Phenazepam synthesis

G.Patton

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Introduction

I would love to represent to BB public classical Phenazepam (Bromdihydrochlorphenylbenzodiazepine; 7-Bromo-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one; Fenazepam; BD 98) synthesis from p-bromoaniline and o-chlorobenzoic acid. This synthesis route assumes the laboratory skills and experience of the chemist in a variety of laboratory techniques. At the same time, this method does not require the use of exotic reagents or harsh methods of processing substances.

Acylation of p-bromoaniline (2) with o-chlorobenzoic acid chloride (3) in the presence of a catalyst - zinc chloride (ZnCl2) -gives 2-(o-chlorobenzoylamino)-5-bromo-2-chlorobenzophenone (4), which is hydrolyzed without isolation with an aqueous solution of H2SO4 to 2-amino-5-bromo-2-chlorobenzophenone (5). 2-Amino-5-bromo-2-chlorobenzophenone (5) is converted into Phenazepam without isolation of intermediate substances as follows: 5 is acylated with aminoacetic acid chloride hydrochloride (6) in chloroform, the resulting 2-(aminomethylcarbonylamino)-5-bromo-2-chlorobenzophenone hydrochloride (7) is converted by the action of aqueous NH3 to base (8), which is thermally cyclized to Phenazepam. 6 is prepared by treating PCl5 glycyrne in chloroform.
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White or white crystalline powder with a cream shade, practically insoluble in water, hardly soluble in ether, alcohol, chloroform, soluble in benzene, toluene, dioxane, dimethylformamide;
Boiling Point: 493.0±45.0 °C/760 mm Hg
Melting Point: 220-222 °C
Molecular Weight: 349.61 g/mol
Density: 1.6±0.1 g/cm3 (20 °C)
Index of Refraction: 1.692
CAS Number: 51753-57-2

Equipment and glassware:

5 L three necked round bottom flasks;
5 L round bottom flask;
Laboratory grade thermometer (0 °C to 200 °C) with flask adapter;
Water bath and Ice;
Heater;
Reflux condenser;
Magnetic stirrer;
Drip funnel 1 L;
5 L x2; 1 L x2; 500 ml x2; 100 ml x2 Beakers;
Conventional large funnels x2 (~20-25 cm);
Buchner flask 5 L and funnel (large);
Water-jet aspirator;
Vacuum desiccator;
Measuring cylinders 100 and 1000 ml;
Glass rod;
Laboratory scale (1 - 1000 g is suitable);
Distillation apparatus with Vigreux column;
Retort stand and clamp for securing apparatus;
Receiver flask (2-3 L);
Filter paper;
Separatory funnel 5 L.

Reagents:

276 g p-Bromoaniline (2);
672 g o-Chlorobenzoic acid (3);
264 g Zinc chloride (ZnCl2);
0.6 L of 14% aq. Hydrochloric acid (HCl) ;
3 L Distilled water;
0.6 L 72% aq. Sulfuric acid (H2SO4);
500 ml 20% aq. Sodium hydroxide (NaOH);
2 L Chloroform;
~3 l
Toluene;
496 g Hydrochloride of aminoacetic acid chloride (6);
~500 ml Ammonia solution NH4OH aq.;
1 L Ethanol (96-98%) (EtOH).

2-amino-5-bromo-2-chlorobenzophenone (5)

A mixture of 276 g of p-bromoaniline (2) and 672 g of o-chlorobenzoic acid (3) in 5 L three necked round bottom flasks with thermometer are heated for 1 hour at 100-110 °C with a reflux condenser, the temperature is raised to 150-160 °C, 264 g of ZnCl2 are added, heated for 2 hours at 190-198 °C and cool. 0.6 L of 14% hydrochloric acid (HCl) is added to the mass via drip funnel, heated to 100 °C, the aqueous layer is separated, the organic layer is washed by boiling with 0.3 l of distilled water. The washing procedure is repeated three times. After washing, 0.6 L of 72% sulfuric acid (H2SO4) is added to the residue, heated for 2 hours at 160 °C and poured into a 5 L baker with a mixture of ice and water. The precipitate is filtered in a large Buchner flask and funnel, washed with distilled water, stirred for 1 hour with a 20% aqueous solution of NaOH, filtered, washed in a separatory funnel with water until pH 7 and dried on air. The yield of technical grade 2-amino-5-bromo-2-chlorobenzophenone (5) 228 g with a basic substance content of 70%.
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7-Bromo-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (Fenzepam) (1)

A solution of 850 g of 2-amino-5-bromo-2-chlorobenzophenone (5) in 2 L of chloroform is dried in 5 L round bottom flask by azeotropic distillation of chloroform and water mixture, 496 g of hydrochloride of aminoacetic acid chloride (6) is added, boiled for 3 hours with a reflux condenser and cooled to room temperature. To the mixture is slowly poured a dilute aqueous ammonia solution to reach pH 8, the organic layer is washed with water in separatory funnel and evaporated to dryness in rotavap apparatus. To the residue is poured 2 L of toluene, heated to boiling, the azeotropic mixture of toluene and water is distilled off, cooled and filtered in a Buchner flask. Technical grade Phenazepam is crystallized (1:60) from toluene in 5 L baker, filtered, the precipitate is washed with toluene, alcohol (EtOH) and dried at 100-110 °C. Yield 250 g (26%).
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Sponge Bob

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Attention Patton: Can you please help me with the Phenazepam synthesis. The reagent, “Hydrochloride of aminoacetic acid chloride”, has left me unsure of exactly what I am dealing with. Wikipedia states in their article on Phenazepam that this compound is, “prepared by chemical treating glycine with phosphorus pentachloride in chloroform”. This article cites a Russian source and that is all the information I have on synthesis of the compound. I have spent a far amount of time researching the sources I have available with little luck. Likewise my knowledge of organic chemistry is very modest at best.

Are there other synthesis besides this one to make this particular compound? No detail of the process are given by the Wikipedia article. It looks to me that the correct CAS # for aminoacetic acid chloride is, 4746-64-9, but this is not the salt form I assume is being referred to in the systhesis. This is were my knowledge of chemistry fails. Can you offer any complete, detailed, pathway to this compound. Thanks so much.
 

G.Patton

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It looks to me that the correct CAS # for aminoacetic acid chloride is, 4746-64-9
Sponge BobHello, It is correct CAS, but you have to process it by HCl to obtain salt form.
“prepared by chemical treating glycine with phosphorus pentachloride in chloroform”
It is the aminoacetic acid chloride synthesis way.
Are there other synthesis besides this one to make this particular compound?
It is the simplest one
This is were my knowledge of chemistry fails.
You can try to buy this substance or produced by yourself. Process glycine with Phosphorus pentachloride in equimolar rate in chloroform
 

Sponge Bob

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Thank you for your quick reply.
 
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