78755-80-3

Basic information

• Product Name: 7-Fluoro-3,4-dihydro-4-methyl-1H-1,4-benzodiazepine-2,5-dione
• Synonyms: 7-Fluoro-3,4-dihydro-4-methyl-1H-1,4-benzodiazepine-2,5-dione;7-Fluoro-4-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione;FluMazenil IMpurity D;1H-1,4-Benzodiazepine-2,5-dione, 7-fluoro-3,4-dihydro-4- Methyl-;3,4-Dihydro-7-fluoro-4-methyl-1H-1,4-benzodiazepine-2,5-dione 97%;3,4-Dihydro-7-fluoro-4-methyl-1H-1,4-benzodiazepine-2,5-dione97%;Flumazenil EP Impurity D;7-Fluoro-3,4-dihydro-4-methyl-1H-benzo[e][1,4]diazepine-2,5-dione
• CAS NO: 78755-80-3
• Molecular Formula: C10H9FN2O2
• Molecular Weight: 208.1890632
• Mol File: 78755-80-3.mol
• Article Data: 9

Chemical Properties

• Boiling Point: 434.5 °C at 760 mmHg
• Flash Point: 216.6 °C
• Appearance: /
• Density: 1.315
• Storage Temp.: 2-8°C
• PKA: 12.02±0.20(Predicted)
• CAS DataBase Reference: 7-Fluoro-3,4-dihydro-4-methyl-1H-1,4-benzodiazepine-2,5-dione(CAS DataBase Reference)
• NIST Chemistry Reference: 7-Fluoro-3,4-dihydro-4-methyl-1H-1,4-benzodiazepine-2,5-dione(78755-80-3)
• EPA Substance Registry System: 7-Fluoro-3,4-dihydro-4-methyl-1H-1,4-benzodiazepine-2,5-dione(78755-80-3)

Safety Data

• Hazardous Substances Data: 78755-80-3(Hazardous Substances Data)

Usage

Uses

7-Fluoro-3,4-dihydro-4-methyl-1H-1,4-benzodiazepine-2,5-dione, is used as a reactant in the synthetic preparation of 18F-labeled radiotracers for γ-aminobutyric acid A (GABAA) receptor positron emission tomography (PET) imaging.

Synthetic route

5-fluoroisatoic anhydride (321-69-7) + sarcosine (107-97-1) → 7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3)

Conditions	Yield
With pyridine at 5℃; for 7h; Reflux;	76%
In dimethyl sulfoxide at 157℃; for 2h;
With pyridine at 100℃; for 8h;	5.34 g

2-amino-5-fluorobenzoic acid (446-08-2) → 7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1,4-dioxane / 1 h / Cooling; Reflux 2: dimethyl sulfoxide / 2 h / 157 °C View Scheme

7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3) → 2-chloro-7-fluoro-4-methyl-3,4-dihydrobenzo[e][1,4]diazepin-5-one (193693-31-1)

Conditions	Yield
With Dimethyl-p-toluidine; trichlorophosphate In toluene at 100℃; for 2h;	86%
With N,N-dimethyl-aniline; trichlorophosphate In acetonitrile at 80 - 90℃; for 3h; Large scale;

7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3) → 7-fluoro-4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (1198204-53-3)

Conditions	Yield
With lithium aluminium tetrahydride In 1,4-dioxane at 0 - 20℃; for 4h; Inert atmosphere;	62%

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;

3-(isocyanomethyl)-5-methyl-1,2,4-oxadiazole (110035-82-0) + 7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3) → 8-Fluoro-5-methyl-3-(5-methyl-[1,2,4]oxadiazol-3-yl)-4,5-dihydro-2,5,10b-triaza-benzo[e]azulen-6-one

Conditions	Yield
Yield given. Multistep reaction;

5-Ethyl-3-isocyanomethyl-1,2,4-oxadiazole (110035-81-9) + 7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3) → 3-(5-Ethyl-[1,2,4]oxadiazol-3-yl)-8-fluoro-5-methyl-4,5-dihydro-2,5,10b-triaza-benzo[e]azulen-6-one

Conditions	Yield
Yield given. Multistep reaction;

3-(isocyanomethyl)-5-isopropyl-1,2,4-oxadiazole (122384-66-1) + 7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3) → 8-Fluoro-3-(5-isopropyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-2,5,10b-triaza-benzo[e]azulen-6-one

Conditions	Yield
Yield given. Multistep reaction;

3-(isocyanomethyl)-5-n-propyl-1,2,4-oxadiazole (122384-67-2) + 7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3) → 8-Fluoro-5-methyl-3-(5-propyl-[1,2,4]oxadiazol-3-yl)-4,5-dihydro-2,5,10b-triaza-benzo[e]azulen-6-one

Conditions	Yield
Yield given. Multistep reaction;

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

7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3) → 2-dimethylamino-7-fluoro-4-methyl-3,4-dihydro-benzo[e][1,4]diazepin-5-one

Conditions	Yield
Multi-step reaction with 2 steps 1: 86 percent / phosphorus oxychloride; N,N-dimethyl-p-toluidine / toluene / 2 h / 100 °C 2: 100 percent / ethanol / 0.5 h View Scheme

7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3) → 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile (78755-89-2)

Conditions	Yield
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 3.1: 100 percent / acetic acid / tetrahydrofuran / Heating View Scheme
Multi-step reaction with 4 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 3.1: tetrahydrofuran / 20 °C 4.1: 100 percent / acetic acid / tetrahydrofuran / Heating View Scheme

7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3) → 2-(7-fluoro-4-methyl-5-oxo-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-ylidene)-malonic acid dimethyl ester

Conditions	Yield
Multi-step reaction with 2 steps 1: 86 percent / phosphorus oxychloride; N,N-dimethyl-p-toluidine / toluene / 2 h / 100 °C 2: 73 percent / LHMDS / tetrahydrofuran / 16 h / -30 °C View Scheme

7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3) → N'-[cyano-(7-fluoro-4-methyl-5-oxo-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-ylidene)-methyl]-N,N-dimethyl-formamidine

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 / 2 h / -30 °C 2.2: N,N-dimethyl-p-toluidine / tetrahydrofuran / -35 °C 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 3.1: tetrahydrofuran / 20 °C View Scheme

7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3) → N'-[cyano-(7-fluoro-4-methyl-5-oxo-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-ylidene)-methyl]-N,N-dimethyl-formamidine

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 / 2 h / -30 °C 2.2: N,N-dimethyl-p-toluidine / tetrahydrofuran / -35 °C View Scheme

7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3) → (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
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 / 2 h / -30 °C 2.2: N,N-dimethyl-p-toluidine / tetrahydrofuran / -35 °C / pH 7 View Scheme

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

7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3) → 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
Multi-step reaction with 2 steps 2: 1) NaH, molecular sieves / 1) THF, r.t., 2) THF, reflux View Scheme

7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3) → FG 8006

Conditions	Yield
Multi-step reaction with 2 steps 2: 1) NaH, molecular sieves / 1) THF, r.t., 2) THF, reflux View Scheme

7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3) → 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
Multi-step reaction with 2 steps 2: 1) NaH, molecular sieves / 1) THF, r.t., 2) THF, reflux View Scheme

7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3) → 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
Multi-step reaction with 2 steps 2: 1) NaH, molecular sieves / 1) THF, r.t., 2) THF, reflux View Scheme

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

diethyl chlorophosphate (814-49-3) + 7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3) → C14H18FN2O5P

Conditions	Yield
Stage #1: 7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione With potassium tert-butylate In tetrahydrofuran at 0℃; for 0.333333h; Inert atmosphere; Stage #2: diethyl chlorophosphate In tetrahydrofuran at -35 - 0℃; Inert atmosphere;

tert-Butyl isocyanoacetate (2769-72-4) + 7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3) → t-butyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate

Conditions	Yield
With sodium hydride; diethyl chlorophosphate In tetrahydrofuran; N,N-dimethyl-formamide

7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3) → methyl (2E)-3-(7-fluoro-4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-1-yl)acrylate (1427086-51-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / 1,4-dioxane / 4 h / 0 - 20 °C / Inert atmosphere 2: methanol / 1 h / 20 °C View Scheme

7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3) → dimethyl 2-(7-fluoro-4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-1-yl)but-2-enedioate

Conditions	Yield
Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / 1,4-dioxane / 4 h / 0 - 20 °C / Inert atmosphere 2: methanol / 1 h / 20 °C View Scheme

7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3) → 1-acetyl-7-fluoro-4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (1427086-54-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / 1,4-dioxane / 4 h / 0 - 20 °C / Inert atmosphere 2: acetonitrile / 1 h / 20 °C / Reflux View Scheme

7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (78755-80-3) → methyl (2E)-3-(1-acetyl-7-fluoro-1,2,3,5-tetrahydro-4H-1,4-benzodiazepin-4-yl)acrylate (1427086-55-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: lithium aluminium tetrahydride / 1,4-dioxane / 4 h / 0 - 20 °C / Inert atmosphere 2: acetonitrile / 1 h / 20 °C / Reflux 3: acetonitrile / 120 h / Reflux View Scheme

Upstream product

• 618-06-4 m-sulfanilic acid diazonium salt 
• 122-39-4 diphenylamine 
• 320-98-9 5-fluoro-2-nitrobenzoic acid 
• 446-08-2 2-amino-5-fluorobenzoic acid 
• 321-69-7 5-fluoroisatoic anhydride 
• 107-97-1 sarcosine 

Downstream Products

• 78755-81-4 flumazenil 
• 92676-39-6 FG 8006 

Relevant articles and documents

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 and application method of stable isotope substituted flumazenil compound

The invention provides a preparation method and an application method of a stable isotope substituted flumazenil compound. The chemical structural general formula of the flumazenil compound is shown in the specification, wherein R1, R2, R3, R5, R6 and/or R7 are hydrogen or deuterium independently; R4 and/or R8 represent branched or linear C1-C4 alkyl, no or one or more hydrogen atoms are substituted by deuterium; at least one hydrogen atom in R1 and R8 is substituted by deuterium. Beneficial effects are that the deuterated flumazenil compound can stably exist in a human body as a contrast agent, the human body cannot be hurt by multiple times of detection, the conversion of deuterium labeling can be directly monitored by using standard magnetic resonance spectrum acquisition hardware and signal processing, the method is simple and practical, the precision is high, the result is reliable, and the metabolic condition can be quantitatively and specifically analyzed.

The development of potential new fluorine-18 labelled radiotracers for imaging the GABAA receptor

Positron emission tomography (PET) using the tracer [11C] Flumazenil has shown changes in the distribution and expression of the GABA A receptor in a range of neurological conditions and injury states. We aim to develop a fluorine-18 labelled PET agent with comparable properties to [11C]Flumazenil. In this study we make a direct comparison between the currently known fluorine-18 labelled GABAA radiotracers and novel imidazobenzodiazepine ligands. A focussed library of novel compound was designed and synthesised where the fluorine containing moiety and the position of attachment is varied. The in vitro affinity of twenty-two compounds for the GABAA receptor was measured. Compounds containing a fluoroalkyl amide or a longer chain ester group were eliminated due to low potency. The fluorine-18 radiochemistry of one compound from each structural type was assessed to confirm that an automated radiosynthesis in good yield was feasible. Eleven of the novel compounds assessed appeared suitable for in vivo assessment as PET tracers.