Method of resolving racemic mixtures

A process for resolving racemates of compounds of the formula I ##STR1## in which a, A, B, D, E, F, M, Q and R have the meanings given in the description is described. The process is carried in a manner known per se but using the optical antipodes of derivatives of phenoxypropionic acid. Also described are salts of deprenyl, ephedrine or tetrahydropapaverine with a phenoxypropionic acid of the formula ##STR2## in which U and T have the meaning stated in the description, and which result as intermediate in the racemate resolution.

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: 
a) Precipitation of the S enantiomer with N-acetylleucine, 
b) Precipitation of the crude (required) R enantiomer with N-acetylleucine 
and 
c) Recrystallization of the R enantiomer bound to N-acetylleucine. 
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 
A: H, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, halogen, nitro or amino, 
B: H, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, halogen, nitro or amino, 
D: H, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy or halogen, 
E: H, 
F: H, C.sub.1-4 -alkyl, C.sub.2-4 -alkenyl, C.sub.1-4 -alkynyl or E and F 
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, 
K: is H, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, halogen, nitro or amino, 
L: is H, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy or halogen, 
M: H, C.sub.1-4 -alkyl or hydroxyl, 
Q: H or C.sub.1-4 -alkyl, 
R: H, C.sub.1-4 -alkyl or cyanomethyl, 
in a manner known per se, wherein the resolution is carried out with the 
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, 
U: H, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, halogen, nitro or cyano, 
V: H, 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: 
a: 1, 
A: H or methoxy, 
B: H or methoxy, 
D: H, 
E: H, 
F: H, or 
E and F together are a radical of the formula III in which G is H or 
methoxy, K is methoxy and L is H, 
M: H or methoxy, 
Q: methyl, 
R: H, methyl or cyanomethyl. 
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 
suction, washed with isopropanol and dried. 0.9 g of a product which 
consisted predominantly of (+)-THP D-2,4-dichlorophenoxypropionate 
remained. 
The resulting product was dissolved in 5 ml of water. The pH of the 
solution was adjusted to 8 and it was then extracted with toluene. After 
removal of the toluene, 0.48 g (93.3%) of the (+) enantiomer was obtained 
in an optical purity of 95.6%. 
EXAMPLE 2 
17.15 g (50 mmol) of THP were heated with 5.85 g (25 mmol) of 
D-2,4-dichlorophenoxypropionic acid in 80 ml of isopropanol with stirring. 
A clear solution was obtained at 45.degree. C. At 50.degree. C., the 
solution was seeded with the (+) isomer of the salt. The solution was then 
cooled to room temperature over the course of 2 h with stirring. 40 ml of 
isopropanol were also added for dilution. The crystals which separated out 
were filtered off with suction, washed with 30 ml of isopropanol and 
dried. The THP was liberated as in Example 1 from the salt obtained in 
this way. 
5.2 g (61%) of (+)-THP were obtained with an optical purity of 90.1%. 
EXAMPLE 3 
1.715 g (5 mmol) of THP and 0.588 g (2.5 mmol) of 
D-2,4-dichlorophenoxypropionic acid were dissolved in 10 ml of toluene at 
the reflux temperature and then slowly cooled. The resulting crystals were 
filtered off with suction and dried. (+)-THP was isolated as in Example 1. 
0.85 g (98.8%) of (+)-THP was obtained. The optical purity was 96.1%. 
EXAMPLE 4 
A solution of 17.15 g (50 mmol) of THP in 55 ml of toluene at 60.degree. C. 
was stirred with a solution of 5.88 g (25 mmol) of 
D-2,4-dichlorophenoxypropionic acid in 55 ml of toluene at 60.degree. C. 
and induced to crystallize. The crystals were filtered off with suction 
and thoroughly washed with toluene and then dried. 
The crystals were worked up to (+)-THP as in Example 1. The yield was 8.6 g 
(98.3%), and the optical purity of the (+)-THP was 98.7%. 
EXAMPLE 5 
8.25 g (50 mmol) of D,L-ephedrine and 5.88 g (25 mmol) of 
D-2,4-dichlorophenoxypropionic acid were taken up in 100 ml of toluene. 
Heating to reflux was followed by slow cooling, and the crystals were 
filtered off with suction and washed with toluene. Drying resulted in 4.2 
g (42%) of ephedrine salt. Liberation of the base as in Example 1 and 
conversion thereof into the hydrochloride resulted in L-ephedrine 
hydrochloride in an overall yield of 40%, [.alpha.].sub.D.sup.20 : 
-33.7.degree..