This invention relates to an improved process for the preparation of 3-dimethylamino-7-methyl- 1,2,4-benzotriazine-l-oxide, hereinafter referred to for simplicity as "benzotriazine oxide", and to benzotriazine oxide prepared by the improved process, and azapropazone made therefrom.

Benzotriazine oxide is of commercial importance because it is an intermediate in the preparation of the anti-inflammatory drug azapropazone. The conventional preparation of benzotriazine oxide involves the reaction of 4-methyl-2-nitroaniline with phosgene and the subsequent treatment of the resulting urea derivative with ammonia to neutralise excess phosgene, followed by purification and treatment with sodium hydroxide. This procedure is disadvantageous in view of the highly toxic nature of phosgene and also because it is necessary to carry out the reaction in several stages involving separate reaction vessels. We have devised a process for the preparation of benzotriazine oxide from l-chloro-2-nitro-4-methyl- benzene and monosodium cyanamide, which can be carried out safely with good yields.

According to one aspect of the present invention, a process for the preparation of benzotriazine oxide (compound IV below) as herein defined comprises reacting a solution of l-chloro-2-nitro-4- ethyl- benzene (compound I below) with alkali metal cyanamide, preferably monosodium cyanamide at elevated temperature, cooling the reaction mixture,

adding HC1 to produce 4-methyl-2-nitro-carbanilino- nitrile (Compound II below) which is reacted with dimethylamine in solution, preferably in alcohol at elevated temperature whereby there is obtained an N,N-dimethyl-N' -(4-methyl-2-nitrophenyl) guanidine (compound III below) as an intermediate convertible to benzotriazine oxide. The guanidine compound may be converted to benzotriazine oxide by subjecting it to a dehydroxylation reaction to effect ring closure and form the said benzotriazine oxide.

The solvent for the l-chloro-2-nitro-4-methyl- benzene is preferably an aprotic solvent such as N,N dimethyl formamide (DMF) and desirably excess solvent is used. The initial reaction mixture at 20°C may conveniently contain 15 to 20% by weight of the benzene compound or more broadly 5 to 50% by weight and 5 to 15% or more broadly 1 to 30% by weight of the alkali metal cyanamide so long as the solution remains free flowing and adapted to be refluxed. The solvent is preferably one also having solvent action for the alkali metal cyanamide. The elevated temperature may be the reflux temperature of the solvent. The reaction may also be carried out at an elevated temperature below reflux and is then desirably accompanied by stirring, 'especially by vigorous stirring.

The dehydroxylation reaction may be carried out by raising the guanidine compound to elevated temperature in the presence of alkali e.g. NaOH, for example by boiling it with alkali.

In a preferred form of the invention the alkali ring closure reaction is carried out using an excess of hydroxyl group containing phase transfer catalyst, e.g. a quaternary ammonium salt catalyst such as tetrabutyl ammonium hydroxide. The guanidine intermediate may be taken up in an organic solvent phase and the 1-oxide product recovered from an aqueous phase, the phase transfer catalyst having solubility in both phases and promoting the ring closure reaction.

The invention also extends to this aspect independently of how the guanidine intermediate is arrived at.

The scheme of the reaction according to the invention is as follows :-

(I)

(ID H

(III)

₂ (IV)

The invention may be carried out in various ways and a number of specific embodiments will be described to illustrate the invention with reference to the accompanying examples.

EXAMPLE 1

4-chloro-3-nitrotoluene (l-chloro-2-nitro- 4-methyl benzene) (10 g) and monosodium cyanamide (10 g) in dimethylformamide (30 ml) were heated under reflux for one hour. The mixture was cooled and filtered. The filtrate was concentrated under reduced pressure and water (50 ml) was added to the residue. The mixture was acidified with hydrochloric acid (2M) and the yellow solid which separated was filtered off, dried, washed with cold hexane, and dried to give a pale yellow crude product. This was recrystallised from ethanol to give pale yellow crystals of 4 -methyl-2-nitroσarbanilonitrile (compound II above) (6.4 g, 62%), m.p. 177-80°. (Found C, 54.38; H, 4.00; N, 23.71. C ₈ H ₇ N ₃ 0 ₂ requires C, 54.24; H, 3.95; ., 23.73%).

The above carbanilonitrile (4.73 g) and dimethylamine (25 g) in industrial methylated spirits (75 ml) was heated at reflux for twenty hours.

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The mixture was cooled and evaporated under reduced pressure to give N,N-dimethyl- '-(4-methyl-2-nitro- phenyl) guanidine (Compound III above) (5.9 g, 95%), m.p. 83-4°.

The guanidine compound was r fluxed with 1M sodium hydroxide solution to produce ring closure and give the desired 1-oxide (compound IV above) .

EXAMPLE 2 Monosodium cyanamide was made as follows:

10 An equivalent of sodium ethoxide in ethanol was added slowly to an ethanolic solution of cyanamide. The mixture was stirred for an hour after which the crystalline product was filtered, wshed with ethanol and dried to give an 86% yield of the required sodium

15 cyanamide. Infrared absorption showed nitrile absorption at 2200 cm--*-, and a sample of the compound gave a positive flame test for sodium.

One equivalent of sodium cyanamide was added to 4-chloro-3-nitrotoluene (l-σhloro-2-nitro-4 methyl

20 benzene) in dimethylformamide. The mixture was heated, cooled, filtered, and the crude product worked up to give a 23% yield of 4-methyl-2-nitro- carbanilonitrile. The structure was confirmed by spectroscopic techniques. The molecular weight was

25 confirmed by the El spectrum which showed the molecular ion at m/z 177 (C3H7N3O2) .

This preparation was repeated with two and a half equivalents of sodium cyanamide added to 4-chloro-3-nitrotoluene in dimethylformamide and the reaction carried out as before to give a 62% yield

after recrystallisation of 4-methyl-2-nitrocarbanilo- nitrile. The structure was confirmed by spectro- scopic techniques.

The carbanilonitrile was added to a large excess of dimethylamine in industrial methylated spirits, and the mixture heated at reflux for 20 hours. The mixture was cooled and the solvent removed under reduced pressure to give a 95% yield of N,N-dimethyl- N'-(4-methyl-2-nitrophenyl) guanidine. The structure was confirmed spectroscopicall .

The guanidine was cyclised to the desired 1-oxide (Compound IV above) as follows:

The guanidine in toluene was heated at reflux for thirty minutes with an excess of tetrabutyl- ammonium hydroxide as a 40% aqueous solution. The mixture was cooled and the organic layer washed arid evaporated to dryness to give the crude product which was recrystallised from ethanol to give an 82% yield of the required 3-dimethylamino-7-methyl-l,2,4— benzotriazine 1-oxide. The structure was confirmed spectroscopically.

This method gives the required 1-oxide (compound IV above) which is a precursor to Azapropazone in 48% yield from the 4-chloro-3-nitrotoluene. This route is of advantage commercially in the synthesis of

Azapropazone since it involves only three steps to the 1-oxide from readily available materials.

As mentioned above the present invention extends to azapropazone produced from benzotriazine oxide made by the processes of the present invention. Thus according to a further aspect of the present invention a process for making azapropazone comprises making benzotriazine oxide by a process in accordance with the present invention and then hydrogenating the benzotriazine oxide, e.g. with Pd/C catalyst, to produce a compound of the formula:

and then reacting this compound with mono-n-propyl malonic acid diethyl eSfcer, namely:

0 11

C ₂ H ₅ 0—C

\

CH—C3H7

C ₂ H ₅ 0—C !l 0

in the presence of sodium methoxide, CH ₃ 0Na, and xylene to produce azapropazone, optionally as the dihydrate.