Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1997-06-25
1999-06-15
Reamer, James H.
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
204 72, 204157, C07D25306
Patent
active
059123451
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a process for producing lamotrigine and its pharmaceutically acceptable acid addition salts.
Lamotrigine is 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine, of formula (I) ##STR3##
It is a known compound, useful in the treatment of disorders of the central nervous system (CNS), in particular epilepsy, described for example in EP-A-0021121. Lamotrigine isethionate, disclosed in EP-A-0247892, is a preferred salt for parenteral administration.
The present invention provides a process for producing lamotrigine, which process comprises subjecting a compound of formula (II: ##STR4## wherein R is CN or CONH.sub.2, in an organic solvent, to ultra violet or visible radiation and, when R is CN, to heat.
Any organic solvent may be used in which the compound of formula (II) is soluble. A preferred example is a C.sub.1 -C.sub.6 alkanol.
A C.sub.1 -C.sub.6 alkanol may be a straight or branched-chain alkanol. It is, for instance, a C.sub.1 -C.sub.4 alkanol, for example methanol, ethanol, n-propanol, i-propanol, n-butanol, s-butanol, or t-butanol, or a mixture thereof.
When R in formula (II) is CN, the process of the invention requires the application of heat to the compound of formula (II). In that case the process is preferably conducted by irradiating and heating the compound of formula (II) in the solvent. The solution may, for instance, be heated on a steam bath. It is suitably heated to the reflux temperature of the organic solvent. The solution may first be irradiated at ambient temperature and then subsequently heated, for example to reflux. Alternatively the solution may first be heated, for example to reflux, and then subsequently irradiated. The solution is suitably maintained at or near reflux temperature whilst irradiation takes place. For instance, the solution may be heated to reflux and then circulated through a falling film photochemical reactor in which it is exposed to radiation of a suitable intensity and duration.
When R in formula (II) is CONH.sub.2 the process of the invention does not necessarily require heat. In that case the solution of the compound of formula (II) in an organic solvent may be irradiated at ambient temperature, for instance at a temperature of from 18.degree. C. to 25.degree. C., or from 20.degree. C. to 25.degree. C., preferably at 25.degree. C. However, the solution may optionally be heated before, during or after irradiation, for instance as described above for compounds of formula (II) wherein R is CN.
Irradiation of a compound of formula (II) in the organic solvent may suitably be performed by exposure to sunlight, to a tungsten lamp, to a fluorescent lamp or to a medium pressure Hg lamp. Irradiation may also be performed by exposure to both sunlight and a tungsten lamp, or to both sunlight and a medium pressure lamp. A tungsten lamp is suitably a 150W lamp.
Irradiation is continued for a sufficient period of time to effect cyclisation of the compound of formula (II) to lamotrigine. The amount of time which is appropriate will depend inter alia on the source or sources of radiation, on the intensity of radiation, on the nature of the reaction vessel and on the temperature and pH of the solution being irradiated. Irradiation may, for instance, be continued for a period of from 2 hours to 5 days, for instance 2 hours to 4 days, or 2 hours to 2 days, or 2 hours to 1 day; or from 4 hours to 4 days, for instance 4 hours to 4 days, or 4 hours to 2 days, or 4 hours to 1 day; or from 2 hours to 24 hours, for instance 2 hours to 0 hours, or 2 hours to 18 hours; or from 4 hours to 24 hours for instance 4 hours to 20 hours, or 4 hours to 18 hours.
When R in formula (II) is CONH.sub.2 the process of the invention is suitably carried out in the presence of a base. Any suitable base may be used, for example an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide. Potassium hydroxide is especially preferred. The alkaline pH created by the use of a base is thought to promote the cyclisation of the compound of formula (II) to lamotrigine i
REFERENCES:
patent: 3637688 (1972-01-01), Rees et al.
patent: 5712277 (1998-01-01), Nakamura et al.
Germain Andrew
Sawyer David Alan
Winter Raymond Geoffrey
Glaxo Wellcome Inc.
Reamer James H.
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