1,1-Dimethylethyl 2-[[(Z)-[1-(2-amino-4-thiazolyl)-2-(2-benzothiazolylthio)-2-oxoethylidene]amino]oxy]-2-methylpropanoate

Pale Yellow Solid

At 21 ° C, 35g cefotaxime side chain acid and 48gDMWas added to a mixture of dichloro and acetonitrile (the mass of the mixture was 250 g and the density was 1.0 g / cm 3)After stirring for 10 min, 1.0 mL of pyridine was added, At 22 ° C, triethylamine (8.0 mL)After the addition was completed, the temperature was raised to 30 ° C., the reaction was incubated for 50 minutes, cooled, 28 ml of triethyl phosphite was added dropwise at 21 ° C, Drop when the process of sharing 2.5h, After the addition was completed, the reaction was incubated at 21 ± 1 ° C for 3.0 h, Then cooled to 3 incubated reaction 30min, suction filtration, And dried at 60 to ceftazidime side chain acid active ester, the yield was 92.6percentThe content is 99.3percent.520 ml of chloroform was added to a clean and dry four-neck reaction flask, 30 ml of t-butanol was added, and the temperature was lowered to 0-5 C.Add 7-APCA 70g, pyridine active ester 105g, control the temperature to add triethylamine, Adjust the pH to 7.0-9.0. The temperature is controlled at 0-10 C for 20-24 hours. After the reaction, 150 ml of pure water was added, stirred for 1-2 hours, and chloroform was separated.Isopropanol precipitation in the drug solutionThe ceftazidime tert-butyl ester was stirred and crystallized at 0-10 C for 2 hours. Filter by suction and wash with isopropyl alcohol.After drying, ceftazidime tert-butyl ester was dried.Weight yield: 145%, purity 98.9%, At 21 ° C, 35g cefotaxime side chain acid and 48gDMWas added to a mixture of dichloro and acetonitrile (the mass of the mixture was 250 g and the density was 1.0 g / cm 3)After stirring for 10 min, 1.0 mL of pyridine was added, At 22 ° C, triethylamine (8.0 mL)After the addition was completed, the temperature was raised to 30 ° C., the reaction was incubated for 50 minutes, cooled, 28 ml of triethyl phosphite was added dropwise at 21 ° C, Drop when the process of sharing 2.5h, After the addition was completed, the reaction was incubated at 21 ± 1 ° C for 3.0 h, Then cooled to 3 incubated reaction 30min, suction filtration, And dried at 60 to ceftazidime side chain acid active ester, the yield was 92.6percentThe content is 99.3percent.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.[00322] A 10-mL round bottom flask equipped with a stir bar was charged with core (25 mg, 0.101 mmol, 1 equiv), followed by wet tetrahydrofuran (0.400 mL). The reaction vessel was placed in an ice water cooling bath. Triethylamine (0.42 mL, 0.305 mmol, 3 equiv) was added and the cooling bath was removed after 5 minutes. The vessel continued to stir at 23 °C as (Z)-iert-butyl 2-(((l-(2-aminothiazol-4-yl)-2-(benzo[d]thiazol-2-ylthio)-2- oxoethylidene)amino)oxy)-2-methylpropanoate (73 mg, 0.152 mmol, 1.5 equiv) was added portion- wise. Reaction progress was monitored by the consumption of the core by LC-MS analysis of aliquots removed from the reaction mixture. After 2.5 h, ethyl acetate (10 mL) and water (10 mL) were added and the layers were separated. The organic layer was washed with 0.5 M aqueous hydrochloric acid solution (2 x 10 mL) and the aqueous extracts were combined and concentrated with no additional heating on the rotovap bath. The crude material was purified via HPLC (Agilent Extend-C18, 90: 10'70:30 water-acetonitrile + 0.1percent formic acid, then 100percent acetonitrile +0.1percent formic acid) to provide the coupled product (3 mg, 5percent) as an off-white solid. 1H NMR (600 MHz, CD3OD), delta: 7.14 (s, 1H), 5.33 (s, 5.00-4.83 (m, 4H), 1.60 (s, 3H), 1.59 (s, 3H), 1.47 (s, 9H). HRMS (ESI): Calcd for (C18H25F2N5O9S2 - H): 556.0989; Found: 556.0985.19.1 g of 2-(2-amino-4-thiazolyl)-(Z)-2-[(l-tert.butoxycarbonyl-l- methylethoxy)imino]thioacetic acid-S-benzothiazol-2-yl-ester, 14.6 g of (6R, 7R)-7-amino-3-(l-pyridiniummethyl)-3-cephem-4-carboxylic acid iodide, monohydrate and 5.6 ml of triethylamine were stirred for 24 hours at 0 C in a mixture of 142.5 ml of dichloromethane and 7.5 ml of methanol. The solid substance was filtered off, washed with dichloromethane and vacuum-dried at room temperature. 16.0 g of the title compound were obtained in crystalline form. This compound was optionally stirred with acetone followed by filtration yield to get pure (6R, 7R)-7-[[2-(2-amino-4-thiazolyl)-(Z)-2-(tert.butoxycarbonyl-l- methylethoxy)imino]acetamido]-3-(l-pyridiniummethyl)-3-cephem-4- carboxylate. This compound thus obtained was treated with HCL in formic acid at 25 C for two hrs. After the completion of the reaction, ethyl acetate was added to the reaction mass and the layers were separated. The aqueous layer was treated with Amberlite resin to adjust the pH to 4.0. The product was filtered, slurry washed with acetone and dried to get Ceftazidime pentahydrate in pure form.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.

An intermediate for the preparation of cephalosporin derivatives.

Molecular Weight:478.6
XLogP3:5.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:11
Rotatable Bond Count:9
Exact Mass:478.08031872
Monoisotopic Mass:478.08031872
Topological Polar Surface Area:199
Heavy Atom Count:31
Complexity:713
Defined Bond Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes