ITRM20000221A1 - NEW TETRAMIDIC MACROCYCLES, PROCEDURE FOR THEIR PREPARATION AND USE AS CHIRAL STATIONARY STAGE RECEPTORS. - Google Patents

Description

Description of the industrial invention entitled: "NEW TETRAMIDE MACROCYCLES, PROCEDURE FOR THEIR PREPARATION AND THEIR USE AS RECEPTORS IN CHIRAL STATIONARY PHASES"

DESCRIPTION

The present invention has as its main object new molecules which can be used as chiral receptors for the separation and purification of enantiomers, and in general stereoisomers, of organic and organometallic compounds, both at the analytical and preparatory level.

In particular, the main object of the present invention is a tetramide macrocycle with a molecule of formula (I)

m which

X is an alkyl, an aryl or a polymethylene fragment - (CH2) n- where n is an integer> 2;

Y is an allyloxy, alkoxy or arylmethoxy group; R is a hydrogen or an alkyl,

and its enantiomer.

Particularly interesting for its application versatility is the tetramide macrocycle in which X is phenyl, Y is allyloxy and R is hydrogen.

The invention also refers to a process for the preparation of the tetramide macrocycle as per claim 1 or 2, characterized in that a bifunctional chiral reagent with two amino groups of formula (II)

m which

X is an alkyl, an aryl or a polymethylene fragment - (CH2) n- where n is an integer> 2; And

R is a hydrogen or an alkyl,

with the activated form of an aromatic carboxylic diacid of formula (III)

in which

Y is an allyloxy, alkoxy or arylmethoxy group.

The bifunctional chiral reagent with two amino groups of formula (II) and the activated form of the aromatic carboxylic diacid of formula (III) can react in equimolar quantities.

The aprotic solvent can be selected from the group comprising tetrahydrofuran; dioxane; chloroform; N, N-dimethylformamide and their combinations.

The tertiary amine can be selected from the group comprising triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine and combinations thereof.

The activated form of the aromatic dicarboxylic diacid of formula (III) can be selected from the group comprising acid dichloride, pnitrophenyl ester, pentafluorophenyl ester and combinations thereof.

The reaction between the bifunctional chiral reagent with two amino groups of formula (II) and the activated form of the aromatic dicarboxylic diacid of formula (III) can be carried out at temperatures ranging from -10 ° C to 100 ° C, preferably -10 ° C and 25 ° C.

The use of the above mentioned tetramide macrocycles as chiral receptors for the separation and purification of enantiomers, and in general of stereoisomers, of organic and organometallic compounds both at the analytical and preparative level, is also an object of the invention. In these applications, the tetramide macrocycle can be in the form linked to an insoluble support or in a liquid / liquid biphasic system.

As is known, the classical methods of separation of enantiomers provide for the formation of diastereomeric derivatives by interactions with a chiral agent and subsequent separation of the diasterisomers by crystallization, distillation, extraction or chromatography. Recent technological developments have made it possible to tackle the problem in a more satisfactory way, exploiting the high efficiency of modern chromatographic techniques and the use of chiral stationary phases, in which an enantiomer of a chiral molecule (selector) is immobilized on an insoluble support. With this approach it is possible to separate, in a short time and in a reproducible way, both analytically (micrograms) and preparative (grams) the enantiomers of various compounds. The possibility of carrying out these separations is of considerable economic and practical importance, and has immediate repercussions in various fields of activity (academic and industrial) concerning the production of bioactive substances and of pharmaceutical interest.

The ability of a molecule (selector) to discriminate the two enantiomers of a second molecule is closely linked to some structural elements that are common to the most effective selectors known in literature: macrocyclic structure, conformational rigidity, presence of highly directional functional groups. Several molecular systems are known which possess these requisites and which show high enantioselectivity for a specific class of compounds. Highly enantioselective chiral macrocycles towards the enantiomers of amino acid derivatives of the R-CONH-CH (R) -CONHCH3 type were prepared starting from a trifunctional aromatic unit and three phenylalanine or tyrosine residues joined by amide bonds (Stili, W.C .; J . Am. Chem. Soc. 113, 1991, 5111). The enantioselectivity of this macrocycle, expressed as the difference in the energies of association with the two enantiomers (ΔΔG between 1 and 3 Kcal / mole) is close in entity to those typical of biological receptors. An analogue receptor prepared starting from two triarylbenzene units and three tyrosine residues connected by amide bonds shows high enantioselectivity (ΔΔG ~ 1 Kcal / mole) for the N-protected amino acid enantiomers (Diederich, F .; J. Chem. Soc. Perkin Trans. 2, 1997, 1891).

Although chiral selectors capable of effectively discriminating the enantiomers of specific classes of organic substances are known, in the state of the art, as has evolved, there are no compounds of practical utility which at the same time have receptor-type enantioselectivity (ΔΔG> 1 Kcal / mole) and are able to separate the enantiomers of compounds belonging to different classes.

The tetramide macrocycle according to the present invention, on the other hand, exhibits a molecular structure that possesses high enantioselectivities with a wide field of application and is of practical utility in the separation of enantiomers and stereoisomers and, in general, in the purification of organic and organometallic compounds.

Therefore, the present invention also relates to a process for the preparation of a chiral stationary phase, useful for the separation of organic and inorganic substances with chromatographic technologies, by means of immobilization of the tetramide macrocycle according to the invention on the surface of a solid support.

The solid support can be selected from the group comprising silica, microporous silica, functionalized polymeric resins such as polyacrylamide, polymethacrylate, polystyrene, polymeric materials such as carbohydrates, aluminates, silicates and their combinations.

In a preferred embodiment of the process for the preparation of a chiral stationary phase according to the present invention, the tetramide macrocycle, in which X is phenyl, Y is allyloxy and R is hydrogen, is immobilized on the 3-mercaptopropylsilanized silica surface by addition radical of the thiol groups to the double bonds of allyl fragments. The radical initiator can be selected from the group comprising α, α -azobisisobutyronitrile (AIBN), dibenzoyl peroxide and combinations thereof.

This chiral stationary phase, with the tetramide macrocycle according to the invention, in which X is phenyl, Y is allyloxy and R is hydrogen, immobilized on silica, is particularly effective and potentially useful in the development and production processes of chiral molecules for the following reasons:

- ease of preparation of the selector and derivatized silica,

- chemical, stereochemical and thermal stability, which make this molecule suitable for use with organic, aqueous solvents and supercritical fluids, containing acid and basic modifiers (CH3COOH, CF3COOH, Et3N) and in extreme temperature conditions (from -80 ° C to 100 ° C);

- high chromatographic efficiencies, due to the effective passivation of the silica surface, which make the chromatographic material suitable for the enantiomeric analysis of traces;

- wide field of application;

- unconventional enantioselectivity (a> 100) towards specific classes of compounds, with differences in elution times for the two enantiomers in the order of hours.

The silica containing the immobilized selector can be used as a packing for the preparation of chromatography columns suitable for high performance liquid chromatography (HPLC). Given the ease of synthesis of the chiral selector, it is possible to prepare relevant quantities (50-100g) of derivatized silica for preparative chromatographic applications, both in batch and S.M.B. (Simulated Moving Bed).

In a number of practical applications, the modified silica was packed by the slurry technique into steel columns (dimensions 1.8 x 250 and 4.0 x 250 mm) and used in the direct resolution of the enantiomers of a wide range of molecules at central, axial and planar chirality and characterized by the presence of various functional groups (alcohols, acids, amides, imides, sulfoxides, phosphinoxides, organometallics).

Finally, the chiral stationary phase which can be obtained with the process described above is also an object of the present invention.

Up to now, a general description of the present invention has been given. With the help of the following examples, a more detailed description of its specific embodiments will now be provided, aimed at better understanding the purposes, characteristics, advantages and methods of application of the invention.

EXAMPLE 1

PREPARATION OF THE TETRAMIDE MACROCYCLE OF THE INVENTION WHERE X IS PHENYL. Y IS ALLYLOX AND R IS HYDROGEN

Preparation of the dichloride of the aromatic carboxylic diacid of formula III with Y = allyloxy

5 mL of acetyl chloride are added to 100 mL of methanol, under magnetic stirring at a temperature of 0 ° C. At the end of the addition, the mixture is stirred for 10 minutes at 25 ° C and 5.0 g (27.45 mmoles) of 5-hydroxyisophthalic acid are added. The mixture is kept at the reflux temperature for 4 hours and, after cooling to room temperature, the solvent is removed under reduced pressure. 5.8 g (27.34 mmoles) of the methyl diester (5-hydroxy dimethylisophthalate) are obtained, recognizable by the following IR and NMR spectra:

IR (KBr): 3361, 1728, 1704, 1597, 1269, 1253, 760 cm-1

1H-NMR (CDC13): d 8.25 (t, 1H, J = 1.6 Hz), 7.75 (d, 2H, J = 1.6 Hz), 3.95 (s, 6H).

A suspension of potassium carbonate (5.5 g, 40.30 mmol) and 5-hydroxy dimethylisophthalate (5.7 g, 26.87 mmol) in 80 mL of N, N-dimethylformamide (DMF) is held under magnetic stirring at room temperature in an Argon atmosphere. After 30 minutes, 3.4 mL (40.30 mmoles) of allyl bromide are added and the mixture is kept under stirring for 12 hours. 60 mL of ethyl acetate are added to the reaction mixture and the solution is extracted with 3 portions (3 * 60 mL) of water. The organic solvent is separated, dehydrated with anhydrous sodium sulfate and removed under reduced pressure. Dimethyl-5-allyloxy-isophthalate is obtained, recognizable by the following IR and NMR spectra:

IR (KBr): 3025, 3018, 3000, 2951, 1737, 1720, 1597, 1269, 760 cm-1

H1-NMR (CDC13) d 8.20 (t, 1H, J = 1.4 Hz), 7.65 (d, 2H, J = 1.4 Hz), 6.05 (m, 1H), 5, 48 (m, 1H), 5.32 (m, 1H), 4.63 (τη, 2H).

A suspension of 0.3 g (1.31 mmol) of 5-allyloxyisophthalic acid, 2 mL of thionyl chloride and 2 mL of benzene are kept at reflux temperature for 4 hours. After cooling, the volatile components are removed by evaporation under reduced pressure and the residue, chloride of the 5-allyloxyisophthalic acid is used directly for the preparation of the tetramide macrocycle of interest.

Preparation of the tetramide macrocycle of title Ad a solution of (R, R) -1, 2-diphenylethylenediamin (0.28 g, 1.31 mmol) and diisopropylethylamine (0.36 mL, 2.6 mmol) in 300 mL of tetrahydrofuran (THF), 0.35 g (1.31 mmoles) of 5-allyloxyisophthalic acid chloride dissolved in 15 mL of THF are added at 0 ° C and under magnetic stirring. After one hour the mixture is brought to room temperature and kept under stirring for 12 hours. After evaporation of the solvent under reduced pressure, the residue is purified by high efficiency preparative chromatography (LiChroprep Si 60, 15-25 μιη, axial compression column 200 * 20 mm I.D., P = 12 Bar, eluent dichloromethane / methanol 97.5 / 2.5). 0.28 g of the Tetramide macrocycle of interest are obtained in which X is C6H5, Y is allyloxy and R is H (yield 56%). The tetramide macrocycle of interest is recognized by the following IR, NMR and MS spectra:

EXAMPLE 2

Immobilization of the tetramide macrocycle of the invention wherein, X is phenyl. 3L is allyloxy and R is hydrogen. on silica particles for chromatographic applications

A mixture of 5 μιη (2.7 g) of Hypersil silica and 100 mL of toluene is kept at the reflux temperature until all the water adsorbed on the silica is removed by azeotropic distillation. After cooling to room temperature, 12.2 ml (64.6 mmol) of 3-mercaptopropyltrimethoxysilane and 5.4 ml of 4-methylmorpholine are added. The mixture is kept at the reflux temperature for 8 hours. After cooling, the modified silica is isolated by filtration and washed in sequence with toluene, methanol, ethyl acetate and hexane (200 mL each) and dried under reduced pressure at 40 ° C.

Elemental analysis:% C, 4.43; % H, 0.92.

A mixture of 3-mercaptopropylsilanized silica (800 mg), of the tetramide macrocycle of Example 1 (114 mg, 0.14 mmol), α, α-bis-azobisisobutyronitrile (7 mg, 0.04 mmol) and dichloromethane (5 mL ) is heated to 50 ° C in a closed steel container and kept at this temperature, under stirring, for 72 hours.

After cooling to room temperature, the modified silica is isolated by filtration and washed in sequence with dichloromethane, methanol, ethyl acetate and hexane (200 mL each) and dried under reduced pressure at 40 ° C.

Elemental analysis:% C, 11.08; % H, 1.43; % N, 0.83

IR (KBr): 1653, 1595, 1531 cm-1.

In the first stage of the following reaction Scheme 1 the preparation of the tetramide macrocycle of Example 1 is shown, while in the second reaction stage the formation of the chiral stationary phase of Example 2 is shown with this macrocycle immobilized on silica particles.

EXAMPLE 3

Formulas of some chiral compounds whose enantiomers are separable with the chiral stationary phase of Example 2 *

* The meaning of the radical R is that indicated in this Example and must not be confused with that of the radical R of formulas I and II

EXAMPLE 4

Some chromatographic results obtained at the analytical level with the chiral stationary phase of Example 2 (column 4.0 x 250 mm)

The chromatographic data reported in the following Tables 1, 2, 3, 4 were obtained respectively with the eluents a, b, c, d, e, g whose meanings are the following

Eluent: a, CH2Cl2 / MeOH 99.5 / 0.5; b, hexane / 2propanol 90/10 0.1% CF3C00H;

C, hexane / 2 -propanol 95/5; d, hexane / 2-propanol 85/15.

g, hexane / 2-propanol 90/10; g CH2Cl2 / MeOH 90/10.

The meaning of R is that indicated for each Table and must not be confused with the meaning of the radical R in formulas I and II indicated in the description.

TABLE 1

TABLE 2

2. Chromatographic data

TABLE 3

Claims (18)

CLAIMS 1. Tetramide macrocycle with molecule of formula (I) in which X is an alkyl, an aryl or a polymethylene fragment - (CH2) n- where n is an integer> 2; Y is an allyloxy, alkoxy or arylmethoxy group; R is a hydrogen or an alkyl, and its enantiomer. 2. Tetramide macrocycle according to claim 1, wherein X is phenyl, Y is allyloxy and R is hydrogen. 3. Process for the preparation of the tetramide macrocycle as per claim 1 or 2, characterized in that a bifunctional chiral reagent with two amino groups of formula (II) reacts in an aprotic solvent in the presence of a tertiary amine m which X is an alkyl, an aryl or a polymethylene fragment - {CH2) n- where n is an integer> 2; And R is a hydrogen or an alkyl, with the activated form of an aromatic carboxylic diacid of formula (III) in which Y is an allyloxy, alkoxy or arylmethoxy group. 4. Process according to claim 3, in which the bifunctional chiral reagent with two amino groups of formula (II) and the activated form of the aromatic carboxylic diacid of formula (III) are reacted in equimolar quantities. 5. Process according to any one of claims 3 and 4, wherein the aprotic solvent is selected from the group comprising tetrahydrofuran; dioxane; chloroform; N, N-dimethylformamide and their combinations. A process as any of claims 3 to 5, wherein the tertiary amine is selected from the group comprising triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine and combinations thereof. 7. Process according to any one of claims 3 to 6, wherein the active form of the aromatic dicarboxylic diacid of formula (III) is selected from the group comprising dichloride acid, pnitrophenyl ester, pentafluorophenyl ester and their combinations. 8. Process according to any one of claims 3 to 7, in which the reaction between the bifunctional chiral reagent with two amino groups of formula (II) and the activated form of the aromatic dicarboxylic diacid of formula (III) is carried out at temperatures between -10 ° C and 100 ° C. 9. Process according to claim 8, in which the reaction between compound of formula (II) and compound of formula (III) takes place at temperatures in the range between -10 ° C and 25 ° C. 10. Use of tetramide macrocycles, as per claim 1 or 2, as chiral receptors for the separation and purification of enantiomers, and in general of stereoisomers, of organic and organometallic compounds, both at the analytical and preparative level. 11. Use according to claim 10, in which the tetramide macrocycle is in the form linked to an insoluble support. Use as per claim 10, wherein the tetramide macrocycle is in a liquid / liquid biphasic system. 13. Process for the preparation of a chiral stationary phase, useful for the separation of organic and inorganic substances with chromatographic technologies, by immobilizing a tetramide macrocycle as per claim 1 or 2 on the surface of a solid support. 14. Process for the preparation of a chiral stationary phase according to claim 13, in which the solid support is selected from the group comprising silica, microporous silica, functionalized polymeric resins such as polyacrylamide, polymethacrylate, polystyrene, polymeric materials such as carbohydrates, aluminates, silicates and their combinations. 15. Process for the preparation of a chiral stationary phase according to claim 13 or 14, in which the tetramide macrocycle of claim 2 is immobilized on the 3 -mercaptopropyl silanized silica surface by radical addition of the thiol groups to the double bonds of the allyl fragments. 16. Process for the preparation of a chiral stationary phase according to claim 15, in which the radical initiator is selected from the group comprising α, α1-azobis-isobutyronitrile (AIBN), dibenzoyl peroxide and their combinations. 17. Chiral stationary phase, characterized in that it can be obtained with the process of claims 13 to 16. 18. New tetramide macrocycles, process for their preparation, their use as receptors in chiral stationary phases and chiral stationary phases thus obtainable, as previously described, exemplified and claimed.