Chemistry
7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine (5.1.40), has been suggested to be synthesized in various ways. The first is the reduction of the carbonyl group in diazepam by lithium aluminum hydride.
- Sternbach, L. H.; Reeder, E.; Archer, G. A. (1963). The Journal of Organic Chemistry 28 (9): 2456. doi:10.1021/jo01044a514. edit
- E. Reeder, L.H. Sternbach, U.S. Patent 3,109,843 (1963).
The second way of making medazepam consists of the initial reduction of the carbonyl group by lithium aluminum hydride into 7-chloro-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin- 2-one—the first intermediate product in the synthesis of diazepam—which is synthesized by the cyclocondensation of 2-amino-5-chlorobenzophenone with glycine ethyl ester into 7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine, and the subsequent methylation of the secondary amine nitrogen atom of the resulting product by methyl iodide, using sodium hydride as a base.
- S. Inaba, H. Nagata, DE 1934385 (1971).
- G.A. Archer, E. Fells, L.H. Sternbach, U.S. Patent 3,131,178 (1964).
The third method of making medazepam consists of a new way of making 7-chloro-2,3- dihydro-5-phenyl-1H-1,4-benzodiazepine, which consists in heterocyclization of 1-(2,5-dichlorophenyl)-1-phenylimine with ethylenediamine. The starting 1-(2,5- dichlorophenyl)-1-phenylimine is synthesized by the reaction of 2,5-dichlorobenzonitrile with phenylmagnesium bromide.
- S. Inaba, H.Nagata, DE 1934385 (1969).
Finally, a method of making medazepam from 4-chloro-N-methylaniline is suggested. The last is reacted with ethyleneimine in the presence of aluminum chloride, giving N- (4-chlorophenyl)-N-methylethylenediamine. Acylation of the resulting product with benzoyl chloride gives the respective amide, which cyclizes into the desired medazepam using phosphorus oxychloride.
- K.H. Heinrich, DE 1695188 (1967).
- K.H. Heinrich, DE 1795811 (1967).
See also:
- Wunsch, K. H.; Dettmann, H.; Schonberg, S.; Chem. Ber. 1969, 102, 3891.
Various modifications of the described methods have been suggested.
- S. Inaba, K. Ishizumi, T. Okamoto, H. Yamamoto, Chem. Pharm. Bull., 20, 1628 (1972).
- M. Mihalic, V. Sunjic, F. Kajfez, M. Zinic, J. Heterocycl. Chem., 14, 941 (1977).
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