An Easy Laboratory Route to Nitrazepam P. Babln and G. Devaux Pharmaceutical Chemistry and Medicinal Chemistry Laboratory, Faculty of Pharmacy, Bordeaux 2 University, 3 Place de la Victoire, 33076 Bordeaux, France T h e discovery in 1957 by L. 0.Randall of the tranquillizing and sedative properties of chlordiazepoxide, prepared two years hefore by L. H. Sternbach a t Hoffmann La Roche Laboratories, was the starting point for much pharmacologic and chemical research leading to the important class of anxiolytic drugs known as benzodiazepines ( I ) . Many suhstances of this group are now used in anxiolytic, hypnotic, and anticonvulsant therapy (2). Within the framework of practical teaching on the synthesis of drugs for pharmacy students, i t seemed to us of interest as a n illustration to have them prepare one of these compounds, nitrazepam, 5. Since the Sternhach process (3,4)is difficult to implement with students in practical teaching sessions, we now propose a n original route for this compound that is perfectly operational in the laboratory. Principle of the Method T h e diazepine cycle is performed in four steps from commercially available 2-amino-5-nitrobenzophenone, 1: (1) amidifieation with bromoacetyl bromide, (2) substitution of the bromine by an azido group, (3) formation of a nonisolated imina~basoboranne.4, and (4) cyelization by Wittig reaction,
The reaction proceeds as follows:
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Journal of Chemical Education
Experimental Amidification with Brommcefyl Bromlde; Preparation of 2Brommcetamido-5-nlhobenzophenone, 2 Bramaacetyl bromide (3.23 g, 1.4 mL, 16mmol) is added dropwise with stirring to a solution of 1(3 g, 12.4 mmol) in toluene (20 mL) at room temoerature. Then the mixture is refluxed for 30 min. After cooling, 2crystallizes (4 g, yield 88% m.p. 156 "C (3)).IR: ~ ~ ~ O U N H , 1680uco~id.,1640uCOtdonF em-'. lH NMR: (in the fallowing three cases, solvent DMSOO-ds; ref TMS-6ppm): 4(ls, CHd; 7.6M.33 (m, aromatic protons); 11.6 under our conditions (Is exchangeable with D20,NH).
Substitution of the Bromine by a n Azido Group: Preparation oi 2-Azidoacetamido-5nihobenro~henone.3 Compound 2 (4 g, 11mmol) and sodium azide (0.9 g, 13.8mmol) in ethanol (30 mL) are refluxed for 30 min. Then acetone (20 mL) is added for dissolving the formed azide. The boiling mixture is filtered to eliminate any excess of sodium azide. The solution is concentrated on a hotplate to about 40 mL, and 3 crystallizes (3 g). From the filtrate a new fraction (0.3 g) is obtained. Compound 3 (3.3 g, 10.1 mmol, yield 90% m.p. 142 'C) is identified by: IR: 2120u~,z~,b,1680vco,ide, 1 6 3 O v c o ~'H ~ ~NMR: . 3.96 (Is, CHd; 1.30-8.30 (m, aromatic protons); 11.2 under our conditions (Is exchangeable with Dz0,NH). Formation of a Nonisolated lminophosphoranne and Cyciization into 1,3-Dihydro-7-nitro-5-phenyl-Zd- 1,4. benzodiazepin-2-one, 5 Compound 3 (3 g, 9.2 mmol) and triphenylphoaphine (2.65 g, 10 mmol) in toluene (20 mL) aremagneticallystirred at room temperature until no more nitroeen is evolved and comnlete solubilization occurs. The mixture is thin refluxed for about 1i.After elimination of toluene under vacuum, the residue is crystallized from 10 mL ethanol to give 5 (1.65 g, 5.8 mmol yield' 63%. m.p. 226 'C (lit. (3) 224-226 OC). (Crystallization may he initiated with a nitrazepam crystal.) Recrystallization in ethanol (20 mL) provides 5 (1g, 3.5 mmol, yield' 4m). The purity of 5 is verified by thin-layer chromatography (mixtureof CHzClz6, toluene 4, acetone 2 (vol.) as eluant). Compound 5 is identified by comparison with an authentic sample. m. 1 6 8 0 ~ ~ ~ , ,em-'; ~ . 'H NMR: 4.06 (18, CHd; 7.168.33 (m, aromatic protons); 10.60 under our conditions (1s exchangeable with D20,NH).
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It may be seen here that the yields are limited. Using a nitrated (and not a chlorated) homologue, nitrazepam may be obtained as before, but the yield is not indicated by the authors (3). Using a hydrogenated, nonchlorated derivative, benzodiazepine can also he ohtained and then nitrated as a para of the amino group; hut here again, th? yield is not indicated (3).
Moreover, in the methods proposed by Sternbach et al. the reaction times are hardlv c o m ~ a t i b l ewith the duration of practical work sessions. And finally, the repeated use of pvridine or ammonia as solvents or rewents is to be pro. scribed as much as possible in a t e a c h i n ~ l a b ~ r a t o r ~ . Owing to its short steps, our procedure is of didactic value since i t illustrates three important reactions of organic chemistry: amidification, preparation of an azide derivative (whose infrared spectrum shows a uNg band in a normally empty region), and Wittig's reaction, whose importance is well known. Although triphenylphosphine and especially sodium a i d e are considered as dangerous, the small quantities used, their ease of manipulation as solids, and their disappearance during the reaction make them easier substances to handle than the liquid ammonia and pyridine used by Sternhach. It should be noted that a n azide derivative has already been obtained in one of the routes for diazepam, and there cyclization was performed by the action of hydrazine in the presence of palladium on activated carbon (5).
D18~ussion T h e comparison of our method with those of Sternbach (3, 4 ) calls for the following comments:
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Using an o-halogenated amide or an initial amine, these authors prepared a rhlorated (and not a nitrated) homologue of nirrazepam according to the following procedures ( 4 ) :
But apart from the fact that hydrazine, which is suspected t o be carcinogenic, is very dangerous, this reaction poses problems in the case of nitrazepam since the nitro group risks beine converted into hvdroxvlamine (.6.). Consequently, cyclization with a n iminophosphoranne intermediate is of value. Moreover, it may be compared to the process of Lambert e t al. (7),w h k h is used for the formation of cyclic imines from w-azido ketones. T h e preparation of nitrazepam by the route here described has been experimented with total success by thirdyear students a t the Pharmacy Faculty of the University of Bordeaux 2.
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Literature Clted 1. Stembaeh. L. H.h. DnuRea. 1978.22.22P2ffi.and ref. eit.
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Yields obtained in practical work sessions, thus indicating a 50% global yield of nitrazepam (32% atter recrystallization), in relation to the initial compound.
4. Stembaeh, L. H.;mer,R. I.;Mdesics, W.;RKder.E.;Saoh,O.;Saucy,G.;Sfempel.A J. Org. Chem. 1962.27.31883802. 5. Petemen, J. B.; Lako&% K. H.Aefo Chem. Scad. 1%9,23,971-914. 6. Rondestvedt, C. R.;Johoson, T. A , Jr. Synthesis 1971,-1. 7. Lambe*, P. H.: Vsultier. M.:Cans. R. J. C h m Soc., Chem. C a m " . 1982,122C
Volume 66
Number 6
June 1969
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