• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Catalytic phase transformation by metals into chiral compounds. More than 90% of the chiral compounds are thermodynamically stable as racemic compounds, which implies that less than 10% are clusters that can be deracemized by crystallization with the usual crystalline growth techniques. The present invention describes a method for obtaining the metastable phase of a compound from another more stable phase by the presence in the system of a metal or metal alloy. This method can be applied to the conversion of "racemic compounds" in their "conglomerate" phase so that, later, they can be deracemized (obtaining a single enantiomer) by applying usual crystalline growth techniques. The method allows to obtain the metastable phase of a compound starting from the most stable phases in a simplified way. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2729732A1
    申请号:ES201900154
    申请日:2019-10-11
    公开日:2019-11-05
    发明作者:Molero Cristobal Viedma
    申请人:Universidad Complutense de Madrid；
    IPC主号:
    专利说明:

    [0001]
    [0002] Catalytic phase transformation by metals into chiral compounds.
    [0003]
    [0004] Technical sector
    [0005]
    [0006] The present invention relates to a separation process of racemic mixtures of special interest in the pharmaceutical industry; more specifically, it refers to a process by which the metastable phase of polymorphs and, in particular, the "conglomerate" phase can be obtained from the "racemic compound" phase in chiral products.
    [0007]
    [0008] Background of the invention
    [0009]
    [0010] The term "polymorphism" denotes the ability of a substance to exist in more than one crystalline structure. These crystalline structures have the same chemical composition but different unit cells, different three-dimensional ordering. Because of this, polymorphs (two crystals with the same chemical composition but different arrangement) have different chemical or physical properties and are considered as two different solid materials.
    [0011]
    [0012] At a certain temperature and pressure, only one of the polymorphs is stable from a thermodynamic point of view (normally, the polymorph with the lowest free energy). Any other polymorph in that situation is considered as metastable. Obtaining the metastable polymorph could be of great advantage in the industry, in general; But polymorphism is very important in the development of pharmaceutical ingredients. Many medicines receive regulatory approval for only one of the polymorphic phases, since polymorphism can have important medical implications. For example, when the medicine is taken orally as a crystalline solid, the dissolution rate depends on the polymorphic phase that is used. The metastable polymorph has greater solubility than the stable one and, therefore, greater bioavailability (ability to be absorbed by the organism).
    [0013]
    [0014] On the other hand, in addition to polymorphism, chirality is also of great importance in the world of medicines, which occurs when the same chemical molecule is presented in two different forms called enantiomers, being one of the left hand and the other of the right. Although 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, later W. Ostwald formulated the theory according to which, in the crystallization processes of polymorphic compounds, The metastable phase or structure originates first and then becomes the most thermodynamically stable phase.
    [0015]
    [0016] One of the characteristics of life is the homoquirality of the main biological molecules. Thus ribose and dexoribose (in RNA and DNA, respectively) are "right-handed" while the amino acids that build proteins are "left-handed." This unique hand of the molecules of life implies that the two enantiomers of the same chiral medicine interact differently with the biological chiral receptors. That is, the molecule of one hand may be effective while the molecule of the other hand (its image in the mirror) could be toxic.
    [0017]
    [0018] Unfortunately, chiral molecule synthesis in laboratories results in the production of left and right molecules in equal proportion (both enantiomers appear). The separation of enantiomers is a topic of great interest since more than 50% of the pharmaceutical active ingredients are chiral and nine of the ten best-selling medicines have chiral active ingredients.
    [0019] For all the above, the production of chiral enantiopuro compounds (one-handed) is one of the biggest challenges of the pharmaceutical industry, since only one of the enantiomers exerts the desired medical effect.
    [0020]
    [0021] The crystallization process provides the most powerful tool to obtain these chiral purity materials, that is, from the desired hand. The chiral molecules can crystallize in two ways: (a) as a "racemic compound", in which each crystal contains the 1: 1 ratio of left (L) - right (D) molecules, that is, the same amount of both enantiomers within the same crystal; (b) crystallize as a "conglomerate" in which each crystal is formed by molecules of the same enantiomer (molecules of the same hand) and, in this case, there are crystals of the right hand and left hand.
    [0022]
    [0023] The selective crystallization of the conglomerates to separate the desired enantiomer from the previous racemic mixture (mixture with both chiral crystals) is one of the most economical and normally used techniques in the industrial one. Examples of these techniques are partial preferential crystallization, total preferential crystallization or the most modern Viedma ripening. By any of these crystallographic techniques, homochiral chiral compounds can be obtained or, what is the same, crystals that are formed by a single enantiomer and that can be marketed as medicine (current laws are increasingly demanding with the homoquirality of the compounds chiral).
    [0024]
    [0025] However, deracemization or enantiomeric crystallization of racemic compounds, since both chiral molecules are within the same crystal, is very difficult and anecdotal in the pharmaceutical industry.
    [0026]
    [0027] Unfortunately, more than 90% of the chiral compounds are thermodynamically stable as racemic compounds, which implies that less than 10% are clusters that can be deracemized by crystallization with the techniques named above. Following the polymorphism nomenclature, in the vast majority of chiral products, the metastable phase is the conglomerate and the stable phase is the racemic compound.
    [0028]
    [0029] 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), combine the Viedma ripening technique with a simultaneous transformation of a metastable racemic conglomerate (C. Xiouras et al. Cryst. Growth Des. 2017 , 17), apply the Viedma ripening technique in a simplified way without the need for create intermediate compounds or introduce additives by providing kinetic energy to generate the metastable phase by collision with steel, zirconia or diamond balls (ES2726180); or apply, in addition to the impact force, ultrasound as a complement to the Viedma ripening technique (C. Xiouras et al. Ultrasonics Sonochemistry, 2018 , 184-192).
    [0030]
    [0031] Despite the enormous effort, methods have not yet been found that systematically increase the percentage of clusters to facilitate the production of enantiomerically pure compounds by crystallization processes.
    [0032]
    [0033] Surprisingly, during the performance of tests to attempt the separation of deracemization aided by the contribution of kinetic energy by balls of hard material, it was found that the presence of metals facilitated such separation.
    [0034] Explanation of the invention.
    [0035]
    [0036] The present invention provides a method that allows to obtain metastable phases of polymorphic compounds, either by converting the stable phase of a polymorph into the metastable phase or by generating and stabilizing the metastable phase directly from a supersaturated solution.
    [0037]
    [0038] In the specific case of chiral compounds, the invention transforms a population of crystals of a racemic compound (stable phase) into another population of crystals that form a conglomerate (metastable phase). Similarly, the theoretically metastable phase (the conglomerate) is generated and stabilized from a supersaturated solution. That is, adequate systems (conglomerates) are generated to undertake the deracemization of chiral compounds by conventional crystalline growth techniques that are routinely and effectively used in the pharmaceutical industry (partial preferential crystallization, total preferential crystallization, Viedma ripening, fluctuation of temperature, etc.).
    [0039]
    [0040] In this way, the restriction imposed by the Thermodynamics of only 10% of the chiral compounds susceptible to be deracemized by crystalline growth techniques is overcome and the pharmaceutical industry is offered a route to new enantiomerically pure products that are crucial in our life daily
    [0041]
    [0042] In the present invention, a population of crystals of a racemic compound is converted into another population of crystals in a conglomerate phase by the addition of a suitable metal in the system that causes this transformation; a solution of chiral molecules of a racemic compound crystallizes generating the conglomerate phase by the catalytic effect of the metal.
    [0043]
    [0044] The separation can be done in the presence of a pure solvent or with an additive that speeds up the process; The solvent can be omitted if a kinetic energy is applied to the racemic crystal-metal system to enhance the transformation of the phases such as shock, grinding, stirring and / or ultrasound.
    [0045]
    [0046] The efficiency of the process increases when the metal is used in the form of dust as the contact surface between the members of the system increases. The phase transformation process is also accelerated when kinetic energy is applied in the form of impact or grinding force.
    [0047]
    [0048] The impact can be made using balls of different nature or particles that are not soluble in the solvent. The use of galvanized balls (with a surface coated with catalyst metal) accelerates the process. The process can also be complemented with ultrasound or mechanical devices such as turbines, metal mills, etc.
    [0049]
    [0050] The process can be carried out at room temperature although the temperatures can oscillate widely without problems until the temperature of freezing and boiling of the solvent when there is it. At temperatures higher than room temperature the transformation process can be accelerated. The temperature can remain constant or suffer variations in the cycle.
    [0051]
    [0052] The conversion time of the racemic product to conglomerate decreases as the amount of metal present in the system increases.
    [0053]
    [0054] The grinding of the crystals can be done previously and then remove the balls or particles and then add the metal powder, or place pieces of metal inside the container. The suspension of crystals can also be allowed to stand together with the metal producing the transformation, although the duration of the process is much longer.
    [0055] Brief description of the drawings
    [0056] To complement the description that is being made and in order to help a better understanding of the characteristics of the invention, a set of drawings is attached as an integral part of said description, where illustrative and non-limiting nature has been represented. following:
    [0057] Figure 1.- Shows a scheme of the transformation of LD-Valine into L-Valine + DValine and its follow-up by X-ray diffraction.
    [0058] Preferred Embodiment of the Invention
    [0059] The present invention is illustrated by the following examples, which are not intended to limit its scope .
    [0060] Example 1
    [0061] This example describes the transformation of the system formed by suspension crystals in ethanol from LD-Valine (racemic compound) to L-Valine D-Valine (conglomerate).
    [0062] A crystal suspension is formed by mixing 0.4 g of LD-Valine and 5 ml of ethanol in a 50 ml Erlenmeyer bottle. 8 g of 3 mm diameter glass balls, a stirring magnet (2.5 cm in length and 5 mm in diameter) and 0.4 g of zinc powder (30 pm) are introduced into this system. The bottle is closed tightly. The system is subjected to continuous agitation (600 rpm) producing an intense grinding phenomenon between the crystals, which provides a rapid growth dissolution process (Ostwald Ripening). The system is maintained at room temperature (22 ° C). In 24 hours the entire system initially formed by the "racemic compound" LD-Valine becomes the "conglomerate" L-Valine D-Valine. The evolution of the transformation is followed by X-ray diffraction (Figure 1).
    [0063] Example 2
    [0064] Transformation of the system formed by suspension crystals in ethanol of LD-Leucine (racemic compound) in L-Leucine D-Leucine (conglomerate).
    [0065] A crystal suspension is formed by mixing 0.4 g of LD-Leucine and 5 ml of ethanol in a 50 ml Erlenmeyer bottle. 8 g of 3 mm diameter glass balls, a stirring magnet (2.5 cm in length and 5 mm in diameter) and 0.4 g of zinc powder (30 pm) are introduced into this system. The bottle is closed hermetically. The system is subjected to continuous agitation (600 rpm) producing an intense grinding phenomenon between the crystals which provides a rapid dissolution-growth process (Ostwald Ripening). The system was maintained at room temperature (22 ° C). In 24 hours the entire system initially formed by the "racemic compound" LD-Leucine has become the "conglomerate" L-Leucine D Leucine. The evolution of the transformation has been followed by X-ray diffraction, checking the complete phase transformation.
    [0066] Example 3
    [0067] Transformation of the system formed by suspension crystals in ethanol of LD-Isoleucine (racemic compound) in L-lsoleucine D-lsoleucine (conglomerate).
    [0068] A crystal suspension is formed by mixing 0.4 g of LD-lsoleucine and 5 ml of ethanol in a 50 ml Erlenmeyer bottle. 8 g of 3 mm diameter glass balls, a stirring magnet (2.5 cm in length and 5 mm in diameter) and 0.4 g of zinc are introduced into this system powder (30 pm). The bottle is closed tightly. The system is subjected to continuous agitation (600 rpm) producing an intense grinding phenomenon between the crystals which provides a rapid dissolution-growth process (Ostwald Ripening). The system was maintained at room temperature (22 ° C). In 24 hours the entire system initially formed by the "racemic compound" LD-lsoleucine has become the "conglomerate" L-lsoleucine D-lsoleucine. As in the previous examples, the evolution of the transformation has been verified by X-ray diffraction.
    [0069]
    [0070] Example 4
    [0071]
    [0072] Table 1 shows a summary of transformations of LD-Valine crystals to L Valine D-Valine conglomerates carried out following the method of the invention under different transformation conditions, using in all of them continuous stirring by means of magnet and mechanochemistry to achieve intense grinding. In each case, monitoring the transformation by X-ray diffraction allows you to check the total desired transformation.
    [0073]
    [0074] Table 1
    [0075]
    [0076]
    权利要求:
    Claims (20)
    [1]
    1. Method for the transformation of phases into polymorphs characterized by the use of metals or metal alloys as a catalyst.
    [2]
    2. Method according to claim 1, wherein the stable phase of a polymorph becomes the metastable phase.
    [3]
    3. Method according to claim 1, wherein the metastable phase of a polymorph is generated and stabilized from a supersaturated solution of the polymorph.
    [4]
    4. Method according to previous claims, wherein the polymorph is a chiral compound.
    [5]
    5. Method according to claims 1, 2 and 4 wherein a population of crystals of a racemic compound is converted into another population of crystals in a conglomerate phase by the addition of a metal catalyst or a metal alloy.
    [6]
    6. A method according to claims 1, 3 and 4 wherein, from a supersaturated solution of a racemic compound, the metastable (conglomerate) phase is generated and stabilized.
    [7]
    7. Method according to any of the preceding claims, wherein the metal catalyst contains zinc.
    [8]
    8. Method according to claim 7, wherein the catalyst is zinc powder.
    [9]
    9. Method according to claim 7, wherein the catalyst is zinc oxide.
    [10]
    10. Method according to any one of claims 1 to 6, wherein the metal catalyst contains copper.
    [11]
    Method according to any of the preceding claims, characterized in that a kinetic energy is applied to the polymorph-metal system to enhance the transformation of the phases.
    [12]
    12. Method according to claim 11, wherein the kinetic energy is contributed by shock, grinding, stirring and / or ultrasound.
    [13]
    13. Method according to claim 12, wherein the kinetic energy is provided in the form of impact or grinding force through balls or particles.
    [14]
    14. Method according to any of the preceding claims, wherein optionally a solvent is added.
    [15]
    15. Method according to claim 14, wherein the solvent is added pure or with an additive that speeds up the process.
    [16]
    16. Method according to any of the preceding claims, wherein the process is carried out at constant temperature or by temperature increases or fluctuations.
    [17]
    17. Method according to any of the preceding claims, wherein the racemic compound is an amino acid.
    [18]
    18. Method according to claim 17, wherein the metastable "conglomerate" phase is obtained from the racemic compound LD-valine.
    [19]
    19. Method according to claim 17, wherein the metastable "conglomerate" phase is obtained from the racemic compound LD-Leucine.
    [20]
    20. Method according to claim 17, wherein the metastable "conglomerate" phase is obtained from the racemic compound LD-lsoleucine.
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    同族专利:
    公开号 | 公开日
    ES2729732B2|2020-03-05|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    ES2726180A1|2018-02-28|2019-10-02|Univ Madrid Complutense|Chiral purity from racemic mixtures by mechanochemistry |
    法律状态:
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