阅读说明：本技术 对映体富集的方法 (Process for enantiomeric enrichment ) 是由 A·喀土泽安 U·黑兹 F·莫塔赫布 K·奥勃霍弗 J·里门斯伯格 H·伊格列夫 R·基 于 2019-07-17 设计创作，主要内容包括：根据本发明提供了对映体富集手性化合物的两种对映体的混合物的方法,方法包括将手性化合物的两种对映体的混合物施加至载体材料的表面上从而产生涂覆的载体,测定经涂覆的载体的第一旋光性值(OA-0),用具有强度至少高于对映体之一从经涂覆的载体的脱附阈值的光束照射该经涂覆的载体,其中如果载体材料是非手性的,则光束是圆偏振的,并且如果载体材料是手性的,则光束是非偏振的、线性偏振的或圆偏振的,和在所述照射之后测定经涂覆的载体的第二旋光性值(OA-e),其中该第二旋光性值(OA-e)不同于第一旋光性值(OA-0)。(According to the present invention there is provided a method of enantiomerically enriching a mixture of two enantiomers of a chiral compound, the method comprising applying the mixture of two enantiomers of the chiral compound to a surface of a support material thereby producing a coated support, determining a first optical rotation value (OA) of the coated support 0 ) Irradiating the coated support with a light beam having an intensity at least above the desorption threshold of one of the enantiomers from the coated support, wherein the light beam is circularly polarized if the support material is achiral and unpolarized, linearly polarized or circularly polarized if the support material is chiral, and determining a second optical rotation value (OA) of the coated support after said irradiation e ) Wherein the second optical rotation value (OA) e ) Is different from the first optical rotation (OA) 0 )。)

1. A process for the enantiomeric enrichment of a mixture (13) of two enantiomers (11R, 11S) of a chiral compound (11), which process comprises

Applying (21) a mixture (13) of two enantiomers (11R, 11S) of a chiral compound (11) onto the surface of a support material (15) to produce a coated support (17),

measuring (23) a first optical rotation value (OA) of the coated support (17)₀)，

Irradiating (25) the coated support (17) with a light beam having an intensity at least above a desorption threshold of one of the enantiomers (11R, 11S) from the coated support (17), wherein the light beam is circularly polarized if the support material (15) is achiral and is unpolarized, linearly polarized or circularly polarized if the support material (15) is chiral, and

determining (27) a second optical rotation value (OA) of the coated support (17) after said irradiating (25)_e) The second optical rotation value (OA)_e) Is different from the first optical rotation (OA)₀)。

2. The method of claim 1, further comprising repeating said irradiating (25) and said determining (25) so as to obtain a final optical rotation value (OA) of the coated support (17)_f) This value corresponds to a given value of optical activity.

3. The method according to claim 1 or 2, wherein the light beam has a wavelength which is resonance matched to the optical transition of the chiral compound (11) by single photons or by multiple photons.

4. The method according to any one of claims 1 to 3, wherein the irradiation (25) has a duration between 0.2ns and 1000 s.

5. The method according to any one of claims 1 to 4, wherein the irradiating (25) comprises irradiating the coated carrier (17) by one of a light emitting diode, a pulsed laser or a continuous wave laser.

6. The method according to any one of claims 1 to 5, wherein said determining (21, 25) comprises determining an optical rotation value by: circular dichroism, photochromic dispersion, second harmonic generation circular dichroism, or second harmonic generation optical rotation.

7. The method according to any one of claims 1 to 6, wherein the applying (21) comprises applying an enantiomeric mixture (13) of the two enantiomers (11R, 11S) by molecular evaporation, spin coating, dip coating or drop coating.

8. The method of any one of claims 1 to 7, wherein the chiral support material (15) belongs to the group of high Miller index surfaces of metals, wherein a high Miller index surface comprises (643) and (531) surfaces.

9. The process according to any one of claims 1 to 7, wherein the achiral support material belongs to the group of low Miller index surfaces of amorphous solids or metals, wherein a low Miller index surface comprises (100), (111) and (110) surfaces.

10. The method according to any one of claims 1 to 9, wherein the mixture (13) of the two enantiomers (11R, 11S) is provided in powder or liquid form.

Technical Field

The present invention relates to a process for enantiomeric enrichment and more particularly to a novel process for enantiomeric enrichment of a mixture of two enantiomers of a chiral compound using optical means.

Background

Enantiomers are molecules whose atoms are identical in composition and bonding, but differ in their 3D arrangement of atoms so as to be mirror images of each other. Usually the two enantiomers are referred to as the L-and D-enantiomers or the S-and R-enantiomers. The separation of enantiomers and the enrichment of their mixtures is rather challenging, since they have the same chemical properties except in a chiral environment and possess the same physical properties except in the case of interaction with polarized light.

The separation of enantiomers of chiral molecules is an important step in a number of disciplines such as the pharmaceutical industry, the cosmetic industry and biotechnology. The separation of enantiomers is of great interest especially for the pharmaceutical industry, since more than 50% of pharmaceutically active ingredients are chiral and nine of the top ten drugs sold worldwide have chiral active ingredients. Although they have the same chemical structure, the enantiomers of most chiral components exhibit significant differences in biological activity, e.g., in pharmacology, toxicology, pharmacokinetics, metabolism. Therefore, it is important in the pharmaceutical industry as well as in the clinic to promote enantiomeric enrichment of racemic drugs (having an equimolar mixture of two enantiomers) in order to reduce the amount of unwanted enantiomer in the mixture (i.e. enrich the mixture) or to completely eliminate the unwanted enantiomer from the mixture (i.e. separate the unwanted enantiomer). In addition, it is desirable to find the best treatment and correct control of therapy for the patient (Nguyen LA, He, Pham-Huy C. chiral Drugs: An Overview; International Journal of biological Science: IJBS.2006; 2(2): 85-100.).

A common method of enantiomeric enrichment of a mixture of two enantiomers of a chiral compound is the chemical conversion of the enantiomers into substances that can be separated by the formation of diastereomers. Unlike enantiomers, diastereomers have completely different physical properties (e.g., boiling point, melting point, NMR shift, solubility) such that they become separable by means conventionally used such as chromatography and crystallization. These methods are known from the prior art.

Another common method of separating enantiomeric mixtures without formation of diastereomers is to use chromatography on a chiral stationary phase that provides a chiral environment. In this case, the different interactions of the enantiomers with the column material lead to their separation.

U.S. patent publication No. 2008/0207944a1 discloses a method of separating compounds that form a chiral system. The method provides a hybrid process comprising a chromatography or enantioselective membrane enrichment step and a crystallization step using supramolecular complexes.

One of the drawbacks or limitations of the known separation methods is that these methods especially comprise interactions with and/or addition of extraneous compounds which have to be removed after enantiomeric enrichment of the mixture. For example, there is a need in the pharmaceutical industry to strictly avoid these extraneous compounds.

The underlying object of the present invention is to provide a process for enantiomerically enriched mixtures of two enantiomers by minimizing the use of foreign compounds (e.g. chemical reagents), which in turn leads to a reduced risk of contamination of the enantiomerically enriched mixture. This object is achieved by the method of claim 1.

Summary of The Invention

According to the present invention there is provided a process for the enantiomeric enrichment of a mixture of two enantiomers of a chiral compound using optical means, thereby minimizing the use of extraneous compounds. The method comprises the following steps: a) applying a mixture of two enantiomers of a chiral compound onto a surface of a support material to form a coated support; b) measuring a first optical rotation value (OA) of the coated support₀) (ii) a c) Irradiating the coated support by optical means with a light beam having an intensity at least above a desorption threshold of one of the enantiomers from the coated support, wherein the light beam is circularly polarized if the support material is achiral and unpolarized, linearly polarized, elliptically polarized or circularly polarized if the support material is chiral; and d) determining a second optical rotation value (OA) of the coated support after said irradiating_e) For determining the level of enantiomeric enrichment.

The term "optical activity value" as used herein refers to the anisotropy factor g or optical activity of the coated support. The anisotropy factor is generally determined by equation (1) and is expressed as follows:

wherein the parameter X_LCPAnd X_RCPRespectively, represent one of the light absorption, second harmonic generation and scattering cross-sections of the coated support upon interaction with left-hand circularly polarized (LCP) light and right-hand circularly polarized (RCP) light.

The optical rotation is defined as the angle between the plane of polarization of the linearly polarized light entering the coated support and the linearly polarized light exiting the coated support.

According to the method of the invention, the coated support is irradiated with a light beam having an intensity at least above the desorption threshold of one of the enantiomers from the coated support. As known to those skilled in the art, the desorption threshold of a compound from a surface is a property that depends on the interaction of the compound with the surface and the beam used for irradiation. The value of the desorption threshold varies for different combinations of compound, carrier material and light beam. Similarly, the desorption threshold of the chiral compound from the coated support material varies with the choice of chiral compound, support material and light beam used for irradiation. Methods for determining whether the intensity of a light beam is greater than a desorption threshold are known to those skilled in the art, and as such one example of such a method will be presented herein. For example, the absorbance of a reference coated support is measured before and after irradiation. If the intensity of the beam used for irradiation is above the desorption threshold, a decrease in absorbance will be observed. If no such reduction is observed, the intensity of the beam progressively increases. These steps are repeated until a decrease in absorbance at the time of irradiation with reference to the coated support is observed.

According to the invention, the meaning of asymmetry is introduced in the system for promoting the enrichment of the enantiomer in the preferentially desorbed enantiomer, i.e. the desorption of one enantiomer at a higher rate than the other. For this purpose, at least one of the support material or the optical beam should provide an asymmetric interaction with both enantiomers. Thus, the support material should be chiral and/or the light beam should be circularly polarized. If the asymmetry of the system is provided by a chiral support material, the polarization of the light beam is not limited.

In a preferred embodiment of the invention, the method further comprises repeating said step of irradiating the coated support and said step of determining its optical activity until a final (desired) optical activity value (OA) of the coated support is obtained_f). The final (desired) value of optical activity depends on the desired level of enrichment. By comparing the optical rotation of the mixture with that of the enantiomerically pure substance, the absolute level of enrichment, i.e. the enantiomeric excess of the mixture, can be determined. The maximum level of enrichment according to the invention maintains a constant value of optical activity when further irradiation is applied.

In a preferred embodiment of the invention, the light beam has a wavelength that is resonance-matched to the absorption band of the chiral compound by one photon or by multiple photons. Tuning the wavelength of the light beam to be resonance matched to the absorption band of the chiral compound advantageously enhances the interaction of the light beam with the coated support.

In a preferred embodiment of the invention, the irradiating step provides a duration of between 0.2ns and 1000 s.

In a preferred embodiment of the invention, the irradiating comprises irradiating the coated support by means of a Light Emitting Diode (LED), a pulsed laser or a continuous wave laser.

In a preferred embodiment of the present invention, said determining the optical rotation of the coated support comprises determining the optical rotation by one of circular dichroism measurements, optical rotation dispersion measurements, second harmonic generation circular dichroism measurements or second harmonic generation optical rotation measurements.

In a preferred embodiment of the invention, the application of the mixture of the two enantiomers to the support material comprises one of the following methods: molecular evaporation, spin coating, dip coating, and drop casting.

In a preferred embodiment of the invention, the chiral support material belongs to the group of high miller index surfaces of metals such as the (643) and (531) surfaces.

Alternatively, in a preferred embodiment of the invention, the achiral support material belongs to the group of low miller index surfaces, such as (111) and (110) surfaces, of amorphous solids or metals.

In a preferred embodiment of the invention, the mixture of the two enantiomers is provided in powder or liquid form.

Brief description of the drawings

Non-limiting embodiments of the present invention will be more fully appreciated with reference to the accompanying drawings, in which:

FIG. 1 shows a schematic illustration of a mixture of two enantiomers and a support material according to an embodiment of the invention;

FIG. 2 shows a block diagram of an enantiomeric enrichment process according to an embodiment of the invention.

Fig. 3 shows the intensity of the generated second harmonic as a function of the illumination time in the upper picture of the image. The lower panel of the image shows the change in optical activity of the coated glass surface as a function of the irradiation time.

The invention will be described in detail using examples

Reference will now be made to non-limiting embodiments of the process according to the invention. It will be appreciated by those skilled in the art that other modifications and equivalents will be apparent in view of the non-limiting embodiments disclosed herein and that such variations are to be considered within the scope of the invention.

Fig. 1 illustrates an example of the components for producing a coated support (17) according to the invention. As an example of chiral compound (11), BINOL is shown as two enantiomers R-BINOL and S-BINOL (11R, 11S). The mixture of chiral compounds (13) may be in the form of a solution or a powder. The composition of the mixture of enantiomers (13) can have all combinations of mole fractions between the two enantiomers with an enantiomeric excess (ee) in the range of 0. ltoreq. ee < 1. A racemic mixture containing equal amounts of the two enantiomers has an ee of 0, while a single pure enantiomer of a chiral compound has an ee of 1. As will be appreciated by those skilled in the art, pure enantiomers may no longer be enantiomerically enriched.

The support material (15) may be chiral, including but not limited to high miller index metal surfaces such as (643) and (531) surfaces. The support material (15) may be achiral including, but not limited to, low miller index metal surfaces such as (100), (110), and (111) surfaces, or amorphous such as glass and amorphous metal surfaces. The coated support (17) according to the invention is produced by applying a mixture (13) of enantiomers to a support material (15).

Turning now to fig. 2, the steps of the enantiomerically enriched process according to the invention are presented. According to the invention, the coated support (17) is produced in a first step (21). For this purpose, a mixture (13) of enantiomers is applied to a support material (15). The mixture of enantiomers (13) can be applied to the support material (15) by common surface coating methods, such as spraying, spin coating, drop coating and dip coating, provided that the mixture of enantiomers (13) is in the form of a solution. In the case of the mixture (13) being in the form of a powder or a solution, molecular evaporation is employed for applying the mixture to the support material (17).

According to a second step (23) of the process of the invention, after the preparation of the coated support (17), the coated support (17) is subjected to a determination of a first optical rotation value (OA)₀). The measured values serve as reference points for the enantiomeric enrichment process. The first optical rotation value (OA) is determined by means of a linear chiral optical (chiral) technique, such as circular dichroism or chiral dispersion, or by means of a nonlinear chiral optical method, such as second harmonic generation circular dichroism or second harmonic optical rotation₀). The choice of the method for determining the optical rotation value of the coated support (17) can vary depending on the optical rotation of the chiral compound (11). In general, nonlinear chiral optical techniques exhibit higher sensitivity than linear techniques, which are easier to implement and interpret.

According to a third step (25) of the method of the invention, the coated support (17) is irradiated with a light beam sufficiently strong to cause desorption of at least one of the enantiomers (11R, 11S) from the coated support (17). The meaning of introducing asymmetry in the system, i.e. the support material (15) is asymmetric yet interacts with both enantiomers (11R, 11S), or the light beam is asymmetric, i.e. circularly polarized. The polarization state of the light beam is thus adjusted depending on the selected carrier material (15). If the support material (15) is achiral, the beam is circularly polarized unless both enantiomers (11R, 11S) will desorb from the coated support (17) at the same rate. The handedness (handedness) of a circularly polarized light beam is the only component that causes a distinction between the two enantiomers (11R, 11S) in the mixture (13). If the support material (15) is chiral, the light beam need not be circularly polarized, since the two enantiomers (11R, 11S) will have different interactions with the support material (15). In this case, the light beam may be unpolarized, linearly polarized, elliptically polarized, or circularly polarized. The interaction of the light beam with the coated support (17) can be enhanced if the wavelength of the light beam is adjusted to resonate with optical transitions in the chiral compound (11). This adjustment can be made by a single photon process or by a multi-photon process.The irradiation step (25) results in enantiomeric enrichment of the coated support (17) by causing desorption of the two enantiomers (11R, 11S) from the coated support (17) at different desorption rates. The enantiomeric enrichment is determined by a further step (27), by means of which a value (OA) different from the first optical rotation value is determined₀) Of the coated support (17) has a second optical rotation value (OA)_e)。

Example 1

The features of the method according to the invention will now be described by way of example describing preferred techniques and experimental results. The examples are provided for the purpose of illustrating the invention and should not be construed as limiting the invention.

A racemic mixture of BINOL (2,2 '-dihydroxy-1, 1' binaphthyl) molecules has been applied by molecular evaporation onto achiral support material BK7 glass in order to produce a coated support. The coated glass support was irradiated with a femtosecond (fs) laser system having a 1kHz repetition rate (pulse duration 20 to 50fs, 0.6 to 2.5 muJ/pulse). Thereafter, the anisotropy factor (optical rotation) of the coated glass support was measured using second harmonic generation circular dichroism.

The lower panel of fig. 3 illustrates the value of the anisotropy factor (Δ g) of the coated glass support as a function of irradiation time. The lower horizontal axis shows the time in elapsed desorption time, while the top horizontal line shows the equivalent irradiation time in exposure time. As shown in Table 1, the first anisotropy factor value g for the coated glass support at time 0₀(i.e., prior to irradiation) Δ g ═ 0 (i.e., ee ═ 0) is applied.

Since an achiral support material (i.e. BK7 glass) is used, the coated support material is irradiated with circularly polarized light. The wavelength of the illumination beam was set to 650nm so that its second harmonic (325nm) resonated with optical transitions in the BINOL molecules.

Referring now to fig. 3, the positive portion of the time axis of the lower picture relates to the desorption time elapsed using Right Circularly Polarized (RCP) light, which increases from time 0 to the right. The negative part of the time axis relates to Left Circularly Polarized (LCP) light (where the absolute value also increases continuously from time 0 to the left). In this example, the second anisotropy factor value was determined after irradiation of the coated carrier with 100000 laser pulses. I.e. 100s elapsed desorption time is equivalent to an exposure time of 2 to 5ns as indicated on the top time axis of fig. 3. The steps of irradiation (causing desorption) and subsequent determination of optical rotation are repeated.

The upper panel of fig. 3 shows the intensity of the generated second harmonic signal as a function of desorption time. The results show that firstly desorption of the enantiomers occurs at different desorption rates and secondly the total desorption of the enantiomers from the coated support is independent of the polarization of the light beam, i.e. similar for both RCP and LCP.

Referring to the lower picture of fig. 3, the optical activity of the coated support (here the anisotropy factor Δ g) changes upon irradiation and takes the opposite sign for the opposite chiral tendency of the irradiating beam. In addition, the optical activity of the coated support changes rapidly upon irradiation and stabilizes after a period of time (elapsed desorption time of-30 minutes or equivalent exposure time of 1800000 laser pulses-36 ns). After this point in time, the optical activity of the coated support no longer changes (see lower panel of fig. 3) causing further desorption of the enantiomer from the coated support even upon irradiation (see upper panel of fig. 3).

Any particular enantiomeric enrichment level between the first value and the final value can be achieved by selecting an appropriate duration of irradiation time.

The upper panel illustrates the intensity of the generated second harmonic provided by BK7 glass coated with a racemic mixture of BINOL molecules as a function of illumination time, illuminated with a right circularly polarized beam (from 0 to right, positive values) and with a left circularly polarized beam (from 0 to left, negative values). The intensity of the second harmonic generated when the molecules desorb from the coated glass is reduced.

The lower panel illustrates the change in optical activity of the coated glass as a function of the illumination time, illuminated with a right circularly polarized beam (from 0 to right, positive values) and with a left circularly polarized beam (from 0 to left, negative values).

Embodiments of the present invention employ a physical process using optical means for enantiomerically enriching a mixture of two enantiomers, thereby providing the desired benefit of significantly reducing the addition of extraneous compounds.