A method for preparing a piperidine ring compound

Abstract

The invention discloses a method for preparing a piperidine ring compound. Specifically, the invention provides a method for preparing a compound of formula 2, which comprises the following steps: in a solvent, in the presence of an alkali metal carbonate and an alkali metal iodide of not less than 300 meshes, a substitution reaction is carried out with a compound of formula 1 and chloromethyl isopropyl carbonate to generate a compound of formula 2; the preparation method provided by the invention has high yield and low impurity content in the product.

Description

Technical Field

[0001] The invention relates to a method for preparing a piperidine ring compound. Background Art

[0002] WO2022022559 discloses an antiplatelet drug and a synthesis method thereof, which includes a method for preparing a piperidine ring compound of formula 2 from a compound of formula 1 as described in the following formula:

[0003] ;

[0004] This method generates impurities as shown in structural formula a, which account for a very high proportion (about 1:1 molar ratio to the product), resulting in a huge waste of raw materials, making it difficult to carry out large-scale production with controllable costs. Conventional optimization of reaction conditions such as temperature and reaction time also makes it difficult to reduce the impurity content to an acceptable range.

[0005] .

[0006] CN116813532A discloses a method for preparing a piperidine ring compound of formula 2 from a compound of formula 1:

[0007] ;

[0008] This method replaces the sodium borohydride and potassium cyanide used in the method disclosed in WO2022022559 with potassium carbonate, which greatly improves the yield and reduces the impurity content shown in formula a. However, the impurity content shown in formula a produced by this method is still relatively high, resulting in a large loss of raw materials. In addition, the presence of a large number of impurities greatly increases the difficulty of purification. On the basis of adding seed crystals for purification, it is still necessary to make a trade-off between yield and purity. Summary of the invention

[0009] The technical problem to be solved by the present invention is to overcome the defects of low yield and high impurity content in the preparation method of the compound of formula 2 in the prior art, and to provide a preparation method with high yield and low impurity content in the product.

[0010] The present invention solves the above technical problems through the following technical solutions:

[0011] The present invention provides a method for preparing a compound of formula 2, comprising the following steps: in a solvent, in the presence of an alkali metal carbonate and an alkali metal iodide of not less than 300 mesh, a substitution reaction is carried out between the compound of formula 1 and chloromethyl isopropyl carbonate to produce a compound of formula 2;

[0012] .

[0013] The solvent is a commonly used solvent for this type of reaction in the art, preferably a ketone solvent; for example, acetone.

[0014] In some embodiments, the alkali metal carbonate is one or more of potassium carbonate and sodium carbonate; preferably potassium carbonate or sodium carbonate; for example potassium carbonate.

[0015] In some embodiments, the mesh size of the alkali metal carbonate is 300 mesh to 600 mesh. In some embodiments, the mesh size of the alkali metal carbonate is 300 mesh to 400 mesh.

[0016] In some embodiments, the alkali metal iodide is sodium iodide.

[0017] In some embodiments, the mass-to-volume ratio of the compound of Formula 1 and the solvent is 1 g: (3-6) ml; preferably 1 g: (4-5) ml; for example 1 g: 4 ml or 1 g: 5 ml.

[0018] In some embodiments, the molar ratio of the compound of formula 1 to the alkali metal carbonate is 1:1.5-6; preferably 1:2.5-6; for example 1:2.5 or 1:5.

[0019] In some embodiments, the molar ratio of the compound of Formula 1 to the alkali metal iodide is 1:(1-1.2); for example, 1:1.1.

[0020] In some embodiments, the molar ratio of the compound of formula 1 to the chloromethyl isopropyl carbonate is 1:(1-1.5); preferably 1:(1.1-1.3); for example 1:1.1 or 1:1.3.

[0021] In some embodiments, the reaction temperature of the substitution reaction is 40-60°C; for example, 50°C.

[0022] The progress of the reaction can be monitored by conventional detection methods in the art (eg, HPLC, TLC or NMR). The disappearance of the compound of formula 1 is generally regarded as the reaction endpoint. The reaction time is generally 18-32 hours, for example, 24 hours.

[0023] In some embodiments, the substitution reaction is carried out under a protective gas atmosphere, and the protective gas is a conventional protective gas for this type of reaction in the art, such as nitrogen, helium or argon; preferably nitrogen.

[0024] In some embodiments, the reaction material of the substitution reaction consists of the compound of Formula 1, the solvent, the alkali metal carbonate, the alkali metal iodide and the chloromethyl isopropyl carbonate.

[0025] In some embodiments, the substitution reaction further comprises the following post-treatment steps: after the reaction is completed, filtering, washing the filter cake, concentrating the organic phase, extracting, washing, and concentrating.

[0026] In some embodiments, in the post-treatment step, acetone is used for washing the filter cake. Preferably, the mass to volume ratio of the compound of Formula 1 and the acetone used for washing the filter cake is 1 g: (1.5-2.5) ml; for example, 1 g: 2 ml.

[0027] In some embodiments, the extraction is performed using a mixed solvent of ethyl acetate and water in a volume ratio of 1:1; preferably, the mass-to-volume ratio of the compound of formula 1 to the mixed solvent is 1 g: (3-7) ml; for example, 1 g: 5 ml.

[0028] In some embodiments, the content of impurity a in the product of the substitution reaction is less than 10%; preferably less than 5%; for example less than 3%; optimally, the content of impurity a in the product of the substitution reaction is less than 2%;

[0029] .

[0030] Unless otherwise specified, the terms used in the present invention have the following meanings:

[0031] The term "alkali metal carbonate of not less than 300 mesh" includes alkali metal carbonate of 300 mesh to the highest mesh number known to those skilled in the art.

[0032] The positive improvement effect of the present invention is that the preparation method provided by the present invention uses an alkali metal carbonate of not less than 300 meshes, which not only reduces the content of impurity a to less than 5%, but also greatly simplifies the purification step, and does not need to add seed crystals for purification, thereby increasing the actual amount of the final product obtained. DETAILED DESCRIPTION

[0033] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples.

[0034]

[0035] Example 1

[0036] In N 2Compound 1 (100 g), acetone (4 V, "V" represents the volume of solvent corresponding to 1 g of raw material, such as "4V" represents the amount of acetone corresponding to 1 g of compound 1 is 4 ml), sodium iodide (1.1 eq), 300 mesh potassium carbonate (McLean, potassium carbonate-300 mesh) (2.5 eq) were mixed, the temperature was raised to 50°C, and then chloromethyl isopropyl carbonate (1.1 eq) was slowly added. After reacting for 24 hours, the mixture was filtered, and the filter cake was washed with acetone (2V). The organic phases were combined and concentrated in vacuo, extracted with ethyl acetate and water (5V, 1:1), and the organic phase was washed with saturated brine and concentrated to obtain compound 2 (yield 80%, purity 97%, impurity a content 2%). .

[0037] Example 2

[0038] In N 2 Compound 1 (300 g), acetone (5 V), sodium iodide (1.1 eq), and 400 mesh potassium carbonate (McLean, potassium carbonate-400 mesh) (5 eq) were mixed under reduced pressure, the temperature was raised to 50°C, and then chloromethyl isopropyl carbonate (1.3 eq) was slowly added and reacted for 24 hours, filtered, and the filter cake was washed with acetone (2 V). The organic phases were combined and concentrated in vacuo, extracted with ethyl acetate and water (5 V, 1:1), and the organic phase was washed with saturated brine and concentrated to obtain compound 2 (yield 82%, purity 93%, impurity a content 3%).

[0039] Example 3

[0040] In N 2 Compound 1 (300 g), acetone (5 V), sodium iodide (1.1 eq), and 600 mesh sodium carbonate (McLean, sodium carbonate-600 mesh) (2.5 eq) were mixed, the temperature was raised to 50°C, and then chloromethyl isopropyl carbonate (1.3 eq) was slowly added. The reaction was continued for 24 h and filtered. The filter cake was washed with acetone (2 V), and the organic phases were combined and concentrated in vacuo. The mixture was extracted with ethyl acetate and water (5 V, 1:1), and the organic phase was washed with saturated brine and concentrated to obtain compound 2 (yield 75%, purity 91%, impurity a content 5%).

[0041] Comparative Example 1

[0042] In N 2 Compound 1 was stirred at 0 °C under N 2 DownwardNaBH 4To a solution of 1.1 g, 28.8 mmol) in DMF (1.0 L) was added NaH (20.7 g, 864.6 mmol). Compound 1 (200.0 g, 576.4 mmol) was added dropwise at 0°C, followed by stirring at 0°C for 1 hour. Subsequently, chloromethyl isopropyl carbonate (100.7 g, 662.8 mmol) was added at 0°C, and the resulting mixture was stirred at room temperature for 1 hour. 2 O (1.0 L) was added to the mixture, followed by extraction with EtOAc (1.0 L*3). The organic layer was washed with brine and 2 SO 4 The mixture was dried and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (petroleum ether / EtOAc = 20 / 1) to obtain compound 2 (135.0 g, 50% yield) and impurity a (126 g) as a colorless oil. The molar ratio of compound 2 to impurity a was approximately 1:1.

[0043] Comparative Example 2

[0044] In N 2 Compound 1 (30.6 kg) was mixed with acetone at 4 °C and the mixture was concentrated. Another portion of acetone was added to the mixture and then K 2 CO 3 (40-100 mesh mixed) (24.4 kg), NaI (16 kg) and chloromethyl isopropyl carbonate (15.6 kg) were added to the mixture in sequence under stirring. After addition, the mixture was stirred at 50±5°C for 16 hours. The mixture was cooled to 20±5°C, filtered and the filter cake was rinsed with acetone. The filtrate was concentrated to 60 L under vacuum. Ethyl acetate and water were added to the mixture at 20±5°C. After stirring and standing, the mixture was separated into two layers and the upper organic phase was collected. The organic phase was washed with water and then concentrated. i-PrOH (120 L) was added to the mixture and the mixture was concentrated. Water and seed crystals were added to the mixture at 20±5°C, and the mixture was then stirred at 5±5°C. After filtration and drying, compound 2 (35.24 kg) was obtained with a yield of 86%, a purity of 80%, and an impurity a content of 12% (if further purification is performed to increase the purity, the yield will be greatly reduced).

[0045] Although the specific embodiments of the present invention are described above, it should be understood by those skilled in the art that this is only for illustration and the protection scope of the present invention is defined by the appended claims. Those skilled in the art may make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but these changes and modifications all fall within the protection scope of the present invention.

Claims

1. A method for preparing a compound of formula 2, characterized in that: It includes the following steps: In a solvent, in the presence of an alkali metal carbonate and an alkali metal iodide having a mesh size of 300 to 600 mesh, a substitution reaction is carried out between the compound of formula 1 and chloromethyl isopropyl carbonate to produce a compound of formula 2; Wherein, the solvent is a ketone solvent; the alkali metal carbonate is one or more of sodium carbonate and potassium carbonate; the alkali metal iodide is sodium iodide; the molar ratio of the compound of formula 1 to the alkali metal carbonate is 1:(2.5-6); 。 2. The preparation method according to claim 1, characterized in that It meets one or more of the following conditions: (1) The mass-to-volume ratio of the compound of formula 1 and the solvent is 1 g: (3-6) ml; (2) The molar ratio of the compound of formula 1 to the alkali metal iodide is 1:(1-1.2); (3) The molar ratio of the compound of formula 1 to the chloromethyl isopropyl carbonate is 1:(1-1.5); (4) The reaction temperature of the substitution reaction is 40-60°C; (5) The reaction time of the substitution reaction is 18 to 32 hours; (6) The substitution reaction is carried out under a protective gas atmosphere; (7) The reaction materials of the substitution reaction are composed of the following: the compound of formula 1, the solvent, the alkali metal carbonate, the alkali metal iodide and the chloromethyl isopropyl carbonate; (8) The content of impurity a in the product of the substitution reaction is less than 5%; .

3. The preparation method according to claim 2, characterized in that: It meets one or more of the following conditions: (1) The solvent is acetone; (2) The alkali metal carbonate is sodium carbonate or potassium carbonate; (3) The mass-to-volume ratio of the compound of formula 1 and the solvent is 1 g: (4-5) ml; (4) The molar ratio of the compound of formula 1 to the alkali metal iodide is 1:1.1; (5) The molar ratio of the compound of formula 1 to the chloromethyl isopropyl carbonate is 1:(1.1-1.3); (6) The reaction temperature of the substitution reaction is 50°C; (7) The reaction time of the substitution reaction is 24 hours; (8) When the substitution reaction is carried out under a protective gas atmosphere, the protective gas is nitrogen, helium or argon; (9) The content of impurity a in the product of the substitution reaction is less than 3%; ; (10) The mesh size of the alkali metal carbonate is 300 mesh to 400 mesh.

4. The preparation method according to claim 3, characterized in that: It meets one or more of the following conditions: (1) The alkali metal carbonate is potassium carbonate; (2) The mass-to-volume ratio of the compound of formula 1 to the solvent is 1 g:4 ml or 1 g:5 ml; (3) The molar ratio of the compound of formula 1 to the alkali metal carbonate is 1:2.5 or 1:5; (4) The molar ratio of the compound of formula 1 to the chloromethyl isopropyl carbonate is 1:1.1 or 1:1.3; (5) When the substitution reaction is carried out under a protective gas atmosphere, the protective gas is nitrogen; (6) The content of impurity a in the product of the substitution reaction is less than 2%; .

5. The preparation method according to claim 1, characterized in that: The substitution reaction further comprises the following post-treatment steps: after the reaction is completed, filtering, washing the filter cake, concentrating the organic phase, extracting, washing and concentrating.

6. The preparation method according to claim 5, characterized in that: The post-processing step satisfies one or both of the following conditions: (1) Acetone is used for washing the filter cake; (2) The extraction is performed using a mixed solvent of ethyl acetate and water in a volume ratio of 1:

1.

7. The preparation method according to claim 6, characterized in that: The post-processing step satisfies one or both of the following conditions: (1) When acetone is used for washing the filter cake, the mass-to-volume ratio of the compound of Formula 1 to the acetone used for washing the filter cake is 1 g: (1.5-2.5) ml; (2) When the extraction is performed using a mixed solvent of ethyl acetate and water in a volume ratio of 1:1, the mass-to-volume ratio of the compound of formula 1 to the mixed solvent is 1 g: (3-7) ml.

8. The preparation method according to claim 7, characterized in that: The post-processing step satisfies one or both of the following conditions: (1) When acetone is used for washing the filter cake, the mass-to-volume ratio of the compound of Formula 1 to the acetone used for washing the filter cake is 1 g:2 ml; (2) When the extraction is performed using a mixed solvent of ethyl acetate and water in a volume ratio of 1:1, the mass-to-volume ratio of the compound of formula 1 to the mixed solvent is 1 g:5 ml.

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