Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1993-03-08
1995-03-28
Lee, Mary C.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
548504, 548507, C07D20908
Patent
active
054018544
DESCRIPTION:
BRIEF SUMMARY
SUMMARY OF THE INVENTION
The invention relates to a process for the production of indole derivatives, new intermediate products for the production of indole derivatives as well as the process for the production of new intermediate products.
Indoles are intermediate products for the synthesis of pharmacologically suitable compounds such as, for example, for the production of tryptamines (C.A. 56, 11701 (1962), tryptophanes (R. V. Heinzelmann et al. Org. Chemie 25, 1548 (1960) and carbolines (EP-A-239667, EP-A-234 173).
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 pharmaceutical research.
However it has turned out that the reaction of the indole with aldehydes and more space demanding primary amines, such as tert. butyl or isopropyl amine in glacial acetic acid is achieved in poor yields and is achieved in better yields when using the corresponding aldimines, and that the yields are greatly influenced by the substituent on the indole.
For example, the imine from methoxyacetaldehyde and isopropylamine reacts with 4- or 5-benzyloxy indole only in a yield of 60 or 64% to the target compound (EP 54 507). If, however, phenoxy indoles substituted with halogen are reacted with imines in glacial acetic acid, then the desired gramine derivatives are not obtained, but,instead besides the initial compound, a dimeric product is isolated [G. Neef et al. Heterocylces 20, 1295,1299 ( 1983 ) ].
Therefore the object was to develop a process, that because of its good yields with good handling and without purification problems, makes possible the industrial production of these .beta.-carboline-intermediate stages independent of the type of substituent on the indole.
Surprisingly, it has now been found that in the reaction of indoles with imines in the presence of phosphoric acid the desired intermediate products for the production of pharmacologically valuable .beta.-carbolines result in good up to very good yields.
Another advantage of the process according to the invention consists in the fact that only easily separable and nonpolluting by-products result.
For example, the alkaline wash waters contain easily soluble dipotassium hydrogen phosphate and aldehyde from the excess imine that is oxidized with hydrogen peroxide to the potassium salt of carboxylic acid. Then the phosphate is removed from the wash waters as the slightly soluble calcium hydrogen phosphate-dihydrate.
The invention relates to the process for the production of compounds of formula I ##STR1## in which R.sup.1 means C.sub.1-4 -alkyl , -alkyl and phenyl-C.sub.1-2 -alkyl radical, and --OR.sup.5 can be single or multiple characterized in that a compound of formula II ##STR2## in which R.sup.5 that has the above indicated meaning is reacted in the presence of phosphoric acid with an imine of formula III
Substituent --OR.sup.5 can be in 4, 5, 6 and/or 7 position singly or multiply, especially single or double, and the single substitution in 4 or 5 position is preferred.
By C.sub.1-4 -alkyl is meant respectively a straight or branched alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, tert. butyl and isobutyl.
As phenyl-C.sub.1-2 -alkyl radical R.sup.5 there can be mentioned, for example, benzyl, phenethyl and .beta.-methylbenzyl. The phenyl radical and the phenyl-C.sub.1-2 -alkyl radical can be substituted singly or doubly in any position and single substitution is preferred.
As substituents of the phenyl radical there can be mentioned, for example, halogens, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, trifluoromethyl, cyano or nitro, and the substitution with halogens is preferred.
As the substituents of the phenyl-C.sub.1-2 -alkyl radical, halogens, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, trifluoromethyl or cyano are especially suitable, and halogens are preferred substituents.
Halogen respectively comprises fluorine, chlorine, bromine or iodine.
As a preferred substituent combination, phenyl optional
REFERENCES:
patent: 4428962 (1984-01-01), Bristol et al.
patent: 4435403 (1984-03-01), Braestrup et al.
patent: 4596808 (1986-06-01), Braestrup et al.
CA 110(1):8073M Indole . . . (Aminomethyl) indoles. Borisova et al., p. 621, 1977.
CA 87(3):22951j An . . . system. Klohr et al., p. 742, 1989, CA 95(5):42809n Bisindoles. 8. . . . oxide. Samsoniya et al., p. 731, 1981.
CA 116(7):59098e Preparation . . . derivatives. Kuebler et al., p. 834, 1992.
CA 117(9):90139p Preparation . . . antagonists. Nakanishi, p. 767, 1992.
Chemical Abstracts, vol. 87, No. 3 (Jul. 18, 1977), Abstract No. 22951J, "Indole derivatives", p. 621.
Chemical Abstracts, vol. 75, No. 9 (Aug. 30, 1971) Abstract No. 63605V, "Indole derivatives and their intermediates", p. 437.
Chemical Abstracts, vol. 86, No. 5 (Jan. 31, 1977), Abstract No. 29624T, "Intermediates for indoles", p. 350.
Borner Helmut
Haffer Gregor
Kubler Wolfgang
Nickisch Klaus
Lee Mary C.
McKane J. K.
Schering Aktiengesellschaft
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