HK1014927B - Method of resolving racemic mixtures - Google Patents

Description

Resolution of racemates

The present invention relates to a novel process for the resolution of racemates.

The resolution of many racemates is known. Nevertheless, resolution of the racemate is problematic because the resolving agents are not stable enough to produce oily enantiomers which are difficult to separate and these agents can only be used in a complicated manner or do not react at all with the racemate. Therefore, it is very advantageous to find a resolving agent suitable for a racemate of a specific composition.

For example, tetrahydropapaverine is resolved into its enantiomers using N-acetylleucine. The resolution method comprises 3 steps:

a) the S enantiomer was precipitated with N-acetylleucine,

b) the crude (desired) R enantiomer is precipitated with N-acetylleucine and

c) the R enantiomer bound to N-acetylleucine was recrystallized.

A serious disadvantage of this process is that for N-acetylleucine, in practice only the natural optically active acid is available for resolution, and the initially occurring precipitate is the undesired S-diastereomeric salt of tetrahydropapaverine. The salt of the R enantiomer can only be precipitated from the mother liquor enriched in this enantiomer.

It is known that racemic 2-amino-1-butanol can be resolved into its enantiomers using (+) -2, 4-dichlorophenoxypropionic acid.

We have now found a simple method for resolving racemates.

The invention relates to a method for resolving racemates of compounds of formula I:

wherein the substituents have the following meanings:

a: 0 or 1

A：H、C_1-4Alkyl radical, C_1-4Alkoxy, halogen, nitro or amino,

B：H、C_1-4alkyl radical, C_1-4Alkoxy, halogen, nitro or amino,

D：H、C_1-4alkyl radical, C_1-4An alkoxy group or a halogen, or a salt thereof,

E：H，

F：H、C_1-4alkyl radical, C_2-4Alkenyl radical, C_1-4Alkynyl, or

E and F together are a group of formula III:

wherein

G: is H, C_1-4Alkyl radical, C_1-4Alkoxy, halogen, nitro or amino,

k: is H, C_1-4Alkyl radical, C_1-4Alkoxy, halogen, nitro or amino,

l: is H, C_1-4Alkyl radical, C_1-4An alkoxy group or a halogen, or a salt thereof,

M：H、C_1-4an alkyl group or a hydroxyl group, and a carboxyl group,

q: h or C_1-4An alkyl group, a carboxyl group,

R：H、C_1-4an alkyl group or a cyanomethyl group,

the resolution process is carried out in a manner known per se, using the optical enantiomer of the phenoxypropionic acid derivative of formula II:

wherein T, U and V have the following meanings:

T：H、C_1-4alkyl radical, C_1-4Alkoxy, halogen, nitro or cyano, or unsubstituted, substituted by C_1-4Alkyl radical, C_1-4Alkoxy or halogen mono-, di-or trisubstituted benzene rings,

U：H、C_1-4alkyl radical, C_1-4Alkoxy, halogen, nitro or cyano,

V：H、C_1-4alkyl radical, C_1-4Alkoxy or halogen.

Suitable and preferred meanings for the substituents in the compounds of the formula I are as follows:

a：1

a: h or a methoxy group, and the like,

b: h or a methoxy group, and the like,

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 a methoxy group, and the like,

q: the methyl group is a group selected from the group consisting of,

r: H. methyl or cyanomethyl.

Particularly suitable compounds of the formula I are deprenyl, ephedrine and, in particular, tetrahydropapaverine.

Suitable and preferred compounds of formula II are those in which T is in the ortho position and is H, fluorine, chlorine or methoxy, U is fluorine, chlorine or methoxy in the para position and V is H.

Particularly suitable compounds of formula II are (+) -or (-) -2- (2, 4-dichlorophenoxy) propionic acid.

Furthermore, the racemate resolution can be carried out at from 0 ℃ to the boiling point of the solvent used. Operation at room temperature is the simplest.

This resolution can be carried out in conventional solvents such as lower alcohols, acetone, toluene, xylene, ethers, tetrahydrofuran and ethyl acetate. Saturated solutions are generally used. Preferably isopropanol or toluene.

In aqueous solution at pH7.5-10, the salt obtained in the racemic resolution can be changed into base, and can be extracted with water-insoluble solvent, such as diethyl ether, toluene or xylene.

The new process differs in that the resolving agent is readily available and stable. In addition, they are highly selective and therefore provide high enantiomeric yields, while also being very pure.

The invention also relates to salts of selegiline, ephedrine and tetrahydropapaverine with phenoxypropionic acids of the formula:

wherein T is H, chloro or methoxy and U is methoxy or chloro. Of these, L-ephedrine D-2, 4-dichlorophenoxypropionate and in particular (+) -THP D-2, 4-dichlorophenoxypropionate are particularly notable.

Example 1

1.029g (3mmol) of THP (THP-tetrahydropapaverine-1- [ (3, 4-dimethoxyphenyl) methyl ] -6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline) was put in 2ml of isopropanol, to which a hot solution of 0.707(3mmol) of D-2, 4-dichlorophenoxypropionic acid in 8ml of isopropanol was added, and the mixture was refluxed briefly. After cooling to room temperature, the resulting crystals are filtered off with suction, washed with isopropanol and dried. 0.9g of a product consisting essentially of (+) -THP D-2, 4-dichlorophenoxypropionate is obtained.

The resulting product was dissolved in 5ml of water. The solution was adjusted to pH 8 and then extracted with toluene. After removal of toluene, 0.48g (93.3%) of (+) enantiomer having an optical purity of 95.6% was obtained.

Example 2

17.15g (50mmol) of THP and 5.85g (25mmol) of D-2, 4-dichloromethoxypropionic acid are heated with stirring in 80ml of isopropanol. A clear solution was obtained at 45 ℃. Seeds of the (+) isomer of this salt were added to the solution at 50 ℃. Then, it was stirred and cooled to room temperature over 2 hours. 40ml of isopropanol were added and diluted. The crystals which appear are filtered off with suction, washed with 30ml of isopropanol and dried. The salt obtained in the above manner was converted to THP as in example 1.

(+) -THP5.2g (61%) was obtained in an optical purity of 90.1%.

Example 3

1.715g (5mmol) of THP and 0.588g (2.5mmol) of D-2, 4-dichloromethoxypropionic acid were dissolved in 10ml of toluene at reflux temperature and then slowly cooled. The crystals obtained are filtered off with suction and dried. (+) -THP was isolated as in example 1 to yield (+) -THP 0.85g (98.8%). The optical purity was 96.1%.

Example 4

A solution of 17.15g (50mmol) of THP in 55ml of toluene at 60 ℃ and a solution of 5.88g (25mmol) of D-2, 4-dichlorophenoxypropionic acid in 55ml of toluene at 60 ℃ are mixed with stirring and crystallization is induced. The crystals were filtered off with suction and washed thoroughly with toluene and then dried.

The crystals were treated as in example 1 to yield (+) -THP. The yield was 8.6g (98.3%), (+) -THP had an optical purity of 98.7%.

Example 5

8.25g (50mmol) of D, L-ephedrine and 5.88g (25mmol) of D-2, 4-dichloromethoxypropionic acid were placed in 100ml of toluene. After heating and refluxing, it was slowly cooled, and the crystals were filtered off with suction and washed with toluene. After drying, 4.2g (42%) of ephedrine salt are obtained. The base was obtained and converted to the hydrochloride salt as in example 1 to give L-ephedrine hydrochloride in 40% overall yield, [ alpha ]]_D ²⁰：-33.7°。

Claims (4)

1. A process for resolving a racemate of a compound of formula I:

wherein the substituents have the following meanings:

a: h or C_1-4An alkoxy group,

b: h or C_1-4An alkoxy group,

E：H，

f: h, or

E and F together are a group of the formula III,

wherein

K is C_1-4An alkoxy group,

l is C_1-4An alkoxy group,

m: h or a hydroxyl group, or a salt thereof,

q: h or C_1-4An alkyl group, a carboxyl group,

r: h or C_1-4An alkyl group, a carboxyl group,

the resolution process is carried out in a manner known per se, in which resolution is carried out with (+) -or (-) -2- (2, 4-dichlorophenoxy) propionic acid.

2. The method of claim 1, wherein the compound of formula I is ephedrine or tetrahydropapaverine.

(+) -THP D-2, 4-dichlorophenoxypropionate.

L-ephedrine D-2, 4-dichlorophenoxypropionate.