Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
  • C07D253/08—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 condensed with carbocyclic rings or ring systems
  • C07D253/10—Condensed 1,2,4-triazines; Hydrogenated condensed 1,2,4-triazines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• 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.
• a process for the preparation of benzotriazine oxide 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.
• 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.
• 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 guanidine compound was r fluxed with 1M sodium hydroxide solution to produce ring closure and give the desired 1-oxide (compound IV above) .
• 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:
• azapropazone optionally as the dihydrate.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=10592069

Family Applications (1)

Country Status (6)

Family Cites Families (2)

• 1986
  • 1986-01-28 GB GB868602038A patent/GB8602038D0/en active Pending
• 1987
  • 1987-01-28 JP JP50089687A patent/JPS63502431A/ja active Pending
  • 1987-01-28 WO PCT/GB1987/000055 patent/WO1987004432A1/en not_active Application Discontinuation
  • 1987-01-28 EP EP19870900865 patent/EP0259362A1/en not_active Withdrawn
  • 1987-09-28 FI FI874249A patent/FI874249A/fi not_active Application Discontinuation
  • 1987-09-28 DK DK510387A patent/DK510387A/da not_active Application Discontinuation

Non-Patent Citations (1)

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