122547-49-3

Basic information

• Product Name: Faropenem sodium
• Synonyms: (5R,6S,8R,2′R)-2-(2′-tetrahydrofuryl)-6-hydroxyethylpenem-3-carboxylate sodium salt;Faropenem sodium hydrate;sodiuM (5S,6R)-6-((S)-1-hydroxyethyl)-7-oxo-3-((R)-tetrahydrofuran-2-yl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate;(5r,6s)-6-(1(r)-hydroxyethyl)-2-(2(r)-tetrahydrofuryl)penem-3-carboxylicacid;6-(1-hydroxyethyl)-7-oxo-3-(tetrahydro-2-furanyl)-,monosodiumsalt,(5r-(3(r*),5-alpha,6-alpha(r*)4-thia-1-azabicyclo(3.2.0)hept-2-ene-2-carboxylicaci;alp201;fropenumsodium;o-3-(tetrahydro-2-furanyl)-,monosodiumsalt,(5r-(3(r*),5-alpha,6-alpha(r*)))
• CAS NO: 122547-49-3
• Molecular Formula: C₁₂H₁₄NO₅S*Na
• Molecular Weight: 307.3
• EINECS: 1592732-453-0
• Product Categories: Pharmaceutical intermediates;chiral;Cnbio;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 122547-49-3.mol
• Article Data: 5

Chemical Properties

• Boiling Point: 570.2 °C at 760 mmHg
• Flash Point: 298.7 °C
• Appearance: white to light brown/
• Vapor Pressure: 2.23E-15mmHg at 25°C
• Storage Temp.: ?20°C
• Solubility: H2O: ≥20mg/mL
• Stability: Hygroscopic
• CAS DataBase Reference: Faropenem sodium(CAS DataBase Reference)
• NIST Chemistry Reference: Faropenem sodium(122547-49-3)
• EPA Substance Registry System: Faropenem sodium(122547-49-3)

Safety Data

• WGK Germany: 3
• Hazardous Substances Data: 122547-49-3(Hazardous Substances Data)

Usage

Chemical Properties

Pale Yellow Crystals

Uses

Faropenem is an orally active beta-lactam antibiotic belonging to the penem group.

General Description

Faropenem sodium hydrate belongs to the penem group of antibiotics prescribed for oral usage. Enterobacteriaceae bacterial infections with cephalosporin resistance are susceptible to faropenem. Faropenem could be an effective antibiotic to treat urinary tract infections caused by extended-spectrum beta-lactamases (ESBL) producing bacteria.

Biochem/physiol Actions

Faropenem sodium is an ultra-broad spectrum, β-lactamase resistant, β-lactam antibiotic active against both Gram-positive and Gram-negative bacteria.

InChI:InChI=1/C12H15NO5S.Na/c1-5(14)7-10(15)13-8(12(16)17)9(19-11(7)13)6-3-2-4-18-6;/h5-7,11,14H,2-4H2,1H3,(H,16,17);/q;+1/p-1/t5-,6-,7+,11-;/m1./s1

Synthetic route

(5R,6S)-6-((R)-1-hydroxyethyl)-2-((R)-tetrahydro-2-furyl)penem-3-carboxylic acid allyl ester (106559-80-2) → Furopenem (122547-49-3)

Conditions	Yield
With bis-triphenylphosphine-palladium(II) chloride; triphenylphosphine; sodium 2-ethylhexanoic acid In water; ethyl acetate at 20℃; for 5h; Inert atmosphere; Large scale reaction;	86.5%
Stage #1: (5R,6S)-6-((R)-1-hydroxyethyl)-2-((R)-tetrahydro-2-furyl)penem-3-carboxylic acid allyl ester With sodium isooctanoate; sodium caprylate; triphenylphosphine In dichloromethane; ethyl acetate at 20℃; Stage #2: With tetrakis(triphenylphosphine) palladium(0) In dichloromethane; ethyl acetate at 25 - 30℃; for 0.666667h; Inert atmosphere;	73.3%
With tetrakis(triphenylphosphine) palladium(0); triphenylphosphine; sodium 2-ethylhexanoic acid In ethyl acetate for 1h; Ambient temperature;

(3R,4R)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-acetoxyazetidin-2-one (76899-07-5, 78963-47-0, 78963-48-1, 78963-60-7, 80951-41-3, 81275-02-7, 85647-75-2, 85954-95-6, 92217-74-8, 104527-11-9, 76855-69-1) → Furopenem (122547-49-3)

Conditions	Yield
Multi-step reaction with 5 steps 1: aq. NaHCO3 / acetone / 4 h / 60 °C 2: Et3N / CH2Cl2 / 0.17 h / -20 °C 3: triethyl phosphite / xylene / 11 h / Heating 4: AcOH, tetra-n-butylammonium fluoride / tetrahydrofuran / 8.5 h / 50 °C 5: Ph3P, tetrakis(triphenylphosphine)palladium, sodium 2-ethylhexanoate / ethyl acetate / 1 h / Ambient temperature View Scheme
Multi-step reaction with 5 steps 1: sodium hydroxide / acetone / 2 h / 0 - 20 °C / pH 8 - 10 2: triethylamine / dichloromethane / 2 h / 0 - 5 °C 3: triethyl phosphite / 5,5-dimethyl-1,3-cyclohexadiene / 5 h / Reflux 4: hydrogenchloride; palladium on activated charcoal; hydrogen / methanol / 16 h / 40 °C / 3040.2 Torr 5: sodium 2-ethylhexanoic acid / tetrahydrofuran; water / 2 h / 20 °C View Scheme

R-(+)-thio tetrahydrofuran-2-carboxylic acid → Furopenem (122547-49-3)

Conditions	Yield
Multi-step reaction with 5 steps 1: aq. NaHCO3 / acetone / 4 h / 60 °C 2: Et3N / CH2Cl2 / 0.17 h / -20 °C 3: triethyl phosphite / xylene / 11 h / Heating 4: AcOH, tetra-n-butylammonium fluoride / tetrahydrofuran / 8.5 h / 50 °C 5: Ph3P, tetrakis(triphenylphosphine)palladium, sodium 2-ethylhexanoate / ethyl acetate / 1 h / Ambient temperature View Scheme
Multi-step reaction with 5 steps 1: sodium hydroxide / acetone / 2 h / 0 - 20 °C / pH 8 - 10 2: triethylamine / dichloromethane / 2 h / 0 - 5 °C 3: triethyl phosphite / 5,5-dimethyl-1,3-cyclohexadiene / 5 h / Reflux 4: hydrogenchloride; palladium on activated charcoal; hydrogen / methanol / 16 h / 40 °C / 3040.2 Torr 5: sodium 2-ethylhexanoic acid / tetrahydrofuran; water / 2 h / 20 °C View Scheme

(R)-Tetrahydro-furan-2-carbothioic acid S-{(2R,3S)-3-[(R)-1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-4-oxo-azetidin-2-yl} ester (106560-32-1) → Furopenem (122547-49-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: Et3N / CH2Cl2 / 0.17 h / -20 °C 2: triethyl phosphite / xylene / 11 h / Heating 3: AcOH, tetra-n-butylammonium fluoride / tetrahydrofuran / 8.5 h / 50 °C 4: Ph3P, tetrakis(triphenylphosphine)palladium, sodium 2-ethylhexanoate / ethyl acetate / 1 h / Ambient temperature View Scheme
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 2 h / 0 - 5 °C 2: triethyl phosphite / 5,5-dimethyl-1,3-cyclohexadiene / 5 h / Reflux 3: hydrogenchloride; palladium on activated charcoal; hydrogen / methanol / 16 h / 40 °C / 3040.2 Torr 4: sodium 2-ethylhexanoic acid / tetrahydrofuran; water / 2 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 3 h / -20 - -15 °C 2: triethyl phosphite / 5,5-dimethyl-1,3-cyclohexadiene / 4.5 h / 150 °C 3: acetic acid; tetrabutyl ammonium fluoride / tetrahydrofuran / 4 h / 30 °C 4: palladium 10% on activated carbon; sodium hydrogencarbonate; hydrogen / ethyl acetate; water / 16 h / 25 - 35 °C View Scheme

allyl (5R,6S)-6((R)-1-t-butyldimethylsilyloxyethyl)-7-oxo-3-((R)-2-tetrahydrofuryl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (120705-67-1) → Furopenem (122547-49-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: AcOH, tetra-n-butylammonium fluoride / tetrahydrofuran / 8.5 h / 50 °C 2: Ph3P, tetrakis(triphenylphosphine)palladium, sodium 2-ethylhexanoate / ethyl acetate / 1 h / Ambient temperature View Scheme

(3S,4R)-1-(allyloxy)oxoacetyl-3-((R)-1-hydroxyethyl)-4-((R)-2-tetrahydrofuranyl)carbonylthio-azetidin-2-one (429691-43-0) → Furopenem (122547-49-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethyl phosphite / xylene / 11 h / Heating 2: AcOH, tetra-n-butylammonium fluoride / tetrahydrofuran / 8.5 h / 50 °C 3: Ph3P, tetrakis(triphenylphosphine)palladium, sodium 2-ethylhexanoate / ethyl acetate / 1 h / Ambient temperature View Scheme

faropenem (106560-14-9) → Furopenem (122547-49-3)

Conditions	Yield
With sodium 2-ethylhexanoic acid In tetrahydrofuran; water at 20℃; for 2h;	125 g

C25H34N2O9SSi → Furopenem (122547-49-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethyl phosphite / 5,5-dimethyl-1,3-cyclohexadiene / 5 h / Reflux 2: hydrogenchloride; palladium on activated charcoal; hydrogen / methanol / 16 h / 40 °C / 3040.2 Torr 3: sodium 2-ethylhexanoic acid / tetrahydrofuran; water / 2 h / 20 °C View Scheme

C19H21NO5S → Furopenem (122547-49-3)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen; sodium hydrogencarbonate In water; ethyl acetate at 25 - 35℃; for 16h;

C25H35NO7SSi → Furopenem (122547-49-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethyl phosphite / 5,5-dimethyl-1,3-cyclohexadiene / 4.5 h / 150 °C 2: acetic acid; tetrabutyl ammonium fluoride / tetrahydrofuran / 4 h / 30 °C 3: palladium 10% on activated carbon; sodium hydrogencarbonate; hydrogen / ethyl acetate; water / 16 h / 25 - 35 °C View Scheme

Furopenem (122547-49-3) + 4-chloromethyl-5-methyl-1,3-dioxol-2-one (80841-78-7) → faropenem medoxomil

Conditions	Yield
With sodium hydrogencarbonate; potassium iodide; benzyltri(n-butyl)ammonium chloride In tetrahydrofuran at 30 - 55℃; for 5h;	99.11%
With sodium hydrogencarbonate; potassium iodide; tetrabutyl-ammonium chloride In acetone at 50℃; for 4h; Conversion of starting material;	94.2%
With benzyltri(n-butyl)ammonium chloride; sodium hydrogencarbonate; potassium iodide In tetrahydrofuran at 30 - 55℃; for 6h; Product distribution / selectivity;	70%
With sodium hydrogencarbonate; benzyltri(n-butyl)ammonium chloride In tetrahydrofuran at 50℃; for 4h; Conversion of starting material;	36.7%

Furopenem (122547-49-3) → Sodium; (5S,6S)-6-((R)-1-hydroxy-ethyl)-7-oxo-3-(R)-tetrahydro-furan-2-yl-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylate (133885-56-0)

Conditions	Yield
In water Irradiation;

chlorosulfuric acid chloromethyl ester (49715-04-0) + Furopenem (122547-49-3) + tetrabutylammonium sulfate (2472-88-0) → chloromethyl (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(R)-2-tetrahydrofuryl]penem-3-carboxylate (141706-77-6)

Conditions	Yield
With potassium hydrogencarbonate In dichloromethane; water

Furopenem (122547-49-3) + (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl iodide (80841-79-8) → (5-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(R)-2-tetrahydrofuryl]penem-3-carboxylate

Conditions	Yield
In water; N,N-dimethyl-formamide

Upstream product

• 106560-14-9 faropenem 
• 429691-43-0 (3S,4R)-1-(allyloxy)oxoacetyl-3-((R)-1-hydroxyethyl)-4-((R)-2-tetrahydrofuranyl)carbonylthio-azetidin-2-one 
• 120705-67-1 allyl (5R,6S)-6((R)-1-t-butyldimethylsilyloxyethyl)-7-oxo-3-((R)-2-tetrahydrofuryl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate 
• 106560-32-1 (R)-Tetrahydro-furan-2-carbothioic acid S-{(2R,3S)-3-[(R)-1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-4-oxo-azetidin-2-yl} ester 
• 153165-72-1 R-(+)-thio tetrahydrofuran-2-carboxylic acid 
• 76899-07-5 (3R,4R)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-acetoxyazetidin-2-one 
• 106559-80-2 (5R,6S)-6-((R)-1-hydroxyethyl)-2-((R)-tetrahydro-2-furyl)penem-3-carboxylic acid allyl ester 

Downstream Products

• 133885-56-0 Sodium; (5S,6S)-6-((R)-1-hydroxy-ethyl)-7-oxo-3-(R)-tetrahydro-furan-2-yl-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylate 

Relevant articles and documents

An efficient method for removal of residual palladium from organic solution of faropenem sodium in the Pd(II)-catalyzed cleavage of allyl faropenem

An improved palladium(II)-catalyzed cleavage of the allyl group in allyl faropenem 2 into faropenem sodium 1 is described. The development of an efficient method for the removal of palladium impurities from the crude product 1 upon treatment with polystyrene-bound 2,4,6-trimercapto-s-triazine (polystyrene-bound TMT) led to a drastic decrease of residual palladium level from 1500-1600 ppm to less than 10 ppm in the final isolated product. The palladium(II)-catalyzed cleavage and palladium removal process demonstrated on 10 kg scale are highly convenient and efficient.

Preparation method of faropenem sodium

The invention discloses a preparation method of faropenem sodium. The preparation method comprises the steps as follows: a raw material compound I is dissolved in a solvent I for a desilylation reaction, and an intermediate II is obtained; the intermediate II is dissolved in the solvent II for an allyl removal reaction, faropenem sodium is obtained, and finally, the faropenem sodium is purified. By use of mixed solvents and a specific catalyst, the reaction speed, the product purity and yield are greatly increased, and meanwhile, palladium residues can meet the requirement without special treatment. The whole preparation method is simple, comprises few operation steps and is low in cost and suitable industrial production of medicines.

Structure-activity relationships of penem antibiotics: crystallographic structures and implications for their antimicrobial activities

Twelve closely related crystal structures of the penem derivatives revealed a characteristic short contact of the oxygen atom in the C2 side-chains with the S1 atom. The side-chain conformations of the crystal structures showed a good correlation with the antimicrobial activity. In particular, the penems which show high antimicrobial activity have similar torsion angles for S1-C2-C1'-C2', suggesting that the disposition of the C2' atom would be important for binding to penicillin-interacting enzymes. Two conformations of the C6 hydroxyethyl group were observed in the crystal structures. Of those two, the conformation with a larger torsion angle (δ = 179.2°) is deduced to be the enzyme-bound conformation in the Michaelis complex.