74288-40-7

Basic information

• Product Name: p-Nitrobenzyl-6-(1-hydroxyethyl)-1-azabicyclo(3.2.0)heptane-3,7-dione-2-carboxylate
• Synonyms: INTERMEDIANTE FOR IMIPENEM;adc 13;6-[(1R)-1-Hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid (5R,6S)-(4-nitrophenyl)methyl ester;4-NITROBENZYL (5R,6S)-6-[(1R)-1-HYDROXYETHYL]-3,7-DIOXO-1-AZABICYCLO[3.2.0]HEPTANE-2-CARBOXYLATE;1-AZABICYCLO[3.2.0]HEPTANE-2-CARBOXYLIC ACID, 6-[(1R)-1-HYDROXYETHYL]-3,7-DIOXO-, (4-NITROPHENYL)METHYL ESTER, (5R,6S)-;P-NITROBENZYL-6-(1-HYDROXYETHYL)-1-AZABICYCLO(3.2.0) HEPTANE-3,7-DIONE-2-CARBOXYLATE;B-CHETO;1-AZABICYCLO[3.2.0]HEPTANE-2-CARBOXYLIC ACID, 6-(1-HYDROXYETHYL)-3,7-DIOXO-, (4-NITROPHENYL)METHYL ESTER, [5R,[5,6(R*)]
• CAS NO: 74288-40-7
• Molecular Formula: C₁₆H₁₆N₂O₇
• Molecular Weight: 348.31
• EINECS: 1806241-263-5
• Product Categories: (intermediate of imipenem,panipenem);Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 74288-40-7.mol
• Article Data: 12

Chemical Properties

• Melting Point: 108-110°C
• Boiling Point: 607.5 °C at 760 mmHg
• Flash Point: 321.2 °C
• Appearance: White to off-white powder
• Density: 1.56 g/cm³
• Vapor Pressure: 2.63E-15mmHg at 25°C
• Refractive Index: 1.631
• Storage Temp.: -20°C Freezer
• Solubility: Chloroform (Slightly), Methanol (Slightly)
• PKA: 11.26±0.40(Predicted)
• CAS DataBase Reference: p-Nitrobenzyl-6-(1-hydroxyethyl)-1-azabicyclo(3.2.0)heptane-3,7-dione-2-carboxylate(CAS DataBase Reference)
• NIST Chemistry Reference: p-Nitrobenzyl-6-(1-hydroxyethyl)-1-azabicyclo(3.2.0)heptane-3,7-dione-2-carboxylate(74288-40-7)
• EPA Substance Registry System: p-Nitrobenzyl-6-(1-hydroxyethyl)-1-azabicyclo(3.2.0)heptane-3,7-dione-2-carboxylate(74288-40-7)

Safety Data

• Hazardous Substances Data: 74288-40-7(Hazardous Substances Data)

Usage

Chemical Properties

White to Off-White Powder

Uses

Imipenem intermediate.

Application

intermediate in orgaic syntheses

storage

sealed in dry, store in freezer, under -20°C

InChI:InChI=1/C16H16N2O7/c1-8(19)13-11-6-12(20)14(17(11)15(13)21)16(22)25-7-9-2-4-10(5-3-9)18(23)24/h2-5,8,11,13-14,19H,6-7H2,1H3

Synthetic route

(3S,4R)-3-[(R)-1-hydroxyethyl)-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxo-3-diazopropyl]azetidin-2-one (74288-39-4) → (5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7)

Conditions	Yield
With dirhodium tetraacetate In toluene at 80℃; for 2.5h; Cyclization;
rhodium (II) octanoate dimer In dichloromethane for 4 - 5h; Heating / reflux;
With nitrogen; rhodium(II) acetate In benzene

rhodium(II) acetate + (3S,4R)-3-[(R)-1-hydroxyethyl)-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxo-3-diazopropyl]azetidin-2-one (74288-39-4) → (5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7)

Conditions	Yield
In toluene

(3S,4R)-3-[(R)-1-hydroxyethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxo-3-diazopropyl]azetidin-2one → (5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7)

Conditions	Yield
With nitrogen; rhodium(II) acetate In benzene

(3S,4R)-benzyl N-(p-toluenesulfonyl)-3-((R)-1-(tert-butyldimethylsilyloxy)ethyl)-azetidin-2-one-4-carboxylate (1180012-46-7) → (5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7)

Conditions	Yield
Multi-step reaction with 6 steps 1: samarium diiodide; samarium; isopropyl alcohol 2: 10% palladium on activated charcoal; hydrogen / tetrahydrofuran 3: lead(IV) tetraacetate / N,N-dimethyl-formamide 4: zinc(II) chloride / dichloromethane 5: hydrogenchloride; methanol 6: dirhodium tetraacetate / toluene View Scheme

(3S,4R)-benzyl 3-((R)-1-(tert-butyldimethylsilyloxy)ethyl)-azetidin-2-one-4-carboxylate (1180012-50-3) → (5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7)

Conditions	Yield
Multi-step reaction with 5 steps 1: 10% palladium on activated charcoal; hydrogen / tetrahydrofuran 2: lead(IV) tetraacetate / N,N-dimethyl-formamide 3: zinc(II) chloride / dichloromethane 4: hydrogenchloride; methanol 5: dirhodium tetraacetate / toluene View Scheme

(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) → (5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: zinc(II) chloride / dichloromethane 2: hydrogenchloride; methanol 3: dirhodium tetraacetate / toluene View Scheme

4-nitrobenzyl 3-((tert-butyldimethylsilyl)oxy)-2-diazobut-3-enoate (93788-48-8) → (5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: zinc(II) chloride / dichloromethane 2: hydrogenchloride; methanol 3: dirhodium tetraacetate / toluene View Scheme

(3S,4R)-3-<(R)-1'-(dimethyl-t-butylsilyloxy)ethyl>-4-oxoazetidin-2-carboxylic acid (115936-64-6) → (5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: lead(IV) tetraacetate / N,N-dimethyl-formamide 2: zinc(II) chloride / dichloromethane 3: hydrogenchloride; methanol 4: dirhodium tetraacetate / toluene View Scheme

(3S,4R)-3-[(1R)-(tert-butyldimethyl-silyloxy)ethyl]-4-[3-(4-nitrobenzyloxy)carbonyl-2-oxo-3-diazopropyl]azetidin-2-one (93861-39-3) → (5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride; methanol 2: dirhodium tetraacetate / toluene View Scheme

(5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) + ethyl 2-sulfanylacetate (623-51-8) → (5R,6S)-4-nitrobenzyl 3-((2-ethoxy-2-oxoethyl)thio)-6-((R)-1-hydroxyethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

Conditions	Yield
Stage #1: (5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester With N-ethyl-N,N-diisopropylamine; chlorophosphoric acid diphenyl ester In acetonitrile at 0℃; for 0.75h; Stage #2: ethyl 2-sulfanylacetate With N-ethyl-N,N-diisopropylamine In acetonitrile at 0℃; for 1h;	74%

(5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) + chlorophosphoric acid diphenyl ester (2524-64-3) + (S)-4-mercapto-2-oxoppyrrolidine → 4-nitrobenzyl (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(R)-5-oxopyrrolidin-3-ylthio]-1-carbapen-2-em-3-carboxylate

Conditions	Yield
Stage #1: (5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester; chlorophosphoric acid diphenyl ester With N-ethyl-N,N-diisopropylamine In acetonitrile for 2h; Substitution; Stage #2: (S)-4-mercapto-2-oxoppyrrolidine With N-ethyl-N,N-diisopropylamine In acetonitrile for 1h; Substitution;	67%

t-butyldimethylsiyl triflate (69739-34-0) + (E)-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)phenyl)methanol + (5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) → (5R,6S)-4-nitrobenzyl 6-((R)-1-((tert-butyldimethylsilyl)oxy)ethyl)-3-((E)-4-(hydroxymethyl)styryl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

Conditions

Yield

Stage #1: (5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester With trifluoromethylsulfonic anhydride; triethylamine In dichloromethane at -78℃; for 0.5h; Inert atmosphere; Stage #2: t-butyldimethylsiyl triflate In dichloromethane at -78℃; for 0.5h; Inert atmosphere; Stage #3: (E)-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)phenyl)methanol With tris-(dibenzylideneacetone)dipalladium(0); potassium hydroxide In dichloromethane; water; N,N-dimethyl-formamide at -78 - 30℃; for 1h; Inert atmosphere;

59%

p-hydroxymethylphenylboronic acid (59016-93-2) + Triethylsilyl trifluoromethanesulfonate (79271-56-0) + (5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) → (5R,6S)-4-nitrobenzyl 3-(4-(hydroxymethyl)phenyl)-7-oxo-6-((R)-1-((triethylsilyl)oxy)ethyl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

Conditions

Yield

Stage #1: (5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester With trifluoromethylsulfonic anhydride; triethylamine In dichloromethane at -78℃; for 0.5h; Inert atmosphere; Stage #2: triethylsilyl trifluoromethyl sulfonate In dichloromethane at -78℃; for 1h; Inert atmosphere; Stage #3: p-hydroxymethylphenylboronic acid With tris-(dibenzylideneacetone)dipalladium(0); potassium hydroxide In water; N,N-dimethyl-formamide at -78 - 30℃; for 1.5h; Inert atmosphere;

33%

trifluoromethylsulfonic anhydride (358-23-6) + trimethylsilyl trifluoromethanesulfonate (27607-77-8) + tributylethynyltin (994-89-8) + (5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) → (5R,6S)-3-Ethynyl-7-oxo-6-((R)-1-trimethylsilanyloxy-ethyl)-1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid 4-nitro-benzyl ester

Conditions

Yield

Stage #1: trifluoromethylsulfonic anhydride; (5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester With diisopropylamine In tetrahydrofuran at -78℃; for 0.25h; Addition; Stage #2: trimethylsilyl trifluoromethanesulfonate With triethylamine In tetrahydrofuran at -78℃; for 0.333333h; Etherification; Stage #3: tributylethynyltin With trifuran-2-yl-phosphane; tris-(dibenzylideneacetone)dipalladium(0); zinc(II) chloride In tetrahydrofuran; 1-methyl-pyrrolidin-2-one; diethyl ether at 20℃; for 2h; Addition; Stille coupling;

32%

cis-1-cyano-4-mercaptocyclohexane (105675-99-8) + (5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) → p-nitrobenzyl (6S)-<(1R)-hydroxyethyl>-2--(5R)-carbapen-2-em-3-carboxylate (105693-26-3)

Conditions	Yield
With diisopropylamine; chlorophosphoric acid diphenyl ester 1) CH3CN, 0 to 5 deg C, 1 h, 2) CH3CN, RT, 20 h; Yield given. Multistep reaction;

cis-3-mercaptocyclopentanecarboxamide (105676-07-1) + (5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) → p-nitrobenzyl (6S)-<(1R)-hydroxyethyl>-2--(5R)-carbapen-2-em-3-carboxylate (105675-86-3, 105814-13-9)

Conditions	Yield
With diisopropylamine; chlorophosphoric acid diphenyl ester 1) CH3CN, 0 to 5 deg C, 1 h, 2) DMF, RT, 3 d; Yield given. Multistep reaction;

cis-4-mercaptocyclohexanecarboxamide (105676-08-2) + (5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) → p-nitrobenzyl (6S)-<(1R)-hydroxyethyl>-2--(5R)-carbapen-2-em-3-carboxylate (105675-88-5)

Conditions	Yield
With diisopropylamine; chlorophosphoric acid diphenyl ester 1) CH3CN, 0 to 5 deg C, 1 h, 2) DMF, RT, 3 d; Yield given. Multistep reaction;

cis-3-mercapto-1-(p-nitrobenzyloxycarboxylamino)cyclopentane (105675-97-6) + (5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) → p-nitrobenzyl (6S)-<(1R)-hydroxyethyl>-2--(5R)-carbapen-2-em-3-carboxylate (105676-04-8, 105814-12-8)

Conditions	Yield
With diisopropylamine; chlorophosphoric acid diphenyl ester 1) CH3CN, 0 to 5 deg C, 1 h, 2) CH3CN, RT, 20 h; Yield given. Multistep reaction;

cis-4-mercapto-1-(p-nitrobenzyloxycarbonylamino)cyclohexane (105675-98-7) + (5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) → p-nitrobenzyl (6S)-<(1R)-hydroxyethyl>-2--(5R)-carbapen-2-em-3-carboxylate (105675-87-4)

Conditions	Yield
With diisopropylamine; chlorophosphoric acid diphenyl ester 1) CH3CN, 0 to 5 deg C, 1 h, 2) CH3CN, RT, 6 d; Yield given. Multistep reaction;

cis-4-(p-nitrobenzyloxycarbonylaminomethyl)cyclohexylthiol (105676-03-7) + (5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) → p-nitrobenzyl (6S)-<(1R)-hydroxyethyl>-2--(5R)-carbapen-2-em-3-carboxylate (105693-27-4)

Conditions	Yield
With diisopropylamine; chlorophosphoric acid diphenyl ester 1) CH3CN, 0 to 5 deg C, 1 h, 2) DMF, RT, 6 d; Yield given. Multistep reaction;

trifluoromethylsulfonic anhydride (358-23-6) + (5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) → p-nitrobenzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-2-trifluoromethylsulphonyloxy-carbapen-2-em-3carboxylate (135439-84-8)

Conditions	Yield
With diisopropylamine In tetrahydrofuran at -70℃; for 0.5h; Addition; Title compound not separated from byproducts;

(5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) + chlorophosphoric acid diphenyl ester (2524-64-3) → p-nitrobenzyl (5R,6S)-2-diphenoxy phosphoryloxy-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (75321-08-3)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 0℃; for 1h; Addition;
With dmap; N-ethyl-N,N-diisopropylamine In acetonitrile

p-toluenesulfonylanhydride (4124-41-8) + (5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) → (5R,6S)-6-((R)-1-Hydroxy-ethyl)-7-oxo-3-(toluene-4-sulfonyloxy)-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (80735-70-2)

Conditions	Yield
With triethylamine In dichloromethane at -60 - 0℃;

diazomethane (186581-53-3, 908094-01-9) + (5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) → (5R,6S)-6-((R)-1-Hydroxy-ethyl)-3-methoxy-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester

Conditions	Yield
In 1,4-dioxane at 20℃; Methylation;

(5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) → (5R,6S)-6-((R)-1-Hydroxy-ethyl)-3-methoxy-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Conditions	Yield
Multi-step reaction with 2 steps 1: dioxane / 20 °C 2: H2 / 10 percent Pd/C / ethyl acetate / 0 °C View Scheme

(5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) → (5R,6S)-6-[(R)-1-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-7-oxo-3-phenyl-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester

Conditions	Yield
Multi-step reaction with 3 steps 1: Et3N / CH2Cl2 / -60 - 0 °C 2: Et3N / CH2Cl2 / 12 h / -70 °C 3: 67 percent / Bu4N(+)Cl(-), K2CO3 / PdCl2(dppf) / tetrahydrofuran; H2O; CH2Cl2 / 1.67 h / 30 °C View Scheme

(5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) → (5R,6S)-6-[(R)-1-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-7-oxo-3-(toluene-4-sulfonyloxy)-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (226700-71-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: Et3N / CH2Cl2 / -60 - 0 °C 2: Et3N / CH2Cl2 / 12 h / -70 °C View Scheme

(5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) → (5R,6S)-2-[(2S,4S)-2-carbamoyl-1,1-dimethylpyrrolidinio-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate

Conditions	Yield
Multi-step reaction with 3 steps 1: N,N-diisopropylethylamine / acetonitrile / 1 h / 0 °C 2: N,N-diisopropylethylamine / acetonitrile 3: H2 / 10 percent Pd-C / tetrahydrofuran; aq. phosphate buffer / 2.5 h / 20 °C / pH 7 View Scheme

(5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) → (2S,4S)-2-Carbamoyl-4-[(5R,6S)-6-((R)-1-hydroxy-ethyl)-2-(4-nitro-benzyloxycarbonyl)-7-oxo-1-aza-bicyclo[3.2.0]hept-2-en-3-ylsulfanyl]-1,1-dimethyl-pyrrolidinium

Conditions	Yield
Multi-step reaction with 2 steps 1: N,N-diisopropylethylamine / acetonitrile / 1 h / 0 °C 2: N,N-diisopropylethylamine / acetonitrile View Scheme

(5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) → p-nitrobenzyl (5R,6S)-2-ethynyl-6-[(1R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate (1026234-25-2)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: diisopropylamine / tetrahydrofuran / 0.25 h / -78 °C 1.2: Et3N / tetrahydrofuran / 0.33 h / -78 °C 1.3: 32 percent / tri(2-furyl)phosphine / tris(dibenzylideneacetone)dipalladium; ZnCl2 / 1-methyl-pyrrolidin-2-one; tetrahydrofuran; diethyl ether / 2 h / 20 °C 2.1: 85 percent / AcOH; aq. Bu4NF / tetrahydrofuran / 1.75 h / 0 - 20 °C View Scheme

(5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) → (5R,6S)-6-((R)-1-Hydroxy-ethyl)-7-oxo-3-thiazol-4-yl-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester

Conditions	Yield
Multi-step reaction with 2 steps 1: diisopropylamine / tetrahydrofuran / 0.5 h / -70 °C 2: Ph3As / ZnCl2, LiCl; tris(dibenzylideneacetone)dipalladium / tetrahydrofuran / 3 h / 20 °C View Scheme

(5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) → (5R,6S)-6-((R)-1-Hydroxy-ethyl)-7-oxo-3-thiazol-5-yl-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (1025902-20-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: diisopropylamine / tetrahydrofuran / 0.5 h / -70 °C 2: Ph3As / ZnCl2, LiCl; tris(dibenzylideneacetone)dipalladium / tetrahydrofuran / 3 h / 20 °C View Scheme

(5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) → p-Nitrobenzyl-(5R,6S)-6-[(1R)-hydroxyethyl]-2-(1-methylpyrazol-3-yl)-carbapen-2-em-3-carboxylate (165743-32-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: diisopropylamine / tetrahydrofuran / 0.5 h / -70 °C 2: Ph3As / ZnCl2, LiCl; tris(dibenzylideneacetone)dipalladium / tetrahydrofuran / 3 h / 20 °C View Scheme

(5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) → (5R,6S)-6-((R)-1-Hydroxy-ethyl)-3-(3-methyl-isoxazol-5-yl)-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (1025809-56-6)

Conditions

Yield

Multi-step reaction with 3 steps 1.1: diisopropylamine / tetrahydrofuran / 0.25 h / -78 °C 1.2: Et3N / tetrahydrofuran / 0.33 h / -78 °C 1.3: 32 percent / tri(2-furyl)phosphine / tris(dibenzylideneacetone)dipalladium; ZnCl2 / 1-methyl-pyrrolidin-2-one; tetrahydrofuran; diethyl ether / 2 h / 20 °C 2.1: 85 percent / AcOH; aq. Bu4NF / tetrahydrofuran / 1.75 h / 0 - 20 °C 3.1: Et3N / CH2Cl2; hexane / 1 h / 20 °C View Scheme

(5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) → (5R,6S)-6-((R)-1-Hydroxy-ethyl)-3-(3-isopropyl-isoxazol-5-yl)-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (1026821-85-1)

Conditions

Yield

Multi-step reaction with 3 steps 1.1: diisopropylamine / tetrahydrofuran / 0.25 h / -78 °C 1.2: Et3N / tetrahydrofuran / 0.33 h / -78 °C 1.3: 32 percent / tri(2-furyl)phosphine / tris(dibenzylideneacetone)dipalladium; ZnCl2 / 1-methyl-pyrrolidin-2-one; tetrahydrofuran; diethyl ether / 2 h / 20 °C 2.1: 85 percent / AcOH; aq. Bu4NF / tetrahydrofuran / 1.75 h / 0 - 20 °C 3.1: Et3N / CH2Cl2; hexane / 1 h / 20 °C View Scheme

(5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) → (5R,6S)-6-((R)-1-Hydroxy-ethyl)-3-(3-methoxymethyl-isoxazol-5-yl)-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (1025968-65-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: diisopropylamine / tetrahydrofuran / 0.5 h / -70 °C 2: Ph3As / ZnCl2, LiCl; tris(dibenzylideneacetone)dipalladium / tetrahydrofuran / 3 h / 20 °C View Scheme

(5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) → p-nitrobenzyl (5R,6S)-6-[(1R)-hydroxyethyl]-2-(1-phenylpyrazol-3-yl)-carbapen-2-em-3-carboxylate (165743-30-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: diisopropylamine / tetrahydrofuran / 0.5 h / -70 °C 2: 67 percent / Ph3As / ZnCl2, LiCl; tris(dibenzylideneacetone)dipalladium / tetrahydrofuran / 3 h / 20 °C View Scheme

(5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester (74288-40-7) → p-nitrobenzyl (5R,6S)-2-[3-(phenyl)isoxazol-5-yl]-6-[(1R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate (204385-18-2)

Conditions

Yield

Multi-step reaction with 3 steps 1.1: diisopropylamine / tetrahydrofuran / 0.25 h / -78 °C 1.2: Et3N / tetrahydrofuran / 0.33 h / -78 °C 1.3: 32 percent / tri(2-furyl)phosphine / tris(dibenzylideneacetone)dipalladium; ZnCl2 / 1-methyl-pyrrolidin-2-one; tetrahydrofuran; diethyl ether / 2 h / 20 °C 2.1: 85 percent / AcOH; aq. Bu4NF / tetrahydrofuran / 1.75 h / 0 - 20 °C 3.1: 62 percent / Et3N / CH2Cl2; hexane / 1 h / 20 °C View Scheme

Upstream product

• 74288-39-4 (3S,4R)-3-[(R)-1-hydroxyethyl)-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxo-3-diazopropyl]azetidin-2-one 
• 75321-07-2 4-[(2S,3R)-3-(1-Hydroxy-ethyl)-4-oxo-azetidin-2-yl]-3-oxo-butyric acid 4-nitro-benzyl ester 
• 78501-85-6 [(2S,3R)-3-(1-Hydroxy-ethyl)-4-oxo-azetidin-2-yl]-acetic acid 
• 105995-50-4 magnesium 4-nitrobenzyl malonate 
• 77120-93-5 (2R,3R,4S)-4-Benzylamino-2-methyl-6-oxo-tetrahydro-pyran-3-carboxylic acid; hydrochloride 
• 77120-97-9 {(2R,3S)-1-(tert-Butyl-dimethyl-silanyl)-3-[(S)-1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-4-oxo-azetidin-2-yl}-acetic acid benzyl ester 
• 77120-94-6 t-4-amino-c-2-methyl-6-oxotetrahydropyran-r-3-carboxylic acid hydrochloride 
• 75321-07-2 4-[(2S,3R)-3-((R)-1-Hydroxy-ethyl)-4-oxo-azetidin-2-yl]-3-oxo-butyric acid 4-nitro-benzyl ester 
• 75321-07-2 4-[(2S,3R)-3-((S)-1-Hydroxy-ethyl)-4-oxo-azetidin-2-yl]-3-oxo-butyric acid 4-nitro-benzyl ester 
• 77120-98-0 {(2R,3S)-1-(tert-Butyl-dimethyl-silanyl)-3-[(S)-1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-4-oxo-azetidin-2-yl}-acetic acid 
• 77120-96-8 benzyl -4-oxoazetidin-2-yl> acetate 
• 79543-87-6 4-[(2S,3R)-3-((S)-1-Formyloxy-ethyl)-4-oxo-azetidin-2-yl]-3-oxo-butyric acid 4-nitro-benzyl ester 
• 77120-92-4 (2R,3S)-3-Benzylamino-2-((R)-1-hydroxy-ethyl)-pentanedioic acid diethyl ester 
• 77120-91-3 (E)-2-Acetyl-3-benzylamino-pent-2-enedioic acid diethyl ester 

Downstream Products

• 77396-81-7 (5R,6S)-6-(1-Hydroxy-ethyl)-7-oxo-3-(toluene-4-sulfonyloxy)-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester 
• 105675-88-5 p-nitrobenzyl (6S)-<(1R)-hydroxyethyl>-2--(5R)-carbapen-2-em-3-carboxylate 
• 75321-08-3 (5R,6S)-3-(Diphenoxy-phosphoryloxy)-6-(1-hydroxy-ethyl)-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester 
• 75321-08-3 (5R,6S)-3-(Diphenoxy-phosphoryloxy)-6-((R)-1-hydroxy-ethyl)-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester 
• 105675-92-1 (6S)-<(1R)-hydroxyethyl>-2-(cis-3-aminocyclohexylthio)-(5R)-carbapen-2-em-3-carboxylic acid 
• 105675-93-2 (6S)-<(1R)-hydroxyethyl>-2-(cis-4-formimidoylaminocyclohexylthio)-(5R)-carbapen-2-em-3-carboxylic acid 
• 64221-86-9 N-formimidoyl thienamycin 
• 85737-71-9 C₂₂H₃₀N₄O₆SSi 
• 64067-13-6 (5R,6S)-6-((R)-1-Hydroxy-ethyl)-3-[2-(4-nitro-benzyloxycarbonylamino)-ethylsulfanyl]-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester 
• 64067-13-6 (5R,6S)-6-(1-Hydroxy-ethyl)-3-[2-(4-nitro-benzyloxycarbonylamino)-ethylsulfanyl]-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester 
• 80951-83-3 p-nitrobenzyl (5R,6S)-3-<(E)-2-acetamidoethylthio>-6-<(R)-1-hydroxyethyl>-7-oxo-1-azabicyclo<3.2.0>hept-2-ene-2-carboxylate 
• 77396-88-4 (5R,6S)-3-(Diethoxy-phosphoryloxy)-6-(1-hydroxy-ethyl)-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester 
• 135439-84-8 (5R,6S)-6-(1-Hydroxy-ethyl)-7-oxo-3-trifluoromethanesulfonyloxy-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester 
• 1621104-13-9 (2S,5R,6S)-4-nitrobenzyl 2-((R)-1-(benzo[d][1,3]dioxol-5-yl)-4-methoxy-3,4-dioxobutyl)-6-((R)-1-hydroxyethyl)-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate 

Relevant articles and documents

A catalytic asymmetric route to carbapenems

Image Presented Efficient syntheses of N-acetyl thienamycin and epithienamycin A in their readily deprotected form are reported where three contiguous stereocenters are established in a single catalytic asymmetric azetidinone-forming reaction. These examples are a template for synthesizing C-5/C-6 cis or trans carbapenems with independent control of the C-8 stereocenter. A library of oxidatively and sterochemically defined azetidinone precursors to a variety of naturally occurring carbapenems and potential biosynthetic intermediates has been prepared to facilitate studies of carbapenem antibiotic biosynthesis.

PROCESS FOR PREPARATION OF ESTERS OF 2-DIAZO-3-TRIMETHYLSILYLOXY-3-BUTENOIC ACID

The present invention relates to a process for the preparation of esters of 2-diazo-3-trimethylsilyloxy-3-butenoic acid which comprises reacting a diazoacetoacetate with iodotrimethylsilane in the presence of an organic base, wherein iodotrimethylsilane is prepared by reacting hexamethyldisilane with iodine. The present invention further relates to converting such esters of 2-diazo-3-trimethylsilyloxy-3-butenoic acid to other compounds, such as a substituted diazoazetidinone, an azetidinone, or a bicyclo ketoester.

Simple and Condensed β-Lactams. Part 9. Elaboration of the 3-(1-Hydroxyethyl) Side Chains of Potential Intermediates of Carbapenem Antibiotics via the 2-Methyl-1,3-dioxolan-2-yl Group

Deketalization of the trans compounds methyl and ethyl (2RS,3RS)-1-(2,4-dimethoxybenzyl)-3-(2-methyl-1,3-dioxolan-2-yl)-4-oxoazetidine-2-carboxylates 5b and 5c, and of the cis isomer (6b) of the latter leads to 85:15 mixtures of the trans- and cis-compounds methyl (2RS,3RS)- and (2RS,3SR)-3-acetyl-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate (7a) and (8a), respectively of the corresponding ethyl esters (7b) and (8b).Sodium borohydride reduction of the mixture of the trans- and cis-esters (7b) and (8b) gives a mixture of the 1'-epimeric trans-compounds ethyl(2RS,3RS)-1-(2,4-dimethoxybenzyl)-3--4-oxazetidine-2-carboxylate (9b) and (10b).Similar mixtures of 1'-epimeric compounds of the types (9) and (10), carrying a variety of substituents attached to position 2 of their azetidine rings were obtained by successive deketalization and reduction of the corresponding trans-(5) and cis-(6) compounds or their mixtures, as well as by other methods.Ring closure of a mixture of the pair of the 1'-epimeric trans-compounds p-nitrobenzyl 2-diazo-4--4-oxo-azetidin-2-yl>-3-oxobutanoates (9n) and (10n) gave a mixture of the 1'-epimeric compounds p-nitrobenzyl 6--2,7-dioxo-(3RS,5RS,6SR)-carbapenam-3-carboxylates (11) and (12) which was converted into a mixture (13) of the 1'-epimeric bis-protected thienamycin analogues p-nitrobenzyl 2-(2-formylaminoethylthio)-6--7-oxo-(5RS,6SR)-carbapen-2-em-3-carboxylates.