78755-81-4

Basic information

• Product Name: Flumazenil
• Synonyms: ethyl 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate;FLUMAZENIL;8-FLUORO-5,6-DIHYDRO-5-METHYL-6-OXO-4H-IMIDAZO[1,5-A][1,4]BENZO-DIAZEPINE-3-CARBOXYLIC ACID ETHYL ESTER;8-FLUORO-5,6-DIHYDRO-5-METHYL-6-OXO-4H-IMIDAZO[1,5-A][1,4]BENZODIAZEPINE-3-CARBOXYLIC ACID ETHYL EST;4H-IMIDAZO[1,5-A][1,4]BENZODIAZEPINE-3-CARBOXYLIC ACID, 8-FLUORO-5,6-DIHYDRO-5-METHYL-6-OXO-, ETHYL ESTER;RO 15-1788;FluMazenil USP;Flumazenil、Flumazepil
• CAS NO: 78755-81-4
• Molecular Formula: C₁₅H₁₄FN₃O₃
• Molecular Weight: 303.29
• EINECS: 1308068-626-2
• Product Categories: ZEBETA;Other APIs;antagonist;API;Active Pharmaceutical Ingredients;GABA/Glycine receptor;GABA;Amines;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 78755-81-4.mol

Chemical Properties

• Melting Point: 201-203°C
• Boiling Point: 528 °C at 760 mmHg
• Flash Point: 273.1 °C
• Appearance: white/solid
• Density: 1.39 g/cm³
• Vapor Pressure: 3.1E-11mmHg at 25°C
• Refractive Index: 1.633
• Storage Temp.: 2-8°C
• Solubility: Soluble in DMSO to 25mM
• PKA: 0.86±0.20(Predicted)
• Water Solubility: 128 mg/L
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
• Merck: 14,4135
• CAS DataBase Reference: Flumazenil(CAS DataBase Reference)
• NIST Chemistry Reference: Flumazenil(78755-81-4)
• EPA Substance Registry System: Flumazenil(78755-81-4)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26-27-36/37/39
• WGK Germany: 2
• RTECS: NI2922170
• Hazardous Substances Data: 78755-81-4(Hazardous Substances Data)

Usage

Preparation

The Synthesis of FlumazenilStarting with 4-fluoroaniline (15) the isatin 17 is synthesized via the Sandmeyer synthesis; isatin is then oxidized with peracetic acid to the isatoic anhydride 18. Reaction with sarcosine in DMF leads to the benzodiazepine-2,5-dione 19. This is converted to the iminochloride by reaction with POCI3 . In the key step the imidazoester is built up by reaction with deprotonated ethyl isocyanoacetate [8]. Since ethyl isocyanoacetate is not very stable, an alternative synthesis based on the synthesis of midazolam was developed for large scale-production. Tnthis synthesis diethylmalonate is used. The diester 21 is then transformed to the monoester 22 hy deethoxycarbonylation. Nitrosation and catalytic reduction lead to the amino compound 23. The final carbon atom is introduced by reaction with the orthoester.

Therapeutic Function

Benzodiazepine receptor antagonist, Anticonvulsant

Biological Activity

Flumazenil is a GABAA receptor antagonist with non-selective for α 1, α 2, α 3 or α 5 (IC50 = 2 nM in a radioligand binding assay using rat cortical synaptosomes). Flumazenil also acts as a partial agonist of GABAA receptors, decreasing the amplitude of electrically stimulated population spikes in rat hippocampal CA1 pyramidal neurons. It increases the number of entries into the open arms of the elevated plus maze in high-anxiety BALB/c, but not C57BL/6, mice when administered at doses ranging from 0.1 to 1,000 μg/kg. Flumazenil (5 and 10 mg/kg) prevents a reduction in burying behavior induced by the GABAA receptor positive allosteric modulator allopregnanolone in ovariectomized rats when administered at doses of 5 and 10 mg/kg. Formulations containing flumazenil have been used to reverse sedation induced by benzodiazepines and in the treatment of benzodiazepine overdose or withdrawal.

Pharmacokinetics

Flumazenil is a competitive antagonist at the GA BAA benzodiazepine binding site for all other ligands. I t rapidly reverses the CN S and dangerous physiological effects of benzodiazepines following iatrogenic overdose or deliberate self-harm. I t has no effect on benzodiazepine metabolism. Flumazenil is rapidly cleared from plasma and metabolised by the liver and has a very short elimination half-life (<1h). Its duration of action depends on the dose administered and the duration of action of the drug to be antagonised; repeated administration or infusions may be necessary.

Clinical Use

Reversal of sedative effects of benzodiazepines in anaesthetic, intensive care, and diagnostic procedures

Veterinary Drugs and Treatments

Flumazenil may be useful for the reversal of benzodiazepine effects after either therapeutic use or overdoses. Flumazenil may be of benefit in the treatment of encephalopathy in patients with severe hepatic failure.

Drug interactions

Potentially hazardous interactions with other drugs None known

Metabolism

Flumazenil is extensively metabolised in the liver. The carboxylic acid metabolite is the main metabolite in plasma (free form) and urine (free form and its glucuronide). This main metabolite showed no benzodiazepine agonist or antagonist activity in pharmacological tests.Flumazenil is almost completely (99%) eliminated by non-renal routes. Practically no unchanged flumazenil is excreted in the urine, suggesting complete metabolic degradation of the drug. Elimination of radiolabelled drug is essentially complete within 72 hours, with 90-95% of the radioactivity appearing in urine and 5-10% in the faeces.

Mode of action

Flumazenil, an imidazobenzodiazepine derivative, antagonizes the actions of benzodiazepines on the central nervous system. Flumazenil competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex. In animal experiments the effects of compounds showing no affinity for the benzodiazepine receptor, e.g. barbiturates, ethanol, meprobamate, GABA mimetics, adenosine receptor agonists and other agents were not affected by flumazenil, but those of nonbenzodiazepine agonists of benzodiazepine receptors, such as cyclopyrrolones (e.g. zopiclone) and triazolopyridazines were blocked.

References

Flumazenil in benzodiazepine overdoseDOI:10.1503/cmaj.160357Pharmacological uses of flumazenil in benzodiazepine use disorders: a systematic review of limited dataDOI:10.1177/0269881120981390

InChI:InChI=1/C15H14FN3O3/c1-3-22-15(21)13-12-7-18(2)14(20)10-6-9(16)4-5-11(10)19(12)8-17-13/h4-6,8H,3,7H2,1-2H3

Synthetic route

(E)-(dimethylamino-methyleneamino)-acetic acid ethyl ester (428507-28-2) + 2-chloro-7-fluoro-4-methyl-3,4-dihydrobenzo[e][1,4]diazepin-5-one (193693-31-1) → flumazenil (78755-81-4)

Conditions	Yield
Stage #1: (E)-(dimethylamino-methyleneamino)-acetic acid ethyl ester With lithium hexamethyldisilazane In tetrahydrofuran at -35℃; for 1.5h; Stage #2: 2-chloro-7-fluoro-4-methyl-3,4-dihydrobenzo[e][1,4]diazepin-5-one With Dimethyl-p-toluidine In tetrahydrofuran at -40 - -35℃; for 3h; Stage #3: With acetic acid In tetrahydrofuran for 6h; pH=5 - 7; Heating;	98%

ethyl 2-cyanoacetate (105-56-6) + 2-chloro-7-fluoro-4-methyl-3,4-dihydrobenzo[e][1,4]diazepin-5-one (193693-31-1) → flumazenil (78755-81-4)

Conditions	Yield
With N,N-dimethyl-aniline; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; for 12h; Reagent/catalyst; Solvent;	61.3%

8-amino-5,6-dihydro-5-methyl-6-oxo-4H-imidazol[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl ester (658075-93-5) → flumazenil (78755-81-4)

Conditions	Yield
With pyridine; hydrogen fluoride; sodium nitrite at 20 - 120℃; for 2.5h;	51%
Multi-step reaction with 2 steps 1: BF3*Et2O; t-butyl nitrite / CH2Cl2 / -15 - 5 °C 2: 160 mg / 0.67 h / 130 °C View Scheme

Ethyl isocyanoacetate (2999-46-4) + 7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3) → flumazenil (78755-81-4)

Conditions	Yield
Multistep reaction;

(dimethylamino-methyleneamino)-(7-fluoro-4-methyl-5-oxo-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-ylidene)-acetic acid ethyl ester → flumazenil (78755-81-4) + (dimethylamino-methyleneamino)-(7-fluoro-4-methyl-5-oxo-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-ylidene)-acetic acid ethyl ester

Conditions	Yield
With acetic acid In tetrahydrofuran pH=5; Heating;

C15H14N5O3(1+)*BF4(1-) → flumazenil (78755-81-4)

Conditions	Yield
at 130℃; for 0.666667h; Balz-Schiemann reaction;	160 mg

Ethyl isocyanoacetate (2999-46-4) → flumazenil (78755-81-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.79 g / sodium hydride / dimethylformamide; tetrahydrofuran / 18 h 2: 97 percent / H2 / Pd/C / tetrahydrofuran; ethanol / 2 h 3: BF3*Et2O; t-butyl nitrite / CH2Cl2 / -15 - 5 °C 4: 160 mg / 0.67 h / 130 °C View Scheme
Multi-step reaction with 3 steps 1: N-methyl-acetamide; water; acetic acid; ethyl acetate 2: potassium carbonate / ethanol; water; trifluoroacetic acid 3: N-methyl-acetamide; water View Scheme

7-nitro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5-(1H)-dione (84377-96-8) → flumazenil (78755-81-4)

Conditions	Yield
Multi-step reaction with 5 steps 1: sodium hydride; diethyl chlorophosphate / tetrahydrofuran; dimethylformamide / 0.5 h / 0 °C 2: 1.79 g / sodium hydride / dimethylformamide; tetrahydrofuran / 18 h 3: 97 percent / H2 / Pd/C / tetrahydrofuran; ethanol / 2 h 4: BF3*Et2O; t-butyl nitrite / CH2Cl2 / -15 - 5 °C 5: 160 mg / 0.67 h / 130 °C View Scheme

8-nitro-5,6-dihydro-5-methyl-6-oxo-4H-imidazol[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl ester (84377-97-9) → flumazenil (78755-81-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: 97 percent / H2 / Pd/C / tetrahydrofuran; ethanol / 2 h 2: BF3*Et2O; t-butyl nitrite / CH2Cl2 / -15 - 5 °C 3: 160 mg / 0.67 h / 130 °C View Scheme

2-chloro-4-methyl-7-nitro-3,4-dihydro-benzo[e][1,4]diazepin-5-one → flumazenil (78755-81-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.79 g / sodium hydride / dimethylformamide; tetrahydrofuran / 18 h 2: 97 percent / H2 / Pd/C / tetrahydrofuran; ethanol / 2 h 3: BF3*Et2O; t-butyl nitrite / CH2Cl2 / -15 - 5 °C 4: 160 mg / 0.67 h / 130 °C View Scheme

7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3) → flumazenil (78755-81-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 86 percent / phosphorus oxychloride; N,N-dimethyl-p-toluidine / toluene / 2 h / 100 °C 2.1: LHMDS / tetrahydrofuran / 1.5 h / -35 °C 2.2: N,N-dimethyl-p-toluidine / tetrahydrofuran / 3 h / -40 - -35 °C 2.3: 98 percent / acetic acid / tetrahydrofuran / 6 h / pH 5 - 7 / Heating View Scheme
Multi-step reaction with 3 steps 1.1: 86 percent / phosphorus oxychloride; N,N-dimethyl-p-toluidine / toluene / 2 h / 100 °C 2.1: LHMDS / tetrahydrofuran / 2 h / -30 °C 2.2: N,N-dimethyl-p-toluidine / tetrahydrofuran / -35 °C / pH 7 3.1: acetic acid / tetrahydrofuran / pH 5 / Heating View Scheme

(E)-(dimethylamino-methyleneamino)-acetic acid ethyl ester (428507-28-2) → flumazenil (78755-81-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: LHMDS / tetrahydrofuran / 2 h / -30 °C 1.2: N,N-dimethyl-p-toluidine / tetrahydrofuran / -35 °C / pH 7 2.1: acetic acid / tetrahydrofuran / pH 5 / Heating View Scheme

2-chloro-7-fluoro-4-methyl-3,4-dihydrobenzo[e][1,4]diazepin-5-one (193693-31-1) → flumazenil (78755-81-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: LHMDS / tetrahydrofuran / 2 h / -30 °C 1.2: N,N-dimethyl-p-toluidine / tetrahydrofuran / -35 °C / pH 7 2.1: acetic acid / tetrahydrofuran / pH 5 / Heating View Scheme

1,1,1,3,3,3-hexamethyl-disilazane (999-97-3) + Dimethyl-p-toluidine (99-97-8) + (E)-(dimethylamino-methyleneamino)-acetic acid ethyl ester (428507-28-2) + 2-chloro-7-fluoro-4-methyl-3,4-dihydrobenzo[e][1,4]diazepin-5-one (193693-31-1) → flumazenil (78755-81-4)

Conditions	Yield
With n-butyllithium; sodium hydrogencarbonate; acetic acid In tetrahydrofuran; ethanol; n-heptane; dichloromethane

ethyl N-<(dimethylamino)methylene>glycinate (30766-78-0) + 1,1,1,3,3,3-hexamethyl-disilazane (999-97-3) + Dimethyl-p-toluidine (99-97-8) + 2-chloro-7-fluoro-4-methyl-3,4-dihydrobenzo[e][1,4]diazepin-5-one (193693-31-1) → flumazenil (78755-81-4)

Conditions	Yield
With n-butyllithium; sodium hydrogencarbonate; acetic acid In tetrahydrofuran; n-heptane; dichloromethane

Ethyl isocyanoacetate (2999-46-4) + potassium tert-butylate (865-47-4) + diethyl chlorophosphate (814-49-3) + 7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3) → flumazenil (78755-81-4)

Conditions	Yield
In N-methyl-acetamide; water; acetic acid

dichloroamine (3400-09-7) + Ethyl isocyanoacetate (2999-46-4) + potassium tert-butylate (865-47-4) + 7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3) → flumazenil (78755-81-4)

Conditions	Yield
With sodium hydrogencarbonate; acetic acid; trichlorophosphate In N-methyl-acetamide; chloroform; water; 2,3-Dimethylaniline

ethyl 8-fluoro-6-oxo-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate (79089-72-8) → flumazenil (78755-81-4)

Conditions	Yield
In N-methyl-acetamide; water

Ethyl isocyanoacetate (2999-46-4) + C14H18FN2O5P → flumazenil (78755-81-4)

Conditions	Yield
With potassium tert-butylate In tetrahydrofuran at -35 - 20℃; Inert atmosphere;	2 g

(3-(ethoxycarbonyl)-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-8-yl)(4-methylphenyl)iodonium tosylate (1350523-27-1) → ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][ 1,4]benzodiazepine-3-carboxylate (78756-03-3) + flumazenil (78755-81-4) + Ro 41-8157 (268566-09-2)

Conditions	Yield
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; cesium fluoride In N,N-dimethyl-formamide; acetonitrile at 90℃; for 2h;

(3-(ethoxycarbonyl)-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-8-yl)(phenyl)iodonium tosylate (1350523-17-9) → ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][ 1,4]benzodiazepine-3-carboxylate (78756-03-3) + flumazenil (78755-81-4) + Ro 41-8157 (268566-09-2)

Conditions	Yield
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; cesium fluoride In N,N-dimethyl-formamide; acetonitrile at 90℃; for 2h;

(3-(ethoxycarbonyl)-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-8-yl)(2-thiophenyl)iodonium tosylate (1350523-19-1) → ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][ 1,4]benzodiazepine-3-carboxylate (78756-03-3) + flumazenil (78755-81-4) + Ro 41-8157 (268566-09-2)

Conditions	Yield
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; cesium fluoride In N,N-dimethyl-formamide; acetonitrile at 90℃; for 2h;

(3-(ethoxycarbonyl)-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-8-yl)(3-thiophenyl)iodonium tosylate (1350523-21-5) → ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][ 1,4]benzodiazepine-3-carboxylate (78756-03-3) + flumazenil (78755-81-4) + Ro 41-8157 (268566-09-2)

Conditions	Yield
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; cesium fluoride In N,N-dimethyl-formamide; acetonitrile at 90℃; for 2h;

(3-(ethoxycarbonyl)-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-8-yl)(4-methoxyphenyl)iodonium tosylate (1350523-23-7) → ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][ 1,4]benzodiazepine-3-carboxylate (78756-03-3) + flumazenil (78755-81-4) + Ro 41-8157 (268566-09-2)

Conditions	Yield
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; cesium fluoride In N,N-dimethyl-formamide; acetonitrile at 90℃; for 2h;

(3-(ethoxycarbonyl)-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-8-yl)(3-methoxyphenyl)iodonium tosylate (1350523-25-9) → ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][ 1,4]benzodiazepine-3-carboxylate (78756-03-3) + flumazenil (78755-81-4) + Ro 41-8157 (268566-09-2)

Conditions	Yield
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; cesium fluoride In N,N-dimethyl-formamide; acetonitrile at 90℃; for 2h;

ethyl 5,6-dihydro-5-methyl-6-oxo-8-tributylstannyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (200408-05-5) → ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][ 1,4]benzodiazepine-3-carboxylate (78756-03-3) + flumazenil (78755-81-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: dichloromethane; acetonitrile / 20 h / 20 °C / Inert atmosphere 2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; cesium fluoride / N,N-dimethyl-formamide; acetonitrile / 2 h / 90 °C View Scheme
Multi-step reaction with 2 steps 1: dichloromethane; acetonitrile / 20 h / 20 °C / Inert atmosphere 2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; cesium fluoride / N,N-dimethyl-formamide; acetonitrile / 2 h / 90 °C View Scheme
Multi-step reaction with 2 steps 1: dichloromethane; acetonitrile / 20 h / 20 °C / Inert atmosphere 2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; cesium fluoride / N,N-dimethyl-formamide; acetonitrile / 2 h / 90 °C View Scheme

4-(2,4-dimethoxybenzyl)-7-fluoro-3,4-dihydro-2H-1,4-benzodiazepine-2,5(1H)-dione → flumazenil (78755-81-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: N-methyl-acetamide; water; acetic acid; ethyl acetate 2: potassium carbonate / ethanol; water; trifluoroacetic acid 3: N-methyl-acetamide; water View Scheme

ethyl 5-(2,4-dimethoxybenzyl)-8-fluoro-5,6-dihydro-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate → flumazenil (78755-81-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate / ethanol; water; trifluoroacetic acid 2: N-methyl-acetamide; water View Scheme

flumazenil (78755-81-4) → 8-Fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid (84378-44-9)

Conditions	Yield
Stage #1: flumazenil With sodium hydroxide In tetrahydrofuran; water at 20℃; Stage #2: With hydrogenchloride In water	100%
With tetra(n-butyl)ammonium hydroxide; water Hydrolysis;

flumazenil (78755-81-4) → C15H13(2)HFN3O3

Conditions	Yield
With [(N,N′-bis(2,6-diisopropylphenyl)-2,3-butanediimine)Ni(μ−H)]2; deuterium In tetrahydrofuran at -196 - 45℃; under 760.051 Torr; for 24h; Reagent/catalyst; Sealed tube;	100%
With ethyl [2]alcohol; di(tertbutyl)phenylphosphine; silver carbonate In dichloromethane at 50 - 80℃; Inert atmosphere;	69%

flumazenil (78755-81-4) → C15H10(2)H4FN3O3

Conditions	Yield
With [(N,N’-bis(1R,2R,3R,5S)-(−)-isopinocampheyl-1,2-ethanediimine-radical)NiI(μ2-H)]2; deuterium In tetrahydrofuran at -196 - 45℃; under 760.051 Torr; for 24h; Reagent/catalyst; Sealed tube;	98%

flumazenil (78755-81-4) → ethyl 6-cyano-8-fluoro-5-methyl-5,6-dihydro-4Hbenzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate

Conditions	Yield
Stage #1: flumazenil With bis(triphenylphosphine)iridium(I) carbonyl chloride In toluene at 20℃; for 0.0833333h; Stage #2: With 1,1,3,3-Tetramethyldisiloxane In toluene at 20℃; for 0.0833333h; Stage #3: With trimethylsilyl cyanide In toluene at 20℃; for 0.5h;	47%

isobutyramide oxime (35613-84-4) + flumazenil (78755-81-4) → 8-Fluoro-3-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-5-methyl-4,5-dihydro-2,5,10b-triaza-benzo[e]azulen-6-one

Conditions	Yield
With molecular sieve; sodium hydride 1) THF, r.t., 2) THF, reflux; Yield given. Multistep reaction;

flumazenil (78755-81-4) + acetamide oxime (118493-85-9, 117771-39-8, 1141922-26-0) → 8-fluoro-5,6-dihydro-5-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one

Conditions	Yield
With molecular sieve; sodium hydride 1) THF, r.t., 2) THF, reflux; Yield given. Multistep reaction;

flumazenil (78755-81-4) + N-hydroxypropanimidamide (29335-36-2) → FG 8006

Conditions	Yield
With molecular sieve; sodium hydride 1) THF, r.t., 2) THF, reflux; Yield given. Multistep reaction;

flumazenil (78755-81-4) + butyramide oxime (27620-10-6) → 8-Fluoro-5-methyl-3-(3-propyl-[1,2,4]oxadiazol-5-yl)-4,5-dihydro-2,5,10b-triaza-benzo[e]azulen-6-one

Conditions	Yield
With molecular sieve; sodium hydride 1) THF, r.t., 2) THF, reflux; Yield given. Multistep reaction;

flumazenil (78755-81-4) → [18F]flumanezil

Conditions	Yield
With 2,4,6-trimethyl-pyridine; potassium hydrogencarbonate In water; acetonitrile at 160℃; under 375.03 Torr;
With potassium carbonate; [2.2.2]cryptande; [18F]fluoride ion, cyclotron produced, NCA In dimethyl sulfoxide at 130℃;

flumazenil (78755-81-4) → 2-[(p-toluenesulfonyl)oxy]ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (676437-17-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrabutylammonium hydroxide; water 2: 63 percent / tetrabutylammonium hydroxide / CH2Cl2 View Scheme

flumazenil (78755-81-4) + isopropyl alcohol (67-63-0) → isopropyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate

flumazenil (78755-81-4) + ethylene glycol (107-21-1) → (2-hydroxyethyl) 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate

Conditions	Yield
In chloroform; ethyl acetate

Upstream product

• 2999-46-4 Ethyl isocyanoacetate 
• 78755-80-3 7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione 
• 865-47-4 potassium tert-butylate 
• 814-49-3 diethyl chlorophosphate 
• 1203852-76-9 C₁₅H₁₄BrN₃O₆ 
• 1203852-75-8 1-(2-(methoxycarbonyl)-4-nitrophenyl)-5-methyl-1H-imidazole-4-carboxylic acid ethyl ester 
• 51605-32-4 Ethyl 5-Methyl-4-imidazolecarboxylate 
• 2965-22-2 methyl 2-fluoro-5-nitro-benzoate 
• 193693-31-1 2-chloro-7-fluoro-4-methyl-3,4-dihydrobenzo[e][1,4]diazepin-5-one 
• 320-98-9 5-fluoro-2-nitrobenzoic acid 
• 105-56-6 ethyl 2-cyanoacetate 
• 200408-05-5 ethyl 5-methyl-6-oxo-8-tributylstannyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate 
• 1350523-25-9 (3-(ethoxycarbonyl)-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-8-yl)(3-methoxyphenyl)iodonium tosylate 
• 1350523-23-7 (3-(ethoxycarbonyl)-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-8-yl)(4-methoxyphenyl)iodonium tosylate 

Downstream Products

• 676437-17-5 2-[(p-toluenesulfonyl)oxy]ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate 
• 133368-73-7 C₁₆H₁₅F₂N₃O₃ 
• 84378-44-9 8-Fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid 
• 92676-39-6 FG 8006 

Relevant articles and documents

Benzodiazepine derivative and preparation method and application thereof

The invention discloses a benzodiazepine derivative as shown in a formula (I), enantiomers, diastereoisomers, racemes and mixtures thereof, pharmaceutically acceptable salts, crystalline hydrates and solvates thereof, a preparation method thereof, and application of the derivative in the preparation of antidotes of GABAA receptor agonists, post-anesthesia awakening agents, anti-epileptic drugs, anti-senile dementia drugs, ethanol poisoning antidotes and awakening agents for treating consciousness loss caused by unknown reasons.

Preparation method of flumazenil

The invention discloses a preparation method of flumazenil, and belongs to the field of medicine synthesis. The method comprises the following steps: by taking 5-fluoro-2-nitrobenzoic acid as a raw material, carrying out condensation on 5-fluoro-2-nitrobenzoic acid and sarcosine ester, and then carrying out ring closing while reducing, so as to obtain 7-fluoro-3, 4-dihydro-4-methyl-1H-[1, 4] benzodiazepine-2, 5-diketone; and finally, carrying out halogenation and cycloaddition reaction to obtain flumazenil. According to the novel synthesis method of the flumazenil key intermediate 7-fluoro-3, 4-dihydro-4-methyl-1H-[1, 4] benzodiazepine-2, 5-diketone, provided by the invention, a green synthesis process is adopted, an intramolecular cyclization reaction is performed while a nitro group is reduced, and compared with a known flumazenil synthesis method, a strong oxidant, a highly toxic reagent (such as ethyl chloroformate) and the like are not needed, and the yield is higher.

Preparation method of high-purity flumazenil suitable for industrial production

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of high-purity flumazenil suitable for industrial production. The flumazenil can beprepared by chlorination and ring closing. According to the preparation method disclosed by the invention, the industrial production time can be shortened, the equipment requirement is reduced, the economic benefit is maximized, and the purity of the obtained flumazenil is as high as 99.9%.

Facile aromatic radiofluorination of [18F]flumazenil from diaryliodonium salts with evaluation of their stability and selectivity

Aromatic radiofluorination of the diaryliodonium tosylate precursor with [18F]fluoride ions has been applied successfully to access [ 18F]flumazenil in high radiochemical yields of 67.2 ± 2.7% (decay corrected). The stability and reactivity of the diaryliodonium tosylate precursor plays a key role in increasing the production of 18F- labelled molecules under the fluorine-18 labelling condition. Various conditions were explored for the preparation of [18F]flumazenil from different diaryliodonium tosylate precursors. Optimum incorporation of [ 18F]fluoride ions in the 4-methylphenyl-mazenil iodonium tosylate precursor (5f) was achieved at 150°C for 5 min by utilizing 4 mg of the precursor, K2.2.2/K2CO3 complex, and the radical scavenger in N,N-dimethylformamide. This approach was extended to a viable method for use in automated synthesis with a radiochemical yield of 63.5 ± 3.2% (decay corrected, n = 26) within 60.0 ± 1.1 min. [ 18F]Flumazenil was isolated by preparative HPLC after the reaction was conducted under improved conditions and exhibited sufficient specific activity of 370-450 GBq μmol-1, with a radiochemical purity of >99%, which will be suitable for human PET studies. The Royal Society of Chemistry 2011.

An improved process for the synthesis of 4H-imidazo[1,5-a][1,4] benzodiazepines

The construction of CNS active imidazo[1,5-a][1,4]benzodiazepines has been improved in a one-pot annulation process. Georg Thieme Verlag Stuttgart.

Coded medication and methods of preparing same for identification and distinguishment

A selected substance is dissolved into a given injectable fluid medication having an initial clear visual appearance. The selected substance is selected from a group of substances which, when dissolved in the injectable fluid medication, will alter the clear appearance to produce a non-clear or altered visual appearance. The altered visual appearance could be a color, which, by code, identifies the given injectable fluid medication, and distinguishes the given injectable fluid medication from a different injectable fluid medication, the clear visual appearance of which has been altered by dissolving another selected substance to produce a colored visual appearance different from the color of the altered visual appearance of the given injectable fluid medication.

A concise and efficient synthesis of flumazenil and its precursor for radiolabeling with fluorine-18

Presently there is a strong interest in developing radioligands for in vivo imaging the GABAA-Bz site with positron emission tomography (PET). Flumazenil (1), a high-affinity GABAA-Bz site inverse agonist, is amenable for 11C and 18F-labeling. The current methods for synthesis of 1 and its precursor for 18F-labeling are not ideal and restrict structure-activity relationship (SAR) development. Herein we present a novel and less troublesome synthesis of 1 and its cognates to aid in the development of improved radioligands for PET imaging of GABAA-Bz site.

The isolation and use of a benzodiazepine iminochloride for the efficient construction of flumazenil

The benzodiazepine iminochloride 2 has been isolated, characterized and its reaction with a glycinate enolate synthon investigated resulting in an efficient synthesis of the imidazobenzodiazepine flumazenil.

Process for the manufacture of imidazodiazepine derivatives

A process for the manufacture of compounds of formula STR1