65052-63-3

Usage

Uses

Used in Pharmaceutical Industry:
Cefetamet hydrochloride is used as an antibiotic for treating a wide range of bacterial infections. Its effectiveness against gram-positive bacteria such as Streptococcus pneumoniae and Streptococcus pyogenes, as well as gram-negative bacteria like Escherichia coli, Proteus, Klebsiella pneumoniae, Haemophilus influenzae, and Neisseria gonorrhoeae, makes it a versatile choice for combating bacterial infections.
Additionally, Cefetamet hydrochloride demonstrates enhanced antibacterial activity against certain strains like Serratia, indole-positive Proteus, Enterobacter, Citrobacter, and Citrobacter, further expanding its utility in the treatment of resistant infections.

Synthesis

Suspend 2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid in tetrahydrofuran, add half amount of phosphorus oxychloride dropwise at 0 °C, keep the temperature not more than 5 lookchem °C, dropwise The reaction was completed for 30 minutes. Dimethylformamide and the other half of phosphorus oxychloride were added, and the reaction was carried out at 0 °C for 1 h to obtain a solution of active ester (I) at -5 °C.7-ADCA, bis-trimethylsilyl urea and ethyl acetate were refluxed at 75-77 °C for 2 h to obtain a solution of 7-ADCA silicon ester, which was cooled to -5 °C. It was combined with the solution of active ester and stirred at -5～0°C lookchem for 2h. Be raised to 15 ℃, add water, stir for 30min. Separate the water layer, adjust to Ph=2.6～3.0 with sodium hydroxide solution, place to separate out crystallization. Filtration, acetone recrystallization to give Cefetamet, yield 82%.

Antimicrobial activity

A semisynthetic cephalosporin formulated for oral use as the prodrug ester, cefetamet pivoxyl. It is less active than cefaclor and cefadroxil against Staph. aureus, but as active against streptococci and more active against enterobacteria, H. influenzae and N. gonorrhoeae, including β-lactamase-producing strains. L. monocytogenes, C. difficile, Sten. maltophilia and Burk. cepacia are all resistant. It is resistant to hydrolysis by common plasmid-mediated enzymes. The absolute bioavailability is about 50%. The plasma peak is delayed by food. Binding to plasma protein is about 20%. The volume of distribution approximates to the extracellular water. It is excreted into urine with a half-life of 2–2.5 h, principally in the glomerular filtrate. Elimination is linearly related to creatinine clearance. Side effects and uses are similar to those of other group 5 cephalosporins.

InChI:InChI=1/C14H15N5O5S2/c1-5-3-25-12-8(11(21)19(12)9(5)13(22)23)17-10(20)7(18-24-2)6-4-26-14(15)16-6/h4,8,12H,3H2,1-2H3,(H2,15,16)(H,17,20)(H,22,23)/b18-7-/t8-,12-/m1/s1

Synthetic route

3-deacetyloxy-7-aminocephalosporanic acid (22252-43-3, 26395-99-3, 70287-30-8, 72059-35-9) + ethyl 2-(2-aminothiazol-4-yl)-2-(anti)-methoxyiminoacetate (64485-88-7) → cefetamet (65052-63-3)

Conditions	Yield
With trimethylaluminum In hexane; dichloromethane at 35℃; for 2h; Concentration;	98.23%

tetrahydrofuran (109-99-9) + ester, 2-mercapto-5-phenyl-1,3,4-oxadiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino acetate + 7-Aminodiacetyloxy cephalosporanic acid → cefetamet (65052-63-3)

Conditions	Yield
With triethanolamine In water	92%

t-butyl 7α-amino-3-methyl-3-cephem-4-carboxylate (33610-06-9) + 2-(2-aminothiazol-4-yl)-2-(methoxy)iminoacetic acid (64485-90-1) → cefetamet (65052-63-3)

Conditions	Yield
(i) DCC, CH2Cl2, (ii) /BRN= 1081573/, Et3N, (iii) aq. HCO2H; Multistep reaction;

Cefetamet pivoxil (65243-33-6) → (2R,6R,7R)-7-{2-(2-Amino-thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino}-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-3-ene-2-carboxylic acid (126747-54-4) + (2R,6R,7R)-7-{2-(2-Amino-thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino}-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-3-ene-2-carboxylic acid 2,2-dimethyl-propionyloxymethyl ester (126617-54-7) + cefetamet (65052-63-3)

Conditions	Yield
With water In N,N-dimethyl-formamide at 37℃; Rate constant; phosphate buffer, var. pH;

ethyl 2-(2-aminothiazol-4-yl)-2-(anti)-methoxyiminoacetate (64485-88-7) → cefetamet (65052-63-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: Et3N / dimethylformamide / 3 h 2: aq. NaOH / dioxane / 0.5 h / Heating 3: (i) DCC, CH2Cl2, (ii) /BRN= 1081573/, Et3N, (iii) aq. HCO2H View Scheme

(Z)-γ-bromo-β-oxo-α-methoxyiminobutyric acid ethyl ester (65872-39-1) → cefetamet (65052-63-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: ethanol; H2O / 1 h / 20 °C 2: Et3N / dimethylformamide / 3 h 3: aq. NaOH / dioxane / 0.5 h / Heating 4: (i) DCC, CH2Cl2, (ii) /BRN= 1081573/, Et3N, (iii) aq. HCO2H View Scheme

ethyl (Z)-2-(methoxyimino)-2-[2-(triphenylmethyl)-aminothiazol-4-yl]acetate (64485-89-8) → cefetamet (65052-63-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: aq. NaOH / dioxane / 0.5 h / Heating 2: (i) DCC, CH2Cl2, (ii) /BRN= 1081573/, Et3N, (iii) aq. HCO2H View Scheme

ester, 2-mercapto-5-phenyl-1,3, 4-oxadiazolyl-(Z)-4-bromo-2-methoxyimino-3-oxo-butyrate + 7-Aminodiacetyloxy cephalosporanic acid → cefetamet (65052-63-3)

Conditions	Yield
With triethanolamine In tetrahydrofuran; water

7-amino-3-desacetoxycephalosporanic acid + 2-mercapto-5-methyl-1,3,4-thiadiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate → 3-Methyl-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-cephem-4-carboxylic acid + cefetamet (65052-63-3)

Conditions	Yield
With triethylamine In tetrahydrofuran; dichloromethane; N,N-dimethyl acetamide; water

3-deacetyloxy-7-aminocephalosporanic acid (22252-43-3, 26395-99-3, 70287-30-8, 72059-35-9) + (Z)-S-benzo[d]thiazol-2-yl 2-(2-aminothiazol-4-yl)-2-(methoxyimino)ethanethioate (80756-85-0) → 2-Mercaptobenzothiazole (149-30-4) + cefetamet (65052-63-3)

Conditions	Yield
Stage #1: 3-deacetyloxy-7-aminocephalosporanic acid; (Z)-S-benzo[d]thiazol-2-yl 2-(2-aminothiazol-4-yl)-2-(methoxyimino)ethanethioate With sodium 2-ethylhexanoate In water; acetone at 5 - 10℃; Stage #2: In water; acetone at 5℃; pH=2.5 - 3.0;

iodomethyl pivaloate (53064-79-2) + cefetamet (65052-63-3) → (6R,7R)-3-methyl-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-acetamido]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid pivaloyloxymethyl ester hydrochloride

Conditions	Yield
Stage #1: cefetamet With tetrapropylammonium iodide In 1-methyl-pyrrolidin-2-one at 20℃; for 0.5h; Stage #2: iodomethyl pivaloate With pyridine In 1-methyl-pyrrolidin-2-one at -10 - 20℃; for 1h; Stage #3: With hydrogenchloride In water Concentration;	94.86%

Upstream product

• 33610-06-9 t-butyl 7α-amino-3-methyl-3-cephem-4-carboxylate 
• 64485-90-1 2-(2-aminothiazol-4-yl)-2-(methoxy)iminoacetic acid 
• 65243-33-6 Cefetamet pivoxil 
• 64485-88-7 ethyl 2-(2-aminothiazol-4-yl)-2-(anti)-methoxyiminoacetate 
• 64485-89-8 ethyl (Z)-2-(methoxyimino)-2-[2-(triphenylmethyl)-aminothiazol-4-yl]acetate 
• 109-99-9 tetrahydrofuran 
• 22252-43-3 3-deacetyloxy-7-aminocephalosporanic acid 
• 758680-79-4 cefotaxime 
• 80756-85-0 (Z)-S-benzo[d]thiazol-2-yl 2-(2-aminothiazol-4-yl)-2-(methoxyimino)ethanethioate 
• 26395-99-3 7-aminodesacetoxycephalosporanic acid 
• 65872-41-5 cefotaxime 
• 116585-13-8 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl chloride hydrochloride 
• 999-97-3 1,1,1,3,3,3-hexamethyl-disilazane 
• 65872-39-1 (Z)-γ-bromo-β-oxo-α-methoxyiminobutyric acid ethyl ester 

Relevant academic research and scientific papers

Cefetamet pivoxil hydrochloride preparation method

The invention relates to a cefetamet pivoxil hydrochloride preparation method, which comprises: generating an intermediate I by using 7-ADCA and ethyl methylaminothiazolyloximate as starting raw materials under the catalysis of AlMe3; and carrying out an esterification reaction on the intermediate I and iodomethyl pivalate under the actions of a phase transfer catalyst and an acid adsorbent, carrying out salt formation on the esterified product, and crystallizing to obtain the target product cefetamet pivoxil hydrochloride. According to the present invention, the method has characteristics ofmild reaction conditions, high product purity, high yield and stable process, and is suitable for industrial production.

A process for the preparation of cephalosporin he beautiful acid

The invention relates to a method for preparing cefetamet acid. The method comprises the procedures of synthesis, decoloring, adsorption and crystallization. Due to improvement of the procedures of synthesis, decoloring and adsorption, impurities are reduced, the yield of cefetamet acid is increased, and the purity is improved. The method for preparing cefetamet acid, which is provided by the invention, is mild in reaction conditions, stable in process and applicable to industrial large-scale production.

IMPROVED PROCESS FOR THE PREPARATION OF CEPHALOSPORIN ANTIBIOTICS

Abstract The present invention more particularly relates to a process for the preparation of cephalosporin antibiotics of the Formula (I) wherein R1 represents hydrogen, trityl, alkyl like CH3, CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Rc represents hydrogen or (C1-C6) alkyl; R2 is carboxylate ion or COORd, where Rd represents hydrogen, ester or a counter ion which forms a salt; R3 represents hydrogen, CH3, CH2OCH3, CH2OCOCH3, CH=CH2, Formula (II).

NOVEL INTERMEDIATES FOR SYNTHESIS OF CEPHALOSPORINS AND PROCESS FOR PREPARATION OF SUCH INTERMEDIATES

A novel 4-halo-2-oxyimino-3-oxo butyric acid-N, N-dimethyl formiminium chloride chlorosulfate of formula (I) useful in the preparation of cephalosporin antibiotics, wherein X is chlorine or bromine; R is hydrogen, C1-4 alkyl group, an easily removable hydroxyl protective group, -CH2COOR5, or -C(CH3)2COOR5, wherein R5 is hydrogen or an easily hydrolysable ester group. The compound of formula (I) is prepared by reacting 4-halo-2-oxyimino-3-oxobutyric acid of formula (IV1), wherein X, R and R5 are as defined above, with N, N-dimethylformiminium chloride chlorosulphate of formula (VII), in an organic solvent at a temperature ranging from -30 °C to -15 °C. The cephalosporins that may be prepared from the intermediate include cefdinir, cefditoren pivoxil, cefepime, cefetamet pivoxil, cefixime, cefmenoxime, cefodizime, cefoselis, cefotaxime, cefpirome, cefpodoxime proxetil, cefquinome, ceftazidime, cefteram pivoxil, ceftiofur, ceftizoxime, ceftriaxone and cefuzonam.

Preparation of new intermediates and their use in manufacturing of cephalosporin compounds

The present invention provides new thioester derivatives of 4-halogeno-2-methoxyimino-3-oxo-butyric acid of the general formula (I), also, the invention provides a method by which the said thioester derivatives can be prepared by reacting 4-halogeno-2-methoxyimino-3-oxo-butyric acid of the general formula (II) with 2-mercapto-5-substituted-1,3,4-oxadiazoles of the general formula (III) in a solvent, in the presence of DMF/POCl3and in presence of an organic base and if desired the so obtained thioester derivatives so obtained are reacted with 7-amino-cephem carboxylic acids of the general formula (V) to produce condensed products which are insitu reacted with thiourea to get cephalosporin antibiotic compounds having the general formula (VI).

Thioester derivatives of thiazolyl acetic acid and their use in the preparation of cephalosporin compounds

The present invention provides novel thioester derivatives of thiazolyl acetic acid of the general formula (I), wherein, R1represents H, trityl, CH3, or CRaRbCOOR3, in which Raand Rb, independently of one another, represents hydrogen or methyl and R3represents H or C1-C7alkyl; and R2represents C1-C4alkyl or phenyl. The invention also provides a method for preparation of the thioester derivatives and reaction of the thioester derivatives with cephem carboxylic acids to produce cephalosporin antibiotic compounds having general formula (II), wherein, R1represents H, trityl, CH3, or CRaRbCOOR3, in which Raand Rb, independently of one another, represents hydrogen or methyl and R3represents H or C1-C7alkyl; R4is CH3, —CH═CH2, CH2OCH3, CH2OCOCH3, and R5is H or a salt or a carboxylic protecting group, comprising, acylating a compound of formula (III), wherein, R4and R5are defined as above, and R6is H or trimethylsilyl; with a compound of formula (I).

Process for producing cephalosporin antibiotics

A process for preparing certain cephalosporin antibiotics, namely, cefotaxime, cefetemet, and ceftriaxone sodium comprising acylation of 7-amino-3-cephem-4-carboxylic acid derivatives with 2-mercapto-5-methyl-1,3,4-thiadiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate having the formula: STR1

Process for the preparation of derivative of 7-[(2-hydroxyimino)-acetamido]-cephalosporanic acid

A novel process for the preparation of syn isomers of cephalosporanic acid derivatives of the formula STR1 comprising reacting first in a solvent and optionally in the presence of a base, a compound of the formula STR2 with a compound of the formula wherein R4 is selected from the group consisting of optionally substituted alkyl, aryl and aralkyl and Hal is a halogen and reacting the resulting product in a solvent and optionally in the presence of a base with a compound of the formula STR3 to obtain the compound of formula I' which are known to possess good antibiotic properties.

NEW SYNTHESIS OF OXIME-TYPE BETA-LACTAM ANTIBIOTICS

Reacton of anhydrous acids II with phosphorus pentachloride afforded hydrochlorides of chlorides III which were used in acylations of N,O-bis(trimethylsilyl) derivatives of 6-aminopenicillanic acid and 7-aminodeacetoxycephalosporanic acid.Change of the (Z)-configuration of the alkoxyimino group during the synthesis was observed only in the methoxyimino series.The prepared penicillins IV are effective against gram-positive as well as gram-negative bacteria.