30246-33-4

Usage

Uses

Used in Pharmaceutical Industry:
7-AMINO-3-[(5-METHYL-1,3,4-THIADIAZOL-2-YL)THIOMETHYL]CEPHALOSPHORANIC ACID is used as a substrate for the assessment of immobilized penicillin G acylase (PGA) orientation. This application is vital for optimizing the efficiency and effectiveness of enzymatic processes in the production of beta-lactam antibiotics.
Additionally, it serves as a crucial component in the synthesis of beta-lactam antibiotics, which are a broad class of antimicrobial agents used to treat a variety of bacterial infections. 7-AMINO-3-[(5-METHYL-1,3,4-THIADIAZOL-2-YL)THIOMETHYL]CEPHALOSPHORANIC ACID's role in this process highlights its importance in the development and manufacturing of life-saving medications.

InChI:InChI=1/C11H12N4O3S3/c1-4-13-14-11(21-4)20-3-5-2-19-9-6(12)8(16)15(9)7(5)10(17)18/h6,9H,2-3,12H2,1H3,(H,17,18)/t6-,9-/m0/s1

Synthetic route

2-mercapto-5-methyl-1,3,4-thiadiazole (29490-19-5) + 3-acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid → 7-amino-3-(5'-methyl-1',3',4'-thiadiazol-2'-ylthiomethyl)cephalosporanic acid (30246-33-4)

Conditions	Yield
With boric acid; triethylamine In water	96%
In water; acetone
In water; acetone

3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0 ]oct-2-ene-2-carboxylic acid sodium salt (3855-09-2) + 2-mercapto-5-methyl-1,3,4-thiadiazole (29490-19-5) → 7-amino-3-(5'-methyl-1',3',4'-thiadiazol-2'-ylthiomethyl)cephalosporanic acid (30246-33-4)

Conditions	Yield
With sodium hydrogencarbonate In water
With sodium hydrogencarbonate In water
With sodium hydrogencarbonate In water
With sodium hydrogencarbonate In water

pyrrolidine (123-75-1) + 7-amino-3-(5'-methyl-1',3',4'-thiadiazol-2'-ylthiomethyl)cephalosporanic acid (30246-33-4) → 7-amino-3-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-2-(pyrrolidine-1-carbonyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-en-8-one

Conditions	Yield
With aluminum oxide at 120℃; for 0.0333333h; microwave irradiation;	93%

2-amino-5-(3-pyridyl)-1,3,4-thiadiazole (68787-52-0) + 7-amino-3-(5'-methyl-1',3',4'-thiadiazol-2'-ylthiomethyl)cephalosporanic acid (30246-33-4) → 7-amino-3-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid (5-pyridin-3-yl-[1,3,4]thiadiazol-2-yl)-amide

Conditions	Yield
With aluminum oxide at 120℃; for 0.0166667h; microwave irradiation;	92%

2-amino-5-undecyl-1,3,4-thiadiazole (100539-95-5) + 7-amino-3-(5'-methyl-1',3',4'-thiadiazol-2'-ylthiomethyl)cephalosporanic acid (30246-33-4) → 7-amino-3-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid (5-undecyl-[1,3,4]thiadiazol-2-yl)-amide

Conditions	Yield
With aluminum oxide at 120℃; for 0.0333333h; microwave irradiation;	90%

piperidine (110-89-4) + 7-amino-3-(5'-methyl-1',3',4'-thiadiazol-2'-ylthiomethyl)cephalosporanic acid (30246-33-4) → 7-amino-3-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-2-(piperidine-1-carbonyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-en-8-one

Conditions	Yield
With aluminum oxide at 120℃; for 0.025h; microwave irradiation;	89%

2-amino-5-phenyl-1,3,4-thiadiazole (2002-03-1) + 7-amino-3-(5'-methyl-1',3',4'-thiadiazol-2'-ylthiomethyl)cephalosporanic acid (30246-33-4) → 7-amino-3-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid (5-phenyl-[1,3,4]thiadiazol-2-yl)-amide

Conditions	Yield
With aluminum oxide at 120℃; for 0.0166667h; microwave irradiation;	87%

7-amino-3-(5'-methyl-1',3',4'-thiadiazol-2'-ylthiomethyl)cephalosporanic acid (30246-33-4) + 2-amino-5-(4-chlorophenyl)-1,3,4-thiadiazole (28004-62-8) → 7-amino-3-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid [5-(4-chloro-phenyl)-[1,3,4]thiadiazol-2-yl]-amide

Conditions	Yield
With aluminum oxide at 120℃; for 0.025h; microwave irradiation;	86%

5-methyl-1,3,4-thiadiazol-2-amine (108-33-8) + 7-amino-3-(5'-methyl-1',3',4'-thiadiazol-2'-ylthiomethyl)cephalosporanic acid (30246-33-4) → 7-amino-3-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid (5-methyl-[1,3,4]thiadiazol-2-yl)-amide

Conditions	Yield
With aluminum oxide at 120℃; for 0.025h; microwave irradiation;	85%

7-amino-3-(5'-methyl-1',3',4'-thiadiazol-2'-ylthiomethyl)cephalosporanic acid (30246-33-4) + 5-nonyl-[1,3,4]thiadiazol-2-ylamine (113836-51-4) → 7-amino-3-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid (5-nonyl-[1,3,4]thiadiazol-2-yl)-amide

Conditions	Yield
With aluminum oxide at 120℃; for 0.025h; microwave irradiation;	83%

7-amino-3-(5'-methyl-1',3',4'-thiadiazol-2'-ylthiomethyl)cephalosporanic acid (30246-33-4) → 7-amino-3-methylenecepham-4-carboxylic acid (36996-01-7, 51795-31-4) + 7-aminodesacetoxycephalosporanic acid (26395-99-3)

Conditions	Yield
With N,N-Bis(trimethylsilyl)urea; ammonium chloride; zinc In N,N-dimethyl-formamide 1.) 25 deg C, 13 min, 2.) 5 deg C, 18 min, 3.) 5 deg C, 30 min;	A 66.5% B 3.0 % Chromat.

7-amino-3-(5'-methyl-1',3',4'-thiadiazol-2'-ylthiomethyl)cephalosporanic acid (30246-33-4) → 7-amino-3-hydroxycepham-4-carboxylic acid (68403-70-3, 115889-60-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 66.5 percent / bis(trimethylsilyl)urea (BSU), NH4Cl, zinc dust / dimethylformamide / 1.) 25 deg C, 13 min, 2.) 5 deg C, 18 min, 3.) 5 deg C, 30 min 2: 1.) MsOH, ozone, 2.) NaBH4, NaOH / 1.) MeOH, -75 deg C, 2.) MeOH/H2O, 0 - 10 deg C View Scheme

7-amino-3-(5'-methyl-1',3',4'-thiadiazol-2'-ylthiomethyl)cephalosporanic acid (30246-33-4) → 3-methylene-7-phenylacetamidocepham-4-carboxylic acid 1-sulfoxide (115824-01-6, 121055-15-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 66.5 percent / bis(trimethylsilyl)urea (BSU), NH4Cl, zinc dust / dimethylformamide / 1.) 25 deg C, 13 min, 2.) 5 deg C, 18 min, 3.) 5 deg C, 30 min 2: 1.) ozone, MsOH, 2.) NaBH4 / 1.) MeOH, -40 deg C, 2.) MeOH/H2O, 3.) pH 6.5 - 7.5 View Scheme

7-amino-3-(5'-methyl-1',3',4'-thiadiazol-2'-ylthiomethyl)cephalosporanic acid (30246-33-4) → 3-hydroxy-7-phenylacetamido-cepham-4-carboxylic acid (90305-32-1, 115889-59-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 66.5 percent / bis(trimethylsilyl)urea (BSU), NH4Cl, zinc dust / dimethylformamide / 1.) 25 deg C, 13 min, 2.) 5 deg C, 18 min, 3.) 5 deg C, 30 min 2: 1.) ozone, MsOH, 2.) NaBH4 / 1.) MeOH, -40 deg C, 2.) MeOH/H2O, 3.) pH 6.5 - 7.5 View Scheme

7-amino-3-(5'-methyl-1',3',4'-thiadiazol-2'-ylthiomethyl)cephalosporanic acid (30246-33-4) → 7-[[2-carboethoxy-2-(1-pyrryl)acetyl]amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

7-aminocephalosporanic acid (108260-00-0) + 7-amino-3-(5'-methyl-1',3',4'-thiadiazol-2'-ylthiomethyl)cephalosporanic acid (30246-33-4) + isobutene (115-11-7) → 3-[(Acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid tert-butyl ester (6187-87-7, 102253-55-4)

Conditions	Yield
With sulfuric acid; sodium hydrogencarbonate In 1,4-dioxane; ethyl acetate; 7-aminodesacetoxycephalosporanic acid

7-amino-3-(5'-methyl-1',3',4'-thiadiazol-2'-ylthiomethyl)cephalosporanic acid (30246-33-4) → 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid t-butyl ester (54895-35-1) + 3-[(Acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid tert-butyl ester (6187-87-7, 102253-55-4)

Conditions	Yield
In 7-aminodesacetoxycephalosporanic acid

Upstream product

• 106134-67-2 (6R,7R)-trimethylsilyl 7-(trimethylsilyl)amino-3-iodomethylceph-3-em-4-carboxylate 
• 29490-19-5 2-mercapto-5-methyl-1,3,4-thiadiazole 
• 111389-99-2 (6R,7R)-Trimethylsilyl 7-[((Trimethylsilyl)oxy)carbonyl]-amino-3-iodomethylceph-3-em-4-carboxylate 
• 957-68-6 7-Aminocephalosporanic acid 
• 7440-44-0 pyrographite 
• 107447-96-1 7-phenylacetylamino-3-(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 
• 31461-04-8 (6R,7R)-Trimethylsilyl 7-(Trimethylsilyl)amino-3-acetoxy methylceph-3-em-4-carboxylate 
• 111390-00-2 (6R,7R)-Trimethylsilyl 7-[((Trimethylsilyl)oxy)carbonyl]-amino-3-acetoxymethylceph-3-em-4-carboxylate 
• 98493-37-9 7-amino-3-<(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl>-Δ³-cephem-4-carboxylic acid hydrochloride 
• 3855-09-2 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0 ]oct-2-ene-2-carboxylic acid sodium salt 

Downstream Products

• 68403-70-3 7-amino-3-hydroxycepham-4-carboxylic acid 
• 115824-01-6 3-methylene-7-phenylacetamidocepham-4-carboxylic acid 1-sulfoxide 
• 90305-32-1 3-hydroxy-7-phenylacetamido-cepham-4-carboxylic acid 
• 21732-17-2 1H-tetrazol-1-ylacetic acid 
• 25953-19-9 cefazolin 
• 63521-15-3 (6R,7R)-3-[[(5-methyl-1,3,4-thiadiazolyl-2-yl)thio]methyl]-7-[2-(3,5-dichloro-4-pyridone-1-acetylamido)]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt 
• 27164-46-1 cefazolin sodium 
• 63491-75-8 (6R)-7t-((R)-2-amino-2-phenyl-acetylamino)-3-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-8-oxo-(6rH)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid (Ξ)-3-oxo-1,3-dihydro-isobenzofuran-1-yl ester; mono-(toluene-4-sulfonate) 
• 61296-38-6 (6R)-7t-((R)-2-tert-butoxycarbonylamino-2-phenyl-acetylamino)-3-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-8-oxo-(6rH)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid (Ξ)-3-oxo-1,3-dihydro-isobenzofuran-1-yl ester 
• 63491-70-3 (6R)-7t-((R)-2-tert-butoxycarbonylamino-2-phenyl-acetylamino)-3-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-5ξ,8-dioxo-(6rH)-5λ⁴-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2,2-dimethyl-propionyloxymethyl ester 
• 63491-72-5 (6R)-7t-((R)-2-tert-butoxycarbonylamino-2-phenyl-acetylamino)-3-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-8-oxo-(6rH)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2,2-dimethyl-propionyloxymethyl ester 
• 63491-69-0 (6R)-7t-((R)-2-tert-butoxycarbonylamino-2-phenyl-acetylamino)-3-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-5ξ,8-dioxo-(6rH)-5λ⁴-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid acetoxymethyl ester 
• 63491-71-4 (6R)-7t-((R)-2-tert-butoxycarbonylamino-2-phenyl-acetylamino)-3-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-8-oxo-(6rH)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid acetoxymethyl ester 
• 63491-68-9 (6R)-7t-((R)-2-tert-butoxycarbonylamino-2-phenyl-acetylamino)-3-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-5ξ,8-dioxo-(6rH)-5λ⁴-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid 

Relevant academic research and scientific papers

A rapid and cheap synthesis of cephalosporins

A fast, cheap and pollution free microwave assisted method for the synthesis of cephalosporin and its comparison with conventional method in terms of yield and reaction time were described.

Cefazedone synthesis method

The invention discloses a cefazedone synthesis method. A compound II reacts with 7-ACA to prepare a compound III, and the compound III reacts with a compound IV to prepare the final product cefazedone. The method has the advantages of simple reaction process, easiness in operation, high total yield and high purity of the product, few byproducts, and suitableness for industrial production.

Preparation technology of cefazedone sodium

The invention belongs to the technical field of medicine, and discloses a preparation technology of cefazedone sodium. 3,5-dichloropyridone acetic acid and pivaloyl chloride are taken as the raw materials to synthesize mixed acid anhydrides; and then cefazedone sodium is obtained after salt forming reactions between mixed acid anhydrides and an intermediate prepared from 7-aminocephalosporanic acid and thiol tetrazole. A mixed solvent is used in 3-substitution, the reaction becomes more stable and softer, the byproducts are reduced; in acylation reactions, mixed acid anhydrides are used, the activity is high, 7-acylation reactions are promoted, and thus the yield and purity of cefazedone sodium are high.

A head west spore alkone sodium synthetic method (by machine translation)

The invention belongs to the field of medical technology, discloses a head-west spore alkone sodium synthetic method. In order to 3, 5 - dichloro pyridone acetic acid and two sulfur thioalcohol thiazole as raw material synthetic active ester, with the 7 - amino cephalosporanic acid and mercapto tetrazole generated intermediate reaction, into west spore alkone sodium salt obtained by the head. The invention in 3 - substituted using mixed in the solvent, the reaction is more stable and smooth, reducing the generation of by-products, in the acylation reaction using the active ester, active high, conducive to the 7 - position of the acylation reaction, the resulting west spore alkone sodium yield and purity are relatively high. (by machine translation)

Preparation method of cefazedone sodium compound

The invention discloses a preparation method of a cefazedone sodium compound. 7-ACA and a compound III react to prepare a compound IV, and the compound IV and a compound V have an amidation reaction,and are salified and refined to obtain a competitive product of cefazedone sodium (I). The process route of the reaction is simple, the total yield and the purity are high, and the method is suitablefor industrial production.

Cephalosporins anti-infective drug preparation method

The invention relates to a preparation method for a cephalosporin anti-infective drug-cefazedone sodium, belonging to the field of pharmaceutical synthesis. According to the invention, the method uses GCLE as a raw material to substitute 7-ACA and overcomes the defects of low yield, high pollution and the like in prior art; the preparation method with mild reaction conditions, little side reaction and simple process is provided; meanwhile, the method has the advantages of cheap and easily-available raw materials, low cost, high product yield, high product purity and applicability to industrial production.

Preparation method of cefazolin sodium with previous research quality and medicine preparation of cefazolin sodium

The invention discloses a preparation method of cefazolin sodium with previous research quality. The preparation method is characterized by comprising the following steps: (1) adding a boron trifluoride-dimethyl carbonate solution into dimethyl carbonate; stirring and adding 2-sulfydryl-5-methyl-1,3,4-thiadiazole and 7-ACA (Acetic Acid) to react; after the reaction is finished, adding dimethyl formamide and dropwise adding hydrochloric acid; adjusting the temperature to 25 to 35 DEG C and reacting for 60 minutes; filtering and washing with acetone; drying in vacuum to obtain a TDA (Toluene Diamine) crude product; (2) preparing mixed anhydride from dichloromethane, tetrazolyl acetic acid, triethylamine and pivaloyl chloride; (3) adding the TDA crude product into a dichloromethane solvent; cooling and dropwise adding tetramethyl guanidine; dropwise adding the mixed anhydride to react, and purifying and refining a crystal through a low-temperature acetonitrile-water extraction process after extraction and crystallization. With the adoption of the preparation method provided by the invention, the moisture content of the product can be reduced and residues of the solvent can be reduced; the increasing of related substances can be effectively reduced, a freeze-drying technology is not used and the production efficiency is improved.

On the substrate preference of glutaryl acylases

The substrate preferences of three acylases - two wild-type enzymes and an evolved variant obtained by directed evolution - which are prototypical enzymes for glutaryl-7-ACA acylase and cephalosporin C acylase subfamilies, have been investigated. A preliminary screening of enzymes' performances on a large set of substrates has been carried out by a colorimetric assay performed in 96-well plates and by a pH-Stat monitoring the hydrolytic activities. Subsequently, kinetic data for selected substrates have been determined, thus elucidating the substrate preference of members of glutaryl-7-ACA acylase vs. cephalosporin C acylase subfamilies. These achievements pave the way to the ability of choosing the best enzyme for the hydrolysis of different compounds of industrial importance.

Glutaryl Acylases: One-Reaction Enzymes or Versatile Enantioselective Biocatalysts?

A significant broad substrate specificity, that crosses over the usual β-lactam derivatives, has been observed with an industrial glutaryl-7-aminocephalosporanic acid acylase (GA). This enzyme possesses significant enantioselective amidase and even esterase activity, with a stereopreference for the S-enantiomer. The easy separation of products from unreacted reagents, possessing different physical-chemical properties, is achieved by solvent extraction, avoiding chromatography or distillation during reaction work-up.

Process for preparing cephalosporin intermediates

Processes for the preparation of stable, crystalline cephalosporin intermediates of the formula STR1 wherein X is HI or HCl, and Nu and Nu≈ are certain N-containing heterocyclic rings attached via a sulfur atom or a ring nitrogen atom, respectively, which are substantially free of the Δ2 isomer; processes for intermediates in the preparation of the above compounds; and processes for the preparation of broad-spectrum cephalosporin antibiotics.