Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-06-23
1996-10-29
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 85, 546 87, A61K 3144, C07D22106
Patent
active
055696619
DESCRIPTION:
BRIEF SUMMARY
This is the national stage application of PCT/DE93/01116 filed Nov. 22, 1993.
The invention relates to a new process for the production of .beta.-carbolines by dehydrogenation of tetrahydro-.beta.-carbolines with trichloroisocyanuric acid.
On the basis of their affinity to the benzodiazepine receptors, .beta.-carbolines show effects on the central nervous system and are suitable for the production of pharmaceutical agents. The industrial-scale production of .beta.-carbolines in operation therefore has met with great interest recently. The synthesis of active ingredients is performed with several stages, and the yields are influenced in the individual stages by the purity of the starting product. Thus it is known, for example, from EP-239667 that .beta.-carbolines can be produced over 3 stages, and an aromatization of the C-ring is performed in the last stage. The 1,2,3,4-tetrahydro-.beta.-carbolines or their 1-carboxylic acid derivatives used as starting products for the dehydrogenation are isolated and, according to EP-190 987, reacted with tert-butyl hypochlorite in the presence of bases. Tert-butyl hypochlorite is poorly suited for industrial-scale syntheses, since it can decompose exothermally in chloromethane and acetone at elevated temperature and with the effect of light. Not only the potential of danger but also the poor dosability of tert-butyl hypochlorite require its replacement in industrial-scale syntheses. It is therefore desirable to develop a process for the production of .beta.-carbolines which does not require the working-up of intermediate stages and makes possible the industrial-scale production of compounds with easily accessible and easily storable substances.
Surprisingly, it has now been found that in the dehydrogenation of tetrahydro-.beta.-carbolines with trichloroisocyanuric acid, which occurs in very good yields, a working-up and isolation of the intermediate products is not necessary. The process according to the invention makes possible that .beta.-carbolines starting from pseudo-gramine derivatives and Schiff bases can be produced in a one-pot reaction. Another advantage of the process according to the invention consists in the fact that trichloroisocyanuric acid is stable in storage and easily dosable as solid and the water-soluble reaction products can be separated easily in the working-up of the reaction mixture with aqueous bases.
The invention relates to the process for the production of compounds of formula I ##STR1## in which R.sup.A means hydrogen halogen, --CHR.sup.1 --R.sup.2 ; phenyl, hetaryl or OR.sup.5 optionally substituted with halogen, C.sub.1-4 alkoxy or amino and can be single to double, and optionally substituted phenyl, benzyl or phenoxy radical, and optionally substituted phenyl, benzyl, hetaryl or benzo-condensed hetaryl radical, and ##STR2## in which
R, R.sup.A and R.sup.4 have the above meaning, is aromatized with trichloroisocyanuric acid in the presence of bases. Substituent R.sup.A can be in the A-ring in position 5-8, preferably in 5-, 6- or 7-position.
In each case, alkyl contains both straight-chain and branched-chain radicals, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl and hexyl.
In each case, cycloalkyl can stand for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and 2methyl-cyclopropyl, and 3-5 carbon atoms are preferred.
If R.sup.5 or R.sup.A means a hetaryl radical, the latter is 5- or 6-membered and contains 1-3 heteroatoms, such as nitrogen, oxygen and/or sulfur. For example, the following 5- and 6-ring heteroaromatic compounds can be mentioned: pyridine, pyrimidine, pyrazine, pyridazine, furan, thiophene, pyrrole, thiazole, imidazole, triazine.
If R.sup.5 means a benzo-condensed hetaryl radical, the latter preferably contains 1-2 nitrogen atoms, such as quinoline, isoquinoline, quinoxaline or benzimidazole.
The substituent of the phenyl, benzyl, hetaryl and benzo-condensed hetaryl radical R.sup.5 can be single to triple in any position. Suitable substitu
REFERENCES:
patent: 4778800 (1988-10-01), Huth
Vader et al Tetrahedron 1989, 45(17), 5595-610.
Haffer Gregor
Nickisch Klaus
Dahlen Garth M.
Ivy C. Warren
Schering Aktiengesellschaft
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