• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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    • 专利摘要:
    Chiral purity from racemic mixtures by mechanochemistry. A method for the deracemization of racemic mixtures is described by applying the Viedma ripening technique ("Attrition-enhanced deracemization") that can be applied to both clusters and racemic compounds. The method allows to reach chiral purity, overcoming the limitations that until now had the technique, starting from a racemic compound and the desired enantiomer in a simplified way, in the presence of a solvent and a kinetic energy that enhances racemization, without using intermediate conglomerates nor add racemizing agents. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2726180A1
    申请号:ES201800048
    申请日:2018-02-28
    公开日:2019-10-02
    发明作者:Molero Cristobal Viedma
    申请人:Universidad Complutense de Madrid；
    IPC主号:
    专利说明:

    [0001]
    [0002] Chiral purity from racemic mixtures by mechanochemistry.
    [0003]
    [0004] Technical sector
    [0005]
    [0006] The present invention relates to a deracemization method to obtain a pure enantiomer. More specifically, a method of solving racemic compounds is described.
    [0007]
    [0008] Background of the invention
    [0009]
    [0010] The property of chirality is that shapes that are mirror images, like our hands, are not superimposable. Chirality can manifest itself at the molecular or macroscopic level. The two forms of a chiral molecule are called enantiomers, which have the same chemical and physical properties but when they interact with other chiral molecules they do so differently.
    [0011]
    [0012] Molecular chirality was discovered by Pasteur in 1848 when he observed that crystals of a salt of tartaric acid appear in two specular morphological types; in some crystals the hemihedral faces lean to the right while in others they lean to the left. Pasteur separated both enantiomers with a cow's hair (not with tweezers as they say) and, by dissolving the enantiomers separately, each solution turned the polarized light in a different sense: it was thus established that chiral crystals were formed by molecules chiral
    [0013]
    [0014] One of the most fascinating problems related to the origin of life is the fact that the most important molecules that make up living organisms are chiral and one-handed. This fact has transcendental importance because it makes us homochiral entities, of a single chirality, which marks the type of relationship with other chiral molecules.
    [0015]
    [0016] The fact that biological molecules have only one chirality (amino acids that constitute the proteins or sugars of RNA and DNA are left-handed (L) and right-handed (D), respectively, is critical for molecular recognition in processes biochemical and could be a prerequisite for the origin of life.This has practical consequences in the response of "chiral organisms" (like humans) to the different enantiomers of a chiral molecule.A paradigmatic and cruel example of this chiral discrimination provides thalidomide, one of whose enantiomers has excellent properties as a nausea reliever in pregnant women but the other enantiomer is fatal in the development of the fetus.During the 60s of the last century, when the drug was administered racemic, thousands of Children were born with serious congenital malformations.
    [0017]
    [0018] Most pharmaceutical compounds are chiral and, after the Thalidomide disaster, regulations for the distribution of these medications have become very strict: we need medicines with the correct enantiomer. Therefore, generating strategies to create compounds of a single enantiomer is still of great importance for the pharmaceutical industry.
    [0019]
    [0020] The synthesis of chiral molecules in the laboratory, under non-directed conditions, generates approximately the same amount of chiral entities on the left and on the right, that is, a "racemic" mixture of enantiomers. This fact has been called "chiral symmetry" and the " chiral symmetry rupture ”implies an“ enantiomeric excess ”(measure of the purity of a chiral compound).
    [0021] Chiral crystallization is one of the most important routes currently used to obtain chirally pure compounds. The racemic mixtures of the chiral compounds can crystallize in two ways: (a) as a "racemic compound" in which each crystal contains the 1: 1 ratio of L: D molecules, that is, the same amount of both enantiomers within the same crystal ; or (b) as a "conglomerate" in which each crystal is formed by molecules of the same enantiomer.
    [0022]
    [0023] In the case of conglomerates, since there are right hand and left hand crystals, they can be physically separated as Pasteur did with his “tweezers.” In recent years, a much more suitable method for solid state deracemization has been established. of conglomerates by grinding or attrition of a suspension of both crystalline enantiomers in their saturated solution. This technique is called "Attrition-enhanced deracemization" or 11 Viedma ripening "(C. Viedma, Phys. Rev. Lett., 2005 , 94 ) and results in a complete deracemization. This technique has been used successfully to deracemize both inorganic and organic substances. However, until now, its great limitation is that it is only applicable to compounds that crystallize as clusters, which does not exceed 15% of chiral compounds, racemic compounds being much more abundant (approximately 85%). It would therefore be desirable to be able to extend the Viedma ripening technique to the racemic compounds in order to cover all the crystalline compounds formed by chiral molecules.
    [0024]
    [0025] Attempts have been made to overcome this limitation such as modifying the crystallization of racemes so that they give rise to a cluster and, from this cluster, apply the Viedma ripening technique (WL Noorduin et al., J. Am. Chem. Soc. 2008 , 130) or create a salt that forms a conglomerate (WO2010 / 089343), introduce a chiral additive during crystallization that blocks the growth of a racemic compound favoring the growth of a specific enantiomer (AHJ Engwerda et al, Chem. Eur. J. 2018 , 24) or combine the Viedma ripening technique with a simultaneous transformation of a metastable racemic conglomerate (C. Xiouras et al. Cryst. Growth Des. 2017 , 17). It would, however, be desirable to be able to address the resolution of racemic compounds by applying the Viedma ripening technique in a simplified manner without the need to create intermediate compounds or introduce additives.
    [0026]
    [0027] Explanation of the invention.
    [0028]
    [0029] In the present invention a method of deracemization of racemic mixtures using the modified Viedma ripening technique is described. The method allows to obtain chiral purity obtaining racemization on the surface of the crystals without the need of any catalytic agent (which would act in the solution), using a suitable solvent and providing the necessary kinetic energy, so the process can be classified as "racemization mechanochemistry. "
    [0030]
    [0031] The Viedma ripenning technique allows the crystals of the unwanted enantiomer to be transformed to the desired enantiomer while the unwanted enantiomer disappears. Basically, until now it was thought that for the solid-solid deracemization process of a compound constituted by chiral molecules by Viedma ripening it is necessary that there be racemization of molecules in solution, that the system be subjected to an accelerated Ostwald process ripening (whereby the smaller crystals dissolve and the large ones grow, usually by grinding or ultrasound attrition) and that the compound to be deracemized is a conglomerate.
    [0032]
    [0033] Surprisingly, it has been found that it would be possible to apply it to address the resolution, that is, to obtain chiral purity from racemic compounds through a new process. wherein the racemic compound is suspended next to the desired enantiomer and the conversion of the racemic compound into the desired enantiomer is caused.
    [0034]
    [0035] For this, the following essential characteristics are introduced to the Viedma ripening method:
    [0036]
    [0037] - The suspension of crystals in equilibrium with the solution is composed of crystals of the racemic to be transformed and crystals of the desired enantiomer.
    [0038] - The solvent is chosen to allow the racemization process that occurs in solution to transfer to a racemization that occurs in contact with the crystalline surface in suspension. The solvent can be added pure or with an additive that speeds up the process.
    [0039] - Kinetic energy is provided to enhance racemization on the crystalline surface in suspension without adding a catalytic agent (which would act in the solution).
    [0040] Kinetic energy can be provided by different methods such as shock, grinding, stirring, ultrasound or combination of them. In the case of the crash, balls of hard and heavy material, high density, such as steel, zirconite or diamond are used. Stirring can be performed, for example, by vibration using an orbital motor.
    [0041]
    [0042] The process can be carried out at a constant temperature or using a ramp or temperature disturbances. Similarly, constant pressure can be maintained or pressure changes can be made.
    [0043]
    [0044] Optionally, a catalytic agent can be added which causes racemization in solution under ambient conditions but without preventing almost all the racemization of the system from being generated on the crystalline surface.
    [0045]
    [0046] Because the use of a solvent and kinetic energy that favor racemization on the surface of the crystals (and not in the solution) is essential, the process has been cataloged as "mechanochemical racemization."
    [0047]
    [0048] At the moment, the method cannot be generalized for any conglomerate or racemic reason why the choice of solvent must be made for each specific case, choosing the one that allows the desired effect. In the case of kinetic energy, an optimization would also be necessary for each specific case, although balls of greater density and weight than those traditionally used in the Viedma ripening technique have been used in the present invention.
    [0049] Preferred Embodiment of the Invention
    [0050]
    [0051] The present invention is illustrated by two examples, which do not imply a limitation on the scope thereof.
    [0052]
    [0053] Example 1:
    [0054]
    [0055] Deracemization of the LD-Alanine and L-Alanine system in suspension in ethanol.
    [0056]
    [0057] A crystal suspension is formed by mixing 0.2 g of LD-Alanine with 0.2 g of L-Alanine and 8 ml of ethanol in a glass tube 12 cm long and 15 mm in diameter. 40 g of 4mm diameter stainless steel balls are introduced into this system and the tube is closed tightly. The tube with its components is subjected to an intense vibration process by an orbital motor which causes strong shocks between the steel balls and the balls and the walls of the tube. The system was maintained at a temperature of 16 ° C using a commercial refrigerator. After 4-6 days all LD-Alanine has become L-alanine. The evolution of the Alanine phases is followed by X-ray diffraction.
    [0058] Example 2:
    [0059]
    [0060] Deracemization of the LD-Valine and L-Valine system in suspension in methanol.
    [0061]
    [0062] Following the procedure of Example 1, a suspension formed by 0.2 g of LD-Valine crystals and 0.2 g of L-Valine crystals with 8 ml of ethanol or methanol in a glass tube 12 cm long and 15 mm in diameter, 40 g of 4 mm diameter stainless steel balls are added and sealed. The tube with its components is subjected to an intense vibration process by an orbital motor, which causes strong shocks between the steel balls and the balls and the walls of the tube. The system was maintained at a temperature of 16 ° C using a commercial refrigerator. After 4-6 days all LD-Valine has become L-Valine. The evolution of the Valine phases is followed by X-ray diffraction.
    权利要求:
    Claims (13)
    [1]
    1. Method for obtaining pure chiral compounds from racemic mixtures using the Viedma ripening technique under the following mechanochemical conditions:
    - The suspension of crystals in equilibrium with the solution is composed of crystals of the racemic to be transformed and crystals of the desired enantiomer.
    - The solvent is chosen to allow the racemization process that occurs in solution to transfer to a racemization that occurs in contact with the crystalline surface in suspension. The solvent can be added pure or with an additive that speeds up the process.
    - Kinetic energy is provided to enhance racemization on the crystalline surface in suspension. Optionally, a catalytic agent that causes racemization in solution can be added at a slower rate than racemization on the crystalline surface.
    [2]
    2. Method for obtaining pure chiral compounds from racemic mixtures, according to claim 1, wherein the kinetic energy is contributed by shock, grinding, stirring and / or ultrasound.
    [3]
    3. Method for obtaining pure chiral compounds from racemic mixtures, according to claim 2, wherein the shock is made using balls of hard and heavy material such as steel, zirconite, diamond.
    [4]
    4. Method for obtaining pure chiral compounds from racemic mixtures, according to claim 2, wherein agitation is achieved by vibration by an orbital motor.
    [5]
    5. Method for obtaining pure chiral compounds from racemic mixtures, according to claim 1, wherein the process is carried out at constant temperature or by temperature increases or fluctuations.
    [6]
    6. Method for obtaining pure chiral compounds from racemic mixtures, according to claim 1, wherein the process is carried out at constant pressure or by pressure increases or fluctuations.
    [7]
    7. Method for obtaining pure chiral compounds from racemic mixtures, according to previous claims, wherein the racemic mixture is a conglomerate.
    [8]
    8. Method for obtaining pure chiral compounds from racemic mixtures, according to claims 1 to 7, wherein in the racemic mixture there is a racemic compound.
    [9]
    9. Method for obtaining pure chiral compounds from racemic mixtures, according to claim 8, wherein the racemic compound is LD-Alanine.
    [10]
    10. Method for obtaining pure chiral compounds from racemic mixtures, according to claim 9, wherein the crystal suspension is formed by a 50% by weight mixture of the racemic compound and the desired enantiomer, the solvent is methanol, the shock It is made using 4 mm diameter stainless steel balls, intense vibration is applied by an orbital motor and the system is maintained at 16 ° C for 4 to 6 days.
    [11]
    11. Method for obtaining pure chiral compounds from racemic mixtures, according to claim 9, wherein the racemic compound is LD-Valine.
    [12]
    12. Method for obtaining pure chiral compounds from racemic mixtures, according to claim 9, wherein the crystal suspension is formed by a 50% mixture by weight of the racemic compound and the desired enantiomer, the solvent is methanol, the shock is made by 4 mm diameter stainless steel balls, intense vibration is applied by an orbital motor and the system is maintained at 16 ° C for 4 a 6 days.
    [13]
    13. Method for obtaining pure chiral compounds from racemic mixtures, according to claim 12, wherein the solvent is ethanol, the shock is performed by 4 mm diameter stainless steel balls, intense vibration is applied by an orbital motor and The system is maintained at 16 ° C for 4 to 6 days.
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    同族专利:
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    ES2726180B2|2020-06-15|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    ES2729732A1|2019-10-11|2019-11-05|Univ Madrid Complutense|Catalytic phase transformation by metals into chiral compounds |
    法律状态:
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    ES201800048A|ES2726180B2|2018-02-28|2018-02-28|Chiral purity from racemic mixtures by mechanochemistry|ES201800048A| ES2726180B2|2018-02-28|2018-02-28|Chiral purity from racemic mixtures by mechanochemistry|
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