Method for preparing and purifying tigliptin intermediate

Abstract

The invention relates to a preparation and purification method of a tigliptin intermediate. The method comprises the following steps: dissolving a precursor of the tigliptin intermediate without Boc protection removal into an organic solvent, adding Lewis acid for reaction, and separating to obtain an organic phase containing the tigliptin intermediate; adding activated carbon into the organic phase for decoloring, and separating to obtain a decolored tigliptin intermediate; reacting the decolorized tigliptin intermediate with organic dibasic acid, and separating to obtain organic dibasic acid salt of the tigliptin intermediate; the method comprises the following steps: reacting organic dibasic acid salt of the tigliptin intermediate with inorganic alkali, and separating to obtain an organic phase containing the tigliptin intermediate; and carrying out reduced pressure distillation on the organic phase, adding a poor organic solvent, and filtering to obtain the purified tigliptin intermediate. Compared with the prior art, the method disclosed by the invention has the advantages of high yield, high purity, simplicity and convenience in operation and the like, and the obtained high-purity intermediate can be further used for synthesizing and preparing tigliptin.

Description

Technical Field

[0001] This invention relates to the field of active pharmaceutical ingredient (API) preparation technology, and in particular to a method for preparing and purifying a ticagliptin intermediate. Background Technology

[0002] Tigagliptin (structural formula 1) is an oral hypoglycemic agent used to treat type 2 diabetes. It belongs to the dipeptidyl peptidase-4 (DPP-4) inhibitor class and was developed by Mitsubishi Tanabe Pharmaceutical Co., Ltd. of Japan. Its brand name is Talian.

[0003] .

[0004] Tanabe Mitsubishi Pharmaceutical reported two methods for preparing compound 1 (refer to US 2009216016A, US7074794B2), both involving compound 2. Method one involves mixing compound 2 and compound 3 with NaBH(OAc)3, undergoing a reductive amination reaction to obtain compound 5, followed by acidification to remove Boc protection, and then forming a salt with HBr to finally obtain compound 1. Method two involves a nucleophilic substitution reaction between compound 2 and activated ester 4 to obtain compound 5; the subsequent preparation of compound 1 is the same as in method one.

[0005] .

[0006] From the above synthesis, compound 2 is a very important intermediate. The industrial preparation method of compound 2 has been reported by Tanabe Mitsubishi Pharmaceutical Co., Ltd., specifically: first, compound 8 is prepared by reacting N-Boc piperazine (6) and diketene (7). The intermediate 9 obtained from the reaction of 8 and phenylhydrazine then undergoes a cyclization reaction in the presence of a phosphine-containing reagent, such as phosphorus oxychloride, phosphorus pentasulfide, or Lawson's reagent, to form compound 10. Subsequently, the Boc protection is removed by trifluoroacetic acid (TFA) to obtain compound 2. Relevant literature on the preparation of compound 2 can be found in Bioorganic & Medicinal Chemistry, 2012, 20, 5705-5719, and related patents such as US 7074794B2 and WO 2012165547A1.

[0007] .

[0008] However, the compound 2 obtained by the above method has low purity, poor yield, poor color, and no effective purification method. It is often purified by column chromatography or the crude product is directly used in subsequent steps. However, column chromatography is not suitable for large-scale industrial preparation; if it is not purified and directly used in subsequent steps, the impurities mixed in with compound 2 will significantly affect the yield and purification of subsequent preparations. Furthermore, compound 2 obtained by the above method has a very dark color, dark brown.

[0009] Therefore, there is an urgent need to develop a novel method for the preparation and purification of ticagliptin intermediates that can be industrialized. Summary of the Invention

[0010] The purpose of this invention is to overcome the shortcomings of the prior art in that the intermediates of ticagliptin are difficult to purify, and to provide a method for the preparation and purification of ticagliptin intermediates.

[0011] The objective of this invention can be achieved through the following technical solutions: This invention provides a method for preparing and purifying a ticagliptin intermediate, the method specifically comprising the following steps: S1: Dissolve the unprotected ticagliptin intermediate precursor in an organic solvent, add a Lewis acid to react, and separate to obtain an organic phase containing the ticagliptin intermediate; S2: Add activated carbon to the organic phase for decolorization, and separate to obtain the decolorized ticagliptin intermediate; S3: The decolorized ticagliptin intermediate is reacted with an organic dicarboxylic acid to separate the ticagliptin intermediate organic dicarboxylic acid salt. S4: React the organic dicarboxylic acid salt of ticagliptin intermediate with an inorganic base to separate the organic phase containing ticagliptin intermediate; S5: The organic phase obtained in S4 was subjected to vacuum distillation, and a poor organic solvent was added. The mixture was then filtered to obtain the purified ticagliptin intermediate. The structural formulas of the ticagliptin intermediate precursor and the ticagliptin intermediate are as follows: , .

[0012] Further, in step S1, the molar ratio of the unprotected ticagliptin intermediate precursor to the Lewis acid is 1:(0.1~5).

[0013] Further, in step S1, the Lewis acid is any one or a combination of boron trifluoride ether, aluminum trichloride, magnesium perchlorate, zinc bromide, and tin tetrachloride.

[0014] Further, in step S1, the organic solvent is any one or a combination of anhydrous dichloromethane, anhydrous tetrahydrofuran, anhydrous toluene, anhydrous isopropyl ether, and anhydrous methyl tert-butyl ether.

[0015] Furthermore, in step S2, the decolorization temperature is the reflux temperature of the corresponding organic solvent in S1.

[0016] Further, in step S3, the organic dicarboxylic acid is any one or a combination of oxalic acid, malonic acid, malic acid, fumaric acid, maleic acid, tartaric acid, and succinic acid.

[0017] Further, in step S3, the molar ratio of the decolorized ticagliptin intermediate to the organic dicarboxylic acid is 1:(1~3).

[0018] Furthermore, in step S3, the organic solvent used in the reaction is any one or a combination of dichloromethane, tetrahydrofuran, ethyl acetate, methanol, ethanol, 1,4-dioxane, and toluene.

[0019] Further, in step S4, the inorganic base is any one or a combination of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium bicarbonate.

[0020] Further, in step S4, the molar ratio of the organic dicarboxylic acid salt to the inorganic base of the ticagliptin intermediate is 1:(1~5).

[0021] Further, in step S4, the organic solvent used in the reaction is any one or a combination of dichloromethane, tetrahydrofuran, ethyl acetate, methanol, ethanol, 1,4-dioxane, and toluene.

[0022] Furthermore, in step S5, when the reduced pressure distillation reaches 15-25% of the solvent remaining, a poor organic solvent is added.

[0023] Further, in step S5, the undesirable organic solvent is any one or a combination of n-hexane, n-heptane, or petroleum ether.

[0024] Compared with the prior art, the present invention has the following technical advantages: (1) The preparation and purification method of the present invention involves Lewis acid de-Boc, decolorization, organic dicarboxylic acid salt formation, alkaline hydrolysis, precipitation, etc., and finally prepares and purifies ticagliptin intermediate with a purity of more than 99%, which can be used for further preparation of ticagliptin.

[0025] (2) This invention abandons the traditional method of using acidic substances such as trifluoroacetic acid to remove Boc, and uses Lewis acids such as boron trifluoride ether to remove Boc for protection, which can reduce the generation of impurities; furthermore, the intermediate of ticagliptin can be separated from impurities by the salt formation of organic dicarboxylic acids, and finally high-purity ticagliptin intermediate is obtained, which can reduce the content of major impurities from 40% to less than 1%.

[0026] (3) The preparation and purification method of the present invention does not require column chromatography purification and multiple recrystallization operations, and is suitable for large-scale industrial preparation. Attached Figure Description

[0027] Figure 1 This is an HPLC chromatogram of the purified ticagliptin intermediate from Example 1.

[0028] Figure 2 The purified ticagliptin intermediate from Example 1 1 H NMR spectrum.

[0029] Figure 3 For the impurity (compound 12) in Comparative Example 1 1 H NMR spectrum. Detailed Implementation

[0030] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments. These embodiments are based on the technical solution of the present invention and provide detailed implementation methods and specific operating procedures. However, the scope of protection of the present invention is not limited to the following embodiments.

[0031] This invention provides a method for preparing and purifying ticagliptin intermediates, the operation of which is as follows: .

[0032] The method specifically includes the following steps: S1: Dissolve the unprotected ticagliptin intermediate precursor in an organic solvent, add a Lewis acid to react, and separate to obtain an organic phase containing the ticagliptin intermediate; ; S2: Add activated carbon to the organic phase for decolorization, and separate to obtain the decolorized ticagliptin intermediate; ; S3: The decolorized ticagliptin intermediate is reacted with an organic dicarboxylic acid to separate the ticagliptin intermediate organic dicarboxylic acid salt. ; S4: React the organic dicarboxylic acid salt of ticagliptin intermediate with an inorganic base to separate the organic phase containing ticagliptin intermediate; ; S5: The organic phase obtained in S4 was subjected to vacuum distillation, and a poor organic solvent was added. The mixture was then filtered to obtain the purified ticagliptin intermediate. .

[0033] The structural formulas of the ticagliptin intermediate precursor and the ticagliptin intermediate are as follows: , .

[0034] In some specific embodiments, in step S1, the molar ratio of the unprotected ticagliptin intermediate precursor to the Lewis acid is 1:(0.1~5).

[0035] In some specific embodiments, in step S1, the Lewis acid is any one or a combination of boron trifluoride ether, aluminum trichloride, magnesium perchlorate, zinc bromide, and tin tetrachloride.

[0036] In some more specific embodiments, in step S1, the Lewis acid is preferably boron trifluoride ether.

[0037] In some specific embodiments, in step S1, the organic solvent is any one or a combination of anhydrous dichloromethane, anhydrous tetrahydrofuran, anhydrous toluene, anhydrous isopropyl ether, and anhydrous methyl tert-butyl ether.

[0038] In some more specific embodiments, in step S1, the organic solvent is preferably dichloromethane.

[0039] In some specific embodiments, in step S1, an aqueous sodium hydroxide solution is added after the reaction for neutralization, and after washing and separation, an organic phase containing the ticagliptin intermediate is obtained.

[0040] In this study, the applicant discovered that during the deBoc protection process using conventional trifluoroacetic acid (TFA) or commonly used hydrochloric acid, sulfuric acid, etc., according to existing technology, a large amount of impurity (12) is generated during the formation of ticagliptin intermediate, with a content of approximately 20% to 45%. This impurity has similar solubility to the ticagliptin intermediate, making it impossible for commonly used recrystallization methods to effectively remove it, resulting in poor purity and low yield of the ticagliptin intermediate. Through the applicant's research, it was unexpectedly discovered that using Lewis acids can effectively reduce the generation of impurity (12), lowering its content to below 5%.

[0041] The structural formula of impurity (12) is as follows: .

[0042] In some specific embodiments, in step S2, the decolorization temperature is the reflux temperature of the corresponding organic solvent in S1. The purpose of using activated carbon for decolorization is to decolorize the reaction solution from brown to light yellow.

[0043] In some specific implementations, in step S2, after decolorization, insoluble matter is removed by filtration.

[0044] In some specific embodiments, in step S3, the organic dicarboxylic acid is any one or a combination of oxalic acid, malonic acid, malic acid, fumaric acid, maleic acid, tartaric acid, and succinic acid.

[0045] In some more specific embodiments, in step S3, the organic dicarboxylic acid is preferably oxalic acid.

[0046] In some specific embodiments, in step S3, the molar ratio of the decolorized ticagliptin intermediate to the organic dicarboxylic acid is 1:(1~3).

[0047] In some specific embodiments, in step S3, the organic solvent used in the reaction is any one or a combination of dichloromethane, tetrahydrofuran, ethyl acetate, methanol, ethanol, 1,4-dioxane, and toluene.

[0048] In some more specific embodiments, in step S3, the organic solvent is preferably dichloromethane.

[0049] In some specific embodiments, in step S3, the organic solvent that has been decolorized in S2 can be evaporated to dryness or re-dissolved by adding organic solvent.

[0050] In the study of this application, the applicant found that compound 2, in the presence of impurity (12), could not be purified by common recrystallization methods and exhibited a semi-solid, semi-liquid form. Impurity (12) also had similar solubility to the subsequent intermediates and could not be effectively removed, thus being carried into the final target product and causing a single impurity to exceed the ICH <0.1% requirement.

[0051] In the study of this application, the applicant also found that impurity (12) does not form salts with any acid. However, compound 2 readily forms salts with common acids, such as hydrochloric acid, sulfuric acid, and acetic acid. However, the salts formed by compound 2 and inorganic acids either fail to form a good solid form (such as the sulfate of compound 2) or the solids formed are very hygroscopic (such as the hydrochloride and acetate of compound 2), absorbing a large amount of water and deliquescing after being left exposed at room temperature for 1 minute, making it difficult to obtain stable and effective solid acid salts of compound 2. Especially in large-scale preparation, this significantly affects the filtration, transfer, and collection of the product. In the study of the salt formation of compound 2, the applicant found that when using organic dicarboxylic acids, compound 2 not only obtains a good solid form, but also has a significantly reduced water absorption, and no obvious deliquescence was observed after being left exposed at room temperature for 1 hour.

[0052] In some specific embodiments, in step S4, the inorganic base is any one or a combination of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium bicarbonate.

[0053] In some more specific embodiments, in step S4, the inorganic base is preferably sodium hydroxide.

[0054] In some specific embodiments, in step S4, the molar ratio of the organic dicarboxylic acid salt to the inorganic base of the ticagliptin intermediate is 1:(1~5).

[0055] In some specific embodiments, in step S4, the organic solvent used in the reaction is any one or a combination of dichloromethane, tetrahydrofuran, ethyl acetate, methanol, ethanol, 1,4-dioxane, and toluene.

[0056] In some more specific embodiments, in step S4, the organic solvent is preferably dichloromethane.

[0057] In some specific embodiments, in step S5, when the reduced pressure distillation reaches 15-25% of the solvent remaining, a poor organic solvent is added.

[0058] In some more specific embodiments, in step S5, when the reduced pressure distillation reaches 20% of the solvent remaining, a poor organic solvent is added, and the mixture is cooled to 0-10 °C.

[0059] In some specific embodiments, in step S5, the undesirable organic solvent is any one or a combination of n-hexane, n-heptane, or petroleum ether.

[0060] Each of the above embodiments can be implemented individually, or in any combination of two or more. The following detailed description of specific examples will further illustrate these embodiments.

[0061] Unless otherwise specified, the reagents, methods, instruments, and equipment used in this invention are conventional in the art. Unless otherwise specified, the reagents and materials used in the following examples are all commercially available.

[0062] The unprotected Boc intermediate precursor of ticagliptin (compound 10) referred to in this invention has the existing chemical structure mentioned in the background art. Its preparation method can be found in Bioorganic & Medicinal Chemistry, 2012, 20, 5705-5719, US 7074794B2 or WO 2012165547A1, but is not intended to limit this application and will not be described further hereafter.

[0063] Example 1: This embodiment provides a method for preparing and purifying a ticagliptin intermediate (compound 2), specifically including the following steps: (1) Synthesis of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (compound 2): Compound 10 (100 g, 0.292 mol) and dichloromethane (500 mL) were added to a reaction flask and stirred at room temperature until the substrate was completely dissolved. Boron trifluoride diethyl ether (42.6 g, 0.3 mol) was added dropwise. The mixture was then heated to reflux and stirred for 12 hours. After cooling to 0–10 °C, a 10% sodium hydroxide aqueous solution was added dropwise to the system until the pH reached 8. The mixture was separated to obtain the organic phase of compound 2.

[0064] (2) Decolorization of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (2): 10 g of activated carbon was added to the organic phase of compound 2, and then the mixture was heated to reflux temperature and stirred for 1 hour. After cooling to room temperature, the activated carbon was removed by filtration, yielding the decolorized organic phase of compound 2.

[0065] (3) Synthesis of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine oxalate (11): Under reflux, oxalic acid (54 g, 0.6 mol) was added in portions to the organic phase of compound 2 after decolorization in the previous step, and the mixture was stirred for 1 hour. After cooling to room temperature, the mixture was filtered, and the resulting solid was thoroughly washed with 500 mL of ethanol.

[0066] (4) Dissociation of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine oxalate (11): The solid compound 11 obtained in the previous step was mixed with 500 mL of dichloromethane and 500 mL of water. Sodium hydroxide was added at room temperature until the pH of the system reached 8. The mixture was separated to obtain a dichloromethane solution of compound 2.

[0067] (5) Purification of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (2): The dichloromethane solution of compound 2 from the previous step was distilled under reduced pressure, leaving approximately 100 mL of dichloromethane. Then, 300 mL of n-hexane was added under reflux, the temperature was lowered to 0-10 °C, and the mixture was stirred for 2 hours. The mixture was filtered, and the solid was dried at 50 °C to obtain 88 g of a pale yellow solid (2), with a yield of 88%.

[0068] After testing, such as Figure 1 As shown, the HPLC purity is 99.36%. Mp: 10³-10⁴ °C. 1¹H NMR (400 MHz, CDCl₃) (ppm): 7.78 (dd, J = 8.8, 1.2 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.24 (t, J = 7.6 Hz, 1H), 5.67 (s, 1H), 2.89–2.81 (m, 8H), 2.27 (s, 3H). Purified ticagliptin intermediate. 1 H NMR see Figure 2 .

[0069] Comparative Example 1: Compound 2 was prepared according to the method reported by Tanabe Mitsubishi Pharmaceutical (Bioorganic & Medicinal Chemistry, 2012, 20, 5705-5719). The specific procedures are as follows: Compound 10 (9.35 g, 0.027 mol) was dissolved in 100 mL of DCM, and 50 mL of trifluoroacetic acid was added at room temperature with stirring for 1.5 hours. The solvent was removed by vacuum distillation, and the residue was added to water and washed with diethyl ether. The mixture was separated, and the resulting aqueous solution was neutralized with sodium bicarbonate solution and extracted with chloroform. After drying, the chloroform was evaporated to obtain a crude product that was a viscous substance with two main spots on TLC. The two main spots were separated by column chromatography to obtain 2.1 g of impurity (12) in approximately 40% yield and 2.6 g of compound 2 in approximately 40% yield.

[0070] In this comparative example, the impurity (12) separated is a white solid, MP: 127-128 ℃. 1 H NMR(400 MHz, CDCl3) (ppm): 7.54 (d, J = 5.6 Hz, 2H), 7.39 (t, J = 5.6 Hz, 2H), 7.18 (t, J = 5.6 Hz, 1H), 3.42 (s, 2H), 2.18 (s, 3H).

[0071] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. A method for preparing and purifying a ticagliptin intermediate, characterized in that, The method includes the following steps: S1: Dissolve the unprotected ticagliptin intermediate precursor in an organic solvent, add a Lewis acid to react, and separate to obtain an organic phase containing the ticagliptin intermediate; S2: Add activated carbon to the organic phase for decolorization, and separate to obtain the decolorized ticagliptin intermediate; S3: The decolorized ticagliptin intermediate is reacted with an organic dicarboxylic acid to separate the ticagliptin intermediate organic dicarboxylic acid salt. S4: React the organic dicarboxylic acid salt of ticagliptin intermediate with an inorganic base to separate the organic phase containing ticagliptin intermediate; S5: The organic phase obtained in S4 was subjected to vacuum distillation, and a poor organic solvent was added. The mixture was then filtered to obtain the purified ticagliptin intermediate. The structural formulas of the ticagliptin intermediate precursor and the ticagliptin intermediate are as follows: ， 。 2. The method for preparing and purifying a ticagliptin intermediate according to claim 1, characterized in that, In step S1, the molar ratio of the unprotected ticagliptin intermediate precursor to the Lewis acid is 1: (0.1~5). The Lewis acid is any one or a combination of boron trifluoride ether, aluminum trichloride, magnesium perchlorate, zinc bromide, and tin tetrachloride.

3. The method for preparing and purifying a ticagliptin intermediate according to claim 1, characterized in that, In step S1, the organic solvent is any one or a combination of anhydrous dichloromethane, anhydrous tetrahydrofuran, anhydrous toluene, anhydrous isopropyl ether, and anhydrous methyl tert-butyl ether.

4. The method for preparing and purifying a ticagliptin intermediate according to claim 1, characterized in that, In step S2, the decolorization temperature is the reflux temperature of the corresponding organic solvent in S1.

5. The method for preparing and purifying a ticagliptin intermediate according to claim 1, characterized in that, In step S3, the organic dicarboxylic acid is any one or a combination of oxalic acid, malonic acid, malic acid, fumaric acid, maleic acid, tartaric acid, and succinic acid.

6. The method for preparing and purifying a ticagliptin intermediate according to claim 1, characterized in that, In step S3, the molar ratio of the decolorized ticagliptin intermediate to the organic dicarboxylic acid is 1:(1~3).

7. The method for preparing and purifying a ticagliptin intermediate according to claim 1, characterized in that, In step S4, the inorganic base is any one or a combination of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium bicarbonate.

8. The method for preparing and purifying a ticagliptin intermediate according to claim 1, characterized in that, In step S4, the molar ratio of the organic dicarboxylic acid salt to the inorganic base in the ticagliptin intermediate is 1: (1~5).

9. The method for preparing and purifying a ticagliptin intermediate according to claim 1, characterized in that, In step S5, when the reduced pressure distillation reaches 15-25% of the solvent remaining, a poor organic solvent is added.

10. The method for preparing and purifying a ticagliptin intermediate according to claim 1, characterized in that, In step S5, the undesirable organic solvent is any one or a combination of n-hexane, n-heptane, or petroleum ether.

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