Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-02-24
2000-01-18
Huang, Evelyn Mei
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546149, 562401, 564335, C07D21720
Patent
active
060159030
DESCRIPTION:
BRIEF SUMMARY
This application is the national phase of PCT/EP96/04030, filed Sep. 13, 1996.
The present invention relates to a novel process for resolving racemates.
A large number of resolutions of racemates are already known. Despite this, resolutions of racemates repeatedly encounter problems because the resolving reagents are not sufficiently stable, result in oily antipodes which are difficult to isolate, can be used only in a very complicated manner, or show virtually no reaction with the racemates. There is thus a great interest in finding resolving reagents suitable for particular groups of racemates.
Tetrahydropapaverine is resolved into its antipodes for example with the aid of N-acetylleucine. This racemate resolution is a 3-stage process: and
The crucial disadvantage of this process is that with N-acetylleucine virtually only the naturally occurring optically active acid is available for the resolution and this precipitates initially the unwanted diastereomeric S salt of tetrahydropapaverine. The salt of the R antipode can be precipitated only from the mother liquor enriched with this antipode.
It is also known that racemic 2-amino-1-butanol can be separated into its antipodes using (+)-2,4-dichlorophenoxypropionic acid.
We have now found a simpler process for resolving racemates.
The invention relates to a process for resolving racemates of compounds of the formula I ##STR3## in which the substituents have the following meanings: a: 0 or 1 together a radical of the formula III ##STR4## in which G: is H, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, halogen, nitro or amino, optical antipodes of derivatives of phenoxypropionic acid of the formula II ##STR5## in which T, U and V have the following meanings: T: H, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, halogen, nitro or cyano, or a phenyl ring which is unsubstituted, mono-, di- or trisubstituted by C.sub.1-4 -alkyl ,C.sub.1-4 -alkoxy or halogen,
Suitable and preferred compounds of the formula I are those in which the substituents have the following meanings: methoxy, K is methoxy and L is H,
Particularly suitable compounds of the formula I are deprenyl, ephedrine and, in particular, tetrahydropapaverine. Suitable and preferred compounds of the formula II are those in which T is in the o position and is H, fluorine, chlorine or methoxy, U is fluorine, chlorine or methoxy in the p position, and V is hydrogen.
A particularly suitable compound of the formula II is (+)- or (-)-2-(2,4-dichlorophenoxy)propionic acid.
The racemate resolution can be carried out at from 0.degree. C. to the boiling point of the solvent used. It is simplest to work at room temperature.
The resolution can be carried out in conventional solvents such as lower alcohols, acetone, toluene, xylenes, ethers, tetrahydrofuran and ethyl acetate. Saturated solutions are normally used. Isopropanol or toluene is preferably used.
The base can be liberated in aqueous solution at pH 7.5-10 from the salt produced in the racemate resolution, and can be extracted with a solvent which is insoluble in water, such as ether, toluene or a xylene.
The novel process is distinguished by the fact that the resolving reagents are easily obtainable and are stable. In addition, they have high selectivity and therefore provide the antipodes in good yields and in very high purity.
The invention also relates to the salts of deprenyl, ephedrine and tetrahydropapaverine with a phenoxypropionic acid of the formula ##STR6## in which T is H, chlorine or methoxy and U is methoxy or chlorine. Among these, specific mention should be made of L-ephedrine D-dichlorophenoxypropionate and, in particular, (+)-THP D-2,4-dichlorophenoxypropionate.
EXAMPLE 1
1.029 g (3 mmol) of THP (THP=tetrahydropapaverine=1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-1, 2,3,4-tetrahydroisoquinoline) were taken up in 2 ml of isopropanol, a hot solution of 0.707 g (3 mmol) of D-2,4-dichlorophenoxypropionic acid in 8 ml of isopropanol was added, and the mixture was briefly refluxed. After cooling to room temperature, the resulting crystals were filtered off with su
REFERENCES:
patent: 4120964 (1978-10-01), Hartenstein
patent: 5199970 (1993-04-01), Tompa
patent: 5453510 (1995-09-01), Hill
patent: 5543414 (1996-08-01), Nestor
Brase Walter
Knopff Juergen
Viergutz Wolfgang
BASF - Aktiengesellschaft
Huang Evelyn Mei
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