Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1992-06-25
1994-10-04
Richter, Johann
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D45900
Patent
active
053527909
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a new process for the preparation of 1.beta.-ethyl-1.alpha.-(hydroxymethyl)-1,2,3,4,6,7,12,12b.alpha.-octahydro -indolo[2,3-a]quinolizine and novel intermediates. More precisely, the invention relates to a process for the preparation of (-)-1.beta.-ethyl-1.alpha.-(hydroxymethyl)-1,2,3,4,6,7,12,12b.alpha.-octah ydro-indolo[2,3-a]quinolizine of the formula (I) ##STR2## and to novel intermediates obtained in this process.
BACKGROUND OF THE INVENTION
The compound of the formula (I) having a peripheral vasodilator effect is well known, its preparation and medicinal effect are disclosed in the British patent specification No. 2,174,701.
The racemic 1-ethyl-1-(acyloxymethyl)-1,2,3,4,6,7,12,12b.alpha.-octahydro-indolo[2,3-a ]quinolizine derivatives used as starting materials in the process described in the British patent specification No. 2,174,701 can be prepared by a method disclosed in the British patent specification No. 1,499,546 by reacting 1-ethyl-2,3,4,6,7,12-hexahydro-indolo[2,3-a]quinolizine of the formula (II) ##STR3## with formaldehyde used in a high excess. In this case the racemic form of the compound of the formula (I) is obtained. As disclosed in the British patent specification No. 2,174,701, the therapeutically effective .beta.-ethyl-derivative of the formula (I) can be prepared by acylating the above racemic compound, then by resolving the acylated compound thus obtained and then by deacylating the separated .beta.-ethyl form in four reaction steps. The yield of the pharmaceutically ineffective .alpha.-ethyl derivative separated in the resolution step is only about 25%, calculated for the starting hexahydro-indolo[2,3-a]quinolizine of the formula (II) when considering the yield data described in Examples 1 and 2 of the British patent specification No. 1,499,546 and Examples 1 and 2 of British patent specification No. 2,174,701.
OBJECT OF THE INVENTION
The object of the invention is to provide a process by which the starting 1-ethyl-hexahydro-indolo[2,3-a ]quinolizine of the formula (II) can be converted into the corresponding .beta.-ethyl derivative in a more simple way and with good efficiency and, optionally, the .alpha.-ethyl derivative wasted in the previous process can be recycled to the beginning of the synthesis route.
In the course of our experiments for carrying out this process we have surprisingly found that by reacting 1-ethyl-hexahydro-indolo[2,3-a]quinolizine of the formula (II) with about an equimolar amount of formaldehyde or with a polymerized form thereof, racemic 1-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-indolo[2,3-a]quinolizine of the formula (III), ##STR4## a new compound, is obtained, from which the target compound can be prepared, in two different ways and in a simple manner, by reducing the novel indolo-quinolizinium salt of the formula (IV) , ##STR5## wherein X.sup.- represents the residue of an optically active acid, thus obtained either equimolar amount, or equimolar amount.
The resolving agent is an optically active acid. Such acids are well known in the art.
SUMMARY OF THE INVENTION
There is provided by this invention a process for the preparation of (-)-1.beta.-ethyl-1.alpha.-(hydroxymethyl)-1,2,3,4,6,7,12,12b.alpha.-octah ydro-indolo[2,3-a]quinolizine of the formula (I). This process is characterized by formula (II) with about an equimolar amount of formaldehyde or with a polymerized form thereof and, after an optional isolation, the novel racemic 1-ethyl-1-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]quinolizi ne of the formula (III) obtained: amount and the novel 1.beta.-ethyl-1.alpha.-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-12H-indolo[2, 3-a]quinolizine-5-ium salt of the formula (IV) obtained is reduced, or amount, then the diastereomer salt pairs of the formulae (IV) and ##STR6## p1 wherein X.sup.- is as defined before, are separated, and the novel 1.beta.-ethyl-1.alpha.-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-12H-indolo[2, 3-a]quinolizine-5-ium salt of the formula (IV) obtained is reduced to
REFERENCES:
patent: 4036841 (1977-07-01), Szantay et al.
patent: 4044012 (1977-08-01), Szantay et al.
patent: 4806545 (1989-02-01), Szantay et al.
Brill, deceased Judit
Czibula Laszlo
Kreidl Janos
nee Juhasz Ida D.
nee Kirjak Maria F.
Dubno Herbert
Myers Jonathan
Richter Johann
Richter Gedeon Vegeyszeti Gyar Rt.
Scalzo Catherine
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