50370-12-2

Basic information

• Product Name: CEFADROXIL
• Synonyms: P-HYDROXYCEPHALEXINE;(6R,7R)-7-[(R)-2-AMINO-2-(4-HYDROXY-PHENYL)-ACETYLAMINO]-3-METHYL-8-OXO-5-THIA-1-AZA-BICYCLO[4.2.0]OCT-2-ENE-2-CARBOXYLIC ACID;CEFAMOX;(6r-(6-alpha,7-beta(r*)))-l)acetyl)amino)-3-methyl-8-oxo;5-thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylicacid,7-((amino(4-hydroxypheny;bidocef;bl-s578;cdx
• CAS NO: 50370-12-2
• Molecular Formula: C₁₆H₁₇N₃O₅S
• Molecular Weight: 363.39
• EINECS: 256-555-6
• Product Categories: Active Pharmaceutical Ingredients;Alphabetic;C;CA - CGForensic and Veterinary Standards;Drugs&Metabolites;Neat Compounds;cephalosporins
• Mol File: 50370-12-2.mol

Chemical Properties

• Melting Point: 197°C (rough estimate)
• Boiling Point: 238°C (rough estimate)
• Flash Point: 431.492 °C
• Appearance: /
• Density: 1.59
• Vapor Pressure: 2.71E-26mmHg at 25°C
• Refractive Index: 1.6390 (estimate)
• Storage Temp.: under inert gas (nitrogen or Argon) at 2–8 °C
• PKA: 3.12±0.50(Predicted)
• CAS DataBase Reference: CEFADROXIL(CAS DataBase Reference)
• NIST Chemistry Reference: CEFADROXIL(50370-12-2)
• EPA Substance Registry System: CEFADROXIL(50370-12-2)

Safety Data

• Hazard Codes: Xn
• Statements: 36/37/38-42/43
• Safety Statements: 26-36
• WGK Germany: 2
• RTECS: XI0337000
• Hazardous Substances Data: 50370-12-2(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Cefadroxil is used as an antibiotic for the treatment of bacterial infections. It is effective against a range of bacteria and is particularly useful due to its oral administration and slow excretion rate, allowing for 8or 12-hour dosing intervals.
Used in Medical Treatment:
Cefadroxil is used as a bacterial transpeptidase inhibitor, which helps in disrupting the bacterial cell wall synthesis and ultimately leading to bacterial cell death. This property makes it a valuable component in the treatment of various bacterial infections.
Used in European Countries:
Cefadroxil is still available for use in several European countries, including Spain, Belgium, Luxembourg, Portugal, and Finland, among others, where it continues to be a preferred choice for treating bacterial infections due to its effectiveness and convenient dosing schedule.

Originator

Oracefal,Bristol,France,1977

Manufacturing Process

1.8 g of sodium N-(1-methoxycarbonyl-1-propen-2-yl)-D(-)-α-amino-(4- hydroxyphenyl)acetate was suspended in 10 ml of acetone, and one droplet of N-methylmorpholine was added thereto, and the mixture was cooled to -15°C.There was added 0.85 g of ethyl chlorocarbonate thereto, and the mixture was reacted at -13°C to -10°C for 30 minutes, and then the reaction solution was cooled to -20°C.On the other hand, 1 g of 7-amino-3-methyl-3-cephem-4-carboxylic acid was suspended in 20 ml of methanol, and 1.4 g of triethylamine was added thereto to be dissolved, and 0.4 ml of acetic acid was further added thereto. This solution was cooled to -20°C and the mixed acid anhydride prepared previously was added thereto. After the mixture was reacted at -20°C for 1 hour, the temperature of the reaction mixture was raised to 0°C over a period of 1 hour, and the mixture was reacted for 3 hours at the same temperature.After the reaction, 1 ml of water was added to the reaction mixture, and the mixture was adjusted to a pH of 1.0 with concentrated hydrochloric acid while being cooled, and then stirred for 30 minutes, The insoluble matters were filtered off, and the filtrate was adjusted to a pH of 5.5 with triethylamine. This solution was concentrated under reduced pressure, and the residue was diluted with 20 ml of acetone to precipitate white crystals. The crystals were collected by filtration and washed with ethanol to obtain 1.46 g of white crystals of 7-[D(-)-α-amino-(4-hydroxyphenyl)acetamido]-3-methyl-3- cephem-4-carboxylic acid having a decomposition point of 197°C.

Therapeutic Function

Antibacterial

Health Hazard

Exposures to cefadroxil cause certain common side effects. These include nausea, vomiting, stomach disorders, rashes, itching, unusual tiredness or weakness, yellowing of the skin or eyes, red, swollen, or blistered skin, unusual bruising or bleeding, sore throat, respiratory distress, tightness in the chest, swelling of the mouth, face, lips, or tongue, decreased urination, dark urine, vaginal itching, odor, or discharge, fever, chills, joint pain, and seizures. Prolonged or long-term use of cefadroxil should be avoided.

Precautions

Cefadroxil should be used only under proper medical health care since it has properties of penicillin allergy, renal function, gastrointestinal tract damage. Pregnant women and breast-feeding women should avoid exposure to cefadroxil.

InChI:InChI=1/C16H17N3O5S/c1-7-6-25-15-11(14(22)19(15)12(7)16(23)24)18-13(21)10(17)8-2-4-9(20)5-3-8/h2-5,10-11,15,20H,6,17H2,1H3,(H,18,21)(H,23,24)/t10-,11-,15-/m1/s1

Synthetic route

cefadroxil/2,7-dihydroxynaphthalene complex → cefadroxil (50370-12-2)

Conditions	Yield
With hydrogenchloride In water; ethyl acetate at 5℃; for 0.5h; pH=4;	95%

cefadroxil → cefadroxil (50370-12-2)

Conditions	Yield
Multistep reaction.;	94%

3-deacetyloxy-7-aminocephalosporanic acid (22252-43-3, 26395-99-3, 70287-30-8, 72059-35-9) + ((R)-(2-ethoxycarbonyl-1-methyl-vinylamino)-(4-hydroxyphenyl)-acetyloxy)-(triphenyl)phosphonium chloride → cefadroxil (50370-12-2)

Conditions	Yield
Stage #1: 3-deacetyloxy-7-aminocephalosporanic acid; ((R)-(2-ethoxycarbonyl-1-methyl-vinylamino)-(4-hydroxyphenyl)-acetyloxy)-(triphenyl)phosphonium chloride With triethylamine In dichloromethane; water at -40 - 0℃; for 3h; Stage #2: With hydrogenchloride In dichloromethane; water for 1h; Stage #3: With sodium hydroxide In dichloromethane; water at 0℃; for 2h; pH=3.2;	83%

D-2-p-hydroxyphenylglycine methyl ester (37763-23-8) + 7-aminodesacetoxycephalosporanic acid (26395-99-3) → cefadroxil (50370-12-2)

Conditions	Yield
immobilised Pen G acylase In water Enzymatic reaction;

C27H39N3O7SSi2 → cefadroxil (50370-12-2)

Conditions	Yield
With hydrogenchloride In water

3-deacetyloxy-7-aminocephalosporanic acid (22252-43-3, 26395-99-3, 70287-30-8, 72059-35-9) + C16H19NO7 (78858-51-2) → C19H21N3O7S + cefadroxil (50370-12-2)

Conditions	Yield
Stage #1: 3-deacetyloxy-7-aminocephalosporanic acid With 1H-imidazole; chloro-trimethyl-silane In dichloromethane for 3 - 4h; Heating / reflux; Stage #2: C16H19NO7 In DMF (N,N-dimethyl-formamide); dichloromethane at -45 - -20℃; for 2.5h; Stage #3: With hydrogenchloride In DMF (N,N-dimethyl-formamide); dichloromethane; water at 0 - 5℃; for 0.25h;

3-deacetyloxy-7-aminocephalosporanic acid (22252-43-3, 26395-99-3, 70287-30-8, 72059-35-9) + D-2-p-hydroxyphenylglycine methyl ester (37763-23-8) → cefadroxil (50370-12-2)

Conditions	Yield
With formic acid; ammonia; immobilized Pen-G acylase mutant Phe-24-Ala In water at 12℃; for 2.5h; pH=7.3; Product distribution / selectivity; Enzymatic reaction;
With penicillin acylasefrom Escherichia coli; water
With penicillin G acylase immobilized on polymer microspheres supported Fe3O4 at 30℃; for 18h; Temperature; Ionic liquid; Enzymatic reaction;

3-deacetyloxy-7-aminocephalosporanic acid (22252-43-3, 26395-99-3, 70287-30-8, 72059-35-9) + D-(-)-4-hydroxyphenylglycineamide → cefadroxil (50370-12-2)

Conditions	Yield
With penicillin acylasefrom Escherichia coli; water

2,5-dihydroxy-N-(2-hydroxyethyl)benzamide (61969-53-7) + cefadroxil (50370-12-2) → 6-{2-[2-(2-hydroxyethylcarbamoyl)-3,6-dioxocyclohexa-1,4-dienylamino]-2-(4-hydroxyphenyl)-acetylamino}-cephalosporanic acid

Conditions	Yield
With air; sodium acetate buffer at 20℃; for 3h; pH=5.6;	88%

ethylenesulfonyl fluoride (677-25-8) + cefadroxil (50370-12-2) → (7R)-7-((R)-2-(bis(2-(fluorosulfonyl)ethyl)ammonio)-2-(4-hydroxyphenyl)acetamido)-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

Conditions	Yield
In ethanol at 50℃;	86%

cefadroxil (50370-12-2) + 4-methyl-1,2-dihydroxybenzene (452-86-8) → 7-[2-(6-methyl-3,4-dioxocyclohexa-1,5-dienylamino)-2-(4-hydroxyphenyl)acetylamino]cephalosporanic acid (1044135-33-2)

Conditions	Yield
With oxygen at 20℃; for 1.5h; pH=5.6; aq. acetate buffer; Enzymatic reaction;	78%

salicylaldehyde (90-02-8) + cefadroxil (50370-12-2) → C23H21N3O6S (871315-52-5)

Conditions	Yield
In methanol for 3h; Reflux;	75.45%
With potassium hydroxide In methanol for 3h; pH=7.4 - 7.6; Reflux;	75.45%
In ethanol for 3h; Inert atmosphere;	75%

acetic anhydride (108-24-7) + cefadroxil (50370-12-2) → N-acetylcefadroxil

Conditions	Yield
for 15h; Ambient temperature;	53.3%

cefadroxil (50370-12-2) + 3-methylbenzene-1,2-diol (488-17-5) → 7-[2-(5-methyl-3,4-dioxocyclohexa-1,5-dienylamino)-2-(4-hydroxyphenyl)acetylamino]cephalosporanic acid (1044135-32-1)

Conditions	Yield
With oxygen at 20℃; for 1.5h; pH=5.6; aq. acetate buffer; Enzymatic reaction;	27%

diazomethane (186581-53-3, 908094-01-9) + cefadroxil (50370-12-2) → 2-[5-(4-Hydroxy-phenyl)-3,6-dioxo-piperazin-2-yl]-5-methyl-3,6-dihydro-2H-[1,3]thiazine-4-carboxylic acid methyl ester + 2-[5-(4-Hydroxy-phenyl)-3,6-dioxo-piperazin-2-yl]-5-methyl-5,6-dihydro-2H-[1,3]thiazine-4-carboxylic acid methyl ester

Conditions	Yield
With disodium hydrogenphosphate 1.) H2O, pH 9.1, 60 deg C, 1 h, 2.) Et2O; Yield given. Multistep reaction. Yields of byproduct given;

formaldehyd (50-00-0) + cefadroxil (50370-12-2) → 2-Hydroxy-3-(4-hydroxyphenyl)-6-methylpyrazine (73226-86-5)

Conditions	Yield
Mechanism;

cefadroxil (50370-12-2) → 3-hydroxy-4-methyl-2(5H)-thiophenone (34876-35-2) + 2-[5-(4-Hydroxy-phenyl)-3,6-dioxo-piperazin-2-yl]-5-methyl-3,6-dihydro-2H-[1,3]thiazine-4-carboxylic acid + 2-[5-(4-Hydroxy-phenyl)-3,6-dioxo-piperazin-2-yl]-5-methyl-5,6-dihydro-2H-[1,3]thiazine-4-carboxylic acid

Conditions	Yield
With disodium hydrogenphosphate In water at 60℃; for 1h; pH 9.1;	A 25 mg B n/a C n/a
In water at 35℃; Rate constant; Product distribution; Thermodynamic data; ionic strength 0.5, pH 7.0; activation enthalpy ΔH<*>; other temperatures, various pH; degradation kinetics of cefadroxil in aqueous solutions, acid and base catalysis, catalytic effect of buffer solutions; possible degradation pathways;
With disodium hydrogenphosphate In water at 60℃; for 1h; pH 9.1; Yields of byproduct given. Title compound not separated from byproducts;

N-(tert-butoxycarbonyl)-D-(4-hydroxyphenyl)glycine (27460-85-1) + cefadroxil (50370-12-2) → 4-hydroxyphenylglycylcefadroxil

Conditions	Yield
Yield given. Multistep reaction;

cefadroxil (50370-12-2) → 3-hydroxy-4-methyl-2(5H)-thiophenone (34876-35-2)

Conditions	Yield
With acid

cefadroxil (50370-12-2) → Δ2-cefadroxil

cefadroxil (50370-12-2) → C16H17N3O6S(2-)*2Na(1+)

Conditions	Yield
With sodium hydroxide for 0.166667h; Ambient temperature;

carbon disulfide (75-15-0) + formaldehyd (50-00-0) + 2-(3,4-dimethoxyphenyl)-ethylamine (120-20-7) + cefadroxil (50370-12-2) → (6R,7R)-7-[(R)-2-{5-[2-(3,4-Dimethoxy-phenyl)-ethyl]-6-thioxo-[1,3,5]thiadiazinan-3-yl}-2-(4-hydroxy-phenyl)-acetylamino]-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Conditions	Yield
Yield given. Multistep reaction;

gentisamide (52405-73-9) + cefadroxil (50370-12-2) → 7-[2-(2-carbamoyl-3,6-dioxocyclohexa-1,4-dienylamino)-2-(4-hydroxyphenyl)-acetylamino]-cephalosporanic acid

Conditions	Yield
With air; sodium acetate buffer at 20℃; for 3h; pH=5.6;

Methyl 2,5-dihydroxybenzoate (2150-46-1) + cefadroxil (50370-12-2) → 7-[2-(4-hydroxyphenyl)-2-(2-methoxycarbonyl-3,6-dioxocyclohexa-1,4-dienylamino)-acetylamino]-desacetoxycephalosporanic acid

Conditions	Yield
With air; sodium acetate buffer at 20℃; for 3h; pH=5.6;

ethyl 2,5-dihydroxybenzoate (3943-91-7) + cefadroxil (50370-12-2) → 7-[2-(2-ethoxycarbonyl-3,6-dioxocyclohexa-1,4-dienylamino)-2-(4-hydroxyphenyl)-acetylamino]-desacetoxycephalosporanic acid

Conditions	Yield
With air; sodium acetate buffer at 20℃; for 3h; pH=5.6;

cefadroxil (50370-12-2) → C16H17N3O5S

Conditions	Yield
With sodium hydroxide In water for 0.5h; Heating;

N-ethyl-L-glutamine (3081-61-6, 5822-62-8, 17010-37-6, 34271-54-0) + cefadroxil (50370-12-2) → L-theanine cefadroxil cocrystal

Conditions	Yield
In water; isopropyl alcohol

cefadroxil (50370-12-2) → D-4-hydroxyphenylglycine (22818-40-2)

Conditions	Yield
With water Enzymatic reaction;

Upstream product

• 144790-28-3 cefadroxil 
• 37763-23-8 D-2-p-hydroxyphenylglycine methyl ester 
• 26395-99-3 7-aminodesacetoxycephalosporanic acid 
• 22252-43-3 3-deacetyloxy-7-aminocephalosporanic acid 
• 54397-23-8 D-(-)-4-hydroxyphenylglycineamide 
• 78858-51-2 C₁₆H₁₉NO₇ 

Downstream Products

• 73226-86-5 2-hydroxy-3-(p-hydroxyphenyl)-6-methylpyrazine 
• 34876-35-2 3-hydroxy-4-methyl-2(5H)-thiophenone 
• 147103-95-5 4-hydroxyphenylglycylcefadroxil 
• 1044135-33-2 7-[2-(6-methyl-3,4-dioxocyclohexa-1,5-dienylamino)-2-(4-hydroxyphenyl)acetylamino]cephalosporanic acid 
• 1044135-32-1 7-[2-(5-methyl-3,4-dioxocyclohexa-1,5-dienylamino)-2-(4-hydroxyphenyl)acetylamino]cephalosporanic acid 
• 871315-52-5 C₂₃H₂₁N₃O₆S 
• 22818-40-2 D-4-hydroxyphenylglycine 

Relevant articles and documents

Efficient synthesis of cefadroxil in [Bmim][NTf2]-phosphate cosolvent by magnetic immobilized penicillin G acylase

For the first time, cefadroxil was synthesized from 7-Amino-3-desacetoxycephalosporanic acid and d-hydroxyphenylglycine methyl ester in [Bmim][NTf2]-phosphate cosolvent capable of dissolving the substrates using the penicillin G acylase (PGA) immobilized on the micrometer-size magnetic polymer microspheres having high activity of 2,083 U/g. The high synthesis/hydrolysis (S/H) ratio of 1.12 was achieved with 79.0% yield, where only the S/H ratio of 0.19 and yield of 20.0% was obtained using free PGA under the identical optimum reaction conditions. Cefadroxil had been synthesized efficiently in [Bmim][NTf2]-phosphate cosolvent by the magnetic immobilized PGA, which illuminated that there are two very critical and essential designs, that is, effective support and suitable solvent system by PGA, in enzymatic synthesis of cefadroxil. Obviously, there is great potential for the magnetic immobilized PGA and ionic liquid solvent in application to biocatalysis.

PROCESS FOR THE SYNTHESIS OF HYDROXYPHENYLGLYCINE ESTERS

The present invention refers to a process for the synthesis of a D-(-)-p-hydroxyphenylglycine (HPG) ester in crystal form, by crystallizing D-HPG ester from a solution containing dissolved D-HPG ester to obtain a suspension comprising D-HPG ester crystals, characterized in that the eeD of the D-HPG ester in the solution and the eeD of the D-HPG ester crystals is above 95%, preferably above 97%, more preferably above 98%, more preferably above 99%, more preferably above 99.5%.

PROCESS FOR THE CRYSTALLISATION OF CEFADROXIL

The present invention relates to a process for the preparation of cefadroxil in crystal form, comprising a) adding an aqueous solution of cefadroxil to a crystallisation vessel and a titrant to keep a pH in the crystallisation vessel of between 7 to 9; and b) lowering the pH in the crystallisation vessel to a value of between 5 and 6.5 to obtain a suspension of the ?-lactam compound in crystal form. The invention further relates to cefadroxil in crystal form obtainable by the process according to the present invention. The invention also relates to cefadroxil in crystal form with a CIE b value of below 12 when stored at a temperature of 25°C for at least 1 month.

PROCESSES FOR THE PREPARATION OF CEPHEM DERIVATIVES

Provided is a process for preparing a compound of formula 1 or its salt, which includes reacting a compound of formula 2 with a compound of formula 3 in the presence of a base.

PROCESS FOR THE PREPARATION OF 7-AMINO (p-HYDROXYPHENYLGLYCYL) CEPHEM COMPOUNDS

The invention relates to pure 7- amino (p-hydroxyphenylglycyl) cephem compounds. The invention also relates to processes for the preparation of pure 7- amino (p-hydroxyphenylglycyl) cephem compounds and pharmaceutical compositions that include the pure 7- amino (p-hydroxyphenylglycyl) cephem compounds.

Process for the preparation of cefadroxil

The present invention relates to an improved process for the preparation of cefadroxil of the formula (I), more particularly, the present invention relates to an improved process for the preparation of cefadroxil having water content in the range of 4-5%.

Synthesis of cephalosporin-type antibiotics by coupling of their β-lactam nucleus and racemic amino acid side chains using a clathration-induced asymmetric transformation

The cephalosporin-type antibiotics Cephalexin, Cephradine and Cefadroxil have been prepared by coupling of their β-lactam nucleus and racemic amino acid side chain precursors. The initially obtained mixture of cephalosporin epimers is subjected to a clathration-induced asymmetric transformation which results in the epimerization of the epi-cephalosporin into the cephalosporin with the correct diastereomeric configuration.

Clathration-induced asymmetric transformation of cefadroxil

The cephalosporin antibiotic Cefadroxil can be epimerized at the α-carbon of its amino acid side chain using pyridoxal as the mediator. By clathration with 2,7-dihydroxynaphthalene, the desired diastereomer can be selectively withdrawn from the equilibrat

Penicillin acylase in the industrial production of β-lactam antibiotics

Immobilized penicillin acylase is a biocatalyst suitable for the kinetically controlled industrial synthesis of semi-synthetic antibiotics in aqueous environments. Amoxiciliin and ampicillin are obtained by condensing 6-aminopenicillanic acid with the amide or ester of D-( - )-4-hydroxyphenyIglycine and D-( - )phenylglycine, respectively. Similarly, the cephalosporin antibiotics cefadroxil and cephalexin can be obtained from 7-aminodesacetoxycephalosporanic acid.