96034-64-9

Basic information

• Product Name: Side chain for meropenem
• Synonyms: SIDE CHAIN FOR MEROPENEM;(2S,4S)-2-(Dimethylaminocarbonyl)-4-Mercapto-1- (P-Nitrobenzyloxycarbonyl)-1- Py;(2S,4S)-2-Dimethylcarbamoyl-4-Mercapto-Pyrrolidine-1-Carboxylic Acid 4-Nitro-Benzyl Ester;Side chain for Meropenem(2S-CIS);SIDE CHAIN FOR MEROPENEM 97+%（HPLC）;(2S,4S)-2-(DIMETHYLAMINOCARBLNYL)-4-MERCAPTO-1-(4'-NITROBENZYLOXYCARBONYL)-1-PYRROLIDINE;(2S-Cis)SideChain(ForMeropenem);(2S,4S)-2-(dimethylaminocarboxyl)-4-mercapto-1-(p-nitrobenzyloxycarbonyl)-1-pyrrolidine
• CAS NO: 96034-64-9
• Molecular Formula: C₁₅H₁₉N₃O₅S
• Molecular Weight: 353.39
• EINECS: 1806241-263-5
• Product Categories: Chemical intermediate for Meropenem;INTERMEDIATESOFMEROPENAM;Organic acids;API intermediates;(intermediate of meropenem);(the sidechain of meropenem);Intermediates & Fine Chemicals;Pharmaceuticals;Pharmaceutical;pharmaceutical intermediates
• Mol File: 96034-64-9.mol

Chemical Properties

• Melting Point: 117.0 to 121.0 °C
• Boiling Point: 555.8 °C at 760 mmHg
• Flash Point: 289.9 °C
• Appearance: White crystalline solid
• Density: 1.36 g/cm³
• Vapor Pressure: 2.17E-12mmHg at 25°C
• Refractive Index: 1.611
• Storage Temp.: under inert gas (nitrogen or Argon) at 2-8°C
• Solubility: DMSO (Slightly), Methanol (Slightly), Water (Slightly)
• PKA: 9.94±0.40(Predicted)
• Stability: Hygroscopic
• CAS DataBase Reference: Side chain for meropenem(CAS DataBase Reference)
• NIST Chemistry Reference: Side chain for meropenem(96034-64-9)
• EPA Substance Registry System: Side chain for meropenem(96034-64-9)

Safety Data

• Hazardous Substances Data: 96034-64-9(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Side chain for meropenem is used as an intermediate in the synthesis of meropenem, a carbapenem antibiotic, for its potent antibacterial properties and effectiveness against a wide range of bacterial infections.
Used in Antibacterial Applications:
Side chain for meropenem is used in the development of meropenem, a carbapenem antibiotic, for its broad-spectrum antibacterial activity, making it a valuable asset in treating various bacterial infections, including those caused by drug-resistant strains.

InChI:InChI=1/C15H19N3O5S/c1-16(2)14(19)13-7-12(24)8-17(13)15(20)23-9-10-3-5-11(6-4-10)18(21)22/h3-6,12-13,24H,7-9H2,1-2H3/t12-,13-/m0/s1

Synthetic route

(2S,4S)-1-p-nitrobenzyloxycarbonyl-2-carboxy-4-mercaptopyrrolidine (127966-47-6) + N,N-dimethylammonium chloride (506-59-2) → (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9)

Conditions	Yield
Stage #1: (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-carboxy-4-mercaptopyrrolidine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 5℃; for 0.166667h; Stage #2: N,N-dimethylammonium chloride In N,N-dimethyl-formamide at 0 - 5℃; for 3h; Concentration;	92.3%
Stage #1: (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-carboxy-4-mercaptopyrrolidine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 5℃; for 0.166667h; Stage #2: N,N-dimethylammonium chloride In N,N-dimethyl-formamide at 0 - 5℃; for 3h;	92.3%

N,N-dimethylammonium chloride (506-59-2) + (2S,4S)-5-p-nitrobenzyloxycarbonyl-2-thia-5-azabicyclo<2.2.1>heptan-3-one (151072-00-3) → (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9)

Conditions	Yield
With triethylamine In tetrahydrofuran for 5h; Ambient temperature;	92%

bi[(2S,4S)-2-dimethylaminocarbonyl-1-PNZ-pyrrolindin-4-yl]disulfide (936226-36-7) → (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9)

Conditions	Yield
With tributylphosphine; water In tetrahydrofuran for 0.5h;	90%
With tributylphosphine In tetrahydrofuran; water for 0.5h;	90%

4-Nitrobenzyl (2S,4S)-4-(acetylthio)-2-[(dimethylamino)carbonyl]pyrrolidine-1-carboxylate (96034-61-6) → (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9)

Conditions	Yield
With acetyl chloride In methanol at 25 - 30℃; for 6h;	80%
With methanol; acetyl chloride at 25℃; for 2.5 - 5h; Product distribution / selectivity; Heating / reflux;	70%
With Lewatit K 2649 - ion exchange resin In methanol at 25 - 67℃; Product distribution / selectivity;

(2S,4R)-4-Hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine-2-carboxylic acid (96034-57-0) → (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: triethylamine; isopropyl chloroformate / dichloromethane / -30 - -20 °C 2.1: triethylamine / dichloromethane / -20 °C 3.1: N,N-dimethyl-formamide / 70 - 80 °C 4.1: sodium hydroxide; water / methanol / 5 - 10 °C 4.2: pH 2 View Scheme

4-nitrobenzyl chloroformate (4457-32-3) → (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: sodium hydroxide / water / 0 - 5 °C 1.2: 0 - 5 °C 1.3: 0 - 5 °C 2.1: triethylamine; isopropyl chloroformate / dichloromethane / -30 - -20 °C 3.1: triethylamine / dichloromethane / -20 °C 4.1: N,N-dimethyl-formamide / 70 - 80 °C 5.1: sodium hydroxide; water / methanol / 5 - 10 °C 5.2: pH 2 View Scheme

4R-4-hydroxyproline (51-35-4) → (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: sodium hydroxide / water / 0 - 5 °C 1.2: 0 - 5 °C 1.3: 0 - 5 °C 2.1: triethylamine; isopropyl chloroformate / dichloromethane / -30 - -20 °C 3.1: triethylamine / dichloromethane / -20 °C 4.1: N,N-dimethyl-formamide / 70 - 80 °C 5.1: sodium hydroxide; water / methanol / 5 - 10 °C 5.2: pH 2 View Scheme
Multi-step reaction with 4 steps 1.1: tributylphosphine / tetrahydrofuran / 25 h / 60 - 65 °C 2.1: diethylamino-sulfur trifluoride / 1,2-dichloro-ethane / 26 h / 0 - 60 °C 3.1: sodium carbonate / acetone; water / 5 h / 0 - 50 °C 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.17 h / 0 - 5 °C 4.2: 3 h / 0 - 5 °C View Scheme

(2S,4R)-1-p-Nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-hydroxypyrrolidine (130625-69-3) → (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: triethylamine / dichloromethane / -20 °C 2.1: N,N-dimethyl-formamide / 70 - 80 °C 3.1: sodium hydroxide; water / methanol / 5 - 10 °C 3.2: pH 2 View Scheme

(2S,4R)-2-dimethylaminocarbonyl-4-mesyloxy-1-p-nitrobenzyloxycarbonylpyrrolidine (130625-70-6) → (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: N,N-dimethyl-formamide / 70 - 80 °C 2.1: sodium hydroxide; water / methanol / 5 - 10 °C 2.2: pH 2 View Scheme

(2S,4R)-2-carboxy-4-(3-fluorophenylthio)pyrrolidine → (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: diethylamino-sulfur trifluoride / ethylenediamine / 26 h / 0 - 60 °C 2.1: sodium carbonate / acetone; water / 0.25 h / 0 - 25 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.17 h / 0 - 5 °C 3.2: 3 h / 0 - 5 °C View Scheme
Multi-step reaction with 3 steps 1.1: diethylamino-sulfur trifluoride / 1,2-dichloro-ethane / 26 h / 0 - 60 °C 2.1: sodium carbonate / acetone; water / 5 h / 0 - 50 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.17 h / 0 - 5 °C 3.2: 3 h / 0 - 5 °C View Scheme

trans-4-hydroxyproline (3398-22-9) → (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: tributylphosphine / tetrahydrofuran / 25 h / 60 - 65 °C 2.1: diethylamino-sulfur trifluoride / ethylenediamine / 26 h / 0 - 60 °C 3.1: sodium carbonate / acetone; water / 0.25 h / 0 - 25 °C 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.17 h / 0 - 5 °C 4.2: 3 h / 0 - 5 °C View Scheme

(4-nitrophenyl)methyl (4R,5R,6S)-3-[(diphenoxyphosphinyl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (93711-81-0, 90776-59-3) + (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9) → p-nitrobenzyl (4R,5S,6S)-3-<(3S,5S)-5-dimethylaminocarbonyl-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio>-6-<(1R)-1-hydroxyethyl>-4-methyl-7-oxo-1-azabicyclo<3.2.0>hept-2-en-2-carboxylate (96036-02-1)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at -15 - -10℃; for 5 - 8h;	91.3%
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at -10℃; for 3.16667h; Product distribution / selectivity;	18%
With N-ethyl-N,N-diisopropylamine In acetonitrile at -10℃; for 3.16667h; Product distribution / selectivity;	17%

(2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9) → bi[(2S,4S)-2-dimethylaminocarbonyl-1-PNZ-pyrrolindin-4-yl]disulfide (936226-36-7)

Conditions	Yield
With iron(III) chloride; oxygen In methanol at 25℃; under 750.075 Torr; for 4h; Pressure; Temperature; Reagent/catalyst;	90%

(p-nitrophenyl)methyl 6-(1-hydroxyethyl)-5-methyl-3,7-dioxoazabicyclo[3.2.0]heptane-2-carboxylate + (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9) → C32H35N5O11S

Conditions	Yield
Stage #1: (p-nitrophenyl)methyl 6-(1-hydroxyethyl)-5-methyl-3,7-dioxoazabicyclo[3.2.0]heptane-2-carboxylate With N-ethyl-N,N-diisopropylamine; Diphenylphosphinic chloride In acetonitrile at -35℃; for 0.5h; Stage #2: (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine With N-ethyl-N,N-diisopropylamine In acetonitrile	85%

bromomagnesium N-isopropyl-N-cyclohexylamide (100207-82-7) + 4-nitrobenzyl (1 R , 5 S , 6 S)-2-(2-diethylcarbamoylphenylsulphinyl)-1-methyl-6-[1(R)-trimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate (158168-61-7) + (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9) → p-nitrobenzyl (4R,5S,6S)-3-<(3S,5S)-5-dimethylaminocarbonyl-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio>-4-methyl-7-oxo-6-<(1R)-1-trimethylsilyloxoethyl>-1-azabicyclo<3.2.0>hept-2-en-2-carboxylate (105344-45-4)

Conditions	Yield
With sodium chloride; ammonium chloride In tetrahydrofuran; (2S)-N-methyl-1-phenylpropan-2-amine hydrate	78%

(p-nitrophenyl)methyl 5-ethyl-6-(1-hydroxyethyl)-3,7-dioxoazabicyclo[3.2.0]heptane-2-carboxylate + (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9) → C33H37N5O11S

Conditions	Yield
Stage #1: (p-nitrophenyl)methyl 5-ethyl-6-(1-hydroxyethyl)-3,7-dioxoazabicyclo[3.2.0]heptane-2-carboxylate With N-ethyl-N,N-diisopropylamine; Diphenylphosphinic chloride In acetonitrile at -35℃; Stage #2: (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine With N-ethyl-N,N-diisopropylamine In acetonitrile	77%

(2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9) + (4R,5S,6S)-6-[(R)-1-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-3-(2-diethylcarbamoyl-benzenesulfonyl)-4-methyl-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (158168-65-1) → (4R,5S,6S)-6-[(R)-1-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-3-[(3S,5S)-5-dimethylcarbamoyl-1-(4-nitro-benzyloxycarbonyl)-pyrrolidin-3-ylsulfanyl]-4-methyl-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; magnesium bromide In tetrahydrofuran for 19h; Ambient temperature;	73%

(R)-4-nitrobenzyl 2-diazo-4-((2R,3S)-3-((R)-1-(methylsulfonamido)ethyl)-4-oxoazetidin-2-yl)-3-oxopentanoate + (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9) → (4R,5S,6S)-4-nitrobenzyl-3-((3S,5S)-5-(dimethylcarbamoyl)-1-(( 4-nitrobenzyloxy)carbonyl)pyrrolidin-3-ylthio)-4-methyl-6-((R)-1-(methylsulfonamido)ethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

Conditions

Yield

Stage #1: (R)-4-nitrobenzyl 2-diazo-4-((2R,3S)-3-((R)-1-(methylsulfonamido)ethyl)-4-oxoazetidin-2-yl)-3-oxopentanoate With rhodium (II) octanoate dimer In acetone for 1h; Reflux; Stage #2: With dmap; N-ethyl-N,N-diisopropylamine; chlorophosphoric acid diphenyl ester In acetone at -50 - 20℃; for 0.5h; Stage #3: (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine With N-ethyl-N,N-diisopropylamine In acetone at -20 - 0℃; for 4h;

48%

(2R,5R,6S)-5-methyl-4-nitrobenzyl ester-6-((R)-1-hydroxyethyl)-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid + (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9) → (5R,6S)-5-methyl-3-[[(3S,5S)5-[(dimethylamino)carbonyl]-1-[[(4-nitrophenyl)methoxy]carbonyl]-3-pyrrolidinyl]thio]-4-nitrobenzyl-6-((R)-1-hydroxyethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

Conditions	Yield
Stage #1: (2R,5R,6S)-5-methyl-4-nitrobenzyl ester-6-((R)-1-hydroxyethyl)-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid With N-ethyl-N,N-diisopropylamine; Diphenylphosphinic chloride In acetonitrile at -40℃; for 0.333333h; Stage #2: (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine With N-ethyl-N,N-diisopropylamine In acetonitrile at -40 - -10℃; for 0.5h;	35%

(2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9) + {(S)-2-[(R)-1-(4-Chloro-phenylsulfanylcarbonyl)-ethyl]-4-oxo-azetidin-1-yl}-acetic acid 4-nitro-benzyl ester → (4R,5S)-3-[(3S,5S)-5-Dimethylcarbamoyl-1-(4-nitro-benzyloxycarbonyl)-pyrrolidin-3-ylsulfanyl]-4-methyl-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester

Conditions

Yield

Stage #1: {(S)-2-[(R)-1-(4-Chloro-phenylsulfanylcarbonyl)-ethyl]-4-oxo-azetidin-1-yl}-acetic acid 4-nitro-benzyl ester With sodium hydride; allyl bromide In tetrahydrofuran at -40℃; Cyclization; Stage #2: With chlorophosphoric acid diphenyl ester at -20℃; Substitution; Stage #3: (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine With N,N-diethyl-N-isopropylamine; 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 0℃; Substitution;

21%

C15H14N2O7 + (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9) → C30H31N5O11S

Conditions	Yield
Stage #1: C15H14N2O7 With N-ethyl-N,N-diisopropylamine; Diphenylphosphinic chloride In acetonitrile at -40℃; for 0.75h; Stage #2: (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine With N-ethyl-N,N-diisopropylamine In acetonitrile for 1.5h;	15%

(2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9) + (4R,5R,6S,8R)-p-nitrobenzyl-3-(diphenylphosphoryloxy)-4-methyl-6-(1-(trimethylsilyloxy)ethyl)-7-oxo-1-azabicyclo<3.2.0>hept-2-ene-2-carboxylate (161692-28-0) → p-nitrobenzyl (4R,5S,6S)-3-<(3S,5S)-5-dimethylaminocarbonyl-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio>-4-methyl-7-oxo-6-<(1R)-1-trimethylsilyloxoethyl>-1-azabicyclo<3.2.0>hept-2-en-2-carboxylate (105344-45-4)

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran; toluene for 2h; Yield given;

(2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9) + p-nitrobenzyl (4R,5R,6S)-6-<(1R)-1-tert-butyldimethylsilyloxyethyl>-3-diphenylphosphoryloxy-4-methyl-7-oxo-1-azabicyclo<3.2.0>hept-2-en-2-carboxylate (105318-43-2) → (4R,5S,6S)-6-[(R)-1-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-3-[(3S,5S)-5-dimethylcarbamoyl-1-(4-nitro-benzyloxycarbonyl)-pyrrolidin-3-ylsulfanyl]-4-methyl-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran; toluene for 2h; Yield given;

(2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9) + (4R,5S,6S)-6-[(R)-1-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-3-(2-diethylcarbamoyl-benzenesulfinyl)-4-methyl-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (158168-62-8) → (4R,5S,6S)-6-[(R)-1-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-3-[(3S,5S)-5-dimethylcarbamoyl-1-(4-nitro-benzyloxycarbonyl)-pyrrolidin-3-ylsulfanyl]-4-methyl-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester

Conditions	Yield
With bromomagnesium N-isopropyl-N-cyclohexylamide 1.) THF, 0 deg C, 5 min, 2.) THF, 0 deg C, 30 min; Yield given. Multistep reaction;

(2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9) → (4R,5S)-3-((3S,5S)-5-Dimethylcarbamoyl-pyrrolidin-3-ylsulfanyl)-4-methyl-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Conditions	Yield
Multi-step reaction with 2 steps 1.1: NaH; allylbromide / tetrahydrofuran / -40 °C 1.2: diphenyl chlorophosphate / -20 °C 1.3: 21 percent / i-PrEt2N; DBU / acetonitrile / 0 °C 2.1: 24 percent / H2 / Pd-C / tetrahydrofuran; aq. phosphate buffer View Scheme

(4-nitrophenyl)methyl (4R,5R,6S)-3-[(diphenoxyphosphinyl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (93711-81-0, 90776-59-3) + (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9) → meropenem trihydrate

Conditions

Yield

Stage #1: (4-nitrophenyl)methyl (4R,5R,6S)-3-[(diphenoxyphosphinyl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate; (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine In N,N-dimethyl-formamide at -50 - 20℃; for 1h; Stage #2: With 4-methyl-morpholine; hydrogen; acetic acid; 5%-palladium/activated carbon In ethyl acetate at 20 - 25℃; for 3h; pH=~ 7; Product distribution / selectivity; Aqueous buffer;

(4-nitrophenyl)methyl (4R,5R,6S)-3-[(diphenoxyphosphinyl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (93711-81-0, 90776-59-3) + (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9) → 4-nitrobenzyl (4R,5S,6S)-3-[[(3S,5S)-5-(dimethylcarbamoyl)-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxy-ethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (141818-52-2)

Conditions	Yield
With diisopropylamine In N,N-dimethyl-formamide at -50 - 20℃; for 1h;

4-nitrobenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate + (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9) → meropenem (96036-03-2)

Conditions

Yield

Stage #1: 4-nitrobenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate; (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at -50 - 25℃; for 1h; Stage #2: With 4-methyl-morpholine; hydrogen; acetic acid; 5%-palladium/activated carbon In water; ethyl acetate; N,N-dimethyl-formamide at 20 - 25℃; for 3h; pH=~ 7;

(4-nitrophenyl)methyl (4R,5R,6S)-3-[(diphenoxyphosphinyl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (93711-81-0, 90776-59-3) + (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9) → meropenem (96036-03-2)

Conditions	Yield
Stage #1: (4-nitrophenyl)methyl (4R,5R,6S)-3-[(diphenoxyphosphinyl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate; (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one; water at -20 - -5℃; Stage #2: With 4-methyl-morpholine; hydrogenchloride; 5% Pd(II)/C(eggshell); hydrogen In 1-methyl-pyrrolidin-2-one; water at 25℃; pH=6.5 - 7;
Stage #1: (4-nitrophenyl)methyl (4R,5R,6S)-3-[(diphenoxyphosphinyl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate; (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at -20 - -5℃; Stage #2: With hydrogen; 5%-palladium/activated carbon In 1-methyl-pyrrolidin-2-one at 25℃; pH=6.5 - 7; N-methylmorpholine - hydrochloric acid - buffer;
Stage #1: (4-nitrophenyl)methyl (4R,5R,6S)-3-[(diphenoxyphosphinyl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate; (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 0 - 5℃; for 5h; Stage #2: With potassium dihydrogenphosphate; zinc In water; ethyl acetate at 25 - 35℃; for 1h;
Stage #1: (4-nitrophenyl)methyl (4R,5R,6S)-3-[(diphenoxyphosphinyl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate; (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine With N-ethyl-N,N-diisopropylamine In ISOPROPYLAMIDE at 0 - 5℃; for 5h; Stage #2: With hydrogenchloride In water; ethyl acetate Stage #3: With potassium dihydrogenphosphate In water; ethyl acetate at 25 - 35℃; for 1h;

4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]-heptane-2-carboxylate (104873-15-6) + (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9) → p-nitrobenzyl (4R,5S,6S)-3-<(3S,5S)-5-dimethylaminocarbonyl-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio>-6-<(1R)-1-hydroxyethyl>-4-methyl-7-oxo-1-azabicyclo<3.2.0>hept-2-en-2-carboxylate (96036-02-1)

Conditions	Yield
Stage #1: 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]-heptane-2-carboxylate With N-ethyl-N,N-diisopropylamine; chlorophosphoric acid diphenyl ester In acetonitrile at 10 - 15℃; for 5h; Stage #2: (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine With N-ethyl-N,N-diisopropylamine In acetonitrile at 10 - 15℃; for 5 - 8h;

p-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[(bis(2,4-dichlorophenyl)phosphono)oxy]-1-methylcarbapen-2-em-3-carboxylate + (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9) → meropenem (96036-03-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / -35 - -30 °C 2: hydrogen; 2,6-dimethylpyridine / palladium 10% on activated carbon / water; tetrahydrofuran / 20 - 25 °C / 13501.4 Torr View Scheme
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / -35 - -30 °C 2: hydrogen; 2,6-dimethylpyridine / palladium 10% on activated carbon / dichloromethane; water; tetrahydrofuran / 20 - 25 °C / 13501.4 Torr View Scheme

p-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[(bis(2,4-dichlorophenyl)phosphono)oxy]-1-methylcarbapen-2-em-3-carboxylate + (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine (96034-64-9) → p-nitrobenzyl (4R,5S,6S)-3-<(3S,5S)-5-dimethylaminocarbonyl-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio>-6-<(1R)-1-hydroxyethyl>-4-methyl-7-oxo-1-azabicyclo<3.2.0>hept-2-en-2-carboxylate (96036-02-1)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at -35 - -30℃;
With N-ethyl-N,N-diisopropylamine In dichloromethane at -35 - -30℃;

Upstream product

• 506-59-2 N,N-dimethylammonium chloride 
• 151072-00-3 (2S,4S)-5-p-nitrobenzyloxycarbonyl-2-thia-5-azabicyclo<2.2.1>heptan-3-one 
• 96034-61-6 4-Nitrobenzyl (2S,4S)-4-(acetylthio)-2-[(dimethylamino)carbonyl]pyrrolidine-1-carboxylate 
• 936226-36-7 bi[(2S,4S)-2-dimethylaminocarbonyl-1-PNZ-pyrrolindin-4-yl]disulfide 
• 96034-57-0 (2S,4R)-4-Hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine-2-carboxylic acid 
• 4457-32-3 4-nitrobenzyl chloroformate 
• 51-35-4 4R-4-hydroxyproline 
• 130625-69-3 (2S,4R)-1-p-Nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-hydroxypyrrolidine 
• 130625-70-6 (2S,4R)-2-dimethylaminocarbonyl-4-mesyloxy-1-p-nitrobenzyloxycarbonylpyrrolidine 
• 127966-47-6 (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-carboxy-4-mercaptopyrrolidine 
• 3398-22-9 trans-4-hydroxyproline 

Downstream Products

• 105344-45-4 p-nitrobenzyl (4R,5S,6S)-3-<(3S,5S)-5-dimethylaminocarbonyl-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio>-4-methyl-7-oxo-6-<(1R)-1-trimethylsilyloxoethyl>-1-azabicyclo<3.2.0>hept-2-en-2-carboxylate 
• 96036-02-1 p-nitrobenzyl (4R,5S,6S)-3-<(3S,5S)-5-dimethylaminocarbonyl-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio>-6-<(1R)-1-hydroxyethyl>-4-methyl-7-oxo-1-azabicyclo<3.2.0>hept-2-en-2-carboxylate 
• 119478-56-7 meropenem trihydrate 
• 141818-52-2 4-nitrobenzyl (4R,5S,6S)-3-[[(3S,5S)-5-(dimethylcarbamoyl)-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxy-ethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate 
• 96036-03-2 meropenem 
• 936226-36-7 bi[(2S,4S)-2-dimethylaminocarbonyl-1-PNZ-pyrrolindin-4-yl]disulfide 

Relevant articles and documents

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