CA2045971A1

CA2045971A1 - Optically active .alpha.-fluoroacrylamides

Info

Publication number: CA2045971A1
Application number: CA002045971A
Authority: CA
Inventors: Rolf Grosser; Walter Lange; Bruno Bomer; Dieter Arlt; Karl-Rudolf Gassen
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 1990-07-03
Filing date: 1991-06-26
Publication date: 1992-01-04
Also published as: JPH04230349A; DE4021106A1; EP0464487A1

Abstract

Optically active .alpha.-fluoroacrylamides Abstract Optically active .alpha.-fluoroacrylamides of the formula in which R1 represents aryl or cycloalkyl which is optionally substituted R2 represents substituted or unsubstituted alkyl or cycyloalkyl, or R1 and R2 together represent a cyclic radical.

Le A 27 661

Description

2 ~

The invention relates to novel optically active ~-fluoro-acrylamides, to a process for their preparation, their polymerisation to give optically active polymers and to the use of these optically active polymers as adsorbents for the chromatographic resolution of racemates into their enantiomers.

In recent years, the resolution of racemates of active compounds has become increasingly important, since it has been shown that the enantiomers of the racemate of an active compound often differ in their biological effects and side effects.

Apart from the classic methods for the resolution of racemates, chromatographic resolution of racemates has proved particularly suitable in recent times. Apart from natural product derivatives, for example based on cel-lulose, synthetic optically active poly(meth)acrylamides have increasingly been u~ed as adsorbents (cf.
G. Blaschke, Chromatogr. Sci. 1988, 40, 179 to 198).

However, when applying the known methods, it was found that they either have an inadequate effect or only have an efficiency which is limited to certain racemates.
-Surprisingly, it has now been found that polymers made ofoptically active ~-fluoroacrylamides are adsorbents with very good racemate-resolving properties.

Le A 27 661 - 1 -q Surprisingly, the substitution of the hydroqen atom or the methyl group in the (meth)acrylamides by the strongly electronegative fluorine atom does not lead to a loss in separation efficiency, as would be expected owing to the opposite electronic effect and the vicinity of the fluorine atom to the amide group, which, as is known, has to interact with the enantiomers of the racemate to be resolved via hydrogen bridges.

It has been found that the ~-fluoroacrylamide polymers according to the invention have good separation efficiencies for many racemates of active compounds from a wide range of classes of substances despite the drastically modified steric and electronic environment of the amide group relevant for the resolution, thus significantly improving in many cases especially the separation selectivity for a number of racemates which are resolved by the corresponding (meth)acrylamide derivatives in an unsatisfactory manner.

This is surprising, since the other expected effect caused by the fluorine atom, i.e. to obtain a more lipophilic non-polar polymer, is certainly observed. The monomers, too, are much more non-polar and have better solubility in solvents, such as petroleum ether and toluene, than the corresponding (meth)acrylamides.

The invention relatQs to optically active ~-fluoro-acrylamides of the formula (I) Le A 27 661 - 2 -.

O ~ 1 F~ C NH CH R2 CH2 (I) in which Rl represents a phenyl, naphthyl, pyridyl or C3-C10-cycloalkyl radical which is unsubstituted or sub-stituted by halogen, C1-C4-alkoxy, NR3CoR4, dioxyalkylene having 1 to 2 C atoms, alkyl or cycloalkyl each having up to 10 C atoms, in which R3 represents hydrogen or Cl-C4-alkyl and R4 represents alkyl or alkoxy each having 1 to 6 1 0 C atoms, phenyl or benzoxy , R2 represents alkyl or cycloalkyl each having up to 8 C atoms, which may be unsubstituted or substituted by halogen or by C1-C~-alkoxy, or R1 and R2 together represent a cyclic radical from the group compris ing terpenyl, 8-alkyl ( C~-C~ ) -menthyl, - 8-aryl(C~-C10)-menthyl, tetrahydropyryl, 2,2-dialkyl(C1-C~)-4-aryl(C5-C10)-l, 3-dioxan-5-yl, 2, 2-dialkyl ( C1-C~ ) -4 -cycloalkyl ( C3-C~ 3-dioxan-5-yl, spirocycloalkyl(C3-Ca)-4-aryl (C6-C10)-Le A 27 661 - 3 -- .

1,3-dioxan-5-yl, spirocycloalkyl( C3-C8 ) - 4-cyclo-alkyl( C3-c8) -1, 3-dioxan-5-yl,Cl-C4-alkyl-substituted C3-C8-cycloalkyl radical.

Compounds of the general formula (I) in which Rl represents naphthyl, pyridyl or phenyl, each of which is unsubstituted or mono- or disubstituted by identical or different substituents from the group comprising fluorine, chlorine, alkyl of 1 to 4 C
atoms, alkoxy of 1 to 4 C atoms, cycloalkyl of 3 to 6 C atoms, methylenedioxy, ethylenedioxy, acetamido, benzamido, carbomethoxyamino, carboethoxyamino, carbobenzoxyamino or represents a cycl o-alkyl radical of 3 to 7 C atoms or a decahydro-naphthyl radical, R2 represents alkyl or cycloalkyl each having up to 8 C atoms, in which the alkyl radical is unsubstituted or substituted by fluorine, chlorine or alkoxy of 1 to 2 C atoms, or Rl and R2 together represent a radical from the group comprising menthyl, neomenthyl, isomenthyl, neoiso-- menthyl, carvomenthyl, bornyl, fenchyl, pinanyl, isopinocampheyl, 8-methylmenthyl, 8-ethylmenthyl, 8-n-propylmenthyl, 8-i-propylmenthyl, 8-n-butyl-menthyl, 8-i-butylmenthyl, 8-s-butylmenthyl, Le A 27 661 - 4 -8-t-butylmenthyl, 8-phenylmenthyl, 8-naphthyl-menthyl, tetrahydropyryl, 2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl, 2,2-dimethyl-4-naphthyl-1,3 dioxan-5-yl, 2,2-diethyl-4-phenyl-1,3-dioxan-5-yl, 2,2-diethyl-4-naphthyl-1,3-dioxan-5-yl, 2,2-di-propyl-4-phenyl-1,3-dioxan-5-yl, 2,2-dipropyl-4-naphthyl-1,3-dioxan-5-yl, 2,2-dibutyl-4-phenyl-1,3-dioxan-5-yl, 2,2-dibutyl-4-naphthyl-1,3-dioxan-5-yl analogously with 2,2-dibutyl-4-cyclohexyl-1,3-dioxan-5-yl, spirocyclopentyl-4,2'-4-phenyl-1,3-dioxan-5-yl, spirocyclopentyl-4,2'-4-naphthyl-1,3-dioxan-5-yl, spirocyclopentyl-4,2'-4-cyclohexyl-1,3-dioxan-5-yl, spirocyclohexyl-5,2'-4-phenyl-1,3-dioxan-5-yl, spirocyclohexyl-5,2'-4-naphthyl-1,3-dioxan-5-yl, spirocyclohexyl-5,2'-4-cyclohexyl-1,3-dioxan-5-yl, 2-methylcyclopentyl, 2-ethylcyclo-pentyl, 2-propylcyclopentyl, 2-i-propylcyclopentyl, 2-n-butylcyclopentyl, 2-i-butylcyclopentyl, 2-s-butylcyclopentyl, 2-t-butylcyclopentyl, 2-methyl-cyclohexyl, 2-ethylcyclohexyl, 2-propylcyclohexyl, 2-i-propylcyclohexyl, 2-n-butylcyclohexyl, 2-i-butylcyclohexyl, 2-s-butylcyclohexyl, 2-t-butyl-cyclohexyl are of particular interest.

Compounds of the general formula (I) in which R1 represents phenyl which i~ unsubstituted or mono-substituted by fluorine, chlorins, methyl, methoxy, nitro, acetamido, benzamido, carbomethoxyamino, Le A 27 661 - 5 -~ ~? ' '~

carboethoxyamino, ethyl, propyl or butyl or represents 1-naphthyl, 2-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, decahydronaphthyl or cyclo-alkyl of 3 to 6 C atoms, R2 represents alkyl of 1 to 4 C atoms, which is un-substituted or substituted by fluorine, chlorine, methoxy or ethoxy, or represents cyclopentyl or cyclohexyl, or Rl and R2 together represent a radical from the group comprising menthyl, neomenthyl, isomenthyl, neoiso-menthyl, carvomenthyl, bornyl, fenchyl, pinanyl, isopinocampheyl, 8-methylmenthyl, 8-phenylmenthyl, tetrahydropyryl, 2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl, 2,2-diethyl-4-phenyl-1,3-dioxan-5-yl, 2,2-diethyl-4-phenyl-1,3-dioxan-5-yl, 2,2-dipropyl-4-phenyl-1,3-dioxan-5-yl, 2,2-dibutyl-4-phenyl-1,3-dioxan-5-yl, 2,2-dimethyl-4-cyclohexyl-1,3-dioxan-5-yl, 2,2-diethyl-4-cyclohexyl-1,3-dioxan-5-yl, 2,2-dipropyl-4-cyclohexyl-1,3-dioxan-5-yl, 2,2-dibutyl-4-cyclohexyl-1,3-dioxan-5-yl, spirocyclopentyl-4,2'-4-phenyl-1,3-dioxan-5-yl, spirocyclopentyl-4,2'-4-cyclohexyl-1,3-dioxan-5-yl, spirocyclohexyl-5,2'-4-phenyl-1,3-dioxan-5-yl, spirocyclohexyl-5,2'-4-cyclohexyl-- 1,3-dioxan-5-yl,2-methylcyclopentyl,2-methylcyclo-hexyl are of very particular interest.

Le A 27 661 - 6 -Very particularly preferred optically active ~-fluoro-acryloylamides, according to the invention, of the formula (I) are 1-phenylethyl-, l-phenylpropyl-, 1-(l-naphthyl)-ethyl-, 1-(2-naphthyl)-ethyl-, 1-cyclohexylethyl, menthyl-, carvomenthyl-, fenchyl-, 2,2-dimethyl-4-phenyl-1,3-dioxan-5- and 2,2-dimethyl-4-cyclohexyl-1,3-dioxan-5~-fluoroacryloylamides.

The optically active ~-fluoroacrylic acid derivatives, according to the invention, of the formula (I). are obtained A) by reaction of optically active amines of the formula (II) Rl1 (II) HzN~ H R2 in which Rl and R2 are as defined under formula (I), or their acid addition products with fluoroacrylic acid derivatives of the formula (III) Le A 27 661 - 7 --F (III

in which Y represents fluorine, chlorine or bromine, if appropriate in the presence of an acid-binding agent in inert organic solvents, or B) by reaction of compounds of the formula (II) with a fluorine compound of the formula A Z O

CH---C C Y (IV) F

in which Y has the abovementioned meaning and A and Z each represent hydrogen, fluorine, chlorine or bromine, in which A and Z never simultane-ously denote hydrogen, 15 80 that the fluoroacryloyl compound (III) can be liberated by elimination of AZ, Le A 27 661 - 8 -where AZ is preferably HF, HCl, HBr, Br2 or Clz.

~-Fluoroacrylic acid derivatives of the formula ~III) or precursors thereof (IV) can be prepared by processes known per se [Zh. Org. Xhim. 28, 1173 (1983)] and can, if desired, also be used in the form of acid anhydrides.

The optically active amines of the formula (II) used as starting compounds are known or can be prepared by processes known per se (see Tetrahedron Lett. 1989, 317).

Suitable acid addition compounds of the amines to be used as starting compounds are salts of these amines with inorganic or organic acids. Mineral acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid or organic acids, such as acetic acid, methane-, ethane-, benzene- or toluenesulphonic acid, are preferred.

Suitable solvents are all organic solvents which are inert under the reaction conditions. Hydrocarbons, such as benzene, toluene, xylene, or petroleum fractions, or halogenated hydrocarbons, such as di-, tri- or tetra-chloromethane, dichloroethane or trichloroethylene, orethers, such as tert.-butyl methyl ether or tert.-amyl ethyl ether, are preferred.

Su$table acid-binding agents are in particular the cu~tomary inorganic or organic bases; alkali metal hydroxides or alkaline earth metal hydroxides, such as Le A 27 661 - 9 -,' ` , ,~ 'J .~- ' sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide or barium hydroxide, alkali metal carbonates or alkaline earth metal carbonates, such as sodium carbonate or potassium carbonate or sodium hydrogen-5 carbonate, alkali metal alcoholates, such as sodiummethoxide, sodium ethoxide, potassium methoxide, potas-sium ethoxide, potassium t-butoxide, or amines, such as triethylamine or pyridine, are preferably used.

The reaction of the ~-fluoroacrylic acid derivatives of the formula (III) with the amine derivatives of the formula (II) is preferably carried out at temperatures of -78 to +lOO~C, in particular -20C to +60DC.

The invention also relates to the optically active polymers and copolymers obtainable by polymerisation or 15 copolymerisation of the optically active ~-fluoroacrylic acid derivatives of the formula (I) and containing at least 40 mol~, preferably at least 50 mol~, of structural units of the formula (V) ~ F ~

O~C~ (V) Nl IH-R2 H R
in which Rl and R2 are as defined under formula (I).

The optically active polymer~, according to the Le A 27 661 - 10 -invention, of the formula (V) are preferably present in the form of crosslinked insoluble or swellable bead polymers or in a form in which they are bound to finely divided inorganic support materials such as, for example, silica gel. They can also be prepared as linear polymers soluble in suitable organic solvents. It is furthermore possible to copolymerise different ~-fluoroacrylic acid derivatives, according to the invention, of the formula (I) and to incorporate 0.1 to 60, preferably 0.1 to 20, mol%, of other copolymerisable monomers in the polymer.

The crosslinked polymers are preferably present in the form of small particles (beads) having a particle diameter of S to 200 ~m. They are prepared, for example, by suspension polymerisation of the optically active ~-fluoroacrylic acid derivatives of the formula (I) with 0.5 to 50 mol%, preferably 1 to 30 mol%, particularly preferably 3 to 20 mol% (relative to the total amount [mol] of the monomers used)~ of a suitable crosslinking agent in a manner known per se.

The degree of swelling of the (bead) polymers can be ad~usted by conventional methods via the type and amount of the crosslinking agents.

In practical use, (bead) polymers having a degree of ~ swelling (Q) of 1.1 to 10, preferably 2.0 to 7.0, have proved suitable.

The degree of swelling Q is determined as follows:

Le A 27 661 - 11 -`
.
~ .

polymer volume (swollen) polymer volume tunswollen) Suitable crosslinking agents are compounds containing at least two polymerisable vinyl groups. Preferred cross-linking agents are alkanediol diacrylates, such as 1,6-hexanediol diacrylate, 1,4-butanediol diacrylate, 1,3-propanediol diacrylate or 1,2-ethylene glycol diacrylate, or alkanediol methacrylates, such as 1,4-butanediol dimethacrylate, 1,3-propanediol dimeth-acrylate or 1,2-ethylene glycol dimethacrylate, aromatic divinyl compounds, such as, for example, divinylbenzene, divinylchlorobenzene or divinyltoluene, vinyl dicarboxy-lates, such as divinyl adipate, divinyl benzenedicar-boxylate, divinyl terephthalate, N,N'-alkylenediacryl-amides, such as N,N'-~ethylenediacrylamide, N,N'-ethylenediacrylamide, N,N'-methylenedimethacrylamide or N,N'-ethylenedimethacrylamide.

Suitable free-radical formers are the conventional free-radical formers. Peroxides, such as, for example,dibenzoyl peroxide, dilauroyl peroxide or di-ortho-tolyl peroxide, or azo compounds, such as, for example, azobisisobutyronitrile (AIBN) are preferred. Mixtures of various free-radical formers can also be used.
-The polymeri~ation components are dissolved in an organicsolvent which is not miscible with water, preferably an aliphatic or aromatic hydrocarbon, such as hexane, Le A 27 661 - 12 -heptane, isododecane, benzene or toluene, a halogenated hydrocarbon, such as di-, tri-, tetrachloromethane or 1,2-dichloroethane or an ester, such as ethyl acetate or butyl acetate.

The organic phase is evenly distributed in the aqueous solution of a protective colloid, preferably in an aqueous solution of polyvinyl alcohol, polyvinyl-pyrrolidone or a copolymer consisting of methacrylic acid and methyl methacrylate, by means of an efficient stirrer. About 1 to 20, preferably 2 to 10, parts by weight of aqueous phase are used per part by weight of organic phase. The polymerisation mixture is heated in an inert gas atmosphere, preferably under nitrogen, to temperatures of 30C to 100C, preferably 40C to 80C, with stirring. The polymerisation time is 2 to 24, preferably 4 to 12, hours. The copolymer obtained in this manner is separated from the liquid phase by filtration, purified by thorough washing with water and with organic solvents, such as methanol, ethanol, benzene, toluene, di-, trichloromethane or acetone, and then dried.

In particular for analytical applications, the optically active polymers according to the invention are preferably used in a form in which they are bound to finely divided inorganic supports. The preparation of optically active 2S -chromatographic phases of this type can be carried out, for example, by the processes described in DE-A-3,706,890.

Le A 27 661 - 13 -~ r ~,, f't ~ L
Preference is given to the polymerisation of the opti-cally active ~-fluoroacrylic acid derivatives of the formula (I) in the presence of silica gel/diol phases esterified with (meth)acrylic acid. This polymerisation can be carried out in the absence of solvents or in the presence of solvents or precipitants for poly-~-fluoro-acrylamides. The free-radical formers used for the preparation of the bead polymers can also be used as initiators.

The polymer-modified silica gels preferably contain 1 to 40~ by weight, in particular 5 to 30% by weight, of optically active polymer (V), relative to the total weight. They are thoroughly washed with solvents for the polymer and dried in vacuo.

It is of course also possible here to use mixtures of two or more of the ~-fluoroacrylic acid derivatives according to the invention, if appropriate also together with further copolymerisable monomers.

The invention furthermore relates to the use of the polymers according to the invention as such or in cross-linked or silica gel-bound form for the chromatographic resolution of racemic mixtures into the optical anti-podes. Examples of readily resolvable racemates are -oxazepam, binaphthol, 1,1'-binaphthyl-2,2'-dicarboxylic acid, thalidomide, chloromezanone, hexahydrocarbazole derivatives, such a~, for example, 3-r-~benzenesul-phonamido)-9-(2-carboxyethyl)-1,2,3,4,4a,9a-hexahydro-Le A 27 661 - 14 -carbazole and dihydropyridines, such as, for example, 5-monoethyl 1,4-dihydro-2,6-dimethyl-4-~2-trifluoro-methylphenyl)-pyridine-3~5-dicarboxylate.

The composition of the eluent can be selected in the usual manner and optimised, depending on the type and the property of the racemate to be resolved. The poly-~-fluoroacrylic acid derivatives according to the inven-tion which are bound to silica gel can be used for chromatographic resolutions of racemates under HPLC
conditions.

The capacity of the polymers for the resolution of racemates is expressed in terms of the capacity ratios (k'l~2) values) for the two enantiomers (1) and (2) and the resulting enantioselectivity value ~. These chromato-graphic parameters are defined as follows:

Capacity ratio k1~2) = t1~2) - tc to Enantioselectivity ~ = k 2 k' to = dead time of the column t1~2) = retention time of the first eluted enantiomer 1 or of the subse~uently eluted enantiomer 2 -The preparative resolution of racemic mixtures into their optical antipode8 using the polymers according to the invention is preferably carried out by column Le A 27 661 - 15 -chromatography. This is particularly advantageously done by carrying out the chromatographic separation using bead polymers of a definite particle size distribution; good separation efficiencies are obta:ined with bead polymers of a particle size distribution of 5 to 200 ~m, preferably 15 to 100 ~m.

The operating procedure of separation by column chromato-graphy is known. Usually, the polymer is suspended in the eluent, and the suspension is poured into a glass column.
After the eluent has been drained, the racemate to be resolved is applied to the column as a solution in a minimal amount of eluent. It is then eluted using the eluent, and the enantiomers in the eluate are detected by photometry and/or polarimetry by means of suitable flow cells.

The eluents used are conventional organic solvents or solvent mixtures which swell the polymer used as the adsorbent and dissolve the racemate to be resolved.
Examples are: hydrocarbons, such as benzene, toluene or xylene, ethers, such as diethyl ether, dioxane or tetra-hydrofuran, halogenated hydrocarbons, such as di- or trichloromethane, acetone, acetonitrile or ethyl acetate, alcohols, such as methanol, ethanol, n-propanol, isopropanol or n-butanol, or else mixtures of the sol--vents mentioned. N~xtures of toluene with tetra-hydrofuran, dioxane or isopropanol have proved particu-larly suitable.

Le A 27 661 - 16 -Examples 1. PreParation of Q-fluoroacrylamides ~monomers) 1.1 N-fluoroacryloyl-S-l -phenethyl ami ne A solution of 20.8 g (0.22 mol) of ~-fluoroacryloyl chloride in 20 ml of anhydrous dichloromethane was added dropwise at -lO~C to a solution of 26.6 g (0.22 mol) of (S)-phenethylamine and 22.2 g (0.22 mol) of triethylamine in 400 ml of anhydrous dichloromethane. Stirring was continued for 2 hours without a cooling bath, the mixture was first washed with water and then with 1 N HCl (2 x), and the organic extract was dried over magnesium sulphate.
After evaporation of the solvent, 41.8 g of solid having a melting point of 87C were obtained.
Recrystallisation from petroleum ether/toluene 2:1 gave 29.7 g (70% of theory) of pure fluoroacrylamide of melting point 93C.
Rotation tc = 1, CHC13) -175.7 1.2 N-fluoroacryloyl-(S)-cyclohexylethylamine Analogously, 38.6 g of crude product were obtained from 26.16 g (0.206 mol) of (S)-cyclohexylethyl-amine. Crystallisation from petroleum ether~toluene 15:1 gave 23 g (58% of theory) of fluoroacrylamide of melting point 86C.
~ Rotation (c = 1, CHCl3) -37.9 1.3 N-fluoroacryloyl-d-menthylamine By using 31 g (0.2 mol) of d-menthylamine, 37.5 g of Le A 27 661 - 17 -crude product were isolated and purified by chroma-tography on silica gel using ether/petroleum ether 1:2.
Yield: 24 g (52%), m.p.: 36C
S Rotation (c = 1, CHCl3) +48.6 1.4 (4S,5S)-5-N-fluoroacryloylamino-2,2-dimethyl-4-phenyl-1,3-dioxane If the reaction is carried out using 41 g (0.2 mol) of (4S,5S)-5-amino-2,2-dimethyl-4-phenyl-1,3-dioxane, 51 g of crude product are obtained.
Purification on silica gel using ether/petroleum ether 7:2 gave 29.4 g of fluoroacrylamide of melting point 94~C.
Rotation (c = 1, CHCl3) +30.5 2. Polymerisation of the ~-fluoroacrylamides 2.1 Preparation in the silica gel-bound form a) 25 g of silica gel modified with 1,2-diol groups (average particle size: 5 ~m, analytical results C:
7.7%, H: 1.5%) are suspended in 500 ml of dioxane with the exclusion of moisture and under nitrogen.
16 ml of methacrylic anhydride and 12.5 ml of triethylamine are added to the suspension. The mixture is stirred At room temperature for 1 hour and stored at room temperature for 24 hours. The silica gel is then filtered off with suction through a sintered glas~ crucible (G4), stirred 3 x with 500 ml each of dioxane for 30 minuteQ, and sucked Le A 27 661 - 18 -~"^~ ~ ' i'' '" '~
thoroughly dry in between. The silica gel modified with methacryloyl groups is dried at room tempera-ture in a vacuum at <0.005 atm.

Yield 24.8 g Elemental analysis: C 9.2%; H 1.7~

b) 3 g of the silica gel modified with methacryloyl groups, the preparation of which is described under a), 6.0 g of optically active N-~-fluoroacryloyl-amine and 60 mg of azobisisobutyronitrile are dissolved or suspended in 25 ml of dry toluene in a 100 ml round-bottom flask equipped with reflux condenser and magnetic stirrer. The apparatus is freed from air by evacuating it and filling it with nitrogen three times, and then filled with nitrogen.
The polymerisation mixture is stirred at room temperature for 1 hour and then rapidly heated to 80C. After stirring at 80C for 45 minutes, 200 mg of 2,6-di-tert.-butyl-4-methylphenol are added, and the reaction mixture is rapidly cooled. The silica gel is filtered off with suction through a sintered glass crucible (G4), washed with toluene and stirred twice with 50 ml each of chloroform, once with 50 ml of toluene and once with 50 ml of isopropanol for 30 minutes each and filtered off with suction in between. The 8ilica gel is finally dried at room temperature in vacuo at ~0.005 atm. In Table 1 below, the N-~-fluoroacryloylamine~ polymerised onto the modified silica gel, the yields of silica gel Le A 27 661 - 19 -L ~ ` ' ', ' ! :., ', .
containing optically active compounds, its nitrogen content and its bound polymer content are sum-marised.

Le A 27 661 - 20 -d ~ , s-~ ,i ~ --o ~
s~ ~

~ ~ ~ o~ -~ ~ o ~ ~ I` t` ~ ~
m o ~ ~

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, .al ~ . u~
~ X o . . ..
E~ ~ Z ~ ~ ~ ~

Le A 27 661 - 21 -,`, ,, ~ . :,1 3. Preparation in the form of bead polymers solution of 13.5 g of optically active N--fluoro-acryloylamine, 1.5 g of ethylene glycol dimethacrylate and 0.3 g of azobisisobutyronitrile in 37.5 g of tri-chloromethane is dispersed in a solution of 3 g ofpolyvinyl alcohol in 130 ml of deionised water, with stirring (350 to 500 rpm). The apparatus is evacuated several times and filled with nitrogen. The polymeri-sation mixture is stirred first at room temperature for 30 minutes under nitrogen and then at 55C (internal temperature) for 16 hours. The polymerisation mixture is then stirred into 2 to 3 1 of water, and the li~uid phase i8 decanted, after the bead polymer has settled. The bead polymer is freed from the fines (polymer having a par-ticle size of <10 ~m) by suspending it in water anddecanting the li~uid phase 3 to 4 times, and, after thorough washing with acetone, dried to constant weight at 60C.

In Table 2 below, the N-~-fluoroacryloylamines used for the polymerisation, the stirring rate at which the polymerisation was carried out, the yields in which the polymers were obtained, the particle size thereof and the volume of the bead polymers obtained in a dry (Vu,) and swollen (V,) state (swell~ng agent: toluene - T or toluene/THF ~ 3s2 v/v mixture ~ T/T) are summarised.

Le A 27 561 - 22 -u~ ~ E~

o co u~ co ~1 o, ~ u~ ~ .

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LeA 27 661 - 23 -.- ,: .
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Use of the optically active polymers of ~-fluoroacrylic acid derivatives as adsorbents for the resolution of racemates The following test racemates were used for the chromato-graphic resolutions:

Racemate No. 1: Oxazepam ,` Racemate No. 2: Binaphthol Racemate No. 3: Chlor~ ezanone Racemate No. 4: 1,1'-binaphthyl-2,2'-dicarboxylic acid Racemate No. 5: Ethyl 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-trifluoromethylphenyl)pyridine-3-carboxylate Racemate No. 6: 3-r-(4-fluorophenylsulphonamido)-9-(2-carboxyethyl)-1~2,3~4~4a~9a-hexahydro-carbazole The results obtained in the chromatographic resolution of the different test racemates 1 to 6 using the adsorbents according to the invention (enantioselectivity ~ and capacity ratio k~) and the eluents used are listed in the table below.

The silica gel-bound polymers were used in steel columns (inner diameter: 4 mm, length~ 25 cm). n-Heptane/tetra-hydrofuran mixtures~ a) 3:2 v/v; b) 1:1 v/v were used as eluents.

The surprising separation efficiency of the polymeric Le A 27 661 - 24 -fluoroacrylamides according to tlle invention becomes obvious by direct comparison with the corresponding polymeric (meth)acrylamides which have the same optically active radical.

The comparisons were carried out using the chiral poly-mers fixed on silica gel.

Thus, for example, the tranquilizer oxazepam (test racemate 1) can be resolved almost completely into the enantiomers on the polyfluoroacrylamide according to the invention of the optically active l-phenethylamine (adsorbent 5), while neither the polymeric acrylamide nor the methacrylamide of l-phenethylamine show separation efficiency.

In a different case, the above polyfluoroacrylamide (adsorbent 5) has separation efficiency for the throm-boxan antagonist 3-r-(benzenesulphonamido)-9-t2-carboxy-ethyl)-l~2r3~4~4a~9a-hexahydrocarbazole (test racemate 6), which i8 present as a racemate, while the correspon-ding polyacrylamide shows no separation whatsoever.

In a similar manner, the polyfluoroacrylamide according to the invention of the optically active l-cyclohexyl-ethylamine (adsorbent 6) resolves oxszepam (test racemate 1) almost completely into the enantiomer~, while the corresponding polymethacrylamide has only very poor ~epar~tion efficiency for the ox~zep~m racemate.

Le A 27 661 - 25 -' The polymeric fluoroacrylamide according to the invention of the optically active menthylamine (adsorbent 7) shows considerable separation efficiency for 6,6~-dimethyl-biphenyl-2,2~-dicarboxylic acid (test racemate 4), while S the corresponding polymeric methacrylamide has only low activation for this racemate (Example 4).

Le A 27 661 - 26 -Table 3 - Silica gel separation Adsorbent Test Enantioselec- Capacity accord. racemate tivity ~ ratio k~' to Ex.

1 1.21 2.59 b 2 1.11 4.95 a 6 1.15 1.88 b 6 1 1.17 2.39 b 7 1 1.25 3.00 a 4 1.23 1.59 a 1.12 0.92 a 8 3 1.10 2.36 a Le A 27 661 - 27 -'` ,

Claims

1. An optically active .alpha.-fluoroacrylamide of the formula (I) (I) in which R1 represents a phenyl, naphthyl, pyridyl or C3-C10-cycloalkyl radical which is unsubstituted or sub-stituted by halogen, C1-C4-alkoxy, NR3COR4, dioxyalkylene having 1 to 2 C atoms, alkyl or cycloalkyl each having up to 10 C atoms, in which R3 represents hydrogen or C1-C4-alkyl and R4 represents alkyl or alkoxy each having 1 to 6 C atoms, phenyl or benzoxy, R2 represents alkyl or cycloalkyl each having up to 8 C atoms, which may be unsubstituted or sub-stituted by halogen or by C1-C4-alkoxy, or R1 and R2 together represent a cyclic radical from the group comprising terpenyl, 8-alkyl(C1-C4)-Le A 27 661 - 28 -menthyl, 8-aryl(C6-C10)menthyl, tetrahydropyryl,

2,2-dialkyl(C1-C4)-4-aryl(C6-C10)-1,3-dioxan-5-yl, 2,2-dialkyl(C1-C4)-4-cycloalkyl(C3-C8)-1,3-dioxan-5-yl, spirocycloalkyl( C3-C8)-2'-4-aryl(C6-C10)-1,3-dioxan-5-yl, spirocycloalkyl(C3-C8)-2'-4-cycloalkyl(C3-C6)-1,3-dioxan-5-yl, C1-C4-alkyl-substituted C3-C6-cycloalkyl radical.

2. The compound according to Claim 1 in which R1 represents naphthyl, pyridyl or phenyl, each of which is unsubstituted or mono- or disubstituted by identical or different substituents from the group comprising fluorine, chlorine, alkyl of 1 to 4 C atoms, alkoxy of 1 to 4 C atoms, cyclo-alkyl of 3 to 6 C atoms, methylenedioxy, ethylenedioxy, acetamido, benzamido, carbo-methoxyamino, carboethoxyamino, carbobenzoxyamino or represents a cycloalkyl radical of

3 to 7 C atoms or a decahydronaphthyl radical, R2 represents alkyl or cycloalkyl each having up to 8 C atoms, in which the alkyl radical is unsub-stituted or substituted by fluorine, chlorine or alkoxy of 1 to 2 C atoms, or R1 and R2 together represent a radical from the group Le A 27 661 - 29 -comprising menthyl, neomenthyl, isomenthyl, neoisomenthyl, carvomenthyl, bornyl, fenchyl, pinanyl, isopinocampheyl, 8-methylmenthyl, 8-ethylmenthyl, 8-n-propylmenthyl, 8-i-propyl-menthyl, 8-n-butylmenthyl, 8-i-butylmenthyl, 8-s-butylmenthyl, 8-t-butylmenthyl, 8-phenylmenthyl, 8-naphthylmenthyl,tetrahydropyryl,2,2-dimethyl-

4-phenyl-1,3-dioxan-5-yl, 2,2-dimethyl-4-naphthyl-1,3-dioxan-5-yl, 2,2-diethyl-4-phenyl-1,3-dioxan-5-yl, 2,2-diethyl-4-naphthyl-1,3-dioxan-5-yl, 2,2-dipropyl-4-phenyl-1,3-dioxan-5-yl, 2,2-dipropyl-4-naphthyl-1,3-dioxan-5-yl, 2,2-dibutyl-4-phenyl-1,3-dioxan-

5-yl, 2,2-dibutyl-4-naphthyl-1,3-dioxan-5-yl analogously with 2,2-dibutyl-4-cyclohexyl-1,3-dioxan-S-yl, spirocyclopentyl-4,2'-4-phenyl-1,3-dioxan-5-yl, spirocyclopentyl-4,2'-4-naphthyl-1,3-dioxan-5-yl, spirocyclo-pentyl-4,2'-4-cyclohexyl-1,3-dioxan-5-yl, spiro-cyclohexyl-5,2'-4-phenyl-1,3-dioxan-5-yl, spiro-cyclohexyl-5,2'-4-naphthyl-1,3-dioxan-5-yl, spirocyclohexyl-5,2'-4-cyclohexyl-1,3-dioxan-5-yl, 2-methylcyclopentyl, 2-ethylcyclopentyl, 2-propylcyclopentyl, 2-i-propylcyclopentyl, 2-n-butylcyclopentyl, 2-i-butylcyclopentyl, 2-s-butylcyclopentyl,2-t-butylcyclopentyl,2-methyl-cyclohexyl, 2-ethylcyclohexyl, 2-propylcyclo-hexyl,2-i-propylcyclohexyl,2-n-butylcyclohexyl, 2-i-butylcyclohexyl, 2-s-butylcyclohexyl, 2-t-butylcyclohexyl.

Le A 2? 661 - 30 -3. The compound according to Claim 1, in which R1 represents phenyl which is unsubstituted or mono-substituted by fluorine, chlorine, methyl, methoxy, nitro, acetamido, benzamido, carbo-methoxyamino, carboethoxyamino, ethyl, propyl or butyl or represents 1-naphthyl, 2-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, decahydronaphthyl or cyclo-alkyl of 3 to 6 C atoms, R2 represents alkyl of 1 to 4 C atoms, which is unsubstituted or substituted by fluorine, chlo-rine, methoxy or ethoxy, or represents cyclo-pentyl or cyclohexyl, or R1 and R2 together represent a radical from the group comprising menthyl, neomenthyl, isomenthyl, neoisomenthyl, carvomenthyl, bornyl, fenchyl, pinanyl, isopinocampheyl, 8-methylmenthyl, 8-phenylmenthyl, tetrahydropyryl, 2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl, 2,2-diethyl-4-phenyl-1,3-dioxan-5-yl, 2,2-diethyl-4-phenyl-1,3-dioxan-5-yl, 2,2-dipropyl-4-phenyl-1,3-dioxan-5-yl, 2,2-dibutyl-4-phenyl-1,3-dioxan-5-yl, 2,2-dimethyl-4-cyclohexyl-1,3-dioxan-5-yl, 2,2-diethyl-4-cyclohexyl-1,3-dioxan-5-yl, 2,2-dipropyl-4-cyclohexyl-1,3-dioxan-5-yl, 2,2-dibutyl-4-cyclohexyl-1,3-dioxan-5-yl, Le A 27 661 - 31 -spirocyclopentyl-4,2'-4-phenyl-1,3-dioxan-5-yl, spirocyclopentyl-4,2'-4-cyclohexyl-1,3-dioxan-5-yl, spirocyclohexyl-5,2'-4-phenyl-1,3-dioxan-5-yl, spirocyclohexyl-5,2'-4-cyclohexyl-1,3-di-oxan-5-yl, 2-methylcyclopentyl, 2-methylcyclo-hexyl.

4. Process for the preparation of optically active .alpha.-fluoroacrylamides of the general formula (I) (I) in which R1 represents a phenyl, naphthyl, pyridyl or C3-C10-cycloalkyl radical which is unsubstituted or sub-stituted by halogen, nitro, C1-C4-alkoxy, NR3COR4, dioxyalkylene having 1 to 2 C atoms, alkyl or cycloalkyl each having up to 10 C atoms, in which R3 represents hydrogen or C1-C4-alkyl and R4 represents alkyl or alkoxy each having l to 6 C atoms, phenyl or benzoxy, R2 represents alkyl or cycloalkyl each having up to 8 C atoms, which may be unsubstituted or sub-stituted by halogen or by C1-C4-alkoxy, Le A 27 661 - 32 -or R1 and R2 together represent a cyclic radical from the group comprising terpenyl, 8-alkyl(C1-C4)-menthyl, 8-aryl(C6-C10)-menthyl, tetrahydropyryl, 2,2-dialkyl(C1-C4)-4-aryl(C6-C10)-1,3-dioxan-5-yl, 2,2-dialkyl(C1-C4)-4-cycloalkyl(C3-C8)-1,3-dioxan-5-yl, spirocycloalkyl(C3-Ca)-2'-4-aryl(C6-C10)-1,3-dioxan-5-yl, spirocycloalkyl(C3-C6)-2'-4-cycloalkyl(C3-C8)-1,3-dioxan-5-yl, C1-C4-alkyl-substituted C3-C8-cycloalkyl radical, characterised in that A) optically active amines of the formula (II) (II) in which R1 and R2 have the meaning given under the formula (I) or their acid addition products are reacted with fluoroacrylic acid derivatives of the formula (III) Le A 27 661 - 33 - (III) in which Y represents fluorine, chlorine or bromine, if appropriate in the presence of an acid-binding agent in inert organic solvents, or B) compounds of the formula (II) are reacted with a fluorine compound of the formula (IV) in which Y has the abovementioned meaning and A and Z each represent hydrogen, fluorine, chlorine or bromine, in which A and Z never simultaneously denote hydrogen, so that the fluoroacrylic acid compound (III) can be Le A 27 661 - 34 -liberated by elimination of AZ.

5. Optically active polymers containing at least 40 mol% of structural units of the formula (V) (V) in which R1 and R2 are as defined in Claim 1.

6. Optically active polymers according to Claim 5, characterised in that they are present in the form of crosslinked insoluble or swellable bead polymers or in a form in which they are bound to finely divided inorganic support materials.

7. Process for the preparation of crosslinked bead polymers according to Claim 6, characterised in that the .alpha.-fluoroacrylic acid derivatives of the general formula (I) are prepared in the presence of 0.5 to 50 mol% of a crosslinking agent by suspension poly-merisation, if appropriate in the presence of free-radical formers and inert organic solvents.

Le A 27 661 - 35 -

8. Process for the preparation of optically active polymers according to Claim 6, bound to inorganic support materials, characterised in that compounds of the general formula (I) according to Claim 1 are esterified in the presence of unsubstituted or (meth)acryloyl-substituted silica gel/diol phases, if appropriate in the presence of free-radical formers and if appropriate in the presence of inert organic solvents.

9. Use of polymers according to Claim 7 for the re-solution of optical isomers.

Le A 27 661 - 36 -