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Synthesis of Clonazolam(Lab setup needed)
- Thread starter Wouldlive
- Start date
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- benzo clonazolam
EDITED DUE TO FALSE INFORMATION IN THE ORIGINAL POST:
Here is a patent for the production of similar compounds. While it's not exactly a description of clonazelam synthesis, it serves to illustrate the complexity of the reaction: https://patents.google.com/patent/EP0072029B1/en
You need the precursors 2-amino-5-chloro-2'-fluorobenzophenone and sodium borohydride to start with, and then it's a really long and intricate synthesis from thereon. Not really clandestine stuff.
"
Here is a patent for the production of similar compounds. While it's not exactly a description of clonazelam synthesis, it serves to illustrate the complexity of the reaction: https://patents.google.com/patent/EP0072029B1/en
You need the precursors 2-amino-5-chloro-2'-fluorobenzophenone and sodium borohydride to start with, and then it's a really long and intricate synthesis from thereon. Not really clandestine stuff.
"
- To a solution of 124.8 g of 2-amino-5-chloro-2'-fluorobenzophenone in 1.1 l of ethanol is a solution of 18.5 g of sodium borohydride in 125 ml of water at 20 to 25 ° within 20 minutes dripped. The reaction mixture is stirred for a further 16 hours. Then 250 ml of methanol are added and the mixture is heated to boiling under reflux for 15 minutes. After evaporating the organic solvent, the residue is diluted with water, whereupon it is acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solutions are washed, dried, concentrated to 100 ml in vacuo and then mixed with 300 ml of petroleum ether. Crystalline 2-amino-5-chloro-2'-fluorobenzhydrol of melting point 97-99 ° is obtained.
- b) 100 g of 2-amino-5-chloro-2'-fluorobenzhydrol, 45.6 g of 3-mercaptopropionic acid and 200 ml of 6N hydrochloric acid are stirred together at 100 ° for 1.5 hours. After the reaction mixture has cooled, the precipitated crystals are filtered off and washed with 6N hydrochloric acid. 3 - [(2-Amino-5-chlorophenyl) (2-fluorophenyl) methylthio] propionic acid hydrochloride of melting point 139-141 ° is obtained.
- c) 140 g of 3- [2-amino-5-chlorophenyl) (2-fluorophenyl) methylthio] propionic acid hydrochloride are suspended in 1.4 l of methylene chloride. The suspension is cooled to 0 °. At this temperature 104 ml of triethylamine were first added, and a solution of 37.1 ml of ethyl chloroformate in 150 ml of methylene chloride was added dropwise within 45 minutes. Then the mixture is stirred at room temperature for 3 hours. The reaction mixture is filtered. The filtrate is washed several times with dilute sulfuric acid and then with water, dried and evaporated. The residue is dissolved in hot toluene and the insoluble fraction is filtered off. The filtrate is strongly concentrated and petroleum ether is added. 8-Chloro-6- (2-fluorophenyl) -1,3,4,6-tetrahydro-2H-5,1-benzothiazocin-2-one crystallizes from the melting point 222 °.
- d) 65 g of 8-chloro-6- (2-fluorophenyl) -1,3,4,6-tetrahydro-2H-5,1-benzothiazocin-2-one are dissolved in 1.95 l of chloroform. A solution of 83.2 g of m-chloroperbenzoic acid in 520 ml of chloroform is added dropwise with cooling over the course of 40 minutes. The temperature is kept between 20 and 22 °. The mixture is stirred for a further 90 minutes at room temperature and then the reaction solution is filtered through 800 g of aluminum oxide (activity level I). The substance eluted with 2 l of chloroform is recrystallized from methanol / toluene. 8-Chloro-6- (2-fluorophenyl) -1,3,4,6-tetrahydro-2-oxo-2H-5,1-benzothiazocin-5,5-dioxide with a melting point of approx. 265 ° (decomposition) is obtained. .
- e) 67.0 g of 8-chloro-6- (2-fluorophenyl) -1,3,4,6-tetrahydro-2-oxo-2H-5,1-benzothiazocin-5,5-dioxide are mixed in a mixture of 670 ml carbon tetrachloride, 670 ml t-butanol and 31.5 ml water suspended. The suspension is preheated to 35 °. Then four portions of 51.5 g of potassium t-butoxide are quickly added while cooling (reaction temperature is 45-50 °). The mixture is stirred for a further 35 minutes, during which the temperature drops to approximately 35 °. The reaction mixture is poured onto ice and extracted with methylene chloride. The organic phase is evaporated and the residue is stirred with ether. The crystalline product is filtered off. 7-Chloro-5- (2-fluorophenyl) -1,3-dihydro-2H-1-benzazepin-2-one with a melting point of 214-215 ° is obtained.
- f) 20.2 g of 7-chloro-5- (2-fluorophenyl) -1,3-dihydro-2H-1-benzazepin-2-one are dissolved in 110 ml of hexamethylphosphoric triamide and mixed with 13.8 g of 2,4-bis - (4-methoxyphenyl) -1,3,2,4-dithiadiphosphetane-2,4-disulfide added. The mixture is warmed to 100 ° for 1 hour, cooled again to room temperature and the reaction mixture is poured into 2.2 l of water. It is extracted three times with ethyl acetate and the organic extracts are washed with water, sodium hydrogen carbonate solution and with saturated sodium chloride solution. The ethyl acetate solutions are evaporated and the residue is chromatographed on 400 g of silica gel. Elution with toluene and toluene / chloroform (19: 1) and recrystallization of the substance obtained from diisopropyl ether gives 7-chloro-5- (2-fluorophenyl) -1,3-dihydro-2H-1-benzazepine-2-thione from Melting point 179-181 °.
- g) 3.9 g of 7-chloro-5- (2-fluorophenyl) -1,3-dihydro-2H-1-benzazepin-2-thione and 4.5 g of acetic acid hydrazide are placed in 60 ml of n-butanol for 16 hours Reflux heated to boiling. The solution is then evaporated in vacuo and the residue is partitioned between chloroform and water. The chloroform solution is evaporated. The residue is chromatographed on 250 g of silica gel. To remove impurities, elute with a toluene / ethyl acetate mixture, with ethyl acetate and with ethyl acetate / ethanol (99: 1 and 95: 5). Crude 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-s-triazolo [4,3-a] [1] benzazepine is eluted with ethyl acetate / ethanol (9: 1 and 8: 2). After recrystallization from isopropanol, the product has a melting point of 224-226 °."
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