Process for the production of gramine derivatives

Details Process for the production of gramine derivatives Process for the production of gramine derivatives

1991-12-26

1993-03-30

Ramsuer, Robert W.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

548507, C07D20914

Patent

active

051985535

DESCRIPTION:

BRIEF SUMMARY
The invention relates to a process for the production of gramine derivatives.
Gramines are intermediate products for the synthesis of pharmacologically applicable compounds, such as, for example, for the production of tryptamines (C.A. 56, 11701 (1962), tryptophans, (R. V. Heinzelmann et al. Org. Chemie [Chemistry] 25, 1548 (1960)) and carbolines (EP-A-239667).
Because of their good binding affinity to the benzodiazepine receptors, .beta.-carbolines show effects on the central nervous system and therefore have just recently met with great interest in the research of pharmaceutical agents. While gramine formation with formaldehyde and secondary amines often occurs problem-free, the reaction of indole with aldehydes and primary amines is possible only with poor yields (H. R. Snyder et al., J. Am. Soc. 79. 2217 (1957)). With the use of the corresponding imines, the yield is actually better, but still always unsatisfactory as a function of the substituents of the indole.
Therefore, the object was to develop a process which, because of its good yields with simultaneously good handling and without expensive separation operations, makes possible the production on an industrial scale of these .beta.-carboline intermediate stages.
Surprisingly, it has now been found that the reaction of indole derivatives with imines occurs with almost quantitative yields, if the primary amines corresponding to the imine are added to the reaction mixture.
Since neither an additional reaction step is required by the addition of amine nor do by-products that are difficult to separate result, this process is very well-suited for the synthesis on an industrial scale of this important intermediate compound for the production of valuable pharmaceutical agents.
The invention relates to the process for the production of compounds of formula I ##STR1## in which R.sup.1 is C.sub.1-4 alkyl, substituted aralkyl radical, R.sup.9 meaning C.sub.1-4 alkyl and R.sup.10 and R.sup.11 are the same or different and mean hydrogen, C.sub.1-4 alkyl or together with the nitrogen atom mean an optionally saturated heterocyclic 5- or 6-ring containing another heteroatom, which is optionally substituted with one to two C.sub.1-4 alkyl groups, characterized in that an indole derivative derivative of formula II ##STR2## in which R.sup.5 has the above-named meaning is reacted with an imine of formula III
R.sup.4 and R.sup.1 have the above-named meaning, under acid catalysis in the presence of primary amines.
Substituent R.sup.5 can be in 4-, 5-, 6- and/or 7-position once or twice, and the substitution is preferably in 4- or 5-position.
C.sub.1-4 alkyl is to be understood to mean respectively a straight or branched alkyl group with 1-4 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and isobutyl.
Suitable cycloalkyl radicals are, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
If R.sup.10 and R.sup.11 together with the nitrogen atom mean a 5- or 6-membered heterocycle optionally containing another heteroatom, such as oxygen, nitrogen or sulfur, this heterocycle represents, for example, morpholine, piperidine, thiomorpholine, piperazine or pyrrolidine and can optionally be substituted with one to two C.sub.1-4 alkyl groups, such as, for example, 2,6-dimethylmorpholine and N-methylpiperazine.
Aralkyl radical R.sup.6 can contain 7-8 carbon atoms and preferably represents the phenyl-C.sub.1-2 alkyl radical, such as, for example, benzyl, phenethyl and .alpha.-methylbenzyl.
As substituents of the aralkyl radical, halogens, such as fluorine, chlorine, bromine or iodine, C.sub.1-4 alkoxy or C.sub.1-4 alkyl are suitable, and the substituent can be in each position of the aryl radical once or twice. As a preferred aralkyl radical, the benzyl radical, which can be substituted with halogen once or twice, such as 3-bromobenzyl and 4-chlorobenzyl, can be considered.
As a preferred substituent combination for the process according to the invention, R.sup.4 meaning C.sub.1-4 alkoxy-C.sub.1-2 alkyl and R.sup.5 me

REFERENCES:
patent: 3459767 (1969-08-01), McManus et al.
Raines, et al., A Study on the Condensation of Pyrroles, J. of Het. Chem., vol. 7, No. 1, pp. 223-225, Feb. 1970.

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