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CAS No. : | 80082-65-1 | MDL No. : | MFCD08061571 |
Formula : | C4H8N2O4S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ISUIVWNWEDIHJD-HRFVKAFMSA-N |
M.W : | 180.18 | Pubchem ID : | 133361 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.75 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 39.48 |
TPSA : | 109.08 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -9.95 cm/s |
Log Po/w (iLOGP) : | -0.04 |
Log Po/w (XLOGP3) : | -3.59 |
Log Po/w (WLOGP) : | -0.95 |
Log Po/w (MLOGP) : | -1.49 |
Log Po/w (SILICOS-IT) : | -2.36 |
Consensus Log Po/w : | -1.69 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 3.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 1.37 |
Solubility : | 4230.0 mg/ml ; 23.5 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 1.88 |
Solubility : | 13800.0 mg/ml ; 76.5 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | 1.15 |
Solubility : | 2530.0 mg/ml ; 14.1 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.71 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
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 |
---|---|---|
With nitrogen;palladium; In methanol; water; | E. [(2S-trans)-3-Amino-2-methyl-4-oxo-1-azetidinesulfonic acid, inner salt 150.0 g of the sodium salt from part D were suspended in 1400 ml of methanol/water (1:1) in a 2-liter, three-necked round bottom flask, equipped with a mechanical stirrer, gas inlet tube, and pH electrode. The flask was flushed with nitrogen, palladium on carbon (30.0 g) was added, and a strong hydrogen stream was passed through the mixture. TLC showed completeness of reaction at pH 7.0. The solution was filtered by suction over Diacel and the cake was washed with 100 ml of methanol/water (1:1). | |
Hydrogenation reaction: take refined aztreonam single ring core 50 kg,The weight percentage of 99.5% concentration of methanol 200 kg,Suction filtration to hydrogenated ax,Cooled to 15 C,5% palladium on carbon was added2 kg,Nitrogen empty two times,And then into the hydrogen,Hydrogenation reaction for 4 hours,The hydrogen was evacuated by nitrogen.Adding 31% of purified hydrochloric acid 20 kg,Was added dropwise to the reaction solution,Cooled to 0 & lt; 0 &Reaction for 6 hours,filter,Drying to obtain aztreonam single ring mother nucleus,The total yield of aztreonam single ring mother nucleus is about 48%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.9% | A mixture of <strong>[80082-65-1](3S)-trans-3-amino-4-methyl-2-oxoazetidine-1-sulfonic acid</strong> [7.30 g, 40.52 mmol, J. Org. Chem., 47, 5160, (1982)], 2-(2-tritylamino)thiazol-4-yl)-(Z)-2-[1,5-dibenzhydryloxy-4-pyridon-2-yl methoxy]imino acetic acid (from step 36.50 g, 40.51 mmol), DCC (9.15 g, 44.34 mmol) and 1-hydroxybenzotriazole (5.47 g, 40.5 mmol) in dry DMF (400 ml) was stirred at room temperature for 30 min. and to this mixture NaHCO3 (3.40 g, 40.52 mmol) was added. The mixture was stirred under nitrogen at room temperature over night and filtered. The mother liquor was evaporated in vacuo to remove DMF and the residue obtained was dissolved in ethyl acetate and distilled water and adjusted to pH ~3. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The product thus obtained was purified over HP-20 column chromatography using a gradient mixture of water:acetonitrile (1:0 to 1:9) to give the title compound. Silica gel column chromatography using a gradient mixture of ethyl acetate: methanol (1:0 to 9:1) gave the title compound Yield: 37.00 g, 85.9% 1H-NMR (DMSO-d6): delta1.29(d, 3H, J=6.0 Hz), 3.54-3.61(1H), 4.30-4.35(m, 1H), 4.70(s, 2H), 5.98(s, 1H), 6.29(s, 2H), 6.71(s, 1H), 7.25-7.35(m, 35H), 7.51(s, 1H), 8.83(s, 1H), 9.39(d, 1H, J=7.7 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The crude azetidinone is treated in 250 ml of ethanol with 0.8 g of 5% palladium on charcoal catalyst and hydrogen is bubbled through the solution. After 90 minutes the mixture is filtered through Celite with 50 ml of ethanol used as a rinse. The addition of 1.2 ml of formic acid to this solution causes an immediate precipitation of the title zwitterion which is filtered after stirring for 1 hour to yield, after drying at 10-1 torr for 1 hour, 1.1 g of product. A second crop of product is obtained upon concentration of the filtrate and addition of more formic acid to give 1.3 g of the title zwitterion. | ||
EXAMPLE 1 (3S-trans)-3-Amino-4-methyl-2-oxo-1-azetidinesulfonic acid, inner salt A solution of 479 mg (0.001 mole) of (3S-trans)-3-methoxycarbonylamino-4-methyl-2-oxo-1-azetidinesulfonic acid, tetrabutylammonium salt in 10 ml of dichloromethane is treated with 139 mul of triethylamine and 112 mul of trichlorosilane. The resulting solution is refluxed for 3 hours and cooled to 0 C. Triethylamine (139 mul) and 0.5 ml of water are added, and the solution is stirred overnight. The resulting slurry is diluted with 20 ml of formic acid, stirred for 1 hour, and the solid filtered to give 117 mg of (3S-trans)-3-amino-4-methyl-2-oxo-1-azetidinesulfonic acid, inner salt. | ||
(D) (3S-trans)-3-Amino-4-methyl-2-oxo-1-azetidinesulfonic acid (3S-trans)-3-[(t-Butoxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinesulfonic acid tetra-n-butylammonium salt (6.3 g) is dissolved in 30 ml of 97% formic acid and stirred for 5 hours during which time a precipitate forms. The slurry is diluted with 30 ml of methylene chloride and filtered. The solids are further washed with methylene chloride and dried to yield 1.53 g of analytically pure product [alphaD21 =-41.0[c=1, water]. |
(D) (3S-trans)-3-Amino-4-methyl-2-oxo-1-azetidinesulfonic acid (3S-trans)-3-[(Benzyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinesulfonic acid tetra-n-butylammonium salt is dissolved in 250 ml of ethanol and 0.8 g of 5% palladium on charcoal is added. Hydrogen is bubbled through the stirred mixture for 90 minutes and the catalyst is filtered out. The addition of 12 ml of formic acid causes an immediate precipitation of the title compound which is filtered and dried. A second crop of the title compound is obtained upon concentration of the filtrate and the addition of more formic acid, yielding a total of 1.3 g of the title compound. | ||
(D) (3S-trans)-3-Amino-4-methyl-2-oxo-1-azetidinesulfonic acid (3S-trans)-3-[(Phenylacetyl)amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, tetra-n-butylammonium salt (3.79 g) is dissolved in 70 ml of methylene chloride, cooled to -15 C. and 2.3 ml of pyridine is added. The cold mixture is treated with 5.8 ml of a 12% mixture of phosgene in benzene and stirred at -10 C. for 90 minutes. Methanol (35 ml) is added and the mixture is stirred for 30 minutes followed by the addition of 1.62 ml of trifluoroacetic acid. The reaction mixture is allowed to warm to room temperature and stirred for 16 hours. The precipitated material is collected by filtration, washed with methylene chloride and dried to yield 0.43 g of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; triethylamine; In dichloromethane; acetonitrile; | (B) (3S-trans)-3-[[[2-(Formylamino)-4-thiazolyl]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, potassium salt To a solution of pyridine (9.6 ml) and methylene chloride (150 ml) in a 1-liter flask equipped with mechanical stirring and thermometer and pre-chilled to -15 C. was added a solution of pivaloyl chloride (15 ml) in methylene chloride (15 ml) at a rate to maintain a temperature below -10 C. After 2 minutes, a prechilled solution (-15 C.) of 2-formylamino-4-thiazolylacetic acid (22.5 g) and triethylamine (18.3 ml) in methylene chloride (240 ml) was added at a rate to maintain an internal temperature of below -5 C. After 5 minutes, a prechilled solution (-15 C.) of (3S-trans)-3-amino-4-methyl-2-oxo-1-azetidinesulfonic acid (21.6 g) and triethylamine (18 ml) in acetonitrile (180 ml) was added at a rate to control internal temperature below 0 C. The reaction mixture was cooled to and maintained at -10 C. for 90 minutes. The reaction was concentrated under reduced pressure to a volume of 150 ml and was then diluted with absolute ethanol to 750 ml. With mechanical stirring a 10% ethanolic potassium acetate solution (225 ml) was added. The resulting precipitate was stirred at -15 C. for 20 minutes, filtered under a nitrogen atmosphere, washed with two 200 ml portions of cold absolute ethanol and dried at 40 C. under vacuum to give 44.35 g of the title compound containing 1 mole of water of crystallization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; triethylamine; In aqueous tetrabutylammonium hydrogensulfate; dichloromethane; acetone; acetonitrile; | (A) (3S-trans)-3-[[[2-(t-Butoxycarbonylamino)-4-thiazolyl]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, potassium salt To a solution of triethylamine (5.1 ml, 36 mmol) and 2-(t-butoxycarbonyl-amino)-4-thiazolylacetic acid (7.74 g, 30 mmol in methylene chloride (80 ml) at -10 C. was added a solution of pivaloyl chloride (4.5 ml, 36 mmol) in methylene chloride (20 ml) over 15 minutes. To the above mixture was then added, in a steady stream over 5 minutes, a solution of (3S-trans)-3-amino-4-methyl-2-oxo-1-azetidinesulfonic acid (5.4 g, 30 mmol), triethylamine (4.65 ml, 33 mmol) and pyridine (2.85 ml, 36 mmol) in acetonitrile (50 ml) at -10 C.; the mixture was allowed to warm to ambient temperature with stirring. After removal of the solvents in vacuo, the residue was dissolved in 10% aqueous tetrabutylammonium hydrogensulfate (100 ml, preadjusted to pH 3.5 with potassium bicarbonate) and extracted with methylene chloride (200 ml). The organic layer was dried over sodium sulfate, filtered and evaporated to dryness to yield 16.3 g of the title compound as the tetrabutylammonium salt. The above salt was dissolved in acetone (75 ml), treated with a solution of potassium perfluorobutanesulfonate (8.45 g, 25 mmol) in acetone (75 ml), stirred at room temperature for 1 hour, and the solvents removed in vacuo. The residue was partitioned between water (75 ml) and methylene chloride-ethyl acetate (1:2, 225 ml), and the aqueous layer was lyophilized to afford 11.68 gm of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N-methyl-acetamide; water; | EXAMPLE 156 (3S-trans)-3-[[(2-Amino-4-thiazolyl)oxoacetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, potassium salt To a solution of diphenylphosphinyl chloride (1.85 g) in dry dimethylformamide (15 ml) cooled in an ice-methanol bath (-15 to -20 C.) is added (2-amino-4-thiazolyl)glyoxylic acid, triethylamine salt (2.14 g). After stirring for 0.5 hour a solution of (3S-trans)-3-amino-4-methyl-2-oxo-1-azetidinesulfonic acid (1.08 g; see example 139) and triethylamine (1.92 ml) in dry dimethylformamide (5 ml) is added to the cold mixed anhydride solution and the reaction mixture is stirred at 5 C. for 24 hours. Solvent is removed in vacuo, the residual dark oil is dissolved in water, and chromatographed on Dowex 50X2-400 resin (K? form, 200 ml). Upon elution with water (15 ml fractions) the crude product is collected in fractions 13-27 (3.37 g). Chromatography on HP-20 resin (200 ml), eluding with water (15 ml fractions), gives the desired product in fractions 18-26. Removal of water in vacuo gives the title compound as an amorphous powder. Anal. Calc'd for C9 H9 N4 O6 S2 K (372.42): C, 29.02; H, 2.44; N, 15.04; S, 17.22; K, 10.50. Found: C, 28.87; H, 2.62, N, 14.85; S, 15.09; K, 10.81. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 1: A 50 ml sample of triethylamine is added to a 0.5 1, three necked glass reactor, equipped with condenser and mechanical stirrer with 100 ml of acetone, and cooled to about 10 to about 15C. Under mixing, 50 g of azetidine is added to the reaction mixture, followed by 43g of TAEM. Stirring is continued for at least about 30 minutes, until the initially formed color disappears. Two additional 43 g portions of TAEM are then added in the same manner. After the reaction ends, typically after about four hours, water is added to quench the reaction, and the acetone is removed by distillation with the water. The reaction mass is acidified with HCl to a pH of about 5.5, and cooled. Mercaptobenzothiazole (MBT) precipitates, and is separated by filtration. The pH of the reaction mass containing tertbutylaztreonam is adjusted to about1.5 with HCl, and diluted with about 400 ml of water. The reaction mass is heated to about 600C and maintained at that temperature for about 5 hours. After verifying chromatographically that the deprotection reaction has ended, the reaction mass is cooled slowly over a period of about 5 hours to about 0 to about 5C. Aztreonam precipitates, and is filtered and washed several times with water. The filter cake is recharged, slurried with 240 ml of absolute ethanol, filtered again, and discharged. About 14Og of wet aztreonam crude is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a suspension of Azetidine of formula III (25 g) in mixture of aq.acetone or aq.THF, triethylamine (29 mL) was added. To the reaction mass, TAEM of formula (IV) (75 g) was added and the reaction mass was stirred at 150C -2O0C till completion of reaction. After completion of reaction was added a mixture of ethyl acetate and water (1 :1) and pH adjusted to 5.0. The by products obtained were removed, and layers separated. Organic layer was again extracted with water. The pH of the aqueous layer was acidified to 2.0 with dil. HCl at 00C -50C. The solid obtained was filtered, washed with water and dried under vacuum at 4O0C to yield title compound in pure form (48 g) | ||
5.4 g Azetidin is dissolved in 20 ml acetonitrile (or dimethyl formamide) with the assistance of 5 ml of triethylamine at room temperature. The solution is cooled to [0C.] A solution of 4 g TAEM in 25 ml THF is added with magnetic stirring. If the color disappears, 8 g TAEM in 50 ml THF is added. After 10 minutes, another 4.1 g TAEM in 25 ml THF is added. The solution is stirred at [0C] for an additional hour. The pH is adjusted to about 4-5 with a freshly prepared TFA solution (TFA-THF 1: 4, [V/V).] Being careful not to evaporate the acetonitrile, the THF is evaporated (weight loss is about 90 g) at30C under vacuum. The remaining residue is diluted with 200 ml ethylacetate and then extracted with 100 ml and then 50 ml of distilled water. The aqueous extracts are combined and washed twice with 50 ml ethylacetate after readjustment of the pH to about 4-5. The dissolved ethylacetate is removed from the aqueous phase by vacuum at [30 C.] 10-15 g [KC1] (or NaCl) is dissolved. The solution is acidified with [HC1] solution (cc. [HCL-DISTILLED] water 1: 4, [V/V)] with stirring (approx. 10 ml). The solution is cooled to [0 C] with slow stirring and crystallization occurs. The resulting suspension is refrigerated overnight (at about [5 C).] The suspension is filtered on a glass filter, and the crystals are washed with chilled water. The washed crystals are dried at room temperature. The product, Aztreonam t-butyl ester, is about 12.5-13 g white solid, which is sufficiently pure for the next step. | ||
65 g Azetidine is dissolved in a mixture of 240 ml acetonitrile and 60 ml triethylamine. When dissolution is complete, TAEM is added in four portions. The suspension is stirred for 20-30 min, then diluted with 500 ml EtOAc and 500 ml water and stirred for [5-10 MIN.] The pH of the emulsion is set to 5 with 2.4 M [HC1] solution. After the phases separate, the pH of the aqueous phase is checked. If the pH is between 4.20 and 5.30, the two phases are filtered and separated, otherwise more [HC1] is added. The upper phase is diluted with 900 ml ethylacetate and extracted with 2 x 500 ml water (faster phase separation). The combined aqueous phase is diluted with 500 ml water and washed with 2 x 500 ml ethylacetate. The dissolved ethylacetate is removed from the aqueous phase by vacuum. The aqueous phase is acidified further to pH 2 with 2.4 M [HC1] solution. The solution is stirred and cooled. Crystallization starts soon. The suspension is stirred and cooled to [0 C,] stirring at this temperature overnight. The suspension is filtered, washed with chilled water, dried at 38 [C] in air-circulated oven for 3 h. The yield is approx. 116-120 g of Aztreonam t-butyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(2Z)-3-[5- (diphenylmethoxy) -1-methyl-4-oxo (2-hydro- pyridyl) ]methoxy}-2-{2- [ (triphenyl methyl) amino] (1, 3-thiazol- 4-yl) }-3-azaprop-2-enoic acid (0.380 g, 0.52 mmol) , dicyclo- hexylcarbodiimide (0.160 g, 0.78 mmol) and l-hydroxy-7- azabenzotriazole (0.106 g, 0.78 mmol) were stirred at room temperature for 3 hours. Then (3S, 4S) -3-amino-4-methyl-2- oxoazetidinesulfonic acid (0.103 g, 1.04 mmol) and a catalytic amount of triethylamine were added to the previous solution which was stirred for 16 hours at room temperature. The epsilonol- vent was evaporated in vacuo and the residue was purified by column chromatography (silica gel, eluent; dichloromethane and methanol, 95/5, v/v) . 100 mg of desired compound was obtained.IH-NMR (DMS0-d5) d: 1.35 (d, 3H, J = 6.0 Hz), 3.55 - 3.60 (m, IH) 3.83 (s, 3H), 4.34 (dd, IH, J = 2.5, 7.7 Hz), 5.21 (s, 2H), 6.75 (m, IH), 6.77 (s, IH), 7.00 (s br, IH), 7.15 - 7.60 (m, 26H), 8.39 (s br, IH) 8.83 (s, IH), 9.33 (d, IH, J = 7.7 Hz) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.9% | A reaction flask was added the primary ring aztreonam (5.0g, 27.8mmol), acetonitrile (30 mL), was slowly added dropwise with stirring pyridine (2.7mL, 33.2mmol), the reaction was stirred until complete dissolution, cooled to -5 deg.] C, was added dropwise the side chain active ester compound (13.3g, 27.8mmol) in 60mL acetonitrile. after completion of the dropwise addition, the reaction was kept 4h, after completion of the reaction with dichloromethane (100mL) and 2% formic acid (about 100mL ), neutralized to pH 6.0, filtered, the organic layer was washed with stratification, washed with water (70mL × 3), the combined aqueous layer and washings using 20% nitric acid solution adjusted to pH 1, was slowly heated to about 35 , reaction heat 2h, active carbon was added 0.5h, filtered and the filtrate was cooled to 0 deg.] C, stirring the precipitated solid was filtered, washed with water, 40 deg.] C and dried in vacuo to give 11.0 g of crude aztreonam, 93.2% yield, 98.9% purity. To the reaction flask was added 10.7g aztreonam crude product (purity 98.9%) and 40ml of distilled water, and stirred to cool under a 71/92 0 saturated aqueous sodium carbonate until the solution is clear, was added dropwise hydrochloric acid (1M), and a white precipitate.Suction filtered and the filter cake was dried in vacuo 35 .The above solid was added absolute ethanol (700mL) and heated to 60 dissolved, heating was stopped, cooled with stirring, suction filtered, the filter cake was dried in vacuo at 35 , aztreonam give beta-type compound. Give a white solid 9.3g, 86.9% yield, 99.9% purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To the solution of (R,Z)-4-(4-(2-((((2-aminothiazol-4-yl)(carboxy)methylene)amino)oxy)-2-(2H-tetrazol-5- yl)ethoxy)phenyl)-l-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-lH-pyrazol-2-ium (18.8 mg, 0.031 mmol) in DMF (2 ml) was added DCC (63.2 mg, 0.306 mmol), and HOBT (23.46 mg, 0.153 mmol). The resulting solution was stirred at room temperature for 30 minutes, then (2S,3S)-3-amino-2-methyl-4-oxoazetidine-l-sulfonic acid (22.1 mg, 0.123 mmol) and sodium bicarbonate (30.9 mg, 0.368 mmol) were added. The resulting mixture was stirred at room temperature for lhour. After filtration of the reaction mixture, the filtrate was purified on reverse phase HPLC using acetonitrile (0.05%TFA)/water(0.05%TFA) as mobile phase to give the title compound. LC/MS: [M]+: 775.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of (S ,Z)-2-((( 1 -(tert-butoxy)-3-((2-(( 1 -(tert-butoxycarbonyl)azetidin-3-yl)amino)benzo [dl -thiazol-6-yl)oxy)- 1 -oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxy-carbonyl)amino)thiazol-4-yl)acetic acid (step G of Example 43) (24 mg, 0.033 mmol) in DMF (2 ml) was added DCC (34 mg, 0.16 mmol) and HOBt (20.01 mg, 0.131 mmol). The resulting mixture was stirred at room temperature for 30 minutes before addition of(25,35)-3-amino-2-methyl-4- oxoazetidine-1-sulfonic acid (23 mg, 0.13 mmol) and sodium bicarbonate (27 mg, 0.33mmol). The resulting mixture was stirred at room temperature for 3 hours. Additional DCC (33.7 mg, 0.163 mmol) was added and the resulting mixture continued to be stirred at room temperature overnight. After filtration, the filtrate was purified on reverse phase HPLC using acetonitrile (0. 05%TFA)/water (0. 05%TFA) as mobile phase to give (25,3 S)-3-((Z)-2-((((S)- 1 -(tert-butoxy)-3 -((2-((1 -(tert-butoxy-carbonyl)azetidin-3 -yl)amino)benzo[djthiazol-6- yl)oxy)- 1 -oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxy-carbonyl)amino)thiazol-4- yl)acetamido)-2-methyl-4-oxoazetidine- 1 -sulfonic acid. LC/MS: (M+ 1 ) = 897.5 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of (S,Z)-2-((( 1 -(tert-butoxy)-3 -((1 -((1 -(tert-butoxycarbonyl)azetidin-3- yl)amino)isoquinolin-6-yl)oxy)- 1 -oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxy-carbonyl)- amino)thiazol-4-yl)acetic acid (from Step E in Example 11) (60mg, 0.082 mmol) in DMF (3 ml) was added DCC (42 mg, 0.21 mmol) and HOBT (32 mg, 0.21 mmol). The resulting solution was stirred at room temperature for 30 minutes before addition of (2S,3S)-3-amino- 2-methyl-4-oxoazetidine-1-sulfonic acid (29.7 mg, 0.165 mmol) and sodium bicarbonate (34.6 mg, 0.412 mmol). The resulting mixture was stirred at room temperature overnight and filtered. The solution was purified on RP-HPLC (Gilson C-18 colunm) eluting with 20-100% ACN/water with 0.05% TFA. The product fraction was lyophilized to give the desiredproduct as a solid. LC-MS [M + HI: m/z 891.75. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(Z)-5-(3-(benzhydryloxy)-2-((((2-((tert-butoxycarbonyl)amino)thiazol-4- yl)(carboxy)methylene)-amino)oxy)-3 -oxopropoxy)- 1 -(3 -((tert-butoxycarbonyl)amino)20 propyl)-2-methyl-1H-indazol-2-ium was prepared from 5-(benzyloxy)-1H-indazole and tertbutyl (3-iodopropyl)carbamate by following the same procedure from steps A-J in Examples 30 and 31. To the solution of (Z)-5-(3-(benzhydryloxy)-2-((((2-((tert-butoxycarbonyl)- amino)thiazol-4-yl)(carboxy)methylene)amino)oxy)-3-oxopropoxy)- 1 -(3 -((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-indazol-2-ium (54 mg, 0.065 mmol) in DMF (2 ml)was added DCC (67 mg, 0.32 mmol) and HOBT (40 mg, 0.26 mmol). The resulting mixture was stirred at room temperature for 30 minutes before addition of(2S,3S)-3-amino-2- methyl-4-oxoazetidine-1-sulfonic acid (47 mg, 0.26 mmol) and sodium bicarbonate (55 mg, 0.65 mmol). The resulting mixture was stirred at room temperature for 5 hours. The mixture was filtered and the filtrate was purified on reverse phase HPLC using acetonitrile(0.05%TFA)/water (0.05%TFA) as mobile phase to give 5-(3-(benzhydryloxy)-2-(((Z)-(1- (2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2S ,3 S)-2-methyl-4-oxo- 1 -sulfoazetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy)- 1 -(3 -((tertbutoxycarbonyl)amino)propyl)-2-methyl- 1H-indazol-2-ium. LC/MS: M= 991.6 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.7 g | With formic acid; at 35 - 40℃; for 4.5h;Inert atmosphere; | Into a 1000 mL four-necked flask, 64.7 g (0.10 mol) of Compound D,500mL anhydrous formic acid,Nitrogen protection,Warmed to 35 ~ 40 ,Stirring reaction 4.5h,Precipitation of a large number of white solid, suction filtration,Aztreonam main ring was crude, aztreonam crude was added 250mL methyl formate,Temperature 0 ~ 5 beating 0.5h, suction filtration,Filter cake 30 vacuum dried 4h 12.7g Aztreonam main ring,The yield was 70.6%, specific rotation was -45 and HPLC purity was 98.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56 g | With ammonia; lithium; at -40℃; for 0.5h; | In a 500ml three-neck bottle,Cool the bottle to -40 C,Passing ammonia gas,Collect about 200ml of liquid ammonia,Add 80g of compound 5,Add 8.7g of lithium with stirring.Stir the reaction for half an hour,Heating the recovered liquid ammonia,Then 100 ml of ethanol was added to the remaining solid in the reaction flask.Concentrated hydrochloric acid 15ml,Stir at room temperature for 2 hours, then filter by suction.The solid was washed with 10 ml of ethanol.Dry the solid at 50-60 C for 10-18 hours.A solid of 56 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | To a solution of 225 <strong>[80082-65-1](2S,3S)-3-amino-2-methyl-4-oxo-1-azetidinesulfonic acid</strong> (55.0 g, 305.2 mmol) in a mixture of 226 EtOH (600 mL) and 227 H2O (300 mL) was added 55 Et3N (159.5 mL, 915.7 mmol) followed by 228 benzyloxycarbonyl N-succinimide (83.7 g, 335.8 mmol). The reaction mixture was stirred at 25 C. for 16 h. Ethanol was removed under vacuum and the residue was diluted with H2O (200 mL). The aqueous layer was extracted with EtOAc (2×100 mL). The EtOAc was discarded. 229 Tetrabutyl ammonium hydroxide (207.9 g, 320.5 mmol) as 40% w/v in H2O was added and the resulting aqueous layer was extracted with CHCl3 (5×150 mL). The organic extract was dried (MgSO4) and concentrated to give the 230 title compound (28) (160 g, 94%) as a solid. 1H-NMR (300 MHz, CDCl3): delta 7.38-7.31 (m, 5H), 4.31 (d, J=7.2 Hz, 1H), 6.01 (s, 2H) 5.50 (s, 1H), 5.12 (s, 2H), 4.31 (d, J=7.2 Hz, 1H), 3.28-3.22 (m, 8H), 1.62-1.59 (m, 8H), 1.46-1.39 (m, 11H), 1.01-0.96 (m, 12H); 13C-NMR (75 MHz, CDCl3): delta 162.9, 155.7, 136.1, 135.7, 128.5, 128.3, 128.2, 128.0, 67.0, 62.7, 59.2, 58.5, 23.9, 19.6, 18.2, 13.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60 g | The aqueous layer obtained in the step 3 was heated to 45 C, and the reaction was stirred for 1.5 hours.Obtaining (3S-trans)-3-tert-butoxycarbonylamino-4-methyl-2-oxo-1-azetidiniumsulfonic acidsodiumAqueous solutionTo the solution obtained in step 4, 120 g of concentrated sulfuric acid was slowly added dropwise, and the internal temperature was controlled to not exceed 30 C during the dropwise addition, and the reaction was completed at 30 C for 6 hours, the reaction was completed, the temperature was lowered to 0 to 5 C, and stirred for 30 minutes. Filtration, filter cake washed with ice pure water and acetone, vacuum dried at 40 C(3S-trans)-3-amino-4-methyl-2-oxo-1-azetidinsulfonic acid finished product 60g, the total yield was 49.6%, the purity was 99.23%, the content was 99.02%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | General procedure: To a solution of 20 (0.30 g, 0.44 mmol) in anhydrous DMF (6 mL)was added DIC (95.0 mg, 0.76 mmol) and HOBT (0.1 g, 0.76 mmol)successively. After stirred at r.t. for 1 h, a solution of 6 (0.11 g,0.58 mmol) in dry DMF (2.0 mL) with absolute triethylamine (0.14 g)was added thereto, then stirred at r.t. overnight. The mixture was dilutedwith water (20 mL) and extracted with EA (50 mL × 3). Theorganic layers were combined and washed with brine (50 mL × 3),concentrated under vacuum to give a brown oily residue. The residuewas purified via flash column chromatography (eluent: from 0 to 10%of methanol in DCM) to afford |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To a solution of 20 (0.30 g, 0.44 mmol) in anhydrous DMF (6 mL)was added DIC (95.0 mg, 0.76 mmol) and HOBT (0.1 g, 0.76 mmol)successively. After stirred at r.t. for 1 h, a solution of 6 (0.11 g,0.58 mmol) in dry DMF (2.0 mL) with absolute triethylamine (0.14 g)was added thereto, then stirred at r.t. overnight. The mixture was dilutedwith water (20 mL) and extracted with EA (50 mL × 3). Theorganic layers were combined and washed with brine (50 mL × 3),concentrated under vacuum to give a brown oily residue. The residuewas purified via flash column chromatography (eluent: from 0 to 10%of methanol in DCM) to afford |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To a solution of 20 (0.30 g, 0.44 mmol) in anhydrous DMF (6 mL)was added DIC (95.0 mg, 0.76 mmol) and HOBT (0.1 g, 0.76 mmol)successively. After stirred at r.t. for 1 h, a solution of 6 (0.11 g,0.58 mmol) in dry DMF (2.0 mL) with absolute triethylamine (0.14 g)was added thereto, then stirred at r.t. overnight. The mixture was dilutedwith water (20 mL) and extracted with EA (50 mL × 3). Theorganic layers were combined and washed with brine (50 mL × 3),concentrated under vacuum to give a brown oily residue. The residuewas purified via flash column chromatography (eluent: from 0 to 10%of methanol in DCM) to afford |
Tags: 80082-65-1 synthesis path| 80082-65-1 SDS| 80082-65-1 COA| 80082-65-1 purity| 80082-65-1 application| 80082-65-1 NMR| 80082-65-1 COA| 80082-65-1 structure
[ 143577-46-2 ]
(R)-Tetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide
Similarity: 0.52
[ 143577-46-2 ]
(R)-Tetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide
Similarity: 0.52
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