Synthesis of BENZODIAZINES

(By the method of disconnections)

The structures of benzodiazines are found in   many alkaloids, mainly as a quinazolone ring system. The other derivatives of benzodiazine, such as cinnolines, quinoxalines and phthalizines, are also an important part of many drugs with a spectrum of significant use, which makes them, in general, very important in organic synthesis and particularly in pharmacochemistry. Thus, they can be found as anti-inflammatory, antihypertensive, antibacterial, analgesic, antibiotic, etc.

Synthesis of the Cinnolines

According to the structure that cinnoline presents, there are the following options for its synthesis:

      von Richter synthesis:

      Widman–Stoermer synthesis:

MOb 114 . Retrosynthetic analysis.   the MOb begins to disconnect, taking into account the Widman-Stoermer synthesis. The rest of the disconnections correspond to very common reactions. Thus,   Ortho-nitrotoluene is used as starting material

Synthesis The formation of the mob 114, due to the proposed design, will be limited by the low yield obtained in the synthesis of ortho-nitrotoluene.

Synthesis of quinazolines.

Inside   Of the classic syntheses for quinazolines, the following can be mentioned:

Yo.         Niementowski synthesis:

ii.       Other variants:

iii.                 More reactions that form good quinazoline precursors:

MOb 115. Retrosynthetic analysis.   The disconnection starts the MO , with an IGF, to disconnect by the CN bond, and arrive at a precursor molecule or synthetic equivalent, which suggests the synthesis of this molecule by one of the variants of the Niementowski synthesis.

Synthesis It can be started from benzene or 3-methoxyacetophenone, easily obtainable from benzene and continue with its nitration, to introduce the amino group, which, transformed into amide and ammonia, allows us to reach the mob 115.

Synthesis of   phthalizines.

The phthalizines , can be prepared based on the following retrosynthetic analysis:

The limitations of this synthesis are related to those that occur in the preparation of the aromatic 1,2-dicarbonyl compound.

MOb 116. Retrosynthetic analysis. With the necessary IGFs on the mob 116, a molecule is formed   precursor whose disconnection shows the use of hydrazine, on an aromatic dicarbonyl compound and thiophene.   The foreseeable starting molecule is phthalic anhydride.

Synthesis.   Phthalic anhydride is a good starting material because of its low cost and easy preparation. The rest of the reactions allow us to show the use of hydrazine. POCl ₃ is used as a direct agent to displace OH and introduce Cl, for the synthesis of the mob 116.

Synthesis of Quinoxalines

Quinaxolines are possibly the easiest benzodiazine isomers to prepare. Thus, the synthesis of Quinaxolines could be faced according to the criteria followed in the initial disconnection of the molecule to be synthesized and the presence of substituents in both rings.

MOb 117.   Retrosynthetic analysis . The fluorine, of the mob 117, is easily substituted by a nucleophile, such as pyrrolidine.   The C=N,imin cleavage occurs in one of the tautomeric forms of the precursor formed.

Synthesis. The diketonic compound and the aromatic diamino present no difficulty in their preparation, as starting materials for the mob 117.

MOb 118. Retrosynthetic analysis . Disconnection begins by the CN bond of the amide present in the mob 118 and later by imine bonds.

Ethyl 3-amino-4-nitrobenzoate can still be cut off to aniline as starting material.

synthesis . From aniline, the intermediate ethyl 3-amino-nitrobenzoate is formed, which combines with oxaldehyde and later with morpholine to form the MOb 118