58001-44-8

Basic information

• Product Name: Clavulanic acid
• Synonyms: (2r-(2-alpha,3z,5-alpha))-xo;3008-b;4-oxa-1-azabicyclo(3.2.0)heptane-2-carboxylicacid,3-(2-hydroxyethylidene)-7-o;antibioticmm14151;brl14151;4,7-DIOXO-[3-(2-HYDROXYETHYLIDENE)]-1-AZABICYCLO[3.2.0]HEPTANE-2-CARBOXYLIC ACID;CLAVULANIC ACID;4-Oxa-1-azabicyclo3.2.0heptane-2-carboxylic acid, 3-(2-hydroxyethylidene)-7-oxo-, (2R,3Z,5R)-
• CAS NO: 58001-44-8
• Molecular Formula: C₈H₉NO₅
• Molecular Weight: 199.16
• EINECS: 261-069-2
• Product Categories: Antibiotics;antibiotic
• Mol File: 58001-44-8.mol

Chemical Properties

• Boiling Point: 545.8 °C at 760 mmHg
• Flash Point: 283.9 °C
• Appearance: Colorless needle-like crystal
• Density: 1.65 g/cm³
• Vapor Pressure: 3.45E-14mmHg at 25°C
• Refractive Index: 1.644
• PKA: 3.68±0.20(Predicted)
• CAS DataBase Reference: Clavulanic acid(CAS DataBase Reference)
• NIST Chemistry Reference: Clavulanic acid(58001-44-8)
• EPA Substance Registry System: Clavulanic acid(58001-44-8)

Safety Data

• Hazardous Substances Data: 58001-44-8(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Clavulanic acid is used as a beta-lactamase inhibitor for enhancing the effectiveness of antibiotics like ampicillin and amoxicillin against β-lactamase-producing bacteria. By inhibiting the enzyme responsible for antibiotic resistance, clavulanic acid allows the primary antibiotic to function more effectively, overcoming resistance and improving treatment outcomes.
Used in Research and Development:
Clavulanic acid is also utilized in the research and development of new antibiotics and pharmaceutical compounds. Its unique mechanism of action as a suicide inhibitor provides valuable insights into the development of novel drugs targeting bacterial resistance and other enzyme-related diseases.

Originator

Augmentin,Beecham,UK,1981

Manufacturing Process

100 ml of sterile water was added to a sporing culture which had been grown on Bennetts agar in a Roux bottle for 10 days at 26°C. A mycelium/sporesuspension was produced and used to inoculate 75 liters of steam sterilized medium of the following composition in tap water.Arkasoy is soybean flour supplied by British Arkady Co., Old Trafford, Manchester, UK The pH of the medium was adjusted to 7.0 The medium was contained in a 100 liter stainless steel baffled fermenter, agitated by a 7.5 inch vaned disc impeller at 140 rpm. Sterile air was supplied at 75 liters per minute and the tank incubated for 72 hours at 26°C. The contents of the seed fermenter were used to inoculate 1,500 liters of steam sterilized medium of the following composition in tap water.10% Pluronic L81 in soybean oil 0.2% V/V The pH of the medium was adjusted to 7.0 The medium was contained in a 2,000 liter stainless steel fully baffled fermenter agitated by two 19 inch vaned disc impellers at 106 rpm. Sterile air was supplied at 1,200 liters per minute. Antifoam was added in 25 ml amounts as required. (10% Pluronic L81 in soybean oil). The fermentation was controlled at 26°C until a maximum yield of clavulanic acid was obtained between 3-5 days when 200-300 μg/ml of clavulanic acid were produced.

Therapeutic Function

Antibacterial

World Health Organization (WHO)

The amoxicillin/clavulanic acid combination should be reserved for infections likely or known to be caused by amoxicillin- resistant beta-lactamase producing strains. Amoxicillin/clavulanic acid is listed in the WHO Model List of Essential Drugs.

Antimicrobial activity

It exhibits broad-spectrum but low intrinsic activity, most MICs being in the range 16–128 mg/L. Enterobacteriaceae and Staph. aureus are among the more sensitive and Ps. aeruginosa the most resistant organisms. MICs of 8 mg/L against H. influenzae and 0.1–4 mg/L for penicillinase-producing N. gonorrhoeae are notable.

Pharmacokinetics

It exhibits broad-spectrum but low intrinsic activity, most MICs being in the range 16–128 mg/L. Enterobacteriaceae and Staph. aureus are among the more sensitive and Ps. aeruginosa the most resistant organisms. MICs of 8 mg/L against H. influenzae and 0.1–4 mg/L for penicillinase-producing N. gonorrhoeae are notable.

Clinical Use

Clavulanic acid is an antibiotic isolated from Streptomycesclavuligeris. Structurally, it is a 1-oxopenam lacking the6-acylamino side chain of penicillins but possessing a 2-hydroxyethylidene moiety at C-2. Clavulanic acid exhibitsvery weak antibacterial activity, comparable with that of6-APA and, therefore, is not useful as an antibiotic. Itis, however, a potent inhibitor of S. aureus β-lactamaseand plasmid-mediated β-lactamases elaborated by Gramnegativebacilli.Combinations of amoxicillin and the potassium saltof clavulanic acid are available (Augmentin) in variousfixed-dose oral dosage forms intended for the treatment ofskin, respiratory, ear, and urinary tract infections causedby -lactamase–producing bacterial strains. These combinationsare effective against β-lactamase–producingstrains of S. aureus, E. coli, K. pneumoniae, Enterobacter,H. influenzae, Moraxella catarrhalis, and Haemophilusducreyi, which are resistant to amoxicillin alone. The oral bioavailability of amoxicillin and potassium clavulanate issimilar. Clavulanic acid is acid-stable. It cannot undergo penicillanicacid formation because it lacks an amide side chain.Potassium clavulanate and the extended-spectrum penicillinticarcillin have been combined in a fixed-dose, injectableform for the control of serious infections caused byβ-lactamase–producing bacterial strains. This combinationhas been recommended for septicemia, lower respiratory tractinfections, and urinary tract infections caused by β-lactamase–producing Klebsiella spp., E. coli, P. aeruginosa,and other Pseudomonas spp., Citrobacter spp., Enterobacterspp., S. marcescens, and S. aureus. It also is used in bone andjoint infections caused by these organisms. The combinationcontains 3 g of ticarcillin disodium and 100 mg of potassiumclavulanate in a sterile powder for injection (Timentin).

Synthesis

Clavulanic acid is isolated from Streptomyces clavuligerus [60–66], and sulbactam, a sulfone of penicillanic acid, is synthesized from 6-APA [67–69]. Both compounds have extremely weak antibacterial properties and act by forming irreversible complexes with beta-lactamase, which inactivates the enzyme, and as a result the beta-lactam antibiotic has time to destroy the microorganism.

InChI:InChI=1/C8H9NO5/c10-2-1-4-7(8(12)13)9-5(11)3-6(9)14-4/h1,6-7,10H,2-3H2,(H,12,13)/b4-1-

Synthetic route

Benzyl Clavulanate (57943-84-7) → clavulanic acid (58001-44-8)

Conditions	Yield
With hydrogen; palladium on activated charcoal In ethanol under 760 Torr; for 0.75h; Ambient temperature;	84%

(2RS,5S)-<5-(3)H>Ornithine (103545-38-6, 103664-39-7, 103664-40-0, 135909-75-0, 135909-76-1) → C8H8(3)HNO5 + clavulanic acid (58001-44-8)

Conditions	Yield
With cultures of Streptomyces clavuligerus (ATCC 27064) in a glycerol-based fermentation medium Product distribution; labelling studies also with incorporation (14)C, acid isolated as p-bromobenzyl ester;

(2RS,5RS)-<5-(3)H>Ornithine → C8H8(3)HNO5 + clavulanic acid (58001-44-8)

Conditions	Yield
With cultures of Streptomyces clavuligerus (ATCC 27064) in a glycerol-based fermentation medium Product distribution; labelling studies also with incorporation (14)C, acid isolated as p-bromobenzyl ester;

(3R,5R) clavulanate-9-aldehyde → clavulanic acid (58001-44-8)

Conditions	Yield
Streptomyces clavuligerus SC 2;

Ornithin-dihydrochlorid (1069-31-4, 3184-13-2, 6211-16-1, 15160-12-0, 16682-12-5, 20724-48-5, 22834-83-9, 26982-21-8, 66837-02-3, 99815-05-1) → (2S,5S)-3-[2-(2-Acetylamino-acetylamino)-eth-(Z)-ylidene]-7-oxo-4-oxa-1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid + clavulanic acid (58001-44-8)

Conditions	Yield
Streptomyces clavuligerus; examination of incorporation by labelled <5-(14)C, 5-(3)H>ornithine;

methyl clavulanate (57943-82-5) → clavulanic acid (58001-44-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 70 percent / sodium hydroxide / H2O / 1.17 h / 0 °C 2: 69 percent / dimethylformamide / 1.5 h / Ambient temperature 3: 84 percent / H2 / palladium on carbon / ethanol / 0.75 h / 760 Torr / Ambient temperature View Scheme

potassium clavulanate (57943-81-4) → clavulanic acid (58001-44-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 69 percent / dimethylformamide / 1.5 h / Ambient temperature 2: 84 percent / H2 / palladium on carbon / ethanol / 0.75 h / 760 Torr / Ambient temperature View Scheme

sodium 3-oxoethylidene-7-oxo-4-oxa-1-azabicyclo-[3.2.0] heptane-2-carboxylate → clavulanic acid (58001-44-8)

Conditions	Yield
With NADPH at 26℃; pH=7.0;

N,N-diisopropyl-1,2-ethanediamine (4013-94-9) + clavulanic acid (58001-44-8) → N,N'-diisopropylethylenediammonium diclavulanate

Conditions	Yield
In methanol; water; ethyl acetate for 0.25h;	96%
In ethyl acetate; isopropyl alcohol	84%
In methanol; ethyl acetate	81%

N-tert-butylbenzylamine (3378-72-1) + clavulanic acid (58001-44-8) → C8H9NO5*C11H17N

Conditions	Yield
In ethyl acetate	83%
In ethanol; ethyl acetate for 1h;	68%
In ethyl acetate; isopropyl alcohol	67%

1-Adamantanamine (768-94-5) + clavulanic acid (58001-44-8) → (2R,5R)-3-[2-Hydroxy-eth-(Z)-ylidene]-7-oxo-4-oxa-1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid; compound with adamantan-1-ylamine (66069-33-8)

Conditions	Yield
In ethyl acetate	81%
In ethanol; ethyl acetate	80%
In methanol; ethyl acetate for 1h;	76%
In ethyl acetate; isopropyl alcohol	76%

tert-butylamine (75-64-9) + clavulanic acid (58001-44-8) → clavulanic acid tert-butylamine (66069-34-9)

Conditions	Yield
In ethyl acetate	81%
In ethyl acetate; isopropyl alcohol for 1h;	77%
In ethanol; ethyl acetate	43%
Stage #1: clavulanic acid With ammonium sulfate In water; ethyl acetate at 5℃; pH=1.30; Stage #2: tert-butylamine In methanol; ethyl acetate at 5℃; for 2h; pH-value; Concentration;

tert-Octylamine (107-45-9) + clavulanic acid (58001-44-8) → (2R,5R)-3-[2-Hydroxy-eth-(Z)-ylidene]-7-oxo-4-oxa-1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid; compound with 1,1,3,3-tetramethyl-butylamine (66069-32-7)

Conditions	Yield
In ethyl acetate	80%
In ethyl acetate; isopropyl alcohol for 1h;	67%
In ethanol; ethyl acetate	35%

clavulanic acid (58001-44-8) → methyl-4-aza-8-hydroxy-6-oxo-oct-2-enoate (83670-77-3)

Conditions	Yield
With methanol; diethylamine for 0.166667h; Ambient temperature;	78%

diazomethane (186581-53-3, 908094-01-9) + clavulanic acid (58001-44-8) → methyl clavulanate (57943-82-5)

Conditions	Yield
In ethanol Ambient temperature;	75%

clavulanic acid (58001-44-8) → 9-chloro-9-deoxyclavulanic acid (477947-66-3)

Conditions	Yield
With pyridine; methanesulfonyl chloride In acetonitrile at 25℃; for 24h;	75%

benzylamine (100-46-9) + clavulanic acid (58001-44-8) → N-benzylclavulanamide (62868-57-9)

Conditions	Yield
With sodium hydroxide; dicyclohexyl-carbodiimide In tetrahydrofuran; dichloromethane; ethyl acetate	67%

N,N'-diethylethylenediamine (111-74-0) + clavulanic acid (58001-44-8) → C6H16N2*2C8H9NO5

Conditions	Yield
In ethanol; ethyl acetate for 0.5h;	61%

diazodiphenylmethane (908093-98-1) + clavulanic acid (58001-44-8) → benzhydryl clavulanate (64018-86-6)

Conditions	Yield
In tetrahydrofuran Ambient temperature;	60%

clavulanic acid (58001-44-8) + phenol (108-95-2) → phenyl clavulanate (57943-88-1)

Conditions	Yield
With dicyclohexyl-carbodiimide In acetonitrile Ambient temperature;	59%

N,N'-Dibenzylethylenediamine (140-28-3) + clavulanic acid (58001-44-8) → 2C8H9NO5*C16H20N2

Conditions	Yield
In ethanol; ethyl acetate for 1h;	54%
In ethyl acetate; isopropyl alcohol	31%
In ethyl acetate	3%

SEC-BUTYLAMINE (33966-50-6) + clavulanic acid (58001-44-8) → C4H11N*C8H9NO5

Conditions	Yield
In ethanol; ethyl acetate for 1h;	52.6%
In ethyl acetate; isopropyl alcohol	52%
In ethyl acetate	8%

2-(2-Hydroxyethyl)pyridine (103-74-2) + clavulanic acid (58001-44-8) → 2-(2-pyridyl)ethyl clavulanate (91022-06-9)

Conditions	Yield
With dicyclohexyl-carbodiimide In acetonitrile Ambient temperature;	50%

N,N,N,N,-tetramethylethylenediamine (110-18-9) + clavulanic acid (58001-44-8) → N,N,N',N'-tetramethylethylenediammonium diclavulanate

Conditions	Yield
In ethyl acetate; isopropyl alcohol for 1h;	37%
In ethyl acetate	30%

clavulanic acid (58001-44-8) → methyl (E)-3-(diethylamino)-2-propenoate (58243-07-5) + methyl 3-(2-hydroxyethyl)-pyrrole-4-carboxylate (83670-73-9) + methyl-4-aza-8-hydroxy-6-oxo-oct-2-enoate (83670-77-3)

Conditions	Yield
With diethylamine In methanol for 48h; Ambient temperature;	A 20% B 14% C 18%
With Diethyl amine In methanol for 48h; Ambient temperature;	A 20% B 14% C 18%

para-thiocresol (106-45-6) + clavulanic acid (58001-44-8) → p-tolyl thioclavulanate (91022-05-8)

Conditions	Yield
With dicyclohexyl-carbodiimide In acetonitrile Ambient temperature;	17%

clavulanic acid (58001-44-8) → (E)-(5R)-3-(2-hydroxyethylidene)-4-oxa-1-azabicyclo<3.2.0>heptan-7-one + (Z)-(5R)-3-(2-hydroxyethylidene)-4-oxa-1-azabicyclo<3.2.0>heptan-7-one

Conditions	Yield
With mercury(II) diacetate In 1,2-dimethoxyethane 1) r.t., 15 min, 2) 90-95 deg C (bath), 20 min;	A 5% B 5.5%

clavulanic acid (58001-44-8) → (5R)-7-oxo-3-vinyl-4-oxa-1-azabicyclo[3.2.0]hept-2-ene (71019-00-6)

Conditions	Yield
With N,N-dimethyl-formamide dimethyl acetal In tetrahydrofuran
With N,N-dimethyl-formamide dimethyl acetal In tetrahydrofuran for 0.133333h; Ambient temperature; Yield given;
With N,N-dimethyl-formamide dimethyl acetal

benzyl chloroformate (501-53-1) + clavulanic acid (58001-44-8) → 1-benzyloxycarbonylamino-4-hydroxybutan-2-one (92632-80-9)

Conditions	Yield
With hydrogenchloride; water; sodium hydrogencarbonate 1.) 2 h, 2.) water, THF, ice-cooling, 40 min; Yield given. Multistep reaction;

3-chloro-benzenecarboperoxoic acid (937-14-4) + clavulanic acid (58001-44-8) → (Z)-(3S,5R)-2-(2-hydroxyethylidene)-3-(m-chlorobenzoyloxy)clavam (71916-37-5)

Conditions	Yield
With dicyclohexyl-carbodiimide In 1,2-dimethoxyethane; dichloromethane 1.) 0 deg C, 3 h, 2.) room temperature, 15 h;	60 mg

methanol (67-56-1) + clavulanic acid (58001-44-8) → methyl clavulanate (57943-82-5) + (Z)-(2R)-5-(2-hydroxyethylidene)-2-methoxycarbonylmethyl-2,5-dihydro-oxazole (88367-33-3) + (Z)-(3S,5R)-2-(2-hydroxyethylidene)-3-methoxyclavam (88391-46-2)

Conditions	Yield
With triethylamine at -30℃; for 0.833333h; electrolysis: platinum electrodes, I=200-250 mA;	A 5 mg B 75 mg C 10 mg
With triethylamine at -30℃; for 0.833333h; electrolysis: platinum electrodes, current 200-250 mA;	A 5 mg B 75 mg C 10 mg

methanol (67-56-1) + clavulanic acid (58001-44-8) → methyl clavulanate (57943-82-5) + (Z)-(3S,5R)-2-(2-hydroxyethylidene)-3-methoxyclavam (88391-46-2) + (E)-(3S,5R)-3-acetoxy-2-formylmethyleneclavam (71916-39-7, 88391-48-4, 88391-49-5) + (Z)-(3S,5R)-3-acetoxy-2-formylmethyleneclavam (88391-49-5)

Conditions	Yield
With triethylamine at -30℃; for 0.833333h; Product distribution; electrolysis, platinum electrodes, current 200-250 mA; reactions of oxidative decarboxylation ( electrolysis, with Pb(OAc)4, decarboxylative rearrangement of diacyl peroxide) of clavulanic acid and its methyl ether;	A 5 mg B 10 mg C n/a D n/a

lead(IV) tetraacetate (546-67-8) + clavulanic acid (58001-44-8) → (Z)-(3S,5R)-3-acetoxy-2-(2-hydroxyethylidene)clavam (88391-50-8) + (Z)-(3S,5R)-3-acetoxy-2-(2-acetoxyethylidene)clavam (88391-47-3) + (E)-(3S,5R)-3-acetoxy-2-formylmethyleneclavam (71916-39-7, 88391-48-4, 88391-49-5) + (Z)-(3S,5R)-3-acetoxy-2-formylmethyleneclavam (88391-49-5)

Conditions	Yield
In 1,2-dimethoxyethane; benzene at 70℃; for 0.333333h;	A 145 mg B 20 mg C n/a D n/a
In 1,2-dimethoxyethane; benzene at 70℃; for 0.333333h; Yields of byproduct given;	A 145 mg B 20 mg C n/a D n/a
In 1,2-dimethoxyethane; benzene at 70℃; for 0.333333h; Yield given. Title compound not separated from byproducts;	A 145 mg B 20 mg C n/a D n/a

Upstream product

• 103545-38-6 (5RS)-<5-(3)H>-L-ornithine 
• 57943-84-7 Benzyl Clavulanate 
• 1069-31-4 Ornithin-dihydrochlorid 
• 57943-82-5 methyl clavulanate 
• 57943-81-4 potassium clavulanate 

Downstream Products

• 57943-82-5 methyl clavulanate 
• 92632-80-9 1-benzyloxycarbonylamino-4-hydroxybutan-2-one 
• 71916-37-5 (Z)-(3S,5R)-2-(2-hydroxyethylidene)-3-(m-chlorobenzoyloxy)clavam 
• 62868-57-9 N-benzylclavulanamide 
• 88367-33-3 (Z)-(2R)-5-(2-hydroxyethylidene)-2-methoxycarbonylmethyl-2,5-dihydro-oxazole 
• 88391-46-2 (Z)-(3S,5R)-2-(2-hydroxyethylidene)-3-methoxyclavam 
• 71916-39-7 (E)-(3S,5R)-3-acetoxy-2-formylmethyleneclavam 
• 88391-49-5 (Z)-(3S,5R)-3-acetoxy-2-formylmethyleneclavam 
• 57943-88-1 phenyl clavulanate 
• 477947-69-6 (2R,5R)-3-[2-{4-[(R)-(Benzhydryl-amino)-((2S,5R,6R)-2-benzhydryloxycarbonyl-3,3-dimethyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-6-ylcarbamoyl)-methyl]-phenoxy}-eth-(Z)-ylidene]-7-oxo-4-oxa-1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid 
• 477947-74-3 C₅₇H₅₂N₄O₁₃S 
• 358641-72-2 (2S,5R)-2-Phenylthio-4-oxa-1-azabicyclo[3.2.0]heptan-3,7-dione 
• 358641-74-4 (E/Z)-(2S,5R)-3-Ethylidene-2-phenylthio-4-oxa-1-azabicyclo[3.2.0]heptan-7-one 
• 358641-73-3 (2S,5R)-2-Phenylsulfinyl-4-oxa-1-azabicyclo[3.2.0]heptan-3,7-dione 

Relevant articles and documents

Evidence that the Immediate Biosynthetic Precursor of Clavulanic Acid is its N-aldehyde Analogue

(3R,5R) Clavulanate-9-aldehyde 1 has been detected in Streptomyces clavuligerus and an NADPH dependent dehydrogenase capable of reducing 1 to clavulanic acid 2 has been isolated from this organism.

The Stereochemical Fate of (2RS,5R)- and (2RS,5S)-Ornithine in Clavulanic Acid Biosynthesis

The 5-pro(R) hydrogen of ornithine is retained in the biosynthesis of clavulanic acid where it assumes the 9-pro(S) position with overall inversion of configuration.

Clavulanic acid aldehyde, beta-lactamase inhibitor

A compound of formula (I): wherein R = H or Na, or a salt thereof and an enzyme, obtainable from Streptomyces species, having clavulanic acid dehydrogenase activity which is capable of converting (I) into clavulanic acid .

Process for the isolation of a pharmaceutically acceptable alkali metal salt of clavulanic acid

The invention relates to the process for the isolation of a pharmaceutically acceptable alkali metal salt of clavulanic acid from a fermentation broth containing impure clavulanic acid comprising the steps of filtration of the fermented broth, extraction of the clavulanic acid to a water immiscible or partly water immiscible solvent at pH from 1.2-2, precipitation of an alkali metal salt A of clavulanic acid by addition of a solution of an alkali metal alkylalkanoate, characterized by the following steps: before the filtration the fermented broth containing clavulanic acid is diluted with water, a flocculating agent is added and the pH is adjusted to 3-5 for further purification the alkali metal salt A of clavulanic acid is converted to clavulanic acid by addition of an inorganic acid and is extracted into a water immiscible or partly water immiscible solvent a solution of a different alkali metal B alkyl alkanoate is added and the alkali metal salt B of clavulanic acid is precipitated.

Process for the preparation of potassium clavulanate

A process for preparation of potassium clavulanate by the direct precipitation of clavulanic acid as the potassium salt by providing a solution of clavulanic acid in an organic solvent and mixing a potassium salt with this solution, with between 0.1 % v:v and 7.5 % v:v of water present in the region where the clavulanic acid and potassium salt contact, then isolating the so-formed potassium clavulanate.

Process for the isolation of a pharmaceutically acceptable alkali metal salt of clavulanic acid

The invention relates to the process for the isolation of a pharmaceutically acceptable alkali metal salt of clavulanic acid from a fermentation broth containing impure clavulanic acid comprising the steps of filtration of the fermented broth, extraction of the clavulanic acid to a water immiscible or partly water immiscible solvent at pH from 1.2 - 2, precipitation of an alkali metal salt A of clavulanic acid by addition of a solution of an alkali metal alkylalkanoate, characterized by the following steps: before the filtration the fermented broth containing clavulanic acid is diluted with water, a flocculating agent is added and the pH is adjusted to 3 - 5 for further purification the alkali metal salt A of clavulanic acid is converted to clavulanic acid by addition of an inorganic acid and is extracted into a water immiscible or partly water immiscible solvent a solution of a different alkali metal B alkyl alkanoate is added and the alkali metal salt B of clavulanic acid is precipitated.

Process for the preparation of clavulanic acid

A process for the preparation and/or purification of clavulanic acid or a pharmaceutically acceptable salt or ester thereof comprises i) contacting impure clavulanic acid or an alkali metal salt thereof in an organic solvent, with an amine of formula (II) where R1 is a group of general formula where R4 and R5 are independently hydrogen, alkyl, amino-substituted alkyl or substituted amino-substituted alkyl, and R2 and R3 are independently selected from hydrogen, alkyl, amino- or hydroxy-substituted alkyl or substituted amino-substituted alkyl, and m is zero or an integer 1 to 5; ii) isolating the amine salt of clavulanic acid formed; iii) converting the thus formed salt into clavulanic acid or a pharmaceutically acceptable salt or ester thereof.

Process for the preparation of clavulanic acid

A process for the preparation and/or purification of clavulanic acid or a pharmaceutically acceptable salt thereof comprises i) contacting impure clavulanic acid or an alkali metal salt thereof in an organic solvent, with tertiary octylamine; ii) isolating the tertiary-octylamine salt of clavulanic acid formed; iii) converting the thus formed salt into clavulanic acid or a pharmaceutically acceptable salt or ester thereof.

The Incorporation of DL- Ornithine into Clavulanic Acid and N0Acetylglycylclavaminic Acid

Both the carbon and deuterium label of DL- ornithine were incorporated into the novel β-lactam metabolite N-acetylglycylclavaminic acid, whereas only the carbon label was incorporated into clavulanic acid.

Amine salts of clavulanic acid as antibacterial agents

The present invention provides the salts of the formula (II): STR1 wherein R1 is a hydrogen atom or a lower alkyl, aralkyl, phenyl or inertly substituted lower alkyl, aralkyl or phenyl group; R2 is a hydrogen atom or a lower alkyl, aralkyl, phenyl or inertly substituted lower alkyl, aralkyl or phenyl group; and R3 is lower alkyl, aralkyl, phenyl or inertly substituted lower alkyl, aralkyl or phenyl group; any of said groups R1, R2 and R3 being optionally interlinked to form a ring of 5-7 ring atoms. The compounds are antibacterials.