isocyanate (1.43 g, 10 mmol) was added, and, after stirring for one hour, triethylamine (2.79 g, 27.54 mmol) was added at 0° C. To this mixture, a prestirred solution (1.5 hours) of N-(2,3-dioxo-1-piperazinyl)-4,5-bis(phenylmethoxy)-2-pyridinecarboxamide (4.10 g, 9.18 mmol) and N-methyl-N-(trimethylsilyl)trifluoroacetamide (5.4 g, 27.54 mmol) in 150 ml of ethyl acetate was added. After stirring overnight at room temperature, 220 ml of ice water was added and the pH was adjusted to 2 (from 10.3) with 3N hydrochloric acid. When the separated organic phase was treated with brine, the title compound precipitated and was filtered, washed with water and dried in vacuo, yielding 5.35 g. When 2.5 g of this material was triturated for one hour with a mixture of 25 ml of water and 37.5 ml of acetone at pH 6.3, 2.12 g of the title compound was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In methanol; water; methanol hydrate; ethyl acetate | 13 (E) (3S)-[1-[(1,4-Dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]-2-[[[[2-oxo-3-[[(phenylmethoxy)carbonyl]amino]-1-azetidinyl]carbonyl]amino]sulfonyl]hydrazino]acetic acid, 1,1-dimethylethyl ester (E) (3S)-[1-[(1,4-Dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]-2-[[[[2-oxo-3-[[(phenylmethoxy)carbonyl]amino]-1-azetidinyl]carbonyl]amino]sulfonyl]hydrazino]acetic acid, 1,1-dimethylethyl ester 9.0 ml (46.2 mmol) of N-methyl-N-trimethylsilyltrifluoroacetamide was added to a suspension of 3.2 g (11.0 mmol) of [1-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]hydrazino]acetic acid, 1,1-dimethylethyl ester in 120 ml of dry ethyl acetate. At room temperature, stirring was continued for 1 hour to give a clear solution (solution A). To a suspension of 2.42 g (11.0 mmol) (S)-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone in 80 ml of dry ethyl acetate 0.99 ml (11.0 mmol) chlorosulfonyl isocyanate was added with stirring. The mixture was stirred for 1 hour at room temperature and then cooled to 0° C. Solution A was dropped in at 0° C. and stirring was continued overnight at room temperature. After the addition of 4 ml of triethylamine, the mixture was evaporated in vacuo. The residue was dissolved in 10 ml of methanol-water (4:1). This solution was dropped into a mixture of 30 ml methanol/water, the pH of which was maintained at pH 2 to leave a residue (10.25 g) which became crystalline by stirring with few ml of water and methanol. The precipitate was purified by successive washing (stirring) with isopropanol/water (4:1), methanol, methanol/ether (1:1) and ether. Yield after drying in vacuo: 2.39 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In methanol; water; ethyl acetate | 14.D (D) (D) (S)-[1-[[[[3-[[[1,4-Dihydro-5-hydroxy-4-oxo-1-(phenylmethyl)-2-pyridinyl]acetyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidin yl]carbamic acid, phenylmethyl ester, monosodium salt 5.86 ml (30.0 mmol) of N-methyl-N-trimethylsilyltrifluoroacetamide was added to a suspension of 3.42 g (10.0 mmol) of 1,4-dihydro-5-hydroxy-4-oxo-N-(2-oxo-1-imidazolidinyl)-1-(phenylmethyl)-2-pyridineacetamide in 50 ml of dry ethyl acetate and stirring was continued for 1 hour at room temperature (solution A). To a solution of 2.20 g (10.0 mmol) of (S)-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone in 50 ml of dry ethyl acetate, 0.90 ml (10.0 mmol) of chlorosulfonyl isocyanate was added with stirring, and the mixture was stirred for 1 hour at room temperature and then cooled to 0° C. Solution A was dropped in with stirring at 0° C. After stirring overnight at room temperature, the mixture was evaporated in vacuo and the residue was taken up in a few ml of methanol and water. The pH was adjusted to 5.5 by the addition of dilute sodium hydroxide and the filtered solution was freeze dried. MPLC on macroreticular styrene-divinylbenzene copolymer eluding with water/acetone (8:1) and freeze drying of the relevant pure fractions yielded 0.40 g of the title compound. The impure fractions were purified by a second MPLC using the same conditions. Yield: 0.60 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; triethylamine In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; water; ethyl acetate; acetone | 22.G (G) (G) (S)-[1-[[[[2-[[3-[[(1,4-Dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]carbonyl]hydrazino]sulfonyl]amino]carbonyl]2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester To a suspension of 5.9 g (0.02 mol) of crude 3-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1-imidazolidinecarboxylic acid, hydrazide, 14.9 ml (0.08 mol) of N-methyl-N(trimethylsilyl)trifluoroacetamide was added and the mixture was stirred at 50° C. to form a solution (solution A). To a suspension of 4.4 g of (S)-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone (0.02 mol) in 160 ml of ethyl acetate, 1.76 ml of chlorosulfonyl isocyanate was added at room temperature. The mixture was stirred for 1 hour (solution B). Solution A was added (with cooling, ice) to solution B. After stirring for 1 hour, 2.8 ml (0.02 mol) of triethylamine was added to the mixture, which was then stirred overnight at room temperature. An additional 2.8 ml of triethylamine (0.02 mol) was added, followed by ice water. The mixture was stirred thoroughly for 1 hour and the layers were separated. The aqueous phase was acidified to pH 3 and the precipitate isolated by filtration. Yield: 5.3 g of crude title compound. The crude material was dissolved in acetone/water and the pH of the solution was adjusted to 6.5 by the addition of 2N sodium hydroxide. After removal of the acetone in vacuo, the aqueous solution was filtered and lyophilized to yield 5.5 g of the crude sodium salt of the title compound. Chromatography of the crude sodium salt on macroreticular styrene-divinylbenzene copolymer yielded 0.64 g of purified material. This was dissolved in water and acidified with 2N hydrochloric acid to precipitate the title compound. Yield: 0.5 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate In water; ethyl acetate; acetone | 1.C (C) To a suspension of 6.1 g (0.0242 mol) of N-(2,5-dioxo-1-imidazolidinyl)-1,4-dihydro-4-oxo-5-hydroxy-2-pyridinecarboxamide in 200 ml of ethyl acetate was added 19.48 ml of N-methyl-N-(trimethylsilyl)trifluoroacetamide (0.105 mol) at room temperature. The mixture was stirred at room temperature for 1 hour. After stirring for 10 minutes, a clear solution was formed (solution A). To a suspension of 5.32 g of (S)-(2-oxo-3-azetidinyl)carbamic acid, phenylmethyl ester (0.242 mol) in 200 ml of ethyl acetate was added at room temperature with stirring 2.11 ml (0.0242 mol) of chlorosulfonylisocyanate. The mixture was stirred at room temperature for 1 hour. After 10 minutes, a clear solution was formed (solution B). Solution A was added, with cooling, to solution B and the mixture was stirred overnight at room temperature. Then the solution was evaporated in vacuo and the remaining syrup dissolved in a mixture of 150 ml of acetone and 150 ml of water. The pH of the clear solution was adjusted to 5-5.5 by the addition of a sodium bicarbonate solution. The solution as kept at this pH for 2 hours. Then the acetone was removed in vacuo, and the aqueous solution lyophilized to yield 14.6 g of crude of (S)-[1-[[[[3-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]-2,4-dioxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, sodium salt. The crude material was purified by chromatography on XAD by elution with water/acetone (9:1). Yield: 2.5 g of purified product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.76 g (64%) | With hydrogenchloride; triethylamine In dichloromethane; ethyl acetate; acetonitrile | 5.F (F) (F) (3S)-[1-[[[[2-[[2-[(1,4-Dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]hydrazino]carbonyl]hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester 4.86 ml (25.0 mmol) of N-methyl-N-trimethylsilyltrifluoroacetamide was added to a suspension of 1.5 g (5.0 mmol) of 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid, 2-(hydrazinocarbonyl)hydrazide, dihydrochloride in 20 ml of dry acetonitrile. After stirring for 45 minutes at room temperature, the clear solution was evaporated in vacuo, and the residue was dissolved in 20 ml of dry ethyl acetate (Solution A). To a suspension of 1.10 g (5.0 mmmol) of (S)-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone in 40 ml dry ethyl acetate was added 0.45 ml (5.0 mmol) of chlorosulfonyl isocyanate with stirring, and the mixture was stirred for 1 hour at room temperature and then cooled to 0° C. After the addition of 10 ml of dry dichloromethane and 2.09 ml (15.0 mmol) of triethylamine, Solution A was dropped in with stirring at 0° C. After stirring overnight at 0° C., the reaction mixture was poured into ice water and the organic layer was separated. Acidification of the aqueous phase to pH 2 by the addition of 1N hydrochloric acid gave the title compound as a sticky precipitate which was collected by suction, washed with water and dried in vacuo. Yield: 1.76 g (64%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; triethylamine In dichloromethane; water; ethyl acetate; acetone | 1.C (C) (C) (S)-[1-[[[[[4-[[[(1,4-Dihydro-5-hydroxy-4-oxo-2-pyridinyl)methyl]amino]carbonyl]phenyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester To a suspension of 1.87 g of 4-amino-N-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)methyl]benzamide, trifluoroacetate salt (0.005 mol) in 20 ml of ethyl acetate was added 2.78 ml of N-methyl-N-(trimethylsilyl)trifluoroacetamide (0.015 mol). After 10 minutes, a solution was formed (solution A). To a suspension of 1.1 of (S)-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone (0.005 mol) in 20 ml of ethyl acetate was added 0.44 ml (0.005 mol) of chlorosulfonylisocyanate to form a solution. The solution was stirred for 1 hour, then 2.09 ml of triethylamine (0.015 mol) and 20 ml of dichloromethane were added, with cooling, followed by solution A. The mixture was stirred overnight at room temperature and evaporated in vacuo. The residue was dissolved in a mixture from acetone and water and the pH of the mixture was adjusted to 6-6.5 by the addition of 2N sodium hydroxide with cooling. After stirring for 2 hours, the acetone was removed in vacuo and the remaining aqueous phase was lyophilized. The crude sodium salt of (S)-[1-[[[[[4-[[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)methyl]amino]carbonyl]phenyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester was purified by MPLC on XAD-2. The compound was eluted with water. The fractions containing pure compound (TLC) were collected, evaporated to a small volume and acidified to precipitate (S)-[1-[[[[[4-[[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)methyl]amino]carbonyl]phenyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; acetonitrile | 4 7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-methoxyiminoacetamido]-3-[2-(2-hydroxyethyl)-1-methylpyrrolidinio]methyl-3-cephem-4-carboxylate: The silylated product was dissolved in acetonitrile (3.6 ml). A solution of 1-methyl-2-pyrrolidinethanol (0.326 ml) and N-methyl-N-(trimethylsilyl)trifluoroacetamide (0.445 ml) in acetonitrile (10 ml) was dropwise added to the resulting solution over 32 minutes under cooling to -30° C. The mixture was stirred at the same temperature for further 26 minutes. A mixture of methanol (1.8 ml) and acetonitrile (1.8 ml) was added to the reaction mixture and the formed precipitates were taken by filtration. The precipitates were purified twice by silica gel column chromatography (eluent: acetone-water) to obtain the desired product (63 mg). |
Yield | Reaction Conditions | Operation in experiment |
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In tetrahydrofuran; chloroform; water; acetonitrile; | EXAMPLE 43 syn-7-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(7-aminoquinolinium-1-ylmethyl)-3-cephem-4-carboxylate A suspension of 9.10 g. of syn-7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid in 40 ml. of chloroform was silylated by adding 12.5 ml. of N-methyl-N-trimethylsilyltrifluoroacetamide to the suspension and stirring for 1.5 hours. To the solution obtained were added 7.68 ml. of trimethylsilyliodide and the mixture was stirred for 15 minutes. The reaction mixture was evaporated to dryness and the solid residue of the silylated 3-iodomethyl derivative was dissolved in 40 ml. of acetonitrile and 1.40 ml. of tetrahydrofuran. The solution was stirred for about 5 minutes. A one-tenth aliquot of the solution of the silylated 3-iodomethyl derivative was added to a solution of 345 mg. of <strong>[580-19-8]7-aminoquinoline</strong> in 2 ml. of acetonitrile containing 853 mul. of N-methyl-N-trimethylsilyltrifluoroacetamide and the mixture was stirred at room temperature for 3 hours. After 235 mul. of water were added by pipette, the impure title compound was separated by filtration and dried. There were obtained 1.15 g. of the product. The product was purified by HPLC and 106 mg. of the purified product were obtained. NMR (DMSOd6/D2 O): signals at 8.84 (d, 1H), 8.63 (d, 1H), 8.16-7.82 (m, 1H), 7.72-6.92 (m, 3H), 6.70 (s, 1H), 5.62 (d, 1H), 5.51 (bs, 2H), 4.97 (d, 1H), 3.77 (s, 3H), and 3.07 (q, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; dichloromethane; acetonitrile; | EXAMPLE 6 syn-7-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(8-hydroxyisoquinolinium-2-ylmethyl)-3-cephem-4-carboxylate. To a suspension of 910 mg (2 mmole) of syn-7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid in 5 ml of methylene chloride were added 1.24 ml (7 mmole) of N-methyl-N-trimethylsilyltrifluoroacetamide and the mixture was warmed to 40 C. After a complete solution was obtained it was cooled to room temperature and 0.77 ml (5.4 mmole) of trimethylsilyliodide was added and the reaction mixture stirred under nitrogen at room temperature for 1.5 hours. The reaction mixture was evaporated and the silylated 3-iodomethyl derivative obtained as an oil was dissolved in 10 ml of acetonitrile. The solution was treated with 0.16 ml of tetrahydrofuran to destroy an TMSi complex or excess TMSi present in the solution. To the above solution of the silylated 3-iodomethyl derivative was added under nitrogen a solution of the trimethylsilyl derivative of <strong>[3482-14-2]8-hydroxyisoquinoline</strong> in acetonitrile (prepared by treating a suspension of 348 mg (2.4 mmole) of <strong>[3482-14-2]8-hydroxyisoquinoline</strong> in 10 ml of acetonitrile with 0.43 ml of mono-trimethylsilyltrifluoroacetamide). The mixture was stirred at room temperature for 2.5 hours and was then diluted with a small amount of diethyl ether and then with water. The product precipitated as a thick, tan precipitate. After stirring the mixture for 10 minutes, the product was separated by filtration and was washed with diethyl ether. The product was dried under vacuum at 40 C. for 1.5 hours to yield 1.27 g of impure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | In N-Bromosuccinimide; dichloromethane | 54 EXAMPLE 54 EXAMPLE 54 324 mg (1.63 mmoles) of N-methyl-N-trimethylsilyltrifluoroacetamide were added to a suspension of 409 mg (1.22 mmoles) of 7-benzamido-3-methyl-3-cephem-4-carboxylic acid-1-oxide in 25 ml of dichloromethane and after stirring at room temperature for 10 minutes, a clear, slightly yellow solution was obtained. This was diluted to 40 ml with dicloromethane and 50 mg of amidosulfonic acid (0.51 mmole) were added. This solution was cooled in an ice-bath and was brominated in one hour with 301 mg (1.70 mmoles) of N-bromosuccinimide to obtain a yield of 59% of trimethylsilyl 7-benzamido-3-bromomethyl-3-cephem-4-carboxylate-1-oxide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | In N-Bromosuccinimide; benzene | 70 EXAMPLE 70 EXAMPLE 70 375 mg (1.88 mmoles) of N-methyl-N-trimethylsilyltrifluoroacetamide were added to a suspension of 387.5 mg (1.16 mmoles) of 7-benzamido-3-methyl-3-cephem-4-carboxylic acid-1-oxide in 40 ml of benzene at room temperature and after stirring at room temperature for half an hour, a clear, yellow solution was obtained. This was cooled to 5° C. and bromination was carried out in half an hour with 306.0 mg (1.72 mmoles) of N-bromosuccinimide as the brominating agent to obtain a 56% yield of trimethylsilyl 7-benzamido-3-bromomethyl-3-cephem-4-carboxylate-1-oxide. |
52% | In N-Bromosuccinimide; dichloromethane | 53 EXAMPLE 53 EXAMPLE 53 To a suspension of 335 mg (1.00 mmole) of 7-benzamido-3-methyl-3-cephem-4-carboxylic acid-1-oxide in 25 ml of dichloromethane, 279 mg of N-methyl-N-trimethylsilyltrifluoroacetamide (1.40 mmoles) were added and the mixture was stirred for 10 minutes at room temperature to obtain a clear, yellow solution. This was cooled in an ice-bath and bromination was carried out in half an hour using 253 mg of N-bromosuccinimide (1.42 mmoles) as the brominating agent to obtain a yield of 52% of trimethylsilyl 7-benzamido-3-bromomethyl-3-cephem-4-carboxylate-1-oxide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With N-Bromosuccinimide In 1,2-dichloro-benzene | 38 EXAMPLE 38 EXAMPLE 38 0.3 ml of N-methyl-N-trimethylsilyltrifluoroacetamide (1.6 mmoles) was added at room temperature to a suspension of 354 mg (1.02 mmoles) of 3-methyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide in 40 ml of o-dichlorobenzene and after stirring for 15 minutes, 20 ml of o-dichlorobenzene were added thereto. Bromination was carried out as described in Example 37 using 310 mg (1.74 mmoles) of N-bromosuccinimide as the brominating agent and irradiation was continued for 80 minutes to obtain trimethylsilyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide in a yield of 45%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In chloroform | 1 syn-7-[2-(2-Aminooxazol-4-yl)-2-methoxyiminoacetamido]-3-(pyrazinium-1-ylmethyl)-3-cephem-4-carboxylate EXAMPLE 1 syn-7-[2-(2-Aminooxazol-4-yl)-2-methoxyiminoacetamido]-3-(pyrazinium-1-ylmethyl)-3-cephem-4-carboxylate syn-7-[2-(2-Aminooxazol-4-yl)-2-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid is suspended in chloroform and the suspension is treated with N-methyl-N-trimethylsilyltrifluoroacetamide at room temperature. The solution of the silylated derivative is treated with a 3-4 molar excess of trimethylsilyliodide (TMSI) to form the corresponding trimethylsilylated 3-iodomethyl compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium hydroxide; triethylamine In methanol; dichloromethane; water; ethyl acetate; Petroleum ether | 14.A (A) (A) (S)-[1-[[[[2-[(3,4-dihydroxyphenyl)[[(phenylmethoxy)carbonyl]amino]acetyl]hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester 3.91 ml (0.020 mol) of N-Methyl-N-trimethylsilyltrifluoroacetamide was added to a suspension of 2.97 g (0.010 mol) of 3,4-dihydroxy-α-[[(phenylmethoxy)carbonyl]amino]benzoic acid, hydrazide of dry ethyl acetate. After stirring for 3 hours at 50° C., the clear solution was evaporated in vacuo and the residue was dissolved in 20 ml of dry ethyl acetate (solution A). To a suspension of 2.20 g (0.010 mol) of (S)-(2-oxo-3-azetidinyl)carbamic acid, phenylmethyl ester in 80 ml of dry ethyl acetate, 0.90 ml (0.010 mol) of chlorosulfonylisocyanate was added with stirring and the mixture was stirred for 1 hour at room temperature and then cooled to 0° C. After the addition of 20 ml of dry dichloromethane and 4.18 ml (0.030 mol) of triethylamine, solution A was dropped in with stirring at 0° C. Stirring was continued for 10 minutes at 0° C. and 2.5 hours at room temperature. Then the reaction mixture was poured into 150 ml of an ice cold buffer solution (citrate pH 3). The pH was maintained by the addition of 2N hydrochloric acid (pH=3). The organic layer was separated and the aqueous phase was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried (magnesium sulfate) and evaporated in vacuo to leave a solid foam. This crude mixture of diastereomers of (S)-[1-[[[[2-[(3,4-dihydroxyphenyl)[[(t-butyloxy)carbonyl]amino]acetyl]hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester was stirred with petroleum ether containing a few ml of ether until it became crystalline; yield: 7.1 g. The crystalline mixture of diastereomers of (S)-[1-[[[[2-[(3,4-dihyroxyphenyl)[[(t-butyloxy)carbonyl]amino]acetyl]hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester was dissolved in 35 ml of methanol. After the addition of 17 ml of water, the pH of the solution was adjusted to 6.0 by the addition of dilute (1%) sodium hydroxide solution. The solution was concentrated in vacuo until an oil was separated which solidified by stirring with ether; yield: 3.3 g. Freeze drying of the aqueous phase yielded, after stirring with ether, an additional 2.5 g of (S)-[1-[[[[2-[(3,4-dihydroxyphenyl)[[(t-butyloxy)carbonyl]amino]acetyl]hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; triethylamine In dichloromethane; ethyl acetate | 9.C (C) (C) (S)-[1-[[[[4-[(3,4-Dihydroxybenzoyl)amino]-2,3-dioxo-1-piperazinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester To a suspension of 1.90 g (7.16 mmol) of N-(2,3-dioxo-1-piperazinyl)-3,4-dihydroxybenzamide in 30 ml of absolute ethyl acetate was added 5.70 g (28.64 mmol) of N-methyl-N-(trimethylsilyl)trifluoroacetamide, and the mixture was stirred for 3 hours at 60° C. The clear solution was evaporated to dryness and the crystalline residue suspended in 30 ml of ethyl acetate (solution A). To a suspension of 1.58 g (7.16 mmol) of (S)-(2-oxo-3-azetidinyl)carbamic acid, phenylmethyl ester in 50 ml of ethyl acetate was added 1.01 g (7.16 mmol) of chlorosulfonyl isocyanate. After stirring for 1 hour at room temperature, the solution was cooled to 0° C. and 24 ml of dichloromethane and 2.17 g (21.48 mmol) of triethylamine were added (solution B). To solution B, solution A was added dropwise at 0° C. After stirring overnight, ice was added and the pH brought to 1 with 3N hydrochloric acid. After stirring for 3 hours, the phases were separated. The organic phase was washed with water and the aqueous phase back-extracted two times with ethyl acetate. The combined organic phases were dried and evaporated to afford 3.0 g of crude material which was triturated with ether to yield 2.94 g of (S)-[1-[[[[4-[(3,4-dihydroxybenzoyl)amino]-2,3-dioxo-1-piperazinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane; ethyl acetate; acetonitrile | 17.C (C) (C) (S)-[1-[ [[[[2-[(3,4-Dihydroxyphenyl]amino]-2-oxoethyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester To a suspension of 1.24 g (6.79 mmol) of 2-amino-N-(3,4-dihydroxyphenyl)acetamide in 30 ml of absolute acetonitrile was added 2.71 g (13.6 mmol) of N-methyl-N-(trimethylsilyl)trifluoroacetamide. After stirring for two hours, the clear solution was evaporated to dryness, finally at high vacuum at 55° C. The residue was dissolved in 30 ml of ethyl acetate (solution A). To a suspension of 1.5 g (6.79 mmol) of (S)-(2-oxo-3-azetidinyl)carbamic acid, phenylmethyl ester in 40 ml of ethyl acetate was added 0.96 g (6.79 mmol) of chlorosulfonyl isocyanate. After stirring for one hour, the solution was cooled to 0° C. and 15 ml of dichloromethane and subsequently 2.06 g (20.37 mmol) of triethylamine (dropwise) was added. To this mixture, solution A was added dropwise and after stirring overnight at room temperature, 30 ml of ice water was added. The pH was adjusted to 1 with 3N hydrochloric acid, the phases were separated and the organic phase was dried over sodium sulfate. After the evaporation of the solvent, the residue was triturated with ether, filtered and dried in vacuo; yield: 1.63 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide | 2.G (G) (G) [3S(Z)]-2-[[[1-(2-Amino-4-thiazolyl)-2-[[1-[[[[[[3-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]tetrahydro-2-oxo-1(2H)-pyrimidinyl]carbonyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methyl-propanoic acid, diphenylmethyl ester To a solution of (S)-[1-[[[[[[3-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)-carbonyl]amino]tetrahydro-2-oxo-1(2H)-pyrimidinyl]-carbonyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-carbamic acid, phenylmethyl ester (5.24 g, 8.44 mmol) in 250 ml N,N-dimethylformamide, N-methyl-N-trimethylsilyl trifluoroacetamide (8.41 g, 42.2 mmol) was added. After 30 minutes 1.8 g palladium on carbon were added and the mixture was hydrogenolyzed for 1 hour. The catalyst was removed by filtration and to the filtrate (Z)-2-amino-α-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid, 1H-benzotriazol-1-yl ester (4.22 g, 7.59 mmol) was added. After stirring overnight the solvent was distilled off and the residue triturated with 100 ml water. The resulting solid was filtered off with suction and dried in vacuo. Yield 6.14 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane; ethyl acetate; Petroleum ether | 16.B (B) (B) (S)-[1-[[[[(2-cyano-4,5-dihydroxyphenyl)amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester To a suspension of 4.5 g (30.0 mmol) of 2-amino-4,5-dimethoxybenzonitrile in 60 ml of absolute ethyl acetate was added 12.0 g (60.0 mmol) of N-methyl-N-(trimethylsilyl)trifluoroacetamide. After stirring for 1.5 hours, the clear solution was evaporated to dryness, finally at high vacuum at 50° C. The residue was dissolved in 55 ml of ethyl acetate (solution A). To a suspension of 6.6 g (30.0 mmol) of (S)-(2-oxo-3-azetidinyl)carbamic acid, phenylmethyl ester in 150 ml of ethyl acetate was added 4.65 g (33.0 mmol) of chlorosulfonyl isocyanate. After stirring for 1 hour, the solution was cooled to 0° C. and 50 ml of dichloromethane and 9.0 g (90.0 mmol) of triethylamine (dropwise) were added. To this mixture, solution A was added dropwise at 0° C. and after stirring overnight at room temperature, the mixture was poured into ice water. The pH was adjusted to 2.0 with 3N hydrochloric acid. The organic phase was separated and the aqueous phase extracted twice with ethyl acetate. The combined organic phases were extracted twice with brine and dried over sodium sulfate. Evaporation of the solvent yielded 13.5 g of crude product which was slurried twice, each time with 200 ml of ether for 2 hours; yield of crystalline material after drying: 6.5 g. When petroleum ether was added to the ether layers, another 3.5 g of pure product was precipitated. Total yield: 10.0 g; melting point 111.9° C., dec. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In methanol; water; ethyl acetate | 7.C (C) (C) (S)-[1-[[[[3-[[(3,4-Dihydroxyphenyl)methylene]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, monosodium salt To a suspension of 4.37 g (19.9 mmol) of (S)-(2-oxo-3-azetidinyl)carbamic acid, phenylmethyl ester in 100 ml of ethyl acetate were added 2.81 g (19.9 mmol) of chlorosulfonyl isocyanate and the mixture was stirred for one hour at room temperature. The resulting solution was cooled to 0° C., and a solution of 8.7 g (19.9 mmol) of 1-[[[3,4-bis[(trimethylsilyl)oxy]phenyl]methylene]amino]-3-(trimethylsilyl)-2-imiazolidinone and 3.96 g of N-methyl-N-(trimethylsilyl)trifluoroacetamide (19.9 mol) in 50 ml of ethyl acetate was added dropwise. The reaction mixture was stirred overnight at ambient temperature, washed twice with brine, dried with sodium sulfate and evaporated in vacuo. The residue was dissolved in methanol/water and the pH adjusted to 6.5 by adding 1N sodium hydroxide. After evaporation of the methanol, the aqueous solution was freeze-dried (yield: 9.3 g; melting point 180° C., dec). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; triethylamine; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane; ethyl acetate; | (A) (S)-[1-[ [[[(3,4-Dihydroxyphenyl)amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester 16.27 g (81.7 mmol) of N-methyl-N-(trimethylsilyl)trifluoroacetamide was added to a solution of 9.76 g (40.8 mmol) of 4-amino-1,2-benzenediol, trifluoroacetate salt in 100 ml of ethyl acetate, and the mixture was stirred for one hour at room temperature. The solvent and most of the N-<strong>[815-06-5]methyltrifluoroacetamide</strong> were evaporated at 60 C. The residue was dissolved in 100 ml of ethyl acetate (solution A). To a suspension of 8.99 g (40.8 mmol) of (S)-(2-oxo-3-azetidinyl)carbamic acid, phenylmethyl ester in 100 ml of ethyl acetate was added 5.78 g (40.8 mmol) of chlorosulfonyl isocyanate, and the mixture was stirred for one hour at room temperature. After the addition of 100 ml of dichloromethane, the solution was cooled to 0 C. 16.52 g (163.3 mmol) of triethylamine and, subsequently, solution A were added. The resulting mixture was stirred overnight at room temperature. After addition of 200 ml of ice water, the pH was adjusted to 2 by adding 2N hydrochloric acid. The organic layer was separated and the aqueous phase extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo and the residue triturated with petroleum ether; yield: 11.40 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; triethylamine In dichloromethane; ethyl acetate | 12.D (D) (D) (S)-[1-[[[[2-[[(3,4-Dihydroxyphenyl)amino]carbonyl]hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester 2.93 ml (15.0 mmol) of N-methyl-N-trimethylsilyltrifluoroacetamide was added to a suspension of 1.10 g (5.0 mmol) of N-(3,4-dihydroxyphenyl)hydrazinecarboxamide, hydrochloride in 10 ml of dry ethyl acetate. After stirring for 1 hour at 50° C., the clear solution was evaporated in vacuo and the residue was redissolved in 10 ml of dry ethyl acetate (solution A). To a suspension of 1.10 g (5.0 mmol) of (S)-(2-oxo-3-azetidinyl)carbamic acid, phenylmethyl ester in 40 ml of dry ethyl acetate, 0.45 ml (5.00 mmol) of chlorosulfonyl isocyanate was added with stirring and the mixture was stirred for 1 hour at room temperature and then cooled to 0° C. After the addition of 10 ml of dry dichloromethane and 2.09 ml (15.0 mmol) of triethylamine, solution A was dropped in with stirring at 0° C. After stirring overnight at 0° C., the reaction mixture was poured into 10 ml of an ice cold buffer solution (citrate pH 2). The pH was maintained by the addition of 2N hydrochloric acid (pH=2). The organic layer was separated and the aqueous phase was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried (magnesium sulfate) and evaporated in vacuo to leave a residue which became crystalline by stirring with a few ml of ethyl acetate. After diluting with dry ether, the precipitate was collected by suction, washed with ether and dried in vacuo; yield: 1.53 g, melting point 130° C. dec. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane; ethyl acetate | 15.B (B) (B) (S)-[1-[[[[2-[(3,4-Dihydroxyphenyl)acetyl]hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester 1.95 ml (10.0 mmol) of N-methyl-N-trimethylsilyltrifluoroacetamide (95%) was added to a suspension of 0.91 g (5.0 mmol) of 3,4-dihydroxyphenylacetylhydrazide in 15 ml of dry ethyl acetate. After stirring for 1 hour at 50°-55° C., the almost clear solution was evaporated in vacuo and the residue was dissolved in 10 ml of dry ethyl acetate (solution A). To a suspension of 1.10 g of (S)-(2-oxo-3-azetidinyl)carbamic acid, phenylmethyl ester (5.0 mmol) in 40 ml of dry ethyl acetate, 0.45 ml (5.0 mmol) of chlorosulfonyl isocyanate was added with stirring. The mixture was stirred for 1 hour at room temperature and then cooled to 0° C. After the dropwise addition of a solution of 2.09 ml (15.0 mmol) of triethylamine in 10 ml of dry dichloromethane and solution A, stirring was continued for 2.5 hours at 0° C. Ice water was added, and the organic layer was separated and washed successively with cold buffer solution (citrate pH 2) and brine. Drying (magnesium sulfate) and evaporation in vacuo gave a residue which solidified by stirring with ether; yield: 2.1 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; triethylamine In dichloromethane; ethyl acetate; acetonitrile | 19 (E) (S)-[1-[[[[[2-(aminocarbonyl)-4,5-dihydroxyphenyl]amino]sulfonyl]amino]carbonyl]- 2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester (E) (S)-[1-[[[[[2-(aminocarbonyl)-4,5-dihydroxyphenyl]amino]sulfonyl]amino]carbonyl]- 2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester To a suspension of 6.1 g (29.8 mmol) of 2-amino-4,5-dihydroxybenzamide, monohydrochloride in 240 ml of absolute acetonitrile was added 17.8 g (89.4 mmol) of N-methyl-N-(trimethylsilyl)trifluoroacetamide to obtain a blue solution. After some minutes, a precipitate was formed. The mixture was stirred for 30 minutes at room temperature and then evaporated to dryness a high vacuum for 60 minutes. The crystalline residue was dissolved in 360 ml of absolute ethyl acetate (solution A). To a suspension of 6.56 g (29.8 mmol) of (S)-(2-oxo-3-azetidinyl)carbamic acid, phenylmethyl ester in 120 ml of absolute ethyl acetate was added 4.22 g (29.8 mmol) of chlorosulfonyl isocyanate. After stirring for 1 hour, the solution was cooled to 0° C. and 90 l of dichloromethane and 9.05 g (89.4 mmol) of triethylamine were added. (Solution B). Solution B was added in four portions to solution A at 0° C. After stirring overnight at room temperature, ice was added, and after 30 minutes, the pH was brought to 2 with 3N hydrochloric acid. The phases were separated, the aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were dried over magnesium sulfate. Evaporation and trituration of the residue with ether yielded 12.2 g of (S)-[1-[[[[[2-(aminocarbonyl)-4,5-dihydroxyphenyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-azeidinyl]carbamic acid, phenylmethyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; triethylamine; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane; ethyl acetate; | (C) (S)-[1-[[[[2-[(3,4-Dihydroxyphenyl)methylene]hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester To a suspension of 7.99 g (30 mmol) of 4-(hydrazonomethyl)-1,2-benzenediol, trifluoroacetate salt in 60 ml of ethyl acetate were added 11.13 ml (60 mmol) of N-methyl-N-(trimethylsilyl)trifluoroacetamide and 4.18 ml (30 mmol) of triethylamine. The mixture was stirred for one hour at 60 C., and the solvent and most of the N-<strong>[815-06-5]methyltrifluoroacetamide</strong> were evaporated in vacuo at 60 C. The resulting residue was suspended in 45 ml of ethyl acetate (solution A). To a suspension of 6.61 g (30 mmol) of (S)-(2-oxo-3-azetidinyl)carbamic acid, phenylmethyl ester in 90 ml of ethyl acetate was added 2.62 ml (30 mmol) chlorosulfonyl isocyanate, and the mixture was stirred for one hour at room temperature. After the addition of 45 ml of dichloromethane, the solution was cooled to 0 C., and 12.54 ml (90 mmol) of triethylamine was added, followed by solution A. The mixture was stirred over the weekend at room temperature and the precipitate filtered off by suction. To the filtrate were added 100 ml of ice water, and the mixture was washed two times with ethyl acetate. The aqueous phase was adjusted to pH 2 by adding 2N hydrochloric acid and extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was triturated with ether, filtered off by suction and dried in vacuo; yield: 5.58 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile | 40 A. A solution of the 2-carboxythieno[3,2-c]pyridine in acetonitrile was treated with MSTFA and the solution of the trimethylsilyl derivative was added to a solution of the 3-iodomethyl silylated cephalosporin to provide the title compound. NMR (DMSOd6): signals at 9.7 (s, 1H), 9.5 (d, 1H), 9.0 (d, 1H), 8.7 (d, 1H), 8.1 (s, 1H), 7.1 (s, 2H), 6.7 (s, 1H), 5.7 (q, 1H), 5.3 (d, 2H), 5.1 (d, 1H), 3.8 (s, 3H), 3.4 (q, 2H) delta. |
Yield | Reaction Conditions | Operation in experiment |
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With TMSI; acetic acid In tetrahydrofuran; dichloromethane; water; acetonitrile | 14.B B. B. Preparation of Title Compound A suspension of 910 mg. (2 mmole) of syn-7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid in 5 ml. of methylene chloride was treated with 1.24 ml. (7 mmole) of N-methyl-N-trimethylsilyltrifluoroacetamide (MSTFA) and the mixture warmed to about 40° C. to achieve silylation. After the solution was formed, the solution was cooled to room temperature and 0.77 ml. (5.4 mmole) of TMSI was added by syringe. The reaction mixture was stirred at room temperature under nitrogen for 1/2 hour and was then evaporated to a brown oil. The oil was dissolved in 5 ml. of acetonitrile and 0.73 ml. (9 mmole) of THF were added. The solution was stirred for 10 minutes. To this solution was added a solution of 286 mg. (2.4 mmole) of furo[3,2-c]pyridine in 5 ml. of acetonitrile to which had been added 0.43 ml. (2.4 mmole) MSTFA. The combined solutions were stirred at room temperature under nitrogen for 2 hours. The reaction mixture was diluted with diethyl ether and 3 drops of water were added to precipitate the product as a thick, tan solid. The mixture was sonicated, filtered, washed with diethyl ether, and dried at 40° C. for 1 hour under vacuum to yield 1.28 g. of the crude cephalosporin product. The product was purified via preparative HPLC using 5% acetonitrile, 2% acetic acid, and 93% water. There were obtained 14 mg. of the 2-cephem product and 580 mg. of the 3-cephem product as a white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chloro-trimethyl-silane; thionyl chloride In dichloromethane | 11.B Method B Method B To a suspension of D-2-(3,4-dihydroxyphenyl)-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]acetic acid, monohydrate (0.30 g; 0.81 mmol) in dry dichloromethane (24 ml), under argon, was added N-methyl-N-trimethylsilyltrifluoroacetamide (1.28 ml; 1.376 g; 6.90 mmol) and trimethylchlorosilane (0.09 ml; 0.077 g; 0.71 mmol). The mixture was stirred at room temperature for ca. 60 h. The solution was evaporated at reduced pressure and the residual oil dried at reduced pressure at ca. 35° C. for 0.5 h followed by 0.5 h at room temperature. The oil was redissolved in dry dichloromethane (15 ml) and reacted with thionyl chloride (0.075 ml; 0.122 g; 1.03 mmol) at room temperature, monitoring by infra red spectroscopy. After ca. 4 h the solution was evaporated at reduced pressure to give the product as a yellow solid (Quant.) which was dried at reduced pressure for 0.25 h and used directly without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With TMSI; acetic acid In dichloromethane; water; acetonitrile | 38 syn-7-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(2-methylfuro[3,2-b]pyridinium-4-ylmethyl)-3-cephem-4-carboxylate EXAMPLE 38 syn-7-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(2-methylfuro[3,2-b]pyridinium-4-ylmethyl)-3-cephem-4-carboxylate syn-7-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid, 910 mg. (2 mmole) were suspended in 5 ml. of methylene chloride and the suspension treated with 1.24 ml. (7 mmole) of MSTFA under nitrogen. The suspension was heated at 40° C. until a solution of the silylated derivative was formed (5 minutes). The solution was cooled to room temperature and 0.77 ml. (5.4 mmole) of TMSI was added with a syringe. The solution was stirred for about 45 minutes at room temperature under nitrogen to form the silylated 3-iodomethyl derivative. Thereafter, a solution of 319 mg. (2.4 mmole) of 2-methylfuro[3,2-b]pyridine in 10 ml. of acetonitrile was added to the reaction solution and the mixture was stirred for about 3 hours. The reaction mixture was then diluted with diethyl ether and two drops of water were added. The thick tan precipitate which formed was sonicated, filtered, washed with diethyl ether and dried under vacuum at 40° C. to give 1.03 g. of the crude product. The product was purified over C18 silica gel reverse phase chromatography using 5% acetonitrile:2% acetic acid:93% water, v:v:v to give 348 mg. of the purified product. NMR (90 MHz, DMSOd6) δ 9.45 (d, 1H), 9.3 (d, 1H), 8.7 (d, 1H), 7.9 (m, 1H), 7.75 (s, 1H), 7.15 (s, 2H), 6.65 (s, 1H), 5.6 (m, 3H), 5.0 (d, 1H), 3.8 (s, 3H), 3.4 (q, 2H), 2.7 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | In tetrahydrofuran; dichloromethane; water | 10 Sodium 7β-[D-2-[(4-Ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-phenylacetamido]-7α-formamido-3-[(2-formamido-1,3,4-thiadiazol-5-yl)thiomethyl]ceph-3-em-4-carboxylate Example 10 Sodium 7β-[D-2-[(4-Ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-phenylacetamido]-7α-formamido-3-[(2-formamido-1,3,4-thiadiazol-5-yl)thiomethyl]ceph-3-em-4-carboxylate Sodium 3-[(2-amino-1,3,4-thiadiazol-5-yl)thiomethyl]-7β-[D-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-phenylacetamido]-7α-formamidoceph-3-em-4-carboxylate (10mg, 0.014mmol) in water (3ml) was acidified to pH 3 with dilute hydrochloric acid, the mixture lyophilised and the resulting material suspended in dichloromethane (10ml) containing N -methyl- N -(trimethylsilyl)trifluoroacetamide (28mg, 0.14mmol). After stirring for 3h under argon, further N -methyl- N -(trimethylsilyl)trifluoroacetamide (28mg, 0.14mmol) was added and the mixture refluxed for 30 min. To the resulting solution was added formic-acetic anhydride (30mg, 0.35mmol) at room temperature and after 1h, the solution was evaporated, the residue taken up in tetrahydrofuran/water, and the pH adjusted to 6.5 with saturated sodium hydrogencarbonate. The solution was then concentrated and the residue chromatographed on 'Diaion' HP20SS resin to afford, after lyophilisation of the relevant fractions, the title product (3mg, 29%); νmax(KBr) 3420, 1770, 1710, 1675, and 1610cmmin1; δH(D2O) (major rotamer only) 1.17 (3H, t, J 7.3Hz), 2.95 and 3.31 (2H, ABq, J 16.7Hz), 3.45-3.60 (2H, m), 3.60-3.75 (2H, m), 3.9-4.1 (2H, m), 3.86 and 4.26 (2H, ABq, J 13.7Hz), 5.24 (1H, s), 5.50 (1H, s), 7.35-7.55 (5H, m), 8.10 (1H, s), and 8.42 (1H, s). [F.A.B. (+ve ion) (thioglycerol) MH+ 740]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | In dichloromethane; water | 14 Sodium 7β-[D,2-(3,4-Dihydroxyphenyl)-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]acetamido]-7α-formamido-3-[(2-formamido-1,3,4-thiadiazol-5-yl)thiomethyl]-ceph-3-em-4-carboxylate Example 14 Sodium 7β-[D,2-(3,4-Dihydroxyphenyl)-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]acetamido]-7α-formamido-3-[(2-formamido-1,3,4-thiadiazol-5-yl)thiomethyl]-ceph-3-em-4-carboxylate Sodium 3-[(2-amino-1,3,4-thiadiazol-5-yl)thiomethyl]-7β-[D,2-(3,4-dihydroxyphenyl)-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]acetamido]-7α-formamidoceph-3-em-4-carboxylate (15mg, 0.02mmol) was dissolved in water (2ml), carefully acidified to pH 2 with 0.1M H2SO4 and the mixture lyophilised. A suspension of this acid product in dry dichloromethane (10ml) containing N -methyl- N -(trimethylsilyl)trifluoroacetamide (56mg, 0.28mmol) was refluxed under argon for 1h, and then stirred at room temperature for 2h. Formic-acetic anhydride (35mg, 0.41mmol) was added and after 1h the title product (7mg, 50%) was isolated as described in Example 10; νmax(KBr) 3295, 1765, 1705, 1690, 1680, and 1605cmmin1; δH(D2O) (major rotamer only) 1.16 (3H, t, J 7.3Hz), 3.03 and 3.40 (2H, ABq, J 16.8Hz), 3.45 (2H, m), 3.6-3.7 (2H, m), 3.88 and 4.20 (2H, ABq, J 13.6Hz), 3.9-4.05 (2H, m), 5.25 (1H, s), 5.32 (1H, s), 6.8-7.0 (3H, m), 8.09 (1H, s) and 8.41 (1H, s). [F.A.B. (+ve ion) (thioglycerol) MH+ 772]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride In dichloromethane | 5.a a) a) D-2-[(4-Ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-(4-trimethylsilyloxyphenyl)acetyl Chloride A suspension of D-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-(4-hydroxyphenyl) acetic acid (207mg, 0.618mmol) in dry dichloromethane (10ml), under argon, was reacted with N -methyl- N -trimethylsilyltrifluoroacetamide (492mg, 2.47mmol) with stirring at room temperature. After 4 hrs the mixture was evaporated at reduced pressure, the residue dissolved in dry dichloromethane (5ml) and reacted with thionyl chloride (88mg, 0.741mmol), monitoring by infra red spectroscopy. A further quantity of thionyl chloride (264mg, 2.22mmol) was added after 1hr and stirring continued for a further period of 18 hr. The mixture was evaporated at reduced pressure to give the product as a light yellow foam which was dissolved in dry dichloromethane (7ml); νmax(CH2Cl2) 1790cmmin1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | In tetrahydrofuran; dichloromethane; water | 11 Sodium 3-[[2-(3,4-Diacetoxybenzoylamino)-1,3,4-thiadiazol-5-yl]thiomethyl]-7β-[2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-phenylacetamido]-7α-formamidoceph-3-em-4-carboxylate Example 11 Sodium 3-[[2-(3,4-Diacetoxybenzoylamino)-1,3,4-thiadiazol-5-yl]thiomethyl]-7β-[2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-phenylacetamido]-7α-formamidoceph-3-em-4-carboxylate Sodium 3-[(2-amino-1,3,4-thiadiazol-5-yl)thiomethyl]-7β-[D-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-phenylacetamido]-7α-formamidoceph-3-em-4-carboxylate (40mg, 0.056mmol) in water (5ml) was acidified to pH 3.0 with dilute hydrochloric acid, the mixture lyophilised and the resulting acid suspended in dichloromethane (15ml) containing N -methyl- N -(trimethylsilyl)trifluoroacetamide (223mg, 1.12mmol) under argon and refluxed for 30 min. The resulting cooled solution was treated with diacetoxybenzoyl chloride (14mg, 0.056mmol) in dichloromethane (0.3ml) and stirred for 1h. The reaction mixture was evaporated, the residue redissolved in tetrahydrofuran/water and the pH adjusted to 6.5 with saturated sodium hydrogen carbonate. The title product (26mg, 50%) was isolated using the procedure described in Example 10; νmax(KBr) 3400, 3300, 1770, 1710, 1675, and 1610cmmin1; δH(D2O - [CD3]2CO) (major rotamer) 1.23 (3H, t, J 7Hz), 2.40 (6H, s), 3.19 and 3.44 (2H, ABq, J 18Hz), 3.55 (2H, q, J 7Hz), 3.76 (2H, m), 4.07 (2H, m), 4.2-4.5 (2H, m), 5.31 (1H, s), 5.63 (1H, s), 7.3-7.6 (8H, m), and 8.18 (1H, s). [F.A.B. (+ve ion) (thioglycerol) MH+ 910]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydrogencarbonate In di-isopropyl ether; Dipropyl ether | 8 Preparation of (+)-methyl (R)-2-pentyl-2-cyclopenten-1-yl malonate EXAMPLE 8 Preparation of (+)-methyl (R)-2-pentyl-2-cyclopenten-1-yl malonate A suspension of racemic 2-(pentyl)-2-cyclopenten-1-ol (100 mg; 0.649 mmol), dimethylmalonate (100 mg; 0.757 mmol), ground KHCO3 (7 mg; 0.05 mmol), diisopropyl ether (1.8 ml) and lipase (100 mg) was stirred in a 10 ml flask at room temperature (20-23° C.). Results are shown in the table below. The reaction was followed by GC method and the ee was determined by treating samples collected at the times indicated with N-methyl-N-trimethylsilyl-trifluoracetamide in dipropyl ether to silylate unreacted alcohol and effecting a chiral GC analysis (Megadex 5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With sodium hydroxide In dichloromethane; water | C.4.a (E)-(6R,7R)-7-(2-Bromo-acetylamino)-3-(1-cyclopropyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1:1) Example C4a (E)-(6R,7R)-7-(2-Bromo-acetylamino)-3-(1-cyclopropyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1:1) (E)-(6R,7R)-7-amino-3-[(1-cyclopropyl-2-oxo-3-pyrrolidinylidene)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid trifluoroacetate (1:0.25) (8.0 g, 22.0 mmol) was suspended in 100 ml dichloromethane and N-methyl-N-(trimethylsilyl)trifluoroacetamide (9.0 ml, 48.4 mmol) was added. After 45 min a solution had formed which was cooled to 0° C. and treated with bromoacetyl bromide (2.10 ml, 24.2 mmol). After 30 min the ice-bath was removed and the reaction was stirred at ambient temperature for 2.5 h. The volatile components were evaporated and the residue was converted into its sodium salt by suspending it in water and adjusting the pH to 6.5 with 1M sodium hydroxide solution. The solution was freeze-dried and the crude lyophilisate was purified by reversed phase chromatography (RP-18 LiChroPrep gel) with a gradient of water:acetonitril (10:0, 9:1). The organic solvent was evaporated and the aqueous phase was freeze-dried. Yield: 60.0% light yellow lyophilisate; MS(ISP): 465.2 (M+H)+; IR(KBr): 1766, 1672, 1620 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.1% | In dichloromethane; water; acetonitrile | C.15.a (E)-(6R,7R)-7-(2-Bromo-acetylamino)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt Example C15a (E)-(6R,7R)-7-(2-Bromo-acetylamino)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (E)-(6R,7R)-7-amino-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (3.50 g, 10.0 mmol) was suspended in 50 ml dichloromethane and N-methyl-N-trimethylsilyltrifluoroacetamide (4.62 ml, 25.0 mmol) was added dropwise. After 1h a solution had formed which was cooled to 0° C. To this solution bromoacetyl bromide (1.04 ml, 12.0 mmol) was added. After 30 min the ice-bath was removed and the solution was stirred for 4 h at room temperature. After evaporation of the volatile components, the residue was suspended in water and the pH was adjusted to 6.8 with 1N sodium hydroxide solution and freeze-dried. The crude lyophilisate was purified by reversed phase chromatography (RP-18 LiChroPrep gel) with a gradient of water:acetonitrile (9:1, 8:2, 7:3). The organic solvent was evaporated and the aqueous phase was freeze-dried. Yield: 67.1% yellow lyophilisate; MS(ISP): 470.0 (M+H)+; IR(KBr): 1766, 1665, 1622 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane Inert atmosphere; Reflux; | The synthesis of the known guanidylated amino acid (1) followed a procedure reported by Feichtinger, K.,Zapf, C., Sings, H.L., and Goodman, M. J Org Chem 1998, 63, 3804. Briefly, a flame-dried round bottomflask containing 1 mmol of the 1-heptanoic acid was diluted with 8 mL of anhydrous dichloromethane(DCM). Then, N-methyl-N-trimethylsilyl-trifluoroacetamide (2.2 mmol) was added, and the reaction washeated to reflux under an argon atmosphere. Upon clarification of the solution, it was cooled andtriethylamine (1.1 mmol) and N,N'-di-Boc-N''-triflylguanidine (1.1 mmol) were added. The reaction wasthen stirred at room temperature for 4-5 hours, diluted with DCM and washed with brine and water. Theorganic phase was dried with sodium sulfate, concentrated and the product purified by columnchromatography (eluted 50:50 ethylacetate:hexanes). The purified yields ranged from 74-85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-ethylbenzophenone With water UV-irradiation; Stage #2: N-methyl-N-trimethylsilyl-2,2,2-trifluoroacetamide In ethyl acetate at 60℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium iodide; 2-hydroxyethanethiol at 60℃; for 0.333333h; | 2.2.4 Fraction collection and solvolysis General procedure: For metabolite characterisation, a LC fractionation of urine samples was performed. Sample preparation described above in Section 2.2.3. was applied to 20 replicates of 5 mL of urine. Prior to evaporation, the organic phases of all the replicates were combined, evaporated, reconstituted and injected in a single injection. Fractions corresponding to the expected retention time (RT ± 0.2 min) of the peaks of each metabolite were manually collected in pre- and post-administration samples. LC fractions were evaporated, and a solvolysis was performed using a procedure described elsewhere [17,26]. Briefly, fractions were reconstituted with 4 mL of ethyl acetate/methanol/sulphuric acid (80:20:0.06, v/v/v) and incubated at 55 °C for 2 h. Extracts were neutralized with 60 μL of 1 M NaOH and evaporated to dryness. The residues were reconstituted in 1 mL of sodium phosphate buffer (0.2 M, pH 7) and 250 μL of 5% K2CO3 solution were added. The extraction was performed with 6 mL of TBME by shacking at 40 mpm for 20 min. After centrifugation (3000g, 5 min), the organic layers were separated and evaporated. The dry extracts were derivatized by adding 50 μL of a mixture of MSTFA/NH4I/2-mercaptoethanol (1000:2:6, v/w/v) and incubating at 60 °C for 20 min. After incubation, the derivatized extracts were transferred to injection vials and 1 μL was analysed by GC-MS. | |
With ammonium iodide; 2-hydroxyethanethiol at 60℃; for 0.333333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In benzene; at 80℃; for 3h; | 254 g (2.0 moles) of N-<strong>[815-06-5]methyltrifluoroacetamide</strong>, 528 g (2.6 moles) of N, O-bis (trimethylsilyl) acetamide (N, O -bis (trimethylsilyl) acetamide) (BSA),And 400 ml of benzene. The reaction mixture was heated to 80 DEG C and stirred for 3 hours. After the reaction mixture was cooled to room temperature and the solvent was evaporated in the after-air,MSTFA was synthesized by fractional distillation under reduced pressure of 52 ~ 53 DEG C and 40 mmHg. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate at 37℃; for 1h; Inert atmosphere; | 2.3 Extraction of enzymes from tea leaves and analyses of enzymatic products The L-phenylalanine transaminase assay was conducted according to a literature method (Gonda et al., 2010) with slight modifications. The detailed enzyme extraction method is shown in the ‘Supplementary information’. A reaction mixture (400μL) containing 5mM [2H8]l-phenylalanine and crude enzyme solution (350μL) was incubated at 30°C for 60min, then acidified with 1M hydrochloric acid (80μL), and then incubated for another 30min at 30°C. The samples were extracted with ethyl acetate (800μL), and then centrifuged at 2500×g to separate the phases. The organic phase was collected, blown dry under a stream of nitrogen gas and derivatized with MSTFA (80μL) at 37°C for 60min. The MSTFA-derivated sample (1μL) was analyzed by gas chromatography-mass spectrometry (GC-MS) (The GC-MS analysis condition is described in the ‘Supplementary information’). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate at 37℃; for 1h; Inert atmosphere; | 2.3 Extraction of enzymes from tea leaves and analyses of enzymatic products The L-phenylalanine transaminase assay was conducted according to a literature method (Gonda et al., 2010) with slight modifications. The detailed enzyme extraction method is shown in the ‘Supplementary information’. A reaction mixture (400μL) containing 5mM [2H8]l-phenylalanine and crude enzyme solution (350μL) was incubated at 30°C for 60min, then acidified with 1M hydrochloric acid (80μL), and then incubated for another 30min at 30°C. The samples were extracted with ethyl acetate (800μL), and then centrifuged at 2500×g to separate the phases. The organic phase was collected, blown dry under a stream of nitrogen gas and derivatized with MSTFA (80μL) at 37°C for 60min. The MSTFA-derivated sample (1μL) was analyzed by gas chromatography-mass spectrometry (GC-MS) (The GC-MS analysis condition is described in the ‘Supplementary information’). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; ethyl acetate; N,N-dimethyl-formamide | 1.G (G) (G) 2-[[[1-(2-Amino-4-thiazolyl)-2-[[1-[[[[3-[[(1,4-dihydro-6,7-dihydroxy-4-oxo-3-quinolinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, diphenylmethyl ester To a solution of [1-[[[[3-[[(1,4-dihydro-6,7-dihydroxy-3-quinolinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester (3.35 g, 5.3 mmol) in 60 ml of N,N-dimethylformamide, N-methyl-N-trimethylsilyl trifluoroacetamide (5.28 g, 26.5 mmol) was added. After 30 minutes, 1.68 g of palladium on carbon was added, and the mixture was hydrogenolyzed for 1 hour. The catalyst was removed by filtration and the filtrate added to a solution of (Z)-2-amino-α-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid, 1-benzotriazole ester (2.96 g, 5.3 mmol) in 30 ml of N,N-dimethylformamide. After stirring for 20 hours, the solvent was distilled off and the residue triturated with 60 ml of water and 75 ml of ethyl acetate. The resulting crystals were filtered off, washed with water and dried in vacuo to give 3.27 g of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; N,N-dimethyl-formamide | 6.K (K) (K) 2-[[[1-(2-Amino-4-thiazolyl)-2-[[1-[[[[3-[[(7,8-dihydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)carbonyl]amino]-2-oxo-1-imidazolidinyl]-sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]-amino]oxy]-2-methylpropanoic acid, diphenylmethyl ester To a solution of [1-[[[[3-[[[4-oxo-7,8-bis(phenylmethoxy)-4H-pyrido[1,2-a]pyrimidin-3-yl]carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester (1.35 g, 1.66 mmol) in 65 ml of N,N-dimethylformamide, N-methyl-N-trimethylsilyl trifluoroacetamide (1.66 g, 8.33 mmol) was added. After 20 minutes 0.45 g of palladium on carbon was added, and the mixture was hydrogenolyzed for 1 hour. The catalyst was removed by filtration, and to the filtrate (Z)-2-amino-α-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid, 1-benzotriazole ester (0.83 g, 1.5 mmol) was added. After stirring overnight, the solvent was distilled off, and the residue triturated with 20 ml of water. The resulting solid was filtered off with suction and dried in vacuo. Yield of crude product: 1.28 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.2 g | With copper(l) chloride In toluene at 100℃; for 24h; | 3 Step 3: 4-Chloro-5-fluoro-6-(2-methoxyethoxy)nicotinonitrile (N-XI) CuCI (0.016 g, 0.16 mmol) followed by 2,2,2-trifluoro-N-methyl-N-(trimethylsilyl)acetamide (3.851 g,19.4 mmol) were added to a stirred solution of 4-chloro-5-fluoro-6-(2- methoxyethoxy)nicotinamide (N-XI-b) (1.60 g, 6.5 mmol) in toluene (20 mL) and the resulting reaction mixture was stirred at 100°C for 24 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases were dried over anhydrous Na2S04 and concentrated. The residue was purified by flash chromatography (silica, hexane/EtOAc; gradient 0% to 15% EtOAc) to afford the title compound (1.20 g) as a colorless powder. 1H NMR (400 MHz, DMSO-cfe) d (ppm) 8.63 (d, J = 08 Hz, 1H), 4.60 - 4.57 (m, 2H), 3.72 - 3.70 (m, 2H), 3.30 (s, 3H). UPLC-MS m/z 230.9 [M+H]+. |
Tags: 24589-78-4 synthesis path| 24589-78-4 SDS| 24589-78-4 COA| 24589-78-4 purity| 24589-78-4 application| 24589-78-4 NMR| 24589-78-4 COA| 24589-78-4 structure
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P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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