67977-91-7

Basic information

• Product Name: (2R,6R,7R)-7-(Benzoylamino)-3-methylene-8-oxo-5-oxa-1-azabicyclo[4.2.0]octane-2-carboxylic acid diphenylmethyl ester
• Synonyms: (2R,6R,7R)-7-(Benzoylamino)-3-methylene-8-oxo-5-oxa-1-azabicyclo[4.2.0]octane-2-carboxylic acid diphenylmethyl ester;Oxacephem nucleus;(2R,6R,7R)-Benzhydryl 7-benzaMido-3-Methylene-8-oxo-5-oxa-1-azabicyclo[4.2.0]octane-2-carboxylate;(2R,6R,7R)-7-(BenzoylaMino)-3-Methylene-8-oxo-5-oxa-1-azabicyclo[4.2.0]octane-2-carboxylic acid diph;(6R,7R)-7-aMino-3-[(z)-2-(4-Methylthiazol-5-yl]ethenyl-8-oxo-5-thia-1-azabicylo [4.2.0]oct-2-ene-2-carboxylic acid;Oxacephem nucleus (2R,6R,7R)-7-(Benzoylamino)-3-methylene-8-oxo-5-oxa-1-azabicyclo[4.2.0]octane-2-carboxylic acid diphenylmethyl ester;(2R,6R,7R)-7-(Benzoylamino)-3-methylene-8-oxo-5-oxa-1-azabicyclo[4.2.0]octane-;Flomoxef main chain
• CAS NO: 67977-91-7
• Molecular Formula: C₂₈H₂₄N₂O₅
• Molecular Weight: 469
• EINECS: 1308068-626-2
• Product Categories: Nucleus of flomoxef
• Mol File: 67977-91-7.mol

Chemical Properties

• Boiling Point: 706.8±60.0 °C(Predicted)
• Appearance: /
• Density: 1.34
• Storage Temp.: 2-8°C
• PKA: 12.30±0.40(Predicted)
• CAS DataBase Reference: (2R,6R,7R)-7-(Benzoylamino)-3-methylene-8-oxo-5-oxa-1-azabicyclo[4.2.0]octane-2-carboxylic acid diphenylmethyl ester(CAS DataBase Reference)
• NIST Chemistry Reference: (2R,6R,7R)-7-(Benzoylamino)-3-methylene-8-oxo-5-oxa-1-azabicyclo[4.2.0]octane-2-carboxylic acid diphenylmethyl ester(67977-91-7)
• EPA Substance Registry System: (2R,6R,7R)-7-(Benzoylamino)-3-methylene-8-oxo-5-oxa-1-azabicyclo[4.2.0]octane-2-carboxylic acid diphenylmethyl ester(67977-91-7)

Safety Data

• Hazardous Substances Data: 67977-91-7(Hazardous Substances Data)

Usage

Uses

Used in Medicinal Chemistry:
(2R,6R,7R)-7-(Benzoylamino)-3-methylene-8-oxo-5-oxa-1-azabicyclo[4.2.0]octane-2-carboxylic acid diphenylmethyl ester is used as a lead compound for the development of new drugs due to its structural resemblance to natural products and drugs. The benzoylamine group may enable interactions with biological targets such as enzymes or receptors, while the carboxylic acid group could enhance solubility and bioavailability.
Used in Drug Discovery:
In the field of drug discovery, (2R,6R,7R)-7-(Benzoylamino)-3-methylene-8-oxo-5-oxa-1-azabicyclo[4.2.0]octane-2-carboxylic acid diphenylmethyl ester serves as a potential candidate for the identification of novel therapeutic agents. Its unique structure and functional groups provide opportunities for optimization and modification to improve pharmacological properties and target specificity.
Used in Pharmaceutical Industry:
(2R,6R,7R)-7-(Benzoylamino)-3-methylene-8-oxo-5-oxa-1-azabicyclo[4.2.0]octane-2-carboxylic acid diphenylmethyl ester is utilized as a key intermediate in the synthesis of pharmaceutical compounds. Its versatile structure allows for the development of new drugs with improved efficacy and safety profiles.
Used in Research and Development:
In academic and industrial research settings, (2R,6R,7R)-7-(Benzoylamino)-3-methylene-8-oxo-5-oxa-1-azabicyclo[4.2.0]octane-2-carboxylic acid diphenylmethyl ester is employed as a subject of study to explore its biological activity, mechanism of action, and potential applications in therapeutic interventions.

Synthetic route

(R)-3-Hydroxymethyl-2-((1R,5S)-7-oxo-3-phenyl-4-oxa-2,6-diaza-bicyclo[3.2.0]hept-2-en-6-yl)-but-3-enoic acid benzhydryl ester (67977-88-2) → (2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7)

Conditions	Yield
boron trifluoride diethyl etherate In ethyl acetate at 25℃;	90%

epi-Secopenicillin (67977-61-1) → (2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7)

Conditions	Yield
Multi-step reaction with 5 steps 1: chlorine / ethyl acetate / 20 - 30 °C 2: NaHCO3 / H2O / 20 - 30 °C 3: 88 percent / NaNO3, methyl p-toluenesulfonate / dimethylsulfoxide / 55 °C / 50 Torr 4: 85 percent / Zn, AcOH / CH2Cl2 / 0 °C 5: 90 percent / BF3*Et2O / ethyl acetate / 25 °C View Scheme
Multi-step reaction with 6 steps 1: chlorine / ethyl acetate / 20 - 30 °C 2: NaHCO3 / H2O / 20 - 30 °C 3: PhSNa / acetone; methanol / 35 °C 4: m-chloroperbenzoic acid / CH2Cl2 / -10 °C 5: methanol; benzene / Heating 6: 90 percent / BF3*Et2O / ethyl acetate / 25 °C View Scheme

(R)-3-chloromethyl-2-((1R)-7-oxo-3-phenyl-(1rH,5cH)-4-oxa-2,6-diaza-bicyclo[3.2.0]hept-2-en-6-yl)-but-3-enoic acid benzhydryl ester (67977-79-1) → (2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: 88 percent / NaNO3, methyl p-toluenesulfonate / dimethylsulfoxide / 55 °C / 50 Torr 2: 85 percent / Zn, AcOH / CH2Cl2 / 0 °C 3: 90 percent / BF3*Et2O / ethyl acetate / 25 °C View Scheme
Multi-step reaction with 4 steps 1: PhSNa / acetone; methanol / 35 °C 2: m-chloroperbenzoic acid / CH2Cl2 / -10 °C 3: methanol; benzene / Heating 4: 90 percent / BF3*Et2O / ethyl acetate / 25 °C View Scheme

(R)-2-((1R,5S)-7-Oxo-3-phenyl-4-oxa-2,6-diaza-bicyclo[3.2.0]hept-2-en-6-yl)-3-phenylsulfanylmethyl-but-3-enoic acid benzhydryl ester (67977-85-9) → (2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: m-chloroperbenzoic acid / CH2Cl2 / -10 °C 2: methanol; benzene / Heating 3: 90 percent / BF3*Et2O / ethyl acetate / 25 °C View Scheme

(R)-3-Nitrooxymethyl-2-((1R,5S)-7-oxo-3-phenyl-4-oxa-2,6-diaza-bicyclo[3.2.0]hept-2-en-6-yl)-but-3-enoic acid benzhydryl ester (67977-90-6) → (2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 85 percent / Zn, AcOH / CH2Cl2 / 0 °C 2: 90 percent / BF3*Et2O / ethyl acetate / 25 °C View Scheme

C34H28N2O5S → (2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: methanol; benzene / Heating 2: 90 percent / BF3*Et2O / ethyl acetate / 25 °C View Scheme

Diphenylmethyl-2-(3R,4R-3-benzamido-4-chlor-2-oxo-azetidin-1-yl)-3-chlormethyl-3-butenoat (74242-86-7) → (2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: NaHCO3 / H2O / 20 - 30 °C 2: 88 percent / NaNO3, methyl p-toluenesulfonate / dimethylsulfoxide / 55 °C / 50 Torr 3: 85 percent / Zn, AcOH / CH2Cl2 / 0 °C 4: 90 percent / BF3*Et2O / ethyl acetate / 25 °C View Scheme
Multi-step reaction with 5 steps 1: NaHCO3 / H2O / 20 - 30 °C 2: PhSNa / acetone; methanol / 35 °C 3: m-chloroperbenzoic acid / CH2Cl2 / -10 °C 4: methanol; benzene / Heating 5: 90 percent / BF3*Et2O / ethyl acetate / 25 °C View Scheme

6-epipenicillin sulfoxide (69780-18-3) → (2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7)

Conditions	Yield
Multi-step reaction with 6 steps 1: 80 percent / PPh3 / toluene; CH2Cl2 / Heating 2: chlorine / ethyl acetate / 20 - 30 °C 3: NaHCO3 / H2O / 20 - 30 °C 4: 88 percent / NaNO3, methyl p-toluenesulfonate / dimethylsulfoxide / 55 °C / 50 Torr 5: 85 percent / Zn, AcOH / CH2Cl2 / 0 °C 6: 90 percent / BF3*Et2O / ethyl acetate / 25 °C View Scheme
Multi-step reaction with 7 steps 1: 80 percent / PPh3 / toluene; CH2Cl2 / Heating 2: chlorine / ethyl acetate / 20 - 30 °C 3: NaHCO3 / H2O / 20 - 30 °C 4: PhSNa / acetone; methanol / 35 °C 5: m-chloroperbenzoic acid / CH2Cl2 / -10 °C 6: methanol; benzene / Heating 7: 90 percent / BF3*Et2O / ethyl acetate / 25 °C View Scheme

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (2S,6R,7R)-7-Benzoylamino-3-chloro-3-hydroxymethyl-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (77945-44-9, 112136-32-0)

Conditions	Yield
With perchloric acid; trichloroisocyanuric acid In acetone at 25℃;	100%

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (6R)-7c-benzoylamino-3-methyl-8-oxo-(6rH)-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (68314-20-5)

Conditions	Yield
With triethylamine In dichloromethane at 25℃; for 1h;

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (2S,6R,7R)-7-Benzoylamino-3-chloro-3-chloromethyl-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (1186615-53-1)

Conditions	Yield
With chlorine In dichloromethane at -20℃; Irradiation;

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (6R,7R)-7-Benzoylamino-3-hydroxy-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (81755-47-7)

Conditions	Yield
With ozone; acetic acid; zinc 1.) CH2Cl2, MeOH, -78 deg C, 2.) CH2Cl2, MeOH; Yield given. Multistep reaction;

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (6R,7R)-7-Benzoylamino-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (81755-50-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1.) O3, 2.) Zn, AcOH / 1.) CH2Cl2, MeOH, -78 deg C, 2.) CH2Cl2, MeOH 2: B2H6 / tetrahydrofuran 3: 1.) mesyl chloride, 2.) triethylamine View Scheme
Multi-step reaction with 3 steps 1: 1.) O3, 2.) Zn, AcOH / 1.) CH2Cl2, MeOH, -78 deg C, 2.) CH2Cl2, MeOH 2: 30 percent / chlorine-triphenylphosphine complex, triethylamine / tetrahydrofuran 3: Zn, acetic acid View Scheme

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (2R,3R,6R,7R)-7-Benzoylamino-3-hydroxy-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (81755-51-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) O3, 2.) Zn, AcOH / 1.) CH2Cl2, MeOH, -78 deg C, 2.) CH2Cl2, MeOH 2: B2H6 / tetrahydrofuran View Scheme

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (6R,7R)-7-Benzoylamino-3-chloro-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (81755-49-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) O3, 2.) Zn, AcOH / 1.) CH2Cl2, MeOH, -78 deg C, 2.) CH2Cl2, MeOH 2: 30 percent / chlorine-triphenylphosphine complex, triethylamine / tetrahydrofuran View Scheme

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (6R,7R)-7-Benzoylamino-3-methoxy-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (81755-48-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) O3, 2.) Zn, AcOH / 1.) CH2Cl2, MeOH, -78 deg C, 2.) CH2Cl2, MeOH 2: 100 percent View Scheme

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (6R,7S)-7-Amino-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester

Conditions	Yield
Multi-step reaction with 5 steps 1: 1.) O3, 2.) Zn, AcOH / 1.) CH2Cl2, MeOH, -78 deg C, 2.) CH2Cl2, MeOH 2: B2H6 / tetrahydrofuran 3: 1.) mesyl chloride, 2.) triethylamine 4: 1.) PCl5, pyridine, 2.) water / 2.) methanol View Scheme
Multi-step reaction with 5 steps 1: 1.) O3, 2.) Zn, AcOH / 1.) CH2Cl2, MeOH, -78 deg C, 2.) CH2Cl2, MeOH 2: 30 percent / chlorine-triphenylphosphine complex, triethylamine / tetrahydrofuran 3: Zn, acetic acid 4: 1.) PCl5, pyridine, 2.) water / 2.) methanol View Scheme

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (6R,7R)-7-Amino-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (81800-15-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) O3, 2.) Zn, AcOH / 1.) CH2Cl2, MeOH, -78 deg C, 2.) CH2Cl2, MeOH 2: B2H6 / tetrahydrofuran 3: 1.) mesyl chloride, 2.) triethylamine 4: 1.) PCl5, pyridine, 2.) water / 2.) methanol View Scheme
Multi-step reaction with 4 steps 1: 1.) O3, 2.) Zn, AcOH / 1.) CH2Cl2, MeOH, -78 deg C, 2.) CH2Cl2, MeOH 2: 30 percent / chlorine-triphenylphosphine complex, triethylamine / tetrahydrofuran 3: Zn, acetic acid 4: 1.) PCl5, pyridine, 2.) water / 2.) methanol View Scheme

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (6R,7S)-7-Amino-3-chloro-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) O3, 2.) Zn, AcOH / 1.) CH2Cl2, MeOH, -78 deg C, 2.) CH2Cl2, MeOH 2: 30 percent / chlorine-triphenylphosphine complex, triethylamine / tetrahydrofuran 3: 1.) PCl5, pyridine, 2.) water / 2.) methanol View Scheme

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (6R,7R)-7-Amino-3-chloro-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (81800-14-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1.) O3, 2.) Zn, AcOH / 1.) CH2Cl2, MeOH, -78 deg C, 2.) CH2Cl2, MeOH 2: 30 percent / chlorine-triphenylphosphine complex, triethylamine / tetrahydrofuran 3: 1.) PCl5, pyridine, 2.) water / 2.) methanol View Scheme

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (6R,7S)-7-Amino-3-methoxy-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) O3, 2.) Zn, AcOH / 1.) CH2Cl2, MeOH, -78 deg C, 2.) CH2Cl2, MeOH 2: 100 percent 3: 1.) PCl5, pyridine, 2.) water / 2.) methanol View Scheme

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (6R,7R)-7-Amino-3-methoxy-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (81800-13-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1.) O3, 2.) Zn, AcOH / 1.) CH2Cl2, MeOH, -78 deg C, 2.) CH2Cl2, MeOH 2: 100 percent 3: 1.) PCl5, pyridine, 2.) water / 2.) methanol View Scheme

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (6R)-7t-amino-7c-methoxy-3-methyl-8-oxo-(6rH)-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (77982-90-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: Et3N / CH2Cl2 / 1 h / 25 °C 3: 1.) PCl5, pyridine, 2.) MeOH / 1.) CH2Cl2, 0 degC, 2.) from 0 deg C to 25 deg C View Scheme

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (6R)-7t-benzoylamino-7c-methoxy-3-methyl-8-oxo-(6rH)-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (68313-93-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: Et3N / CH2Cl2 / 1 h / 25 °C View Scheme

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → 7α-amino-3-methyl-1-oxacephem (77982-88-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: Et3N / CH2Cl2 / 1 h / 25 °C 2: 1.) PCl5, pyridine, 2.) HCl / 1.) CH2Cl2, 25 deg C, 2.) i-BuOH, CH2Cl2, 25 deg C View Scheme

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (6R,7R)-7-Amino-3-(2-chloro-acetoxymethyl)-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (77930-74-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: 100 percent / trichloroisocyanuric acid, aq. HClO4 / acetone / 25 °C 2: pyridine / CH2Cl2 / 0 °C 3: 1,5-diazabicyclo<5.4.0>undec-5-ene (DBU) / CH2Cl2 / -30 °C 4: 1.) PCl5, pyridine, 2.) HCl, i-BuOH / 1.) CH2Cl2, 25 deg C, 2.) CH2Cl2, 25 deg C View Scheme

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (6R,7R)-3-Acetoxymethyl-7-amino-7-methoxy-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (116180-23-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: 100 percent / trichloroisocyanuric acid, aq. HClO4 / acetone / 25 °C 2: 66 percent / pyridine / CH2Cl2 / 0 - 25 °C 4: 1.) PCl5, pyridine, 2.) MeOH / 1.) CH2Cl2, 0deg C, 2.) from 0 deg C to 25 deg C View Scheme

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (6R,7R)-3-Acetoxymethyl-7-benzoylamino-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (77982-91-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 100 percent / trichloroisocyanuric acid, aq. HClO4 / acetone / 25 °C 2: 66 percent / pyridine / CH2Cl2 / 0 - 25 °C View Scheme

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (6R,7R)-7-Benzoylamino-3-(2-chloro-acetoxymethyl)-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (77930-73-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 100 percent / trichloroisocyanuric acid, aq. HClO4 / acetone / 25 °C 2: pyridine / CH2Cl2 / 0 °C 3: 1,5-diazabicyclo<5.4.0>undec-5-ene (DBU) / CH2Cl2 / -30 °C View Scheme

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (6R,7R)-3-Acetoxymethyl-7-benzoylamino-7-methoxy-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (77210-18-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 100 percent / trichloroisocyanuric acid, aq. HClO4 / acetone / 25 °C 2: 66 percent / pyridine / CH2Cl2 / 0 - 25 °C View Scheme

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (6R,7R)-7-Benzoylamino-3-chloro-3-(2-chloro-acetoxymethyl)-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester

Conditions	Yield
Multi-step reaction with 2 steps 1: 100 percent / trichloroisocyanuric acid, aq. HClO4 / acetone / 25 °C 2: pyridine / CH2Cl2 / 0 °C View Scheme

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (6R,7R)-7-Benzoylamino-8-oxo-3-(2,2,2-trichloro-acetylcarbamoyloxymethyl)-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (77930-70-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 100 percent / trichloroisocyanuric acid, aq. HClO4 / acetone / 25 °C 2: CH2Cl2 / 25 °C 3: 1,5-diazabicyclo<5.4.0>undec-5-ene (DBU) / CH2Cl2 / -35 °C View Scheme

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (6R,7R)-7-(5-tert-Butoxycarbonylamino-5-carboxy-pentanoylamino)-7-methoxy-3-methyl-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (77930-84-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: Et3N / CH2Cl2 / 1 h / 25 °C 3: 1.) PCl5, pyridine, 2.) MeOH / 1.) CH2Cl2, 0 degC, 2.) from 0 deg C to 25 deg C 4: Et3N, pyridine / CH2Cl2 / 0 °C 5: Zn, 90percent acetic acid / 25 °C View Scheme

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (2S,6R,7R)-7-Benzoylamino-3-chloro-8-oxo-3-(2,2,2-trichloro-acetylcarbamoyloxymethyl)-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester

Conditions	Yield
Multi-step reaction with 2 steps 1: 100 percent / trichloroisocyanuric acid, aq. HClO4 / acetone / 25 °C 2: CH2Cl2 / 25 °C View Scheme

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (6R,7R)-3-Acetoxymethyl-7-(5-tert-butoxycarbonylamino-5-carboxy-pentanoylamino)-7-methoxy-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (77930-85-9)

Conditions	Yield
Multi-step reaction with 6 steps 1: 100 percent / trichloroisocyanuric acid, aq. HClO4 / acetone / 25 °C 2: 66 percent / pyridine / CH2Cl2 / 0 - 25 °C 4: 1.) PCl5, pyridine, 2.) MeOH / 1.) CH2Cl2, 0deg C, 2.) from 0 deg C to 25 deg C 5: Et3N, pyridine / CH2Cl2 / 0 °C 6: Zn, 90percent acetic acid / 25 °C View Scheme

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (6R,7R)-7-[5-tert-Butoxycarbonylamino-5-(2,2,2-trichloro-ethoxycarbonyl)-pentanoylamino]-7-methoxy-3-methyl-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (77930-79-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: Et3N / CH2Cl2 / 1 h / 25 °C 3: 1.) PCl5, pyridine, 2.) MeOH / 1.) CH2Cl2, 0 degC, 2.) from 0 deg C to 25 deg C 4: Et3N, pyridine / CH2Cl2 / 0 °C View Scheme

(2R,6R,7R)-7-Benzoylamino-3-methylene-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester (67977-91-7) → (6R,7R)-3-Acetoxymethyl-7-[5-tert-butoxycarbonylamino-5-(2,2,2-trichloro-ethoxycarbonyl)-pentanoylamino]-7-methoxy-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (77930-80-4)

Conditions	Yield
Multi-step reaction with 5 steps 1: 100 percent / trichloroisocyanuric acid, aq. HClO4 / acetone / 25 °C 2: 66 percent / pyridine / CH2Cl2 / 0 - 25 °C 4: 1.) PCl5, pyridine, 2.) MeOH / 1.) CH2Cl2, 0deg C, 2.) from 0 deg C to 25 deg C 5: Et3N, pyridine / CH2Cl2 / 0 °C View Scheme

Upstream product

• 67977-88-2 (R)-3-Hydroxymethyl-2-((1R,5S)-7-oxo-3-phenyl-4-oxa-2,6-diaza-bicyclo[3.2.0]hept-2-en-6-yl)-but-3-enoic acid benzhydryl ester 
• 67977-61-1 epi-Secopenicillin 
• 67977-79-1 (R)-3-chloromethyl-2-((1R)-7-oxo-3-phenyl-(1rH,5cH)-4-oxa-2,6-diaza-bicyclo[3.2.0]hept-2-en-6-yl)-but-3-enoic acid benzhydryl ester 
• 83262-30-0 diphenylmethyl 7α-benzoylamino-3β-phenylseleno-3α-chloromethyl-1-oxacepham-4α-carboxylate 
• 69780-18-3 6-epipenicillin sulfoxide 
• 74242-86-7 Diphenylmethyl-2-(3R,4R-3-benzamido-4-chlor-2-oxo-azetidin-1-yl)-3-chlormethyl-3-butenoat 
• 67977-90-6 (R)-3-Nitrooxymethyl-2-((1R,5S)-7-oxo-3-phenyl-4-oxa-2,6-diaza-bicyclo[3.2.0]hept-2-en-6-yl)-but-3-enoic acid benzhydryl ester 
• 67977-85-9 (R)-2-((1R,5S)-7-Oxo-3-phenyl-4-oxa-2,6-diaza-bicyclo[3.2.0]hept-2-en-6-yl)-3-phenylsulfanylmethyl-but-3-enoic acid benzhydryl ester 

Downstream Products

• 68314-20-5 (6R)-7c-benzoylamino-3-methyl-8-oxo-(6rH)-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester 
• 1186615-53-1 (2S,6R,7R)-7-Benzoylamino-3-chloro-3-chloromethyl-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester 
• 77945-44-9 (2S,6R,7R)-7-Benzoylamino-3-chloro-3-hydroxymethyl-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester 
• 81755-47-7 (6R,7R)-7-Benzoylamino-3-hydroxy-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester 
• 81755-50-2 (6R,7R)-7-Benzoylamino-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester 
• 81755-51-3 (2R,3R,6R,7R)-7-Benzoylamino-3-hydroxy-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]octane-2-carboxylic acid benzhydryl ester 
• 81755-49-9 (6R,7R)-7-Benzoylamino-3-chloro-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester 
• 81755-48-8 (6R,7R)-7-Benzoylamino-3-methoxy-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester 
• 81800-15-9 (6R,7R)-7-Amino-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester 
• 81800-14-8 (6R,7R)-7-Amino-3-chloro-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester 
• 81800-13-7 (6R,7R)-7-Amino-3-methoxy-8-oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester 
• 77982-90-2 (6R)-7t-amino-7c-methoxy-3-methyl-8-oxo-(6rH)-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester 
• 68313-93-9 (6R)-7t-benzoylamino-7c-methoxy-3-methyl-8-oxo-(6rH)-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester 
• 77982-88-8 7α-amino-3-methyl-1-oxacephem 

Relevant articles and documents

New route to 3-(substituted) methyl 1-oxa- and (1-thia)cephems from 3-exomethylene intermediates via sulfenyl chloride adducts

Addition of methane- and benzenesulfenyl chlorides to 3-exomethylene-1-oxacephams 10 and 14 gave 3β-sulfenyl-3α-chloromethyl adducts 11 and 15. Nucleophilic substitution of the adducts proceeded facilely to afford compounds 18-23, which were converted into Δ3-dervatives 26 and 27 by oxidative elimination. This new route, as illustrated by the sequence 6 → 7 → 8 → 3, has an essential advantage in using the saturated intermediated 7 and 8 with a stabler β-lactam ring which is compatible in nucleophilic substitution, alkaline ester hydrolysis and further manipulations. These synthetic features are well demonstrated by successful synthesis of 1-oxacefamandol 35 and 7β-(2-thienylacetyl-amino)-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-ceph em-4-carboxylic acid (45).

STEREOCONTROLLED, STRAIGHTFORWARD SYNTHESIS OF 3-SUBSTITUTED METHYL 7α-METHOXY-1-OXACEPHEMS

Stereocontrolled and industrially feasible synthesis of a new antibiotic 1a and related derivates, which is characterized by using all the carbon atoms of the penicillin skeleton, is described.