120788-07-0

Basic information

• Product Name: Sulopenem
• Synonyms: Sulopenem;(S)-3-[[(5R)-2-Carboxy-6β-[(R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio]tetrahydrothiophene 1-oxide;CP-65207-S;CP-70429
• CAS NO: 120788-07-0
• Molecular Formula: C₁₂H₁₅NO₅S₃
• Molecular Weight: 349.451
• EINECS: 604-604-1
• Mol File: 120788-07-0.mol
• Article Data: 5

Chemical Properties

• Boiling Point: 693.1°Cat760mmHg
• Flash Point: 373°C
• Appearance: /
• Density: 1.74g/cm³
• Vapor Pressure: 3.2E-22mmHg at 25°C
• Refractive Index: 1.768
• PKA: 3.88±0.40(Predicted)
• CAS DataBase Reference: Sulopenem(CAS DataBase Reference)
• NIST Chemistry Reference: Sulopenem(120788-07-0)
• EPA Substance Registry System: Sulopenem(120788-07-0)

Safety Data

• Hazardous Substances Data: 120788-07-0(Hazardous Substances Data)

Usage

Description

Sulopenem is a parenteral penem that demonstrates high activity against Gram-positive, Gram-negative, and anaerobic bacteria. Since it is stable in relation to renal dehydropeptidase I, it does not require concomitant administration of an inhibitor of this enzyme.

Uses

Different sources of media describe the Uses of 120788-07-0 differently. You can refer to the following data:
1. Antibacterial.
2. Sulopenem is a β-Lactamase inhibitor which is used in treatment of microbial infections. It is an important reagent for many drugs synthesized against bacterial infections.

Mechanism of action

Sulopenem is one of the penems and, as such, interacts with penicillin-binding proteins (PBPs). From in vitro studies, sulopenem has shown a high affinity for PBP1a, 1b, 2, and 3 in E. coli.

Pharmacokinetics

When 1 g of CP-65,207 [containing 46.3% of S-isomer (sulopenem) and 53.7% of R-isomer] was administered by 10-minute intravenous infusions, the peak concentration of sulopenem in serum was 36.0 mg/ ml, its half-life was 52.8 minutes, and the area under the serum concentration-versus-time curve (AUC) from 0 to 8 hours was 21.0 mg/ml per hour.

InChI:InChI=1/C12H15NO5S3/c1-5(14)7-9(15)13-8(11(16)17)12(20-10(7)13)19-6-2-3-21(18)4-6/h5-7,10,14H,2-4H2,1H3,(H,16,17)/t5-,6+,7+,10-,21?/m1/s1

Synthetic route

(3S)-3-({(5R,6S)-6-[(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl]-2-carboxy-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-en-3 yl}sulfanyl)tetrahydrothiophenium-1-olate (770673-33-1) → (3S)-3-({(5R, 6S)-2-carboxy-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-en-3-yl}sulfanyl)tetrahydrothiophenium-1-olate (120788-07-0)

Conditions	Yield
With tetrabutyl ammonium fluoride In tetrahydrofuran at 25℃; for 18h; Inert atmosphere;	72%

2-Chloroallyl (5R,6S)-6-(1(R)-hydroxyethyl)-2-<(1(R)-oxo-3(S)-thiolanyl)thio>-2-penem-3-carboxylate (120788-06-9) → (3S)-3-({(5R, 6S)-2-carboxy-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-en-3-yl}sulfanyl)tetrahydrothiophenium-1-olate (120788-07-0)

Conditions	Yield
With hydrogenchloride; tetrakis(triphenylphosphine) palladium(0); triphenylphosphine; sodium 2-ethylhexanoic acid 1.) rt, 2.) H2O, 0 - 5 deg C, 45 min; Yield given. Multistep reaction;

3(S)-thiolane 1(R)-oxide sodium salt (120735-10-6, 120735-20-8, 126688-47-9) → (3S)-3-({(5R, 6S)-2-carboxy-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-en-3-yl}sulfanyl)tetrahydrothiophenium-1-olate (120788-07-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: propan-2-ol; CS2 / 0.5 h / 3 °C 2: 98 percent / N,N-diisopropylethylamine / CH2Cl2 / 0.25 h / -55 - -50 °C 3: 56 percent / P(OEt)3 / CHCl3 / 10 h / Heating 4: 83 percent / glacial acetic acid, tetrabutylammonium fluoride / tetrahydrofuran / 16 h / Ambient temperature 5: 1.) triphenylphosphine, tetrakis(triphenylphosphine)palladium(0), sodium 2-ethylhexamoate, 2.) 1 N HCl / 1.) rt, 2.) H2O, 0 - 5 deg C, 45 min View Scheme
Multi-step reaction with 5 steps 1: acetone; tetrahydrofuran / 0.5 h / 0 °C 2: 98 percent / N,N-diisopropylethylamine / CH2Cl2 / 0.25 h / -55 - -50 °C 3: 56 percent / P(OEt)3 / CHCl3 / 10 h / Heating 4: 83 percent / glacial acetic acid, tetrabutylammonium fluoride / tetrahydrofuran / 16 h / Ambient temperature 5: 1.) triphenylphosphine, tetrakis(triphenylphosphine)palladium(0), sodium 2-ethylhexamoate, 2.) 1 N HCl / 1.) rt, 2.) H2O, 0 - 5 deg C, 45 min View Scheme

(3S,4R)-3-<(1R)-1-<(Dimethyl-tert-butylsilyl)oxy>ethyl>-4-<<<(1(R)-oxo-3(S)-thiolanyl)thio>thiocarbonyl>thio>-2-azetidinone (112206-93-6, 112295-83-7, 115793-24-3, 142507-63-9) → (3S)-3-({(5R, 6S)-2-carboxy-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-en-3-yl}sulfanyl)tetrahydrothiophenium-1-olate (120788-07-0)

Conditions

Yield

Multi-step reaction with 4 steps 1: 98 percent / N,N-diisopropylethylamine / CH2Cl2 / 0.25 h / -55 - -50 °C 2: 56 percent / P(OEt)3 / CHCl3 / 10 h / Heating 3: 83 percent / glacial acetic acid, tetrabutylammonium fluoride / tetrahydrofuran / 16 h / Ambient temperature 4: 1.) triphenylphosphine, tetrakis(triphenylphosphine)palladium(0), sodium 2-ethylhexamoate, 2.) 1 N HCl / 1.) rt, 2.) H2O, 0 - 5 deg C, 45 min View Scheme

2-Chloroallyl (5R,6S)-6-<1(R)-<(dimethyl-tert-butylsilyl)oxy>ethyl>-2-<(1(R)-oxo-3(S)-thiolanyl)thio>-2-penem-3-carboxylate (120788-05-8) → (3S)-3-({(5R, 6S)-2-carboxy-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-en-3-yl}sulfanyl)tetrahydrothiophenium-1-olate (120788-07-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 83 percent / glacial acetic acid, tetrabutylammonium fluoride / tetrahydrofuran / 16 h / Ambient temperature 2: 1.) triphenylphosphine, tetrakis(triphenylphosphine)palladium(0), sodium 2-ethylhexamoate, 2.) 1 N HCl / 1.) rt, 2.) H2O, 0 - 5 deg C, 45 min View Scheme

(3S,4R)-N-<<(2-Chlorallyl)oxy>oxalyl>-3-<1(R)-1-<(dimethyl-tert-butylsilyl)oxy>ethyl>-4-<<<(1(R)-oxo-3(S)-thiolanyl)thio>thiocarbonyl>thio>-2-azetidinone (120788-04-7) → (3S)-3-({(5R, 6S)-2-carboxy-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-en-3-yl}sulfanyl)tetrahydrothiophenium-1-olate (120788-07-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 56 percent / P(OEt)3 / CHCl3 / 10 h / Heating 2: 83 percent / glacial acetic acid, tetrabutylammonium fluoride / tetrahydrofuran / 16 h / Ambient temperature 3: 1.) triphenylphosphine, tetrakis(triphenylphosphine)palladium(0), sodium 2-ethylhexamoate, 2.) 1 N HCl / 1.) rt, 2.) H2O, 0 - 5 deg C, 45 min View Scheme

C15H29NO2S3Si → (3S)-3-({(5R, 6S)-2-carboxy-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-en-3-yl}sulfanyl)tetrahydrothiophenium-1-olate (120788-07-0)

Conditions	Yield
Multi-step reaction with 6 steps 1: triethylamine / mineral oil; tert-butyl methyl ether / -10 - 20 °C 2: methyldiethoxyphosphine / toluene / 4 h / 90 °C / Inert atmosphere 3: urea hydrogen peroxide adduct; 1,1,1,3',3',3'-hexafluoro-propanol / toluene / 20 - 25 °C 4: triethylamine / Isopropyl acetate; n-heptane / 2 h / -20 - 5 °C 5: palladium diacetate; triethyl phosphite; sodium benzenesulfonate / tetrahydrofuran; water / 4 h / 25 °C / Inert atmosphere 6: tetrabutyl ammonium fluoride / tetrahydrofuran / 18 h / 25 °C / Inert atmosphere View Scheme
Multi-step reaction with 6 steps 1: triethylamine / mineral oil; tert-butyl methyl ether / -10 - 20 °C 2: methyldiethoxyphosphine / toluene / Heating 3: urea hydrogen peroxide adduct; 1,1,1,3',3',3'-hexafluoro-propanol / toluene / 20 - 25 °C 4: triethylamine / Isopropyl acetate; n-heptane / 2 h / -20 - 5 °C 5: palladium diacetate; triethyl phosphite; sodium benzenesulfonate / tetrahydrofuran; water / 4 h / 25 °C / Inert atmosphere 6: tetrabutyl ammonium fluoride / tetrahydrofuran / 18 h / 25 °C / Inert atmosphere View Scheme

allyl 2-((3R,4S)-3-((R)-1-((tert-butyldimethylsilyl)oxy)ethyl)-2-oxo-4-(((propylthio)carbonothioyl)thio)azetidin-1-yl)-2-oxoacetate (1392406-54-0) → (3S)-3-({(5R, 6S)-2-carboxy-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-en-3-yl}sulfanyl)tetrahydrothiophenium-1-olate (120788-07-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: methyldiethoxyphosphine / toluene / 4 h / 90 °C / Inert atmosphere 2: urea hydrogen peroxide adduct; 1,1,1,3',3',3'-hexafluoro-propanol / toluene / 20 - 25 °C 3: triethylamine / Isopropyl acetate; n-heptane / 2 h / -20 - 5 °C 4: palladium diacetate; triethyl phosphite; sodium benzenesulfonate / tetrahydrofuran; water / 4 h / 25 °C / Inert atmosphere 5: tetrabutyl ammonium fluoride / tetrahydrofuran / 18 h / 25 °C / Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1: methyldiethoxyphosphine / toluene / Heating 2: urea hydrogen peroxide adduct; 1,1,1,3',3',3'-hexafluoro-propanol / toluene / 20 - 25 °C 3: triethylamine / Isopropyl acetate; n-heptane / 2 h / -20 - 5 °C 4: palladium diacetate; triethyl phosphite; sodium benzenesulfonate / tetrahydrofuran; water / 4 h / 25 °C / Inert atmosphere 5: tetrabutyl ammonium fluoride / tetrahydrofuran / 18 h / 25 °C / Inert atmosphere View Scheme

(5R,6S)-allyl 6-((R)-1-(tert-butyldimethylsilyloxy)ethyl)-7-oxo-3-(propylthio)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (93603-76-0) → (3S)-3-({(5R, 6S)-2-carboxy-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-en-3-yl}sulfanyl)tetrahydrothiophenium-1-olate (120788-07-0)

Conditions

Yield

Multi-step reaction with 4 steps 1: urea hydrogen peroxide adduct; 1,1,1,3',3',3'-hexafluoro-propanol / toluene / 20 - 25 °C 2: triethylamine / Isopropyl acetate; n-heptane / 2 h / -20 - 5 °C 3: palladium diacetate; triethyl phosphite; sodium benzenesulfonate / tetrahydrofuran; water / 4 h / 25 °C / Inert atmosphere 4: tetrabutyl ammonium fluoride / tetrahydrofuran / 18 h / 25 °C / Inert atmosphere View Scheme

(5R,6S)-allyl 6-((R)-1-(tert-butyldimethylsilyloxy)ethyl)-7-oxo-3-(propylsulfinyl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1392406-55-1) → (3S)-3-({(5R, 6S)-2-carboxy-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-en-3-yl}sulfanyl)tetrahydrothiophenium-1-olate (120788-07-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine / Isopropyl acetate; n-heptane / 2 h / -20 - 5 °C 2: palladium diacetate; triethyl phosphite; sodium benzenesulfonate / tetrahydrofuran; water / 4 h / 25 °C / Inert atmosphere 3: tetrabutyl ammonium fluoride / tetrahydrofuran / 18 h / 25 °C / Inert atmosphere View Scheme

4-(bromomethyl)-5-(2-methylpropyl)-1,3-dioxol-2-one (1026105-99-6) + (3S)-3-({(5R, 6S)-2-carboxy-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-en-3-yl}sulfanyl)tetrahydrothiophenium-1-olate (120788-07-0) → (5-(2-methylpropyl)-2-oxo-1,3-dioxol-4-yl)methyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[[(1R,3S)-tetrahydro-1-oxido-3-thienyl]thio]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1026105-86-1)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetone at 25℃; for 9h;	69%

Upstream product

• 120788-06-9 2-Chloroallyl (5R,6S)-6-(1(R)-hydroxyethyl)-2-<(1(R)-oxo-3(S)-thiolanyl)thio>-2-penem-3-carboxylate 
• 120735-10-6 3(S)-<thio>thiolane 1(R)-oxide sodium salt 
• 112206-93-6 (3S,4R)-3-<(1R)-1-<(Dimethyl-tert-butylsilyl)oxy>ethyl>-4-<<<(1(R)-oxo-3(S)-thiolanyl)thio>thiocarbonyl>thio>-2-azetidinone 
• 120788-05-8 2-Chloroallyl (5R,6S)-6-<1(R)-<(dimethyl-tert-butylsilyl)oxy>ethyl>-2-<(1(R)-oxo-3(S)-thiolanyl)thio>-2-penem-3-carboxylate 
• 120788-04-7 (3S,4R)-N-<<(2-Chlorallyl)oxy>oxalyl>-3-<1(R)-1-<(dimethyl-tert-butylsilyl)oxy>ethyl>-4-<<<(1(R)-oxo-3(S)-thiolanyl)thio>thiocarbonyl>thio>-2-azetidinone 
• 1392406-54-0 allyl 2-((3R,4S)-3-((R)-1-((tert-butyldimethylsilyl)oxy)ethyl)-2-oxo-4-(((propylthio)carbonothioyl)thio)azetidin-1-yl)-2-oxoacetate 
• 93603-76-0 (5R,6S)-allyl 6-((R)-1-(tert-butyldimethylsilyloxy)ethyl)-7-oxo-3-(propylthio)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate 
• 1392406-55-1 (5R,6S)-allyl 6-((R)-1-(tert-butyldimethylsilyloxy)ethyl)-7-oxo-3-(propylsulfinyl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate 
• 770673-33-1 (3S)-3-({(5R,6S)-6-[(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl]-2-carboxy-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-en-3 yl}sulfanyl)tetrahydrothiophenium-1-olate 

Relevant articles and documents

Development of a practical and convergent process for the preparation of sulopenem

Previous synthetic processes for the preparation of sulopenem involved multistep linear sequences in which the chiral sulfoxide side chain was introduced early in the process. This contribution summarizes the development of a practical and convergent process for the large-scale preparation of 1. The key step in the synthesis involves cyclization of an oxalimide intermediate to provide the thiopenem core. This convergent strategy allows for late introduction of the expensive and labile chiral sulfoxide subunit. Additionally, a regioselective sulfur oxidation and an improved deprotection sequence were developed. The latter provides API of high purity without the need for recrystallization.

Process for removal of allyl group or allyloxycarbonyl group

This invention relates to a process for the removal of an allyl or allyloxycarbonyl group from an allyl or allyloxycarbonyl group protected compound (such as an allylic ester, carbonate, carbamate, O-allyl derivatives or N-allyl derivatives), which comprises contacting the allyl or allyloxycarbonyl group protected compound with a sulfinic acid compound, in the presence of a palladium catalyst in a reaction-inert solvent. Preferably, the sulfinic acid compound is represented by the formula: X-SO2M (I)wherein X is C1 20 alkyl, substituted C1 20 alkyl (wherein the substituent(s) are independently halo, nitro, sulfo, oxo, amino, cyano, carboxy, hydroxy or moieties derived therefrom), phenyl, substituted phenyl (wherein the substituent(s) are independently C1 3 alkyl, halo nitro, sulfo, oxo, amino, cyano, carboxy, hydroxy, acetamido or moieties derived therefrom), furyl or thienyl; and M is hydrogen, an alkali metal or ammonium salt residue. Of these, most preferred sulfinic acid compound is lithium p-toluenesulfinate, sodium p-toluenesulfinate, potassium p-toluenesulfinate, p-toluenesulfinic acid, ammonium p-toluenesulfinate, lithium benzenesulfinate, sodium benzenesulfinate, potassium benzenesulfinate, benzenesulfinic acid or ammonium benzenesulfinate. This invention is well suited to a process for the conversion of an allyl ester of 5R,6S-6-(1R-hydroxyethyl)-2-(1R-oxo-3S-thiolanylthio)-2-penem-3-carboxylic acid to 5R,6S-6-(1R-hydroxyethyl)-2-(1R-oxo-3S-thiolanylthio)-2-penem-3-carboxylic acid.

Diastereomeric 5R,6S-6-(1R-hydroxyethyl)-2-(cis-1-oxo-3-thiolanylthio)-2-penem-3-carboxylic acids

Diastereomeric 5R,6S-6-(1R-hydroxyethyl)-2-(1S-oxo-3R-thiolanylthio)-2-penem-3-carboxylic acid and 5R,6S-6-(1R-hydroxyethyl)-2-(1R-oxo-3S-thiolanylthio )-2-penem-3-carboxylic acid, and pharmaceutically-acceptable salts and in vivo hydrolyzable esters thereof, useful as systemic antibacterial agents; and intermediates and processes which are useful in the said synthesis of said diastereoisomers.