Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1992-07-01
1994-03-29
Springer, David B.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
548230, 548554, C07D20726, C07D26326
Patent
active
052986284
DESCRIPTION:
BRIEF SUMMARY
SUMMARY OF THE INVENTION
The invention relates to the process for the production of optically active 4-aryl-2-pyrrolidinones as well as the process for the production of the optically active initial compounds, which are suitable as intermediate products for the production of 4S or 4R enantiomers of 4-aryl-2-pyrrolidinones.
It is known from U.S. Pat. No. 4,012,495 and from WO 86/02268, that 4-aryl-2-pyrrolidinones are compounds with good effectiveness, which are suitable for the treatment of neuroleptic and mental disorders and can also be used for topical treatment of inflammations.
From among the 4-aryl-2-pyrrolidinones, the 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidinone was thoroughly pharmacologically studied. By means of a very costly process and a process that cannot be duplicated on an industrial scale, this compound was converted into its optical antipode and it was noted that both enantiomers represent pharmacologically effective compounds.
Since it is desirable that in chiral active ingredients of pharmaceutical agents only one antipode each is used for the production of pharmaceutical preparations, the object was to develop an industrially applicable process for the production of optically active 4-aryl-2-pyrrolidinones.
According to the process of the invention the desired (4S)-or (4R)-4-aryl-2-pyrrolidinones can be produced in a simple synthesis from the easily accessible optically active initial compounds and can be isolated in high optical purity and good yield without costly separative operations. The recovery of the auxiliary material is to be considered as an additional advantage of the process according to the invention.
The invention relates to a process for the production of (4S)- or (4R)-4-aryl-2-pyrrolidinones of formula I ##STR1## in which
R.sup.1 is a hydrogen or a hydrocarbon radical with up to 7 carbon atoms optionally interrupted with an oxygen atom and
R.sup.2 is a C.sub.1-4 alkyl characterized in that an optically active compound of formula II ##STR2## in which
R.sup.1 has the meaning of R1 or represents an easily cleavable group and cleavable group is optionally cleaved off and the thus obtained hydroxy group is etherified.
As hydrocarbon radical R.sup.1, saturated or unsaturated, straight-chain or branched alkyl groups with 1-6 carbon atoms, preferably 1-4 carbon atoms, are suitable, also C.sub.4-6 -cycloalkylalkyl and cycloalkyl groups with 3-7 carbon atoms and the benzyl group as well as cycloalkyl groups interrupted by an oxygen atom.
As saturated alkyl groups, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl, tert. butyl, pentyl, 2,2-dimethylpropyl and hexyl each are suitable.
As alkenyl and alkynyl groups there can preferably be mentioned: 2-propenyl, 2-propinyl. If hydrocarbon radical R.sup.1 means a cycloalkyl group, then cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl are meant, preferably C.sub.3-5 -cycloalkyl groups. Cyclopropylmethyl, cyclopropylethyl and cyclopentylmethyl are to be considered as preferred for the cycloalkylalkyl group.
If the hydrogen carbon radical is interrupted by an oxygen atom, then the cycloalkyl radical, in which a CH.sub.2 group is replaced by an oxygen atom is especially meant, and as cyclic ether radical, for example, 3-tetrahydrofuranyl and 3-tetrahydropyranyl can be mentioned.
If the molecule contains a cyclic ether radical, thus another asymmetric center can be present that can be converted to the antipodes in the usual way.
The phrase "easily cleavable group" within the scope of this invention means that the hydroxy protective group is easily cleavable in the usual way either under the reaction conditions or subsequently. As protective groups, for example, the methoxymethyl, methoxy-ethoxymethyl and also the benzyl group can be mentioned.
As catalysts for the reaction according to the invention the hydrogenation catalysts usually used are suitable such as, for example, Raney nickel or noble metal catalysts such as platinum oxide and palladium/carbon. The reaction takes place at room t
REFERENCES:
patent: 4012495 (1977-03-01), Schmiechen et al.
patent: 4153713 (1979-05-01), Huth et al.
patent: 4193926 (1980-03-01), Schmiechen et al.
Marivet et al., "Inhibition of Cyclic Adenosine-3',5'-Monophosphate Phosphodiesterase from Vascular Smooth Muscle by Rolipram Analogues," J. Med. Chem. 32:1450-1457 (1989).
Mulzer Johann H.
Zuhse Ralf H.
Schering Aktiengesellschaft
Springer David B.
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