153-61-7

Usage

Uses

Used in Pharmaceutical Industry:
(6R,7R)-3-(Acetoxymethyl)-8-oxo-7-(2-(thiophen-2-yl)acetamido)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid is used as an active pharmaceutical ingredient for the development of novel antibiotics. Its unique structure allows it to target specific bacterial enzymes, exhibiting a wide range of antibacterial activity against both gram-positive and gram-negative bacteria.
Used in Research and Development:
In the field of medicinal chemistry, (6R,7R)-3-(Acetoxymethyl)-8-oxo-7-(2-(thiophen-2-yl)acetamido)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid serves as a valuable research tool for studying the structure-activity relationships of antibiotics. It can be used to design and synthesize new generations of antibiotics with improved efficacy and reduced side effects.
Used in Respiratory Disease Treatment:
(6R,7R)-3-(Acetoxymethyl)-8-oxo-7-(2-(thiophen-2-yl)acetamido)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid is used as a therapeutic agent for respiratory diseases caused by bacterial infections. Its effectiveness against various bacterial strains makes it a promising candidate for treating respiratory infections.
Used in Neuromuscular Junction Studies:
(6R,7R)-3-(Acetoxymethyl)-8-oxo-7-(2-(thiophen-2-yl)acetamido)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid is also utilized in the study of neuromuscular junctions, where it can help researchers understand the interactions between bacteria and the nervous system, potentially leading to new insights into the development of neurological disorders.

Originator

Keflin,Lilly,US,1964

Manufacturing Process

7-(2'-Thienylacetamido)cephalosporanic acid sodium salt may be produced from 2-thienylacetyl chloride, obtainable by treatment of 2-thienylacetic acid [Ernst, Berichte, 19 (1886) 3281] with thionyl chloride in a conventional manner. The 2-thienylacetyl chloride is then reacted with 7- aminocephalosporanic acid and then converted to the sodium salt using sodium hydroxide.

Therapeutic Function

Antibacterial

Acquired resistance

Cephalothin is relatively susceptible to β-lactamases. Enterobacter, Klebsiella and Citrobacter species have acquired resistance by chromosomal constitutively produced βlactamases that are not inhibited by clavulanic acid. Bacteroides species develop resistance to β-lactams both by plasmids and chromasomally; however Bacteroides resistance remains susceptible to clavulanic acid. P aeruginosa is resistant to first and second generation cephalosporins because of problems with cell permeability/uptake, porin channels and drug efflux. Stenotrophomonas maltophila and Aeromonas species can be resistant through effects on porin channels and drug efflux, while S aureus can also be resistant due to drug efflux.

Mechanism of action

Inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs) which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested.

Clinical Use

Cephalothin is a relatively short acting first generation cephalosporin that is administered injectably. Although cephalothin is not approved for use in any animal species in the United States, the drug is used clinically in veterinary medicine. Cephalothin can cause nephrotoxicity.

Side effects

Manifestations may include urticarial or maculopapular rash, bronchospasm, and drug fever. Anaphylaxis, including severe hypotension and cardiac arrest, is reported. Rare cases of renal insufficiency associated with cephalothin may be hypersensitivity-mediated since fever, eosinophilia, and rash are often also present.https://www.drugs.com

InChI:InChI=1/C16H16N2O6S2/c1-8(19)24-6-9-7-26-15-12(14(21)18(15)13(9)16(22)23)17-11(20)5-10-3-2-4-25-10/h2-4,12,15H,5-7H2,1H3,(H,17,20)(H,22,23)/t12-,15-/m0/s1

Synthetic route

2-thienylacetic acid chloride (39098-97-0) + 7-Aminocephalosporanic acid (957-68-6) → cephalothin (153-61-7)

Conditions	Yield
Stage #1: 7-Aminocephalosporanic acid With N,O-bis-(trimethylsilyl)-acetamide In dichloromethane at 25 - 30℃; Inert atmosphere; Stage #2: 2-thienylacetic acid chloride In dichloromethane at 10℃; for 1h; Temperature; Solvent; Reagent/catalyst; Inert atmosphere;	92%
With N,O-bis-(trimethylsilyl)-acetamide In acetonitrile Inert atmosphere;	85%
With tetrabutylammomium bromide; sodium hydrogencarbonate In dichloromethane; water at -5 - 0℃; Temperature;

Thiophene-2-acetic acid (1918-77-0) + 7-Aminocephalosporanic acid (957-68-6) → cephalothin (153-61-7)

Conditions	Yield
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 30℃; for 2h; Time; Reagent/catalyst; Green chemistry;	85%

Thiophene-2-acetic acid (1918-77-0) + 1-methanesulfonyloxy-1,2,3-benzotriazole (54769-22-1) + 3-acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid → cephalothin (153-61-7)

Conditions	Yield
With sodium acetate; acetic acid; triethylamine In dichloromethane	70%

3-(trimethylsiloxy)-8-oxo-7-(2-(2-thienyl) acetamido)-5-thiazabicyclo [4.2.0]Carboxylic acid (80927-95-3) → cephalothin (153-61-7)

Conditions	Yield
With water; hydrogen cation Yield given;

2,2,2-trichloroethyl (6R,7R)-3-acetoxymethyl-7-(thien-2-ylacetamido)ceph-3-em-4-carboxylate (5317-29-3) → cephalothin (153-61-7)

Conditions	Yield
With Deacidite FF ion-exchange resin; zinc(II) chloride; zinc 1.) formic acid, RT, 5 h; Multistep reaction;

acetic acid (64-19-7) + 5-Methylene-2-[propylcarbamoyl-(2-thiophen-2-yl-acetylamino)-methyl]-5,6-dihydro-2H-[1,3]thiazine-4-carboxylic acid → propylamine (107-10-8) + cephalothin (153-61-7)

Conditions	Yield
With potassium chloride In water at 30℃; Equilibrium constant;

2-thienylacetic acid chloride (39098-97-0) → cephalothin (153-61-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: 92 percent / ethylene oxide / CH2Cl2 / 0.07 h 2: 68 percent / acetic acid / dimethylformamide / 3 h / 22 °C 3: 65 percent / potassium iodide, acetyl chloride / acetic acid / 0.17 h / 20 °C 4: 1.) Zn, ZnCl2; 2.) Deacidite FF ion-exchange resin / 1.) formic acid, RT, 5 h View Scheme
Multi-step reaction with 5 steps 1: 1.) phosphorus oxychloride; 2.) dimethylacetamide / 1.) MeOH, 45-55 deg C; 2.) CH2Cl2, 0-5 deg C, 45 min 2: 66 percent / sodium iodide / acetone / 1.5 h 3: 50 percent / acetic acid / dimethylformamide / 3 h / 22 °C 4: 65 percent / potassium iodide, acetyl chloride / acetic acid / 0.17 h / 20 °C 5: 1.) Zn, ZnCl2; 2.) Deacidite FF ion-exchange resin / 1.) formic acid, RT, 5 h View Scheme

Thiophene-2-acetic acid (1918-77-0) → cephalothin (153-61-7)

Conditions	Yield
Multi-step reaction with 5 steps 1: 46.3 percent / N,N'-dicyclohexylcarbodiimide / CH2Cl2 / 1 h / 20 °C 2: 66 percent / sodium iodide / acetone / 1.5 h 3: 50 percent / acetic acid / dimethylformamide / 3 h / 22 °C 4: 65 percent / potassium iodide, acetyl chloride / acetic acid / 0.17 h / 20 °C 5: 1.) Zn, ZnCl2; 2.) Deacidite FF ion-exchange resin / 1.) formic acid, RT, 5 h View Scheme

2,2,2-trichloroethyl (1S,6R,7R)-3-chloromethyl-7-(thien-2-ylacetamido)ceph-3-em-4-carboxylate 1-oxide (85904-87-6) → cephalothin (153-61-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: 66 percent / sodium iodide / acetone / 1.5 h 2: 50 percent / acetic acid / dimethylformamide / 3 h / 22 °C 3: 65 percent / potassium iodide, acetyl chloride / acetic acid / 0.17 h / 20 °C 4: 1.) Zn, ZnCl2; 2.) Deacidite FF ion-exchange resin / 1.) formic acid, RT, 5 h View Scheme

2,2,2-trichloroethyl (1S,6R,7R)-3-bromomethyl-7-(thien-2-ylacetamido)ceph-3-em-4-carboxylate 1-oxide (33492-83-0) → cephalothin (153-61-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: 68 percent / acetic acid / dimethylformamide / 3 h / 22 °C 2: 65 percent / potassium iodide, acetyl chloride / acetic acid / 0.17 h / 20 °C 3: 1.) Zn, ZnCl2; 2.) Deacidite FF ion-exchange resin / 1.) formic acid, RT, 5 h View Scheme

2,2,2-trichloroethyl (1S,6R,7R)-3-iodomethyl-7-(thien-2-ylacetamido)ceph-3-em-4-carboxylate 1-oxide (33465-64-4) → cephalothin (153-61-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: 50 percent / acetic acid / dimethylformamide / 3 h / 22 °C 2: 65 percent / potassium iodide, acetyl chloride / acetic acid / 0.17 h / 20 °C 3: 1.) Zn, ZnCl2; 2.) Deacidite FF ion-exchange resin / 1.) formic acid, RT, 5 h View Scheme

2,2,2-trichloroethyl (1S,6R,7R)-3-acetoxymethyl-7-(thien-2-ylacetamido)ceph-3-em-4-carboxylate 1-oxide (33492-84-1) → cephalothin (153-61-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 65 percent / potassium iodide, acetyl chloride / acetic acid / 0.17 h / 20 °C 2: 1.) Zn, ZnCl2; 2.) Deacidite FF ion-exchange resin / 1.) formic acid, RT, 5 h View Scheme

2,2,2-trichloroethyl (1S,6R,7R)-7-amino-3-bromomethylceph-3-em-4-carboxylate 1-oxide hydrobromide (85904-86-5) → cephalothin (153-61-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: 92 percent / ethylene oxide / CH2Cl2 / 0.07 h 2: 68 percent / acetic acid / dimethylformamide / 3 h / 22 °C 3: 65 percent / potassium iodide, acetyl chloride / acetic acid / 0.17 h / 20 °C 4: 1.) Zn, ZnCl2; 2.) Deacidite FF ion-exchange resin / 1.) formic acid, RT, 5 h View Scheme

2,2,2-trichloroethyl (1S,6R,7R)-7-amino-3-chloromethylceph-3-em-4-carboxylate 1-oxide (85904-84-3) → cephalothin (153-61-7)

Conditions	Yield
Multi-step reaction with 5 steps 1: 46.3 percent / N,N'-dicyclohexylcarbodiimide / CH2Cl2 / 1 h / 20 °C 2: 66 percent / sodium iodide / acetone / 1.5 h 3: 50 percent / acetic acid / dimethylformamide / 3 h / 22 °C 4: 65 percent / potassium iodide, acetyl chloride / acetic acid / 0.17 h / 20 °C 5: 1.) Zn, ZnCl2; 2.) Deacidite FF ion-exchange resin / 1.) formic acid, RT, 5 h View Scheme

2,2,2-trichloroethyl (1S,6R,7R)-3-bromomethyl-7-formamidoceph-3-em-4-carboxylate 1-oxide (33465-56-4) → cephalothin (153-61-7)

Conditions	Yield
Multi-step reaction with 5 steps 1: 1.) phosphorus oxychloride; 2.) dimethylacetamide / 1.) MeOH, 45-55 deg C; 2.) CH2Cl2, 0-5 deg C, 45 min 2: 66 percent / sodium iodide / acetone / 1.5 h 3: 50 percent / acetic acid / dimethylformamide / 3 h / 22 °C 4: 65 percent / potassium iodide, acetyl chloride / acetic acid / 0.17 h / 20 °C 5: 1.) Zn, ZnCl2; 2.) Deacidite FF ion-exchange resin / 1.) formic acid, RT, 5 h View Scheme
Multi-step reaction with 4 steps 1: 1.) phosphorus oxychloride; 2.) dimethylacetamide / 1.) MeOH, 45-55 deg C; 2.) CH2Cl2, 0-5 deg C, 45 min 2: 68 percent / acetic acid / dimethylformamide / 3 h / 22 °C 3: 65 percent / potassium iodide, acetyl chloride / acetic acid / 0.17 h / 20 °C 4: 1.) Zn, ZnCl2; 2.) Deacidite FF ion-exchange resin / 1.) formic acid, RT, 5 h View Scheme
Multi-step reaction with 5 steps 1: 98 percent / phosphorus tribromide / methanol; diethyl ether / 1.17 h / 0 - 10 °C 2: 92 percent / ethylene oxide / CH2Cl2 / 0.07 h 3: 68 percent / acetic acid / dimethylformamide / 3 h / 22 °C 4: 65 percent / potassium iodide, acetyl chloride / acetic acid / 0.17 h / 20 °C 5: 1.) Zn, ZnCl2; 2.) Deacidite FF ion-exchange resin / 1.) formic acid, RT, 5 h View Scheme
Multi-step reaction with 6 steps 1: 46.2 percent / conc. hydrochloric acid / tetrahydrofuran / 30 h / 6 °C 2: 46.3 percent / N,N'-dicyclohexylcarbodiimide / CH2Cl2 / 1 h / 20 °C 3: 66 percent / sodium iodide / acetone / 1.5 h 4: 50 percent / acetic acid / dimethylformamide / 3 h / 22 °C 5: 65 percent / potassium iodide, acetyl chloride / acetic acid / 0.17 h / 20 °C 6: 1.) Zn, ZnCl2; 2.) Deacidite FF ion-exchange resin / 1.) formic acid, RT, 5 h View Scheme

p-methoxybenzyl 7β-(2-thienylacetamido)-3-(acetoxymethyl)-3-cephem-4-carboxylate (52646-45-4) → cephalothin (153-61-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: CH2Cl2 / 0.25 h / 20 °C 2: H2O, H(1+) View Scheme

(6R,7R)-3-Acetoxymethyl-8-oxo-7-(2-thiophen-2-yl-acetylamino)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid 4-methyl-benzyl ester (80927-93-1) → cephalothin (153-61-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: CDCl3 / 0.25 h / 20 °C 2: H2O, H(1+) View Scheme

(6R,7R)-3-Acetoxymethyl-8-oxo-7-(2-thiophen-2-yl-acetylamino)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2-methyl-benzyl ester (80927-92-0) → cephalothin (153-61-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: CDCl3 / 0.25 h / 20 °C 2: H2O, H(1+) View Scheme

(6R)-3-acetoxymethyl-8-oxo-7t-(2-thiophen-2-yl-acetylamino)-(6rH)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (35607-83-1) → cephalothin (153-61-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: CH2Cl2 / 0.25 h / 20 °C 2: H2O, H(1+) View Scheme

2-thienylacetic acid chloride (39098-97-0) + 2-diethylamino-1,3,2-dioxaphospholane (3741-34-2) + 3-acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid → cephalothin (153-61-7)

Conditions	Yield
With sodium hydroxide; chloro-trimethyl-silane In water; ethyl acetate; acetonitrile

2-thienylacetic acid chloride (39098-97-0) + 2-chloro-[1,3,2]dioxaborolane (1192-03-6) + 7-Aminocephalosporanic acid (957-68-6) → cephalothin (153-61-7)

Conditions	Yield
With sodium hydrogencarbonate; triethylamine In dichloromethane; water; acetone

methyl 2-thiopheneacetate (19432-68-9) + 7-Aminocephalosporanic acid (957-68-6) → cephalothin (153-61-7)

Conditions	Yield
With ammonium hydroxide; penicillin G amidase In water at 20℃; pH=6.5 - 7; Enzymatic reaction;

2-thiopheneacetyl N-hydroxysuccinimide ester (93799-48-5) + 7-Aminocephalosporanic acid (957-68-6) → cephalothin (153-61-7)

Conditions	Yield
In 1,2-dimethoxyethane at 15 - 25℃; for 1h; Solvent; Temperature; Concentration; Irradiation;	154 g

pyrographite (7440-44-0) + thiophenol (108-98-5) + 1,2-dichloro-ethane (107-06-2) + cephalothin (153-61-7) → 3-((PHENYLTHIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4-CARBOXYLIC ACID

Conditions	Yield
With sodium hydrogencarbonate In methanol; ethanol; Isopropyl acetate; water; ethyl acetate	19.4%

cephalothin (153-61-7) → sodium cephalothin (58-71-9)

Conditions	Yield
With sodium 2-ethylhexanoic acid In acetone	26%

2,2,2-trichloroethyl glycinate*HBr (40126-72-5) + cephalothin (153-61-7) → {[(6R,7R)-3-Acetoxymethyl-8-oxo-7-(2-thiophen-2-yl-acetylamino)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carbonyl]-amino}-acetic acid 2,2,2-trichloro-ethyl ester (113322-14-8)

Conditions	Yield
With triethylamine; diisopropyl-carbodiimide In dichloromethane	28%

H2N-TrpOTce (113322-02-4) + cephalothin (153-61-7) → (S)-2-{[(6R,7R)-3-Acetoxymethyl-8-oxo-7-(2-thiophen-2-yl-acetylamino)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carbonyl]-amino}-3-(1H-indol-3-yl)-propionic acid 2,2,2-trichloro-ethyl ester (113322-16-0)

Conditions	Yield
With methyl(diethylamino)acetylene In dichloromethane	31%

1-methyl-5-mercaptotetrazole (13183-79-4) + cephalothin (153-61-7) → 3-(((1H-TETRAZOL-5-YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4-CARBOXYLIC ACID

Conditions	Yield
In acetic acid	31%

2-mercapto-5-methyl-1,3,4-thiadiazole (29490-19-5) + cephalothin (153-61-7) → 3-(((5-METHYL-1,3,4-THIADIAZOL-2-YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4-CARBOXYLIC ACID

Conditions	Yield
In acetonitrile	33.9%

N-(2-hydroxyethyl)nicotinamide (6265-73-2) + cephalothin (153-61-7) → 2-<(3-pyridinylcarbonyl)amino>ethyl 7-(2-thienylacetamido)cephalosporante Δ2 + 2-<(3-pyridinylcarbonyl)amino>ethyl 7-(2-thienylacetamido)cephalosporante Δ3 (154777-98-7)

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide at 20 - 25℃; for 20h;	A 17.9% B 35.9%

1-(carboxymethyl)-1-H-tetrazole-5-thiol + cephalothin (153-61-7) → 3-(((1-(CARBOXYMETHYL)-1H-TETRAZOL-5-YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4-CARBOXYLIC ACID

Conditions	Yield
In hexane; ethyl acetate; acetonitrile	38%

Octanethiol (111-88-6) + cephalothin (153-61-7) → N-((6R,7R)-3-((octylthio)methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-yl)-2-(thiophen-2-yl)acetamide

Conditions	Yield
With 6,6′-[(3,3′-di-tert-butyl-5,5′-dimethoxy-1,1′-biphenyl-2,2′-diyl)bis(oxy)]bis(di-benzo[d,f][1,3,2]dioxaphosphepin); bis(dibenzylideneacetone)-palladium(0) In acetonitrile at 60℃; for 5h; Tsuji-Trost Allylation; Schlenk technique; regioselective reaction;	39%

vinyldiazomethane (2032-04-4) + acetonitrile (75-05-8) + cephalothin (153-61-7) → allyl 7β-(2-(thien-2-yl)acetamido)-3-(acetoxymethyl)-3-cephem-4-carboxylate (104949-45-3) + C21H23N3O6S2

Conditions	Yield
In diethyl ether	A 40% B 36%

para-thiocresol (106-45-6) + cephalothin (153-61-7) → (6R,7R)-8-oxo-7-(2-(thiophen-2-yl)acetamido)-3-((p-tolylthio)methyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Conditions	Yield
With 6,6′-[(3,3′-di-tert-butyl-5,5′-dimethoxy-1,1′-biphenyl-2,2′-diyl)bis(oxy)]bis(di-benzo[d,f][1,3,2]dioxaphosphepin); bis(dibenzylideneacetone)-palladium(0) In acetonitrile at 40℃; for 7h; Tsuji-Trost Allylation; Schlenk technique; regioselective reaction;	41%

pyrographite (7440-44-0) + 1-methyl-5-mercaptotetrazole (13183-79-4) + cephalothin (153-61-7) → 3-(((1-methyl-1H-tetrazol-5-yl)thio)methyl)-7-(2-(2-thienyl)acetamido)-3-cephem-4-carboxylic acid

Conditions	Yield
With methanesulfonic acid; sodium hydrogencarbonate In water; ethyl acetate; butanone	41.6%

5-mercapto-3-methyl-1,2,4-oxadiazole + cephalothin (153-61-7) → 3-(((3-METHYL-1,2,4-OXADIAZOL-5-YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4-CARBOXYLIC ACID

Conditions	Yield
With sodium chloride; sodium hydrogencarbonate In 1,1,2-trichloroethane; ethyl acetate	48%

5-[(tetrazol-1-yl)methyl]-1,3,4-thiadiazole-2-thiol (202116-96-9) + cephalothin (153-61-7) → 7-{[(thiophen-2-yl)acetyl]amino}-3-{[5-[(tetrazol-1-yl)methyl]-1,3,4-thiadiazol-2-ylthio]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Conditions	Yield
With boron trifluoride diethyl etherate In acetic acid for 0.025h; Condensation; microwave irradiation;	51%

5-[(quinolin-8-yloxy)methyl]-1,3,4-thiadiazole-2-thiol (239468-65-6) + cephalothin (153-61-7) → 7-{[(thiophen-2-yl)acetyl]amino}-3-{[5-[(quinolin-8-yloxy)methyl]-1,3,4-thiadiazol-2-ylthio]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Conditions	Yield
With boron trifluoride diethyl etherate In acetic acid for 0.0166667h; Condensation; microwave irradiation;	53%

5-[(5-methyl-1,3,4-thiadiazol-2-ylthio)methyl]-1,3,4-thiadiazole-2-thiol (202116-95-8) + cephalothin (153-61-7) → 7-{[(thiophen-2-yl)acetyl]amino}-3-{[5-[(5-methyl-1,3,4-thiadiazol-2-ylthio)methyl]-1,3,4-thiadiazol-2-ylthio]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Conditions	Yield
With boron trifluoride diethyl etherate In acetic acid for 0.0166667h; Condensation; microwave irradiation;	54%

H2N-OTroc-TyrOTce (113351-77-2) + cephalothin (153-61-7) → (S)-2-{[(6R,7R)-3-Acetoxymethyl-8-oxo-7-(2-thiophen-2-yl-acetylamino)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carbonyl]-amino}-3-[4-(2,2,2-trichloro-ethoxycarbonyloxy)-phenyl]-propionic acid 2,2,2-trichloro-ethyl ester (113322-17-1)

Conditions	Yield
With methyl(diethylamino)acetylene In dichloromethane	55%

sodium hydrogencarbonate (144-55-8) + 1-methyl-5-mercaptotetrazole (13183-79-4) + cephalothin (153-61-7) → 3-(((1-methyl-1H-tetrazol-5-yl)thio)methyl)-7-(2-(2-thienyl)acetamido)-3-cephem-4-carboxylic acid

Conditions	Yield
In diethyl ether; nitromethane; ethyl acetate	56.2%

4-Fluorothiophenol (371-42-6) + cephalothin (153-61-7) → (6R,7R)-3-(((4-fluorophenyl)thio)methyl)-8-oxo-7-(2-(thiophen-2-yl)acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Conditions	Yield
With 6,6′-[(3,3′-di-tert-butyl-5,5′-dimethoxy-1,1′-biphenyl-2,2′-diyl)bis(oxy)]bis(di-benzo[d,f][1,3,2]dioxaphosphepin); bis(dibenzylideneacetone)-palladium(0) In acetonitrile at 40℃; for 7h; Tsuji-Trost Allylation; Schlenk technique; regioselective reaction;	58%

5-[(4-methylquinolin-2-yloxy)methyl]-1,3,4-thiadiazole-2-thiol (239468-67-8) + cephalothin (153-61-7) → 7-{[(thiophen-2-yl)acetyl]amino}-3-{[5-[(4-methylquinolin-2-yloxy)methyl]-1,3,4-thiadiazol-2-ylthio]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Conditions	Yield
With boron trifluoride diethyl etherate In acetic acid for 0.0333333h; Condensation; microwave irradiation;	59%

thioacetic acid (507-09-5) + cephalothin (153-61-7) → (6R,7R)-3-(acetylthiomethyl)-8-oxo-7-(2-(thiophen-2-yl)acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (23958-17-0)

Conditions	Yield
With sodium hydrogencarbonate	60%

2-mercapto-5-methyl-1,3,4-thiadiazole (29490-19-5) + cephalothin (153-61-7) → 7β-(thiophen-2-acetamido)-3-<(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl>-ceph-3-em-4-carboxylic acid (26970-95-6)

Conditions	Yield
With phosphate buffer pH 6.4; sodium hydrogencarbonate at 60℃; for 5h;	62%
With phosphate buffer; sodium carbonate at 55 - 60℃; for 6h;

3-methyl-5-mercapto-1,2,4-thiadiazole (36988-21-3) + cephalothin (153-61-7) → 3-(((3-METHYL-1,2,4-THIADIAZOL-5-YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4-CARBOXYLIC ACID

Conditions	Yield
In ethyl acetate; 1,2-dichloro-ethane	65%

2-sulfanylpyrimidine (131242-36-9) + cephalothin (153-61-7) → 3-(((2-PYRIMIDINYL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4-CARBOXYLIC ACID

Conditions	Yield
With sodium acetate In acetic acid	70.5%
In acetonitrile

N-cyclohexyl-cyclohexanamine (101-83-7) + 1-methyl-5-mercaptotetrazole (13183-79-4) + cephalothin (153-61-7) → 3-(((1-methyl-1H-tetrazol-5-yl)thio)methyl)-7-(2-(2-thienyl)acetamido)-3-cephem-4-carboxylic acid

Conditions	Yield
In ethanol; acetonitrile	71%
In ethanol; propiononitrile	39%
In ethanol; acetonitrile
In ethanol; 1,2-dichloro-ethane

3-mercapto-4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazine (21094-62-2) + cephalothin (153-61-7) → 3-(((4,5-DIHYDRO-6-HYDROXY-4-METHYL-5-OXO-1,2,4-TRIAZIN-3-YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4-CARBOXYLIC ACID

Conditions	Yield
In acetonitrile	72.6%

Upstream product

• 80927-95-3 3-(trimethylsiloxy)-8-oxo-7-(2-(2-thienyl) acetamido)-5-thiazabicyclo [4.2.0]Carboxylic acid 
• 5317-29-3 2,2,2-trichloroethyl (6R,7R)-3-acetoxymethyl-7-(thien-2-ylacetamido)ceph-3-em-4-carboxylate 
• 64-19-7 acetic acid 
• 85904-84-3 2,2,2-trichloroethyl (1S,6R,7R)-7-amino-3-chloromethylceph-3-em-4-carboxylate 1-oxide 
• 33465-56-4 2,2,2-trichloroethyl (1S,6R,7R)-3-bromomethyl-7-formamidoceph-3-em-4-carboxylate 1-oxide 
• 39098-97-0 2-thienylacetic acid chloride 
• 1192-03-6 2-chloro-[1,3,2]dioxaborolane 
• 957-68-6 7-Aminocephalosporanic acid 
• 1918-77-0 Thiophene-2-acetic acid 
• 54769-22-1 1-methanesulfonyloxy-1,2,3-benzotriazole 
• 19432-68-9 methyl 2-thiopheneacetate 
• 52646-45-4 p-methoxybenzyl 7β-(2-thienylacetamido)-3-(acetoxymethyl)-3-cephem-4-carboxylate 
• 52154-65-1 (6R)-3-acetoxymethyl-7t-(4-nitro-benzylideneamino)-8-oxo-(6rH)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid 4-methoxy-benzyl ester 
• 16361-79-8 (6R)-3-acetoxymethyl-7t-amino-8-oxo-(6rH)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid 4-methoxy-benzyl ester 

Downstream Products

• 41625-53-0 p-nitrobenzyl 7β-(2-thienylacetamido)-3-(acetoxymethyl)-3-cephem-4-carboxylate 
• 41095-78-7 benzyl 7β-(2-thienylacetamido)-3-(acetoxymethyl)-3-cephem-4-carboxylate 
• 10590-10-0 cefoxitin lactone 
• 113322-32-0 cephalothin-tyrosine 
• 56737-24-7 diphenylmethyl 7β-(thiophen-2-acetamido)-3-<(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl>-ceph-3-em-4-carboxylate 
• 120155-15-9 (6R,7R)-3-(5-Methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-5,8-dioxo-7-(2-thiophen-2-yl-acetylamino)-5λ⁴-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester 
• 120155-16-0 (6R,7R)-3-(5-Methyl-[1,3,4]thiadiazole-2-sulfinylmethyl)-5,8-dioxo-7-(2-thiophen-2-yl-acetylamino)-5λ⁴-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester 
• 120155-18-2 (6R,7R)-3-(5-Methyl-[1,3,4]thiadiazole-2-sulfonylmethyl)-5,8-dioxo-7-(2-thiophen-2-yl-acetylamino)-5λ⁴-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester 
• 120155-19-3 (6R,7R)-3-(5-Methyl-[1,3,4]thiadiazole-2-sulfonylmethyl)-5,5,8-trioxo-7-(2-thiophen-2-yl-acetylamino)-5λ⁶-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester 
• 90026-87-2 benzhydryl 7-(2-thienyl)acetamido-3-acetoxymethyl-3-cephem-4-carboxylate 1S(β)-oxide 
• 66094-91-5 benzhydryl 7-(2-thienyl)acetamido-2-methylene-3-acetoxymethyl-3-cephem-4-carboxylate 1S(β)-oxide 
• 121534-61-0 benzhydryl 7-(2-thienyl)acetamido-2-spirocyclopropyl-2',2'diphenyl-3-acetoxymethyl-3-cephem-4-carboxylate 1S(β)-oxide 
• 121534-61-0 benzhydryl 7-(2-thienyl)acetamido-2-spirocyclopropyl-2',2'diphenyl-3-acetoxymethyl-3-cephem-4-carboxylate 1S(β)-oxide 
• 153-61-7 (6R)-3-acetoxymethyl-8-oxo-7t-(2-thiophen-2-yl-acetylamino)-(6rH)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid 

Relevant academic research and scientific papers

Synthesis method of cefoxitin sodium key intermediate

The invention provides a synthesis method of a cefoxitin sodium key intermediate, and belongs to the technical field of heterocyclic compounds. The method comprises the following steps: by taking a cephalotin solution as a treatment object, adding organic alkali, adding a halogenating agent, carrying out halogenating methoxyl reaction, adding acetic acid and saline water, regulating acid and layering, drying an organic layer, concentrating, adding cyclohexylamine to form salt, filtering and drying to obtain a key intermediate 7-alpha methoxyl cephalothin cyclohexylamine salt According to the method, one-step synthesis of the 7-alpha methoxyl cephalothin cyclohexylamine salt is realized, subsequent main impurities of cefoxitin sodium are effectively reduced from the source, the quality and purity of the product are improved, the competitiveness of the cefoxitin product is improved, the product is stable and reliable, the yield is high, the synthesis process is greatly simplified, and the method has an industrial prospect.

Preparation method of cefoxitin lactone

The invention discloses a preparation method of a cefoxitin lactone. The method comprises the following steps: (1) under catalysis of N,O-bis(trimethylsilyl)acetamide or triethylamine, 2-thiopheneacetyl chloride and 7-ACA are subjected to an amidation reaction in an organic solvent to obtain a compound 2; (2) the compound 2 is subjected to a hydrolysis reaction under enzyme catalysis to obtain an[(6R,7R)-3-methylol-8-oxo-7-(2-thiopheneacetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid] compound 1; and (3) the compound 1 is subjected to an intramolecular esterification reaction in an alcohol solvent under the action of an acid, and after the reaction is completed, the cefoxitin lactone is obtained by post-treatment. The preparation method has mild reaction conditions, simpleoperation, and high reaction yield, and the obtained cefoxitin lactone has high purity, and can be used as an impurity reference substance in the process of drug consistency re-research.

Progress towards a stable cephalosporin-halogenated phenazine conjugate for antibacterial prodrug applications

Resistant bacteria successfully evade the action of conventional antibiotic therapies during infection, often leading to significant illness and death. Our lab has discovered halogenated phenazine (HP) analogues which demonstrate potent antibacterial activities through a unique iron-starving mechanism. Herein, we describe synthetic efforts towards a stable cephalosporin-HP conjugate prodrug with the aim of translating HPs into useful clinical agents. Cephalosporin-antibiotic conjugates offer multiple advantages for antibacterial design, including the release of active agents through the targeting of intracellular cephalosporinase following selective ring-opening of the beta-lactam warhead. During these studies, carbonate-linked cephalosporin-HP conjugate 16 was synthesized; however, we were unable to successfully remove the ester group required for cephalosporinase processing. Cephalosporin-HP 16 was then utilized as a probe to investigate the stability of the carbonate linker in antibacterial assays and, as predicted, this compound proved to be inactive against Staphylococcus aureus (MIC > 100 μM). The lack of 16’s antibacterial activity can be attributed to the carbonate linker remaining intact throughout the MIC assay, thus not liberating the active HP moiety. These efforts have led to a more stable cephalosporin-HP conjugate joined through a carbonate linker compared to a highly unstable ether linked analogue we previously reported.

Application of cefoxitin sodium pharmaceutical preparations in preoperative infection prevention for transvaginal hysterectomy, laparoscopic hysterectomy and cesarean section

The present invention provides cefoxitin sodium or a composition thereof, a preparation method of the cefoxitin sodium or the composition thereof, a prescribed preparation, a compound preparation, anduse. In the cefoxitin sodium or the composition thereof, the mass content of the cefoxitin is 93% or above. The cefoxitin sodium or the composition thereof has good quality stability and a low impurity content, facilitating improvement in clinical curative effects and safety. The cefoxitin sodium or the composition thereof has a uniform particle size range, facilitating reduction in the process difficulty for preparing preparations. The cefoxitin sodium or the composition thereof can be used for preoperative infection prevention and postoperative infection treatment for transvaginal hysterectomy, laparoscopic hysterectomy and cesarean section.

Preparation method of cephalotin acid

The invention relates to a preparation method of cephalotin acid and belongs to the technical field of pharmaceutical synthesis. In order to solve existing problems of serious environment pollution and high reaction temperature, the invention provides the preparation method of the cephalotin acid; the method comprises the following steps: in the presence of organic alkali, mixing 2-thiopheneaceticacid and EDC (1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride); after activating carboxyl, adding 7-ACA and carrying out one-pot boiling under the condition that the temperature is 25 DEG C to 35 DEG C to obtain the cephalotin acid. The method provided by the invention has the advantages that reaction conditions are moderate, a beta-lactam compound is not degraded and the method is environmentally friendly; the technology operation is simplified and the cost is reduced.

A method for preparing cephalosporin thiophen acid

The invention relates to a preparation method of cephalotin acid and belongs to the technical field of drug synthesis. In order to solve the existing problem that the environment is severely polluted and the reaction temperature is high, the invention provides the preparation method of cephalotin acid. The method comprises the following steps: on the premise of an organic alkali, carrying out reaction on 2-thiopheneacetic acid and trifluoroacetic succinimide at (-20-40 DEG C) to obtain a solution containing activated esters; and then carrying out condensation reaction on the solution containing activated esters and 7-ACA at 10-35 DEG C to obtain the cephalotin acid. The method provided by the invention has the effects that the reaction condition is mild, the beta-lactam compound is not degraded and the method is environment-friendly, and the process operation is simplified.

A head cefoxitin acid synthesis technology

The invention provides a novel synthesis method of cefoxitin acid. Cefoxitin acid is used as a raw material for synthesizing cefoxitin sodium and belongs to second-generation cephalosporin. The cefoxitin acid has balanced antibacterial spectra and has a strong antibacterial effect on gram-negative bacteria. Due to the existence of 7alpha methoxy in the cefoxitin acid, the hydrolysis action of the cefoxitin acid on beta-lactamase can be reduced greatly, so that the beta-lactamase can exist stably in the cefoxitin acid. In the invention, 3-deacetylase cefoxitin acid which is an intermediate is produced by adopting an enzyme process through two-step continuous reaction, materials react in a mild reaction condition, and the process is simple and is convenient to operate. By adopting the novel synthesis method, time and labor can be saved, and the yield and quality of the product can be improved. Because the two-step reaction is carried out in a water phase at room temperature, the consumption of energy and the discharge of organic wastewater can be reduced greatly. The novel synthesis method meets the requirements of large-scale industrial production.

CEPHALOSPORIN DERIVATIVES USEFUL AS β-LACTAMASE INHIBITORS AND COMPOSITIONS AND METHODS OF USE THEREOF

The present invention relates to cephalosporin derivatives having β- lactamase inhibitory activity. The compounds are useful in preventing or treating bacterial resistance to an antibiotic, e.g. a β-lactam antibiotic. Disclosed herein are compounds that are inhibitors of class B metallo-β-lactamases, as well as class A, C, and D serine β-lactamases. In some preferred embodiments, the compounds are 3'- thiobenzoate derivatives of a cephalosporin. Pharmaceutical compositions, methods, uses, kits and commercial packages comprising the compounds are also disclosed.

Fluorogenic and chromogenic β-lactamase substrates

Chromogenic and fluorogenic substrates for β-lactamase, methods for synthesis thereof and methods for detecting β-lactamase in a sample are provided. The substrates are substantially colorless or substantially nonfluorescent β-lactam compounds which include an electronegative leaving group. The leaving group comprises a carbamate, carbonate, thiocarbamate or thiocarbonate linkage and a fluorescent moiety or a moiety capable of producing a visually detectable colored product. Upon cleavage of the lactam ring by β-lactamase, the leaving group is liberated and fluorescence or a colored product is produced.

Mechanism of β-lactam ring opening in cephalosporins

The mechanism of the aminolysis of cephalosporins is a stepwise process. A tetrahedral intermediate is formed by the reversible addition of the amine to the beta -lactam carbonyl carbon. Expulsion of the attacking amine from the tetrahedral intermediate occurs faster than fission of the beta -lactam C-N bond. The reaction proceeds by trapping the intermediate with base. Expulsion of a leaving group at C-3 prime in cephalosporins is not concerted with nucleophilic attack of the amine on the beta -lactam carbonyl carbon and makes little difference to the rate of beta -lactam C-N bond fission.