Processes for the preparation of derivatives of 4a, 5, 9,...

Details Processes for the preparation of derivatives of 4a, 5, 9,... Processes for the preparation of derivatives of 4a, 5, 9,...

2001-03-23

2002-04-09

Kifle, Bruck (Department: 1624)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06369238

ABSTRACT:

The invention relates to processes for the preparation of derivatives of 4a, 5,9,10,11,12-hexahydro-6H-benzofuro [3a,3,2-ef] [2]benzazepine, of the general formula (I)
or of salts thereof, wherein R
2
, R
4
, X
1
, X
2
, Y
1
and Y
2
are either identical or different and are hydrogen, fluorine, chlorine, bromine, iodine, a hydroxyl or alkoxy group, a lower, optionally branched alkyl group which is optionally substituted by, for example, at least one halogen, a lower, optionally branched alkenyl, group, a lower, optionally branched alkynyl group, an optionally substituted aryl, aralkyl or aryloxyalkyl group, the alkyl chain of which is optionally branched and the aromatic nucleus of which is optionally substituted, formyl or unbranched or branched alkylcarbonyl, arylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, aralkylsulfonyl or arylsulfonyl which are unsubstituted or substituted by one or more halogens, or Y
1
and Y
2
together are =0 and wherein A is a benzene nucleus which is optionally mono- or polysubstituted by at least one lower, optionally branched alkyl group, at least one lower, optionally branched alkene group, at least one lower, optionally branched alkyne group, at least one lower, optionally branched alkoxy group, by fluorine, chlorine, bromine or iodine or by several identical or different halogens, at least one alkyl group substituted by one halogen or by several identical or different halogens, such as chloromethyl and trifluoromethyl, at least one optionally substituted aralkyl group and/or at least one hydroxyl group, primary, secondary or tertiary amino group, nitro group, nitrile group, alkylamino group, arylamino group, aldehyde group, carboxylic acid group or all derivatives of the carboxylic acid group, such as eaters, asides and halides.
The invention furthermore relates to processes for the preparation of derivatives of 4a,3,9,10,11,12-hexahydro-6H-benzofuro[3a,3,2-ef] [2]benzazepine, of the general formula (II)
wherein R
2
, R
4
, X
1
, X
2
, Y
1
, and Y
2
and A have the meanings given above for formula (I), Z
−
is an organic anion of a pharmaceutically useful acid, such as tartrate, lactate, citrate, acetate or maleate, or an inorganic anion, such as fluoride, chloride, bromide, iodide, sulfate, phosphate or chlorate, R
5
is hydrogen, formyl, unbranched or branched alkyl, alkenyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl which are unsubstituted or substituted by at least one halogen, or branched or branched alkyloxycarbonyl aryloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, arylsulfonyl or aralkylsulfonyl which are unsubstituted or substituted by one or more halogens.
Preferred meanings of the substituents R
1
-R
6
, X
1,2
Y
1,2
are R
1
, R
2
, R
3
, R
6
: hydrogen, unbranched or branched alkyl, alkenyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl which are unsubstituted or substituted by one or more halogens, or any combination of these radicals, X
1
, X
2
: H, F, Cl, Br, I
−
, t-butyl and any combination, Y
1
, Y
2
: H, O-R
6
, and Y
1
and Y
2
=0, R
4
, R
5
: the preferred meanings mentioned for R
1
, R
2
, R
3
, R
6
and unbranched or branched alkyloxycarbonyl, aryloxycarbonyl aralkyloxycarbonyl, alkylsulfonyl, arylsulfonyl or aralkylsulfonyl which are unsubstituted or substituted by one or more halogens.
Galanthamine is an alkaloid of high pharmacological activity which occurs chiefly in plants of the Amaryllidaceae type. Its action as a selective acetylcholinesterase inhibitor and its associated use for Alzheimer's diseases are to be emphasized in particular. Galanthamine has been isolated to date from the caucasian snowdrop Galanthus woronoyi in amounts of a few kg annually at a cost of more than US$ 30,000/kg. Galanthamine syntheses have been known in principle since the end of the nineteen-sixties, but long, uneconomical reaction paths with poor overall yields have been used.
The synthesis of some compounds of the general formulae (I) and (II) given above is known per se and described in the literature. Thus N-(3-hydroxy-4-methoxyphenyl)-N-methyl -4-hydroxy -phenylethylamine has been subjected to oxidative cyclization with the aid of various oxidizing agents to give narwedine derivatives (narwedine is the precursor to galanthamine, but already has the ring structure characteristic of galanthamine) [Lit. 1-2], the yields as a rule being less than 1% of theory. Although the structure could thus be demonstrated galanthamine could not be prepared in kg amounts of pharmaceutical interest.
Optimized processes (above all Kametani, Lit. 3-7,22) describe this cyclization an N-methyl-benzamide and phenylacetamide derivatives in yields of up to 40%, but the poor overall yields render industrial utilization impossible. The literature furthermore reports the cyclization of N,N-disubstituted phenylethylamine derivatives (Lit. 8) and electrochemical (Lit. 9-12), microbiological, enzymatic (Lit. 8) and biomimetic methods (Lit. 14-15). Lit. 23 describes the preparation of narwedine from isovanillin in an overall yield of 44%, but the use of equimolar amounts of palladium and also thallium trifluoroacetate render this synthesis uneconomical. (+/−) Narwedine obtained by this route (Lit. 23) is enriched in the desired (−) narwedine in Lit. 24 and converted into galanthamine with L-Selektride in a good yield.
Lit. 8 proposes a synthesis in which the oxidative cyclization is described with a yield of 21%, but separation of the enantiomers is absent. The reduction of bromonarwedine with LiAlH
4
in THF to form a 53:31 diastereomer mixture of (+/−) galanthamine and (+/−) epigalanthamine is also known.
The invention is based an the object of developing a synthesis process with which larger amounts of the title substances can be prepared in a reproducible manner and in improved yields both of the individual steps and of the overall yield.
This object is achieved according to the invention by the processes according to claim
1
and
2
, the sub-claims relating to preferred and advantageous variants and embodiments of the invention. In particular, the following measures of the invention have proved to be advantageous:
Replacement of halogenated solvents, for example chloroform, by toluene. Halogenated solvents are nowadays scarcely still employed as industrial solvents because of their toxicity, the difficulties of their disposal and their ecological unacceptability. Toluene, in contrast, does not have these disadvantages.
Working up by extraction requires organic solvents. With the invention, the working up operations of most stages can be optimized such that the reaction product can usually be obtained in crystalline form from the solution. Chromatographic purification stages or extractions can thus mostly be avoided.
Furthermore, the yields can be reproduced within a very narrow range in the invention by improving the parameters and the purity of the main products and the content of by-products can be defined according to these reactions. Improved and reproducible yields of the individual stages and of, the overall yield are possible with the process of the invention. The invention provides, inter alia, a process in which bromoformylnarwedine is reduced with reducing agents. L-Selektride can be used as the reducing agent, the reduction leading diastereoselectively to N-demethylbromogalanthamine in a high yield (for example 85%), which can be converted into (±) galanthamine by N-methylation according to Eschweiler-Clark and debromination. In this process, it has not been possible to detect (+/−) epigalanthamine in the reaction product by chromatographic methods. Galanthamine and galanthamine derivatives can be prepared on an industrial scale by the process according to the invention via intermediates which are not described in the literature (see the compounds mentioned in claims
64
to
67
).
The processes of the p

Affiliated with

Also associated with

Rating

Processes for the preparation of derivatives of 4a, 5, 9,... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Processes for the preparation of derivatives of 4a, 5, 9,..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Processes for the preparation of derivatives of 4a, 5, 9,... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2891755