Organic compounds -- part of the class 532-570 series – Organic compounds – Chalcogen in the nitrogen containing substituent
Patent
1994-08-31
1996-05-28
Gupta, Yogendra N.
Organic compounds -- part of the class 532-570 series
Organic compounds
Chalcogen in the nitrogen containing substituent
544105, C07D49816
Patent
active
055213103
DESCRIPTION:
BRIEF SUMMARY
This invention describes a new process for the synthesis of benzoxazine derivatives of general formula (I) ##STR2## where: R.sub.1 is H, an alkyl radical of up to 6 carbon atoms, preferably methyl, an alkenyl radical of up to 6 carbon atoms or an aryl group; and
These compounds of formula (I) are advanced and key intermediates for the commercial synthesis of antibacterial compounds such as the Ofloxazine (racemate) and its enantiomerically pure forms, among them the levofloxacine.
BACKGROUND OF THE INVENTION
The formula of the Ofloxacine [9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3 dihydro-7H-pyrid(1,2,3-de) (1,4)-benzoxazine-6-carboxylic acid] is: ##STR3##
It is described in Patents: Japanese No. 1,444,043; U.S. Pat. No. 4,382,892 and European No. EP-B-0,047,005. The Ofloxazine is an excellent synthetical antimicrobial agent as mentioned in the application for Japanese Patent No. 46986/92 (OPI) which has been marketed in many countries.
The Ofloxazine has an asymmetric carbon atom in position 3 and is normally obtained as racemate through processes already known. However, through the process of this invention, it is possible to directly obtain any of its optically active forms without the need to carry out any resolution stage.
The researches made by the authors of this invention have shown that the 3-(S)- isomer of the Ofloxazine, known as Levofloxazine, has (1) an antimicrobial activity twice higher than that of the racemic thus confirming the statements of European Patent No. EP-A-0,206,283 and (ii) an acute toxicity (LD.sub.50) weaker than that of the racemic compound which has been determined in mice through intravenous administration. Furthermore, it has been possible to assess that the isomer (R) presents (i) an antimicrobial activity between ten and one hundred times lower than that of the racemic compound and (ii) it has an acute toxicity basically similar to that of such racemic one. Consequently, the (S) form of Ofloxazine (Levofloxazine) presents very interesting properties, such as an increased antimicrobial activity and a reduced toxicity. Therefore it can be assumed that this compound will be--from a pharmaceutical point of view--more useful than the racemic one.
Indeed, it has been possible to determine that the water solubility of both the (R)-Ofloxazine form and the (S)-Ofloxazine form in free form is higher than that of the (R,S) compound and, therefore, it can be used for injectable preparations.
The description of the Ofloxazine and of the Levofloxazine as well as their application to human and veterinary clinics appear in the German Patents No. DE 3522406 A1 and DE 3639465 A1 respectively.
The Spanish Patent No. 553520 describes a process to obtain the Ofloxacine by hydrolysis of the preceding nitrile9-fluorine-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7 H-pyrid(1,2,3-de)-(1,4)-benzoxazine-6-carbonitrile.
In general terms, all the synthesis processes of the Ofloxacine and of the Levofloxazine normally used are based on expensive products and call for a resolution stage to separate the pure enantiomers. On the contrary, the procedure of this invention offers the following advantages when compared with the previous technique: Ofloxazine without the need of a resolution stage; and than that used in other previous patents (2,3-difluorine-6-nitrophenol).
DETAILED DESCRIPTION OF THE INVENTION
This invention provides a process to prepare bezoxazine derivatives of formula (I): ##STR4## where: R.sub.1 is H, an alkyl radical of up to 6 carbon atoms, preferably methyl, an alkenyl radical of up to 6 carbon atoms or an aryl group; and
The term "alkyl radical of up to 6 carbon atoms" shall be understood--as used in this description--as any radical derived from a lineal or ramified alkane chain of up to 6 carbon atoms inclusive such as methyl, ethyl, propyl, isopropyl.
Analogically, the term "alkenyl radical of up to 6 carbon atoms" shall be understood as any radical derived from a lineal or ramified alkene chain of up 6 carbon atoms inclusive which has one or more un
REFERENCES:
patent: 4382892 (1983-05-01), Hayakawa et al.
Carretero Gonzalvez Juan-Carlos
Garcia Ruano Jose-Luis
Vicioso Sanchez Mercedes
Derivados del Etilo, S.A.
Gupta Yogendra N.
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