A method for one-pot preparation of organic acid lithium-l-proline salt

Abstract

The application discloses a one-pot method for preparing organic acid lithium-L-proline salt, and belongs to the technical field of compound preparation. The method comprises the following steps: completely dissolving organic acid and L-proline in a reaction solvent, then adding lithium hydroxide to stir and dissolve, and stirring under heat reflux for 3-8 hours to react; after the reaction is completed, the reaction solution is concentrated to a supersaturated solution state through vacuum rotary evaporation, a crystallization solvent is added until no white solid is precipitated, and thus the organic acid lithium-L-proline salt is obtained. The preparation method has the advantages of low raw material cost, stable one-pot preparation process, short reaction steps and simple operation. On the premise of keeping the same structure, the yield and process stability are significantly better than those of the yield of the organic acid lithium-L-proline salt prepared by a single solvent crystallization method and a mixed solvent crystallization method, and the method has great application prospect.

Description

Technical Field

[0001] This invention belongs to the field of compound preparation technology, specifically, it relates to a one-pot method for preparing organic acid lithium-L-proline salt. Background Technology

[0002] Lithium isobutyrate-L-proline salt (nibulin) is an organic lithium amino acid salt, mainly used in the preparation of drugs for treating neurodegenerative diseases or mental illnesses. In contrast, Chinese invention patent CN114081881A discloses two methods for preparing nibulin: a single solvent method and a mixed solvent crystallization method, where the reaction solvent or crystallization solvent is a mixture of n-butanol, ethanol, and tetrahydrofuran, respectively.

[0003] However, the mass yields of these two preparation methods are only 53.06% and 33.75%, respectively. The synthesis yield is low and the process is unstable. The ratio of lithium isobutyrate to proline in the synthesized Nibulin salt structure is prone to change and is not fixed or easily produces discoloration. It is easily affected by operation and reaction conditions, making it difficult to obtain the complete target compound. There are certain technical difficulties and risks for the actual industrial production and research needs of drugs. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention aims to provide a high-yield process for preparing lithium-L-proline organic acid salts. To achieve this objective, the technical solution adopted by this invention is as follows:

[0005] This invention provides a one-pot method for preparing lithium-L-proline salt of organic acid, wherein the organic acid is a carboxylic acid, and the method includes the following steps:

[0006] The organic acid and L-proline were completely dissolved in the reaction solvent, and then lithium hydroxide was added and stirred to dissolve. The reaction was carried out under hot reflux for 3 to 8 hours.

[0007] After the reaction was complete, the reaction solution was concentrated by vacuum rotary evaporation to a supersaturated state. A crystallization solvent was then added until no white solid precipitated, yielding lithium organic acid-L-proline salt.

[0008] Wherein, R is hydrogen, substituted or unsubstituted C1-C12 hydrocarbon group, aryl or heteroaryl, and the substituted substituent is selected from hydroxyl, carboxyl, amino, thio, guanidine, amide, C6-C8 aryl, C3-C8 heteroaryl, hydroxyl-substituted C6-C12 aryl, C3-C6 cycloalkyl, amino-substituted C3-C6 cycloalkyl, C1-C3 alkylthio.

[0009] In some embodiments of the present invention, the carboxylic acid is selected from one of oxalic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, valproic acid, lactic acid, citric acid, tartaric acid, malic acid, benzoic acid, salicylic acid, and caffeic acid.

[0010] In some preferred embodiments of the present invention, the carboxylic acid is isobutyric acid.

[0011] In some embodiments of the present invention, the molar ratio of the organic acid, L-proline, and lithium hydroxide is 1:1 to 2:1 to 2. In some preferred embodiments of the present invention, the molar ratio of the organic acid, L-proline, and lithium hydroxide is 1:1:1.

[0012] In some embodiments of the present invention, the reaction solvent (i.e., good solvent) is selected from one or more of purified water, methanol, and ethanol.

[0013] In some embodiments of the present invention, the crystallization solvent (i.e., the undesirable solvent) is selected from one or more of acetonitrile and tetrahydrofuran.

[0014] In some preferred embodiments of the present invention, the reaction solvent is purified water, and the crystallization solvent is acetonitrile. The two work together to maximize the yield of the organic acid lithium-L-proline salt.

[0015] In some embodiments of the present invention, the temperature of the heat reflux is 85–105°C.

[0016] In some embodiments of the present invention, the mixture is stirred under hot reflux for 5 hours.

[0017] Beneficial effects of the present invention

[0018] Compared with the prior art, the present invention achieves the following beneficial effects:

[0019] The novel one-pot synthesis process for nibulin developed in this invention technically solves the problems existing in the synthesis technology of the prior art, such as the Chinese invention patent CN114081881A. Organic acid and L-proline are dissolved in purified water, and lithium hydroxide is added to carry out the reaction. The organic acid lithium-L-proline salt is prepared in one pot. The synthesis process is stable, has high yield, short reaction steps, simple operation, and a wider range of raw material sources.

[0020] The preparation method of the present invention uses organic acid, lithium hydroxide and L-proline as raw materials, and purified water and other solvents as reaction solvents, which is low in cost.

[0021] The preparation method of the present invention yields high-yield organic lithium-L-proline salts. While maintaining structural consistency, the yield is much higher than that of single-solvent crystallization method and mixed-solvent crystallization method, and has great application prospects. Attached Figure Description

[0022] Figure 1The X-ray diffraction pattern of lithium isobutyrate-L-proline salt prepared by one-pot method in Example 1 of the present invention is shown.

[0023] Figure 2 The hydrogen spectrum of lithium isobutyrate-L-proline salt prepared by one-pot method in Example 1 of the present invention is shown. Detailed Implementation

[0024] Unless otherwise stated, implied from the context, or as is customary in the art, all parts and percentages in this application are based on weight, and all testing and characterization methods used are concurrent with the filing date of this application. Where applicable, any patent, patent application, or disclosure relating to this application is incorporated herein by reference in its entirety, and its equivalent patent families are also incorporated herein by reference, in particular the definitions of relevant terms in the art disclosed in such documents. If any definition of a specific term disclosed in the prior art is inconsistent with any definition provided in this application, the definition provided in this application shall prevail.

[0025] The numerical ranges used in this application are approximate values ​​and therefore may include values ​​outside the range unless otherwise stated. A numerical range includes all values ​​from the lower limit to the upper limit, increasing by one unit, provided there is an interval of at least two units between any lower and any higher value. For ranges containing values ​​less than 1 or fractions greater than 1 (e.g., 1.1, 1.5, etc.), one unit is appropriately considered as 0.0001, 0.001, 0.01, or 0.1. For ranges containing single digits less than 10 (e.g., 1 to 5), one unit is generally considered as 0.1. These are merely specific examples of what is intended to be expressed, and all possible combinations of values ​​between the listed minimum and maximum values ​​are considered to be clearly described in this application.

[0026] The terms “comprising,” “including,” “having,” and their derivatives do not exclude the presence of any other components, steps, or processes, regardless of whether such other components, steps, or processes are disclosed in this application. To eliminate any doubt, unless expressly stated otherwise, all compositions using the terms “comprising,” “including,” or “having” in this application may contain any additional additives, excipients, or compounds. Conversely, except for those necessary for operational performance, the term “substantially constitutes…” excludes any other components, steps, or processes described below with respect to that term. The term “consisting of…” does not include any components, steps, or processes not specifically described or listed. Unless expressly stated otherwise, the term “or” refers to the individual members listed or any combination thereof.

[0027] To make the technical problems solved by the present invention, the technical solutions and the beneficial effects of the present invention clearer, the present invention will be further described in detail below with reference to the embodiments.

[0028] Example

[0029] The following examples are used to illustrate preferred embodiments of the invention. Those skilled in the art will understand that the techniques disclosed in the examples represent techniques discovered by the inventors that can be used to implement the invention, and therefore can be considered preferred embodiments for implementing the invention. However, those skilled in the art should understand from this specification that many modifications can be made to the specific embodiments disclosed herein, still yielding the same or similar results, without departing from the spirit or scope of the invention.

[0030] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains, and all materials publicly cited herein and referenced by them are incorporated herein by reference.

[0031] Those skilled in the art will recognize, or can learn through routine experimentation, many equivalents of the specific embodiments of the invention described herein. These equivalents will be included in the claims.

[0032] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the instruments and equipment used in the following examples are all conventional laboratory instruments and equipment; unless otherwise specified, the experimental materials used in the following examples were all purchased from conventional biochemical reagent stores.

[0033] Example 1: Preparation process of lithium isobutyrate-L-proline salt

[0034] 1. One-pot preparation of lithium isobutyrate proline salt

[0035] Weigh 881.1 mg (0.01 mol) of isobutyric acid and 1.151 g (0.01 mol) of L-proline into a 150 mL round-bottom flask, add about 80 mL of purified water (a good solvent) to dissolve them completely, then weigh 239.5 mg (0.01 mol) of lithium hydroxide into the round-bottom flask and stir to dissolve. Heat under reflux at 95 °C in an oil bath and stir for 5 h to react.

[0036] After the reaction was complete, the solution was concentrated under vacuum using a rotary evaporator until it reached a supersaturated state. Anhydrous acetonitrile, a poor solvent, was slowly added, resulting in the precipitation of crystal particles. Approximately 30 mL of anhydrous acetonitrile was added until no white solid precipitated. The solid was filtered and dried under vacuum to constant weight to obtain 1.98 g of pure white solid; the yield was 94.66%.

[0037] 2. Preparation of lithium isobutyrate-L-proline salt by single-solvent crystallization method according to Chinese invention patent CN114081881A

[0038] Referring to the method disclosed in Chinese Invention Patent CN114081881A (Example 1): Approximately 55 mL of the good solvent n-butanol was added to equimolar amounts of lithium isobutyrate (500 mg) and L-proline (612 mg). The lithium isobutyrate and L-proline were completely dissolved under reflux. The mixture was stirred for approximately 3 hours, filtered while hot, allowed to cool naturally to crystallize, and the solid was filtered and vacuum dried to constant weight to obtain 589.3 mg of white solid, with a yield of 53.06%.

[0039] The inventors repeated the method for preparing lithium isobutyrate-L-proline salt by single solvent crystallization disclosed in Chinese invention patent CN114081881A for the second time. Under the same conditions, the solid was crystallized by natural cooling, filtered, and vacuum dried to constant weight to obtain 720.0 mg of off-white or light yellow solid, with a mass yield of 64.75%.

[0040] 3. Preparation of lithium isobutyrate-L-proline salt by mixed solvent crystallization method according to Chinese invention patent CN114081881A

[0041] Referring also to the method disclosed in Chinese Invention Patent CN114081881A (Example 2): 50 mL of a good solvent, ethanol, was added to equimolar amounts of lithium isobutyrate (500 mg) and L-proline (612 mg). The mixture was heated under reflux until just dissolved. Then, 30 mL of a poor solvent (tetrahydrofuran) was added until just precipitated. 7 mL of a good solvent was added to redissolve the solid. The mixture was refluxed for 3 h, allowed to cool naturally to crystallize, and the solid was filtered and vacuum dried to constant weight to obtain 374.8 mg of white solid, with a yield of 33.75%.

[0042] The inventors repeated the mixed solvent crystallization method for preparing lithium isobutyrate-L-proline salt disclosed in Chinese invention patent CN114081881A twice. Under the same conditions, the solid was crystallized by natural cooling, filtered, and vacuum dried to constant weight to obtain 557.4 mg of pale yellow solid, with a yield of 50.13%.

[0043] Example 2: XRD test of lithium isobutyrate-L-proline salt

[0044] The white solid lithium isobutyrate-L-proline salt obtained in the one-pot preparation in Example 1 was characterized by X-ray diffraction (XRD) using a Bruker D8 Venture X-ray single crystal diffractometer, with the following parameters:

[0045] X-ray source: Cu;

[0046] Voltage: 40KV;

[0047] Current: 40mA;

[0048] Scanning range: 3–40°;

[0049] Scan step size: 0.02°;

[0050] Dwell time per step: 0.1s.

[0051] X-ray diffraction pattern as follows Figure 1 As shown in Table 1, the 2θ characteristic peaks are as follows:

[0052] Table 1. XRD characteristic peaks of lithium isobutyrate-L-proline salt.

[0053]

[0054]

[0055] The XRD results are basically consistent with those of lithium isobutyrate-L-proline salt prepared by the method disclosed in Chinese invention patent CN114081881A, proving that the solid obtained by the one-pot method in Example 1 is lithium isobutyrate-L-proline salt.

[0056] Example 3: 1H NMR Spectroscopy of Lithium Isobutyrate-L-Proline Salt

[0057] The white solid obtained by the one-pot method in Example 1 was examined by proton NMR spectroscopy (deuterated reagent: CD3OD).

[0058] The results are as follows Figure 2 As shown: 1 H NMR (400MHz, Methanol-d4) δ4.02 (dd, J=8.7, 6.1Hz, 1H), 3.41-3.33 (m, 1H), 3.26 (dt, J=11.4 , 7.3Hz, 1H), 2.43-2.24 (m, 2H), 2.15-2.05 (m, 1H), 2.03-1.89 (m, 2H), 1.09 (d, J=7.0Hz, 6H).

[0059] The hydrogen spectrum detection results are basically consistent with the hydrogen spectrum detection results of lithium isobutyrate-L-proline salt prepared by the method disclosed in Chinese invention patent CN114081881A, further proving that the solid obtained by the one-pot method in Example 1 is lithium isobutyrate-L-proline salt.

[0060] Example 4: Effect of good and bad solvent selection on the yield of lithium isobutyrate-L-proline salt in one-pot preparation

[0061] Regarding the one-pot preparation process of lithium isobutyrate-L-proline salt in Example 1, the inventors used purified water, methanol, and ethanol as good solvents, and acetonitrile and tetrahydrofuran as poor solvents. The results are shown in Table 2.

[0062] Table 2. Yields of lithium isobutyrate-L-proline salt obtained with different combinations of good and bad solvents.

[0063]

[0064] Therefore, the reaction solvent (good solvent) and the crystallization solvent (poor solvent) need to be combined to obtain high yields and good stability of the synthesis process, while also ensuring short reaction steps and simple operation. The optimal choice is a combination of purified water (good solvent), methanol, and anhydrous acetonitrile (poor solvent), resulting in a pure white solid powder with uniform particle size and pure white color. Using n-butanol, ethanol, or a mixture of these solvents tends to produce off-white or pale yellow solids or lumpy solids.

[0065] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A one-pot method for preparing lithium-L-proline organic acid salt, characterized in that, The organic acid is a carboxylic acid, and the method includes the following steps: The organic acid and L-proline were completely dissolved in the reaction solvent, and then lithium hydroxide was added and stirred to dissolve. The reaction was carried out under hot reflux for 3-8 hours. After the reaction was complete, the reaction solution was concentrated by vacuum rotary evaporation to a supersaturated state. A crystallization solvent was then added until no white solid precipitated, yielding lithium organic acid-L-proline salt. Wherein, the carboxylic acid is isobutyric acid, the reaction solvent is selected from one or more of purified water, methanol and ethanol, and the crystallization solvent is acetonitrile.

2. The method for one-pot preparation of lithium-L-proline organic acid salt according to claim 1, characterized in that, The molar ratio of the organic acid, L-proline, and lithium hydroxide is 1:1~2:1~2.

3. The method for one-pot preparation of organic acid lithium-L-proline salt according to claim 1, characterized in that, The reaction solvent is purified water.

4. A method for preparing lithium-L-proline organic acid salt in a one-pot process according to any one of claims 1 to 3, characterized in that, The temperature of the heat reflux is 85~105℃.

5. A method for preparing lithium-L-proline organic acid salt in a one-pot process according to any one of claims 1 to 3, characterized in that, Stir under hot reflux for 5 hours.

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