7-Chlor-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Warnung

• Gefahrenhinweise

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• Sicherheit

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MEDAZEPAM Chemische Eigenschaften,Einsatz,Produktion Methoden

• Originator

  Nobrium,Roche,Italy,1969

• Verwenden

  Tranquilizer (minor).

• Definition

  ChEBI: Medazepam is an organic molecular entity.

• Manufacturing Process

  (A) Preparation of 4-Acetyl-7-Chloro-1,2,3,4-Tetrahydro-1-Methyl-5H-1,4- Benzodiazepin-5-one: A mixture of 68.5 g (0.37 mol) of 5-chloro-Nmethylanthranilic acid, 51 g (0.51 mol) of calcium carbonate, 76 g (0.37 mol) of bromoethylamine hydrobromide and 2.5 liters of water was stirred and heated under reflux for 3 hours. A solution of 23.4 g (0.26 mol) of anhydrous oxalic acid in 250 ml of water was slowly added to the refluxing mixture. The precipitated calcium oxalate was filtered off, and the filtrate adjusted to pH 7 with concentrated ammonium hydroxide. The filtrate was then concentrated to dryness in vacuo and the residue heated on the steam bath with 400 ml of 6 N ethanolic hydrogen chloride until the residue was crystalline. Filtration gave 122 g of N-(aminoethyl)-5-chloro-N-methylanthranilic acid hydrochloride as a solid.
  A mixture of 100 g of this solid and 1 liter of acetic anhydride was stirred and heated under reflux for 1.5 hours and then allowed to stand for 18 hours at room temperature. The excess acetic anhydride was removed in vacuo, and the residue was treated with one liter of water and ice and sufficient sodium bicarbonate to make neutral. The solid was collected, sucked dry on the filter, and triturated with hot ethanol. The ethanol solution on cooling gave 30.8 g of 4-acetyl-7-chloro-1,2,3,4-tetrahydro-1-methyl-5H-1,4-benzodiazepin-5-one.
  (B) Preparation of 7-Chloro-1,2,3,4-Tetrahydro-1-Methyl-5H-1,4- Benzodiazepin-5-one: A mixture of 25.25 g (0.1 mol) of 4-acetyl-7-chloro1,2,3,4-tetrahydro-1-methyl-5H-1,4-benzodiazepin-5-one, 33.3 ml (0.1 mol) of 3 N sodium hydroxide and 350 ml of ethanol was heated under reflux for 15 minutes and then concentrated to dryness in vacuo. The residue was treated with 500 ml of water, collected and washed with ethanol to give 20.2 g of 7-chloro-1,2,3,4-tetrahydro-1-methyl-5H-1,4-benzodiazepin-5-one.
  (C) Preparation of 7-Chloro-2,3-Dihydro-1-Methyl-5-Phenyl-1H-1,4- Benzodiazepine: A mixture of 4.7 g (22.6 mol) of 7-chloro-1,2,3,4-tetrahydro1-methyl-5H-1,4-benzodiazepin-5-one and 100 ml of phosphorus oxychloride was heated in an oil bath at 100°C for 15 minutes. The solution was concentrated to dryness in vacuo. The residue was partitioned between methylene chloride and cold saturated sodium bicarbonate solution. The methylene chloride phase was dried over sodium sulfate and sodium bicarbonate, filtered, diluted with benzene and concentrated in vacuo to produce crude 5,7-dichloro-2,3-dihydro-1-methyl-1H-1,4-benzodiazepine.
  The residue was dissolved in 75 ml of tetrahydrofuran, treated with charcoal, and sodium sulfate and filtered. This solution was added to a solution in 250 ml of tetrahydrofuran of phenyl magnesium bromide prepared from 17.7 ml (0.17 mol) of bromobenzene. This mixture was stirred and heated under reflux for 1 hour. It was then cooled and diluted with 400 ml of ether and sufficient 3 N hydrochloric acid to make it acidic. The aqueous phase was separated, adjusted to pH 8 with 3 N sodium hydroxide and extracted 3 times with 200 ml of ether. The ether extracts were combined, washed with water and dried over sodium sulfate. The residue left on removal of the ether in vacuo was crystallized from petroleum ether to give 3.3 g of 7-chloro-2,3- dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine, according to US Patent 3,624,703.
  A variety of alternative routes are outlined by Kleeman and Engel.

• Trademarks

  Nobrium (Hoffmann-LaRoche).

• Therapeutic Function

  Tranquilizer

• Synthesis Reference(s)

  The Journal of Organic Chemistry, 37, p. 3755, 1972 DOI: 10.1021/jo00797a001

MEDAZEPAM Upstream-Materialien And Downstream Produkte

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