Purification method of 3-amino-5-methylpiperidine with amino group protected by Boc

Abstract

This application provides a method for purifying 3-amino-5-methylpiperidine with an amino group protected by Boc. The method includes: adding a solvent to crude 3-amino-5-methylpiperidine with an amino group protected by Boc, heating to dissolve, and obtaining a mixture; adding an acid and an amine crystallization aid to the mixture, stirring and dispersing, and obtaining a dispersion; cooling the dispersion to crystallize, separating and drying, to obtain salt crystals of 3-amino-5-methylpiperidine with an amino group protected by Boc. This application improves the product properties of 3-amino-5-methylpiperidine with an amino group protected by Boc, increases the product yield and purity, and achieves a purity of ≥99.5% for 3-amino-5-methylpiperidine with an amino group protected by Boc and a diastereomeric impurity content of ≤0.15%. Simultaneously, it simplifies the operation steps for salting out 3-amino-5-methylpiperidine with an amino group protected by Boc, shortens the operation time, and reduces production costs.

Description

Technical Field

[0001] This application relates to the field of organic synthesis technology, and more specifically, to a method for purifying 3-amino-5-methylpiperidine with an amino group protected by Boc. Background Technology

[0002] 3-Amino-5-methylpiperidine is an intermediate in drug synthesis, for example, as a side chain in the synthesis of a quinolone antibiotic, (3S,5S)-7-[3-amino-5-methylpiperidine]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid. Because related substances and optical isomers in drugs can produce significant toxic side effects, it is necessary to strictly control the levels of related impurities in the starting material 3-amino-5-methylpiperidine.

[0003] Currently, 3-amino-5-methylpiperidine is generally produced from natural D-glutamic acid with its amino group protected by Boc through a multi-step reaction process (as shown below).

[0004]

[0005] D-glutamic acid already contains a high-purity chiral amino group; therefore, the main optical impurity in 3-amino-5-methylpiperidine is its diastereomer, and the removal of this impurity is crucial for product quality control. Patent US20070232650A1 reports a method for synthesizing 3-amino-5-methylpiperidine with a Boc-protected amino group, but it lacks purification in the post-processing, resulting in a waxy solid product that fails to yield high-purity crystals. Patent US20100152452A1 adds oxalic acid to the reaction system to form an oxalate intermediate, but it lacks further post-processing to remove diastereomer impurities. Using common crystallization methods, the crystallization rate is slow, and the pre-crystallization product is gel-like. Strict control of the cooling process and crystallization time is necessary; otherwise, some unconverted product can adsorb onto the precipitated solid, leading to high impurity levels in the product. Summary of the Invention

[0006] The main objective of this application is to provide a method for purifying 3-amino-5-methylpiperidine with amino group protected by Boc, in order to solve the problems of difficult crystallization and low purity of 3-amino-5-methylpiperidine with amino group protected by Boc in the prior art.

[0007] To achieve the above objectives, according to one aspect of this application, a method for purifying 3-amino-5-methylpiperidine, whose amino group is protected by Boc as shown in Formula I, is provided, comprising the following steps:

[0008]

[0009] Step S1: Add solvent to crude 3-amino-5-methylpiperidine with amino group protected by Boc, heat to dissolve, and obtain a mixture; the crude product contains the (3S,5S) configuration product shown in Formula I(a) and / or the (3R,5R) configuration product shown in Formula I(b); Step S2: Add acid and amine crystallization aid to the mixture, stir and disperse to obtain a dispersion; Step S3: Cool the dispersion to crystallize, separate and dry to obtain salt crystals of 3-amino-5-methylpiperidine with amino group protected by Boc.

[0010] Furthermore, in step S1, the solvent is one or more of methanol, ethanol, n-propanol, and isopropanol.

[0011] Further, in step S1, the liquid-to-solid ratio of the solvent to the crude 3-amino-5-methylpiperidine with the amino group protected by Boc is (4-16):1.

[0012] Further, in step S1, the heating temperature is the reflux temperature of the solvent; preferably, the heating temperature is 40 to 100°C.

[0013] Further, in step S2, the acid is an organic acid, preferably one or more of formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, oxalic acid, succinic acid, lactic acid, and tartaric acid; more preferably, the acid is one or more of oxalic acid, lactic acid, and tartaric acid.

[0014] Further, in step S2, 0.001 to 0.01 mol of acid is added to each gram of crude 3-amino-5-methylpiperidine with amino group protected by Boc in the mixture.

[0015] Further, in step S2, the amine crystallization aid is one or more of ammonia, ethylamine, ethylenediamine, triethylamine, benzylamine, aniline, monoethanolamine and dimethylformamide; preferably, the amine crystallization aid is benzylamine and / or aniline.

[0016] Further, in step S2, the mass ratio of the amine crystallization aid to the crude 3-amino-5-methylpiperidine with its amino group protected by Boc in the mixture is (0.0001 to 0.1):1; preferably, the mass ratio of the amine crystallization aid to the crude 3-amino-5-methylpiperidine with its amino group protected by Boc in the mixture is (0.001 to 0.01):1.

[0017] Further, in step S2, the dispersion temperature is the reflux temperature of the solvent; preferably, the dispersion temperature is 40–100°C.

[0018] Furthermore, in step S3, the crystallization temperature is -20 to 30°C; preferably, the crystallization temperature is 0 to 10°C.

[0019] Compared with the prior art, the progress of this application is reflected in at least the following aspects:

[0020] (1) This application improves the product properties of 3-amino-5-methylpiperidine with amino protected by Boc as salt crystallization, and improves the product yield and purity. The purity of 3-amino-5-methylpiperidine with amino protected by Boc in the product is ≥99.5%, and the content of diastereomer impurities is ≤0.15%.

[0021] (2) This application simplifies the salting-out crystallization process of 3-amino-5-methylpiperidine with amino group protected by Boc, shortens the operation time, further improves product purity, and reduces production costs. Attached Figure Description

[0022] The accompanying drawings, which form part of this application, are used to provide a further understanding of this application. The illustrative embodiments and descriptions of this application are used to explain this application and do not constitute an undue limitation of this application. In the drawings:

[0023] Figure 1 The liquid phase chromatograms of related substances of crude 3-amino-5-methylpiperidine with amino groups protected by Boc according to the embodiments of this application are shown.

[0024] Figure 2 The liquid phase spectrum of the purified product according to Example 1 of this application is shown;

[0025] Figure 3 The liquid phase chromatograms of the purified product according to Comparative Example 1 of this application are shown; and

[0026] Figure 4 The liquid phase spectrum of the purified product according to Comparative Example 2 of this application is shown. Detailed Implementation

[0027] It should be noted that, unless otherwise specified, the embodiments and features described in this application can be combined with each other. This application will now be described in detail with reference to the accompanying drawings and embodiments.

[0028] It should be noted that the crude 3-amino-5-methylpiperidine with amino groups protected by Boc described in this application is obtained by chemically synthesizing 3-amino-5-methylpiperidine from D-glutamic acid or L-glutamic acid with amino groups protected by Boc, with reference to patent US20070232650A1 or other feasible synthetic routes.

[0029] Explanation of terms:

[0030] Boc: tert-Butoxycarbonyl, CH3C(CH3)2OCO-*, where "*" indicates a linking bond.

[0031] Liquid-to-solid ratio: The ratio of solution volume (ml) to solid material (g).

[0032] As described in the background section of this application, the prior art suffers from difficulties in crystallizing 3-amino-5-methylpiperidine with its amino group protected by Boc, resulting in low purity. It should be noted that "purity" here primarily refers to the purity of 3-amino-5-methylpiperidine with its amino group protected by Boc in the (3S,5S) configuration (SS configuration) and / or (3R,5R) configuration (RR configuration) of the crystallized product.

[0033] To address the aforementioned problems, in a typical embodiment of this application, a method for purifying 3-amino-5-methylpiperidine, whose amino group is protected by Boc as shown in Formula I, is provided, comprising the following steps:

[0034]

[0035] Step S1: Add solvent to crude 3-amino-5-methylpiperidine with amino group protected by Boc, heat to dissolve, and obtain a mixture; the crude product contains the (3S,5S) configuration product shown in Formula I(a) and / or the (3R,5R) configuration product shown in Formula I(b), as well as a small amount of (3S,5R) configuration and (3R,5S) configuration diastereomer impurities; Step S2: Add acid and amine crystallization aid to the mixture, stir and disperse to obtain a dispersion; Step S3: Cool the dispersion to crystallize, separate and dry to obtain salt crystals of 3-amino-5-methylpiperidine with amino group protected by Boc.

[0036] This application first adds a solvent to Boc-protected 3-amino-5-methylpiperidine, heats under reflux to dissolve it, and obtains a mixture; then, acid is added for preliminary purification. During this process, an amine crystallization aid is added and stirred to disperse, obtaining a dispersion. Without the amine crystallization aid, the precipitated solid product is gel-like, indicating that the molecular arrangement at the microscopic level is disordered; after adding the amine crystallization aid, the molecular arrangement is rearranged, and crystals precipitate for further purification. Finally, the mixture is separated and dried to obtain high-purity, high-yield Boc-protected 3-amino-5-methylpiperidine crystals. Depending on the configuration characteristics of the reactant D-glutamic acid or L-glutamic acid, when the reactant is single-chiral, the final product is SS-configuration 3-amino-5-methylpiperidine crystals and lower levels of other configurational impurities, or RR-configuration 3-amino-5-methylpiperidine crystals and lower levels of other configurational impurities.

[0037] This application improves the product properties of the salt crystallization of 3-amino-5-methylpiperidine with amino group protected by Boc, increasing the product yield and purity. The purity of 3-amino-5-methylpiperidine with amino group protected by Boc in the product is ≥99.5%, and the content of diastereomers is ≤0.15%. Simultaneously, it simplifies the crystallization process of 3-amino-5-methylpiperidine salt with amino group protected by Boc, shortening the operation time and reducing production costs.

[0038] This application does not have special requirements for the solvent used to dissolve the crude product, as long as it can form a good dissolution of the crude product and does not affect the subsequent reaction after adding acid and amine crystallization aids. In a preferred embodiment, in step S1, the solvent is one or more of methanol, ethanol, n-propanol and isopropanol. Isopropanol is preferred for the purpose of making the solvent used more compatible with the purification system of this application.

[0039] In a preferred embodiment, in step S1, the liquid-to-solid ratio of the solvent to the crude 3-amino-5-methylpiperidine with amino groups protected by Boc is (4-16):1, which enables a more suitable dissolution of the crude product and provides a more suitable liquid environment, preparing for the subsequent purification of the product.

[0040] Typical, but not limiting, liquid-to-solid ratios of the solvent to crude 3-amino-5-methylpiperidine with an amino group protected by Boc are 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, or any two of these ratios within a range.

[0041] The heating and dissolution temperature after adding the solvent should not be too low, otherwise it will cause the product to precipitate a gel-like solid in advance during subsequent operations, affecting the impurity removal effect; if it is too high, it will have little effect on improving the yield and purity of the product, and will also lead to increased costs. Therefore, in a preferred embodiment, in step S1, the heating temperature is the reflux temperature of the selected solvent; for the purpose of further improving the yield and purity, the heating temperature is preferably 40 to 100°C.

[0042] To further ensure the smooth reaction between the acid and 3-amino-5-methylpiperidine during the salt formation process, thereby achieving both high yield and purity, in a preferred embodiment, the acid in step S2 is an organic acid, preferably one or more of formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, oxalic acid, succinic acid, lactic acid, and tartaric acid; more preferably, the acid is one or more of oxalic acid, lactic acid, and tartaric acid, and more preferably oxalic acid. When the above-mentioned acid is used for the salt formation reaction, the purity of the product is higher, and the detection amount of diastereomer impurities can reach below 0.1%.

[0043] In a preferred embodiment, in step S2, 0.001 to 0.01 mol of acid is added to each gram of crude 3-amino-5-methylpiperidine with amino group protected by Boc in the mixture, thereby further improving the salt formation effect and increasing the yield and purity of the product.

[0044] Typically, but not limitingly, the amount of acid added to the mixture per gram of crude 3-amino-5-methylpiperidine with amino group protected by Boc is 0.001 mol, 0.002 mol, 0.003 mol, 0.004 mol, 0.005 mol, 0.006 mol, 0.007 mol, 0.008 mol, 0.009 mol, 0.01 mol, or any two of these values.

[0045] As mentioned above, the crystallization rate in the prior art is relatively slow, requiring strict control of the cooling process and crystallization time. In contrast, this application uses amine crystallization aids to improve crystallization properties, shorten crystallization time, and prevent the adsorption of unconverted products onto the precipitated solid due to excessively long crystallization time, thus avoiding high impurity levels in the product. In a preferred embodiment, in step S2, the amine crystallization aid is one or more of ammonia, ethylamine, ethylenediamine, triethylamine, benzylamine, aniline, monoethanolamine, and dimethylformamide, which can yield crystalline piperidine salts and shorten the crystallization time. Preferably, the amine crystallization aid includes benzylamine and / or aniline, more preferably benzylamine. These amine crystallization aids can further improve yield and purity, and the detection level of diastereomer impurities can reach below 0.1%.

[0046] When the amount of amine crystallization aid added is too low, some products will remain in a gel-like state or adsorbed on the precipitated crystals due to incomplete crystallization, resulting in reduced product purity and excessive detection of diastereomer impurities. When the amount added is too high, the excess amine will consume the corresponding amount of acid, resulting in insufficient salt formation of piperidine products and reduced yield. Therefore, in a preferred embodiment, in step S2, the mass ratio of the amine crystallization aid to the crude 3-amino-5-methylpiperidine with amino groups protected by Boc in the mixture is (0.0001~0.1):1. Preferably, the mass ratio of the amine crystallization aid to the crude 3-amino-5-methylpiperidine with amino groups protected by Boc in the mixture is (0.001~0.01):1. The above mass ratio includes, but is not limited to, the above range, and limiting it to the above range is beneficial to further improve the product yield and purity.

[0047] Typical, but not limiting, mass ratios of amine crystallization aids to crude 3-amino-5-methylpiperidine with Boc-protected amino groups in the mixture are 0.0001:1, 0.0005:1, 0.001:1, 0.005:1, 0.01:1, 0.05:1, 0.1:1, or any two of these ratios within a range.

[0048] This application adds acid and amine crystallization aids to the mixture and then keeps it warm and stirs to obtain a dispersion. Therefore, the dispersion temperature and the heating and dissolution temperature should be kept consistent. Thus, in a preferred embodiment, in step S2, the dispersion temperature is the reflux temperature of the selected solvent; preferably, the dispersion temperature is 40 to 100°C.

[0049] When the crystallization temperature is too low, the product purity will decrease and the detection amount of diastereomer impurities will increase. When it is too high, the yield will decrease due to incomplete crystallization. Therefore, in a preferred embodiment, the crystallization temperature in step S3 is -20 to 30°C; preferably, the crystallization temperature is 0 to 10°C, which can further reduce the detection amount of diastereomer impurities and improve the product purity.

[0050] Typical, but not limiting, crystallization temperatures are -20°C, -10°C, 0°C, 10°C, 20°C, 30°C, or any two of these values.

[0051] The present application will be further described in detail below with reference to specific embodiments, which should not be construed as limiting the scope of protection claimed in the present application.

[0052] Unless otherwise specified, the crude 3-amino-5-methylpiperidine with Boc-protected amino groups used in the following examples and comparative examples was chemically synthesized from Boc-protected D-glutamic acid or L-glutamic acid, following patent US20070232650A1 or other feasible synthetic routes. The crude product was found to contain 90.2% of the main component, 3-amino-5-methylpiperidine with Boc-protected amino groups, in SS and / or RR configurations, and 6.9% of diastereomers. It was moderately alkaline. The related substances HPLC chromatogram of the crude product is shown below. Figure 1 .

[0053] Unless otherwise specified, the liquid phase purity and diastereomer detection amounts in the following examples and comparative examples refer to mass percentages.

[0054] Example 1

[0055] 10g of the crude product was added to 100ml of isopropanol and heated to reflux at 90℃. 4.2g of oxalic acid and 0.05g of benzylamine were added, and the mixture was stirred for 30min. The mixture was then cooled to 5℃ in an ice-water bath to crystallize. The crystals were filtered, and the filter cake was dried to obtain a white solid with a yield of 86% and a liquid chromatography purity of 99.9%. No diastereomers were detected. The related substances HPLC chromatogram of the product is shown below. Figure 2 .

[0056] Example 2

[0057] Take 10g of crude product and add it to 100ml of methanol. Heat under reflux at 40℃, add 4.2g of oxalic acid and 0.05g of benzylamine. Keep warm and stir for 30min. Cool to 5℃ in an ice water bath to crystallize. Filter and dry the filter cake to obtain a white solid with a yield of 53% and a liquid phase purity of 99.9%. No diastereomers were detected.

[0058] Example 3

[0059] Take 10g of crude product and add 100ml of ethanol. Heat to reflux at 75℃, add 4.2g of oxalic acid and 0.05g of benzylamine. Keep warm and stir for 30min. Cool to 5℃ in an ice water bath to crystallize. Filter and dry the filter cake to obtain a white solid with a yield of 78% and a liquid phase purity of 99.9%. No diastereomers were detected.

[0060] Example 4

[0061] Take 10g of crude product and add 100ml of n-propanol. Heat to reflux at 100℃, add 4.2g of oxalic acid and 0.05g of benzylamine. Keep warm and stir for 30min. Cool to 5℃ in an ice water bath to crystallize. Filter and dry the filter cake to obtain a white solid with a yield of 83% and a liquid phase purity of 99.9%. No diastereomers were detected.

[0062] Example 5

[0063] Take 10g of crude product and add 40ml of isopropanol. Heat to reflux at 90℃, add 4.2g of oxalic acid and 0.05g of benzylamine. Keep warm and stir for 30min. Cool to 5℃ in an ice water bath to crystallize. Filter and dry the filter cake to obtain a white solid with a yield of 89%, a liquid phase purity of 99.5%, and 0.14% diastereomers.

[0064] Example 6

[0065] Take 10g of crude product and add 160ml of isopropanol. Heat to reflux at 90℃, add 4.2g of oxalic acid and 0.05g of benzylamine. Keep warm and stir for 30min. Cool to 5℃ in an ice water bath to crystallize. Filter and dry the filter cake to obtain a white solid with a yield of 73%, a liquid phase purity of 99.9%, and 0.01% diastereomers.

[0066] Example 7

[0067] Take 10g of crude product and add 100ml of isopropanol. Heat to reflux at 90℃, add 4.2g of lactic acid and 0.05g of benzylamine. Keep warm and stir for 30min, then cool to 5℃ in an ice water bath. Filter and dry the filter cake to obtain a white solid with a yield of 80%, a liquid phase purity of 99.8%, and 0.04% diastereomers.

[0068] Example 8

[0069] Take 10g of crude product and add 100ml of isopropanol. Heat to reflux at 90℃, add 7.0g of tartaric acid and 0.05g of benzylamine. Keep warm and stir for 30min, then cool to 5℃ in an ice water bath. Filter and dry the filter cake to obtain a white solid with a yield of 82%, a liquid phase purity of 99.8%, and 0.03% diastereomers.

[0070] Example 9

[0071] Take 10g of crude product and add 100ml of isopropanol. Heat to reflux at 90℃, add 2.2g of formic acid and 0.05g of benzylamine. Keep warm and stir for 30min, then cool to 5℃ in an ice water bath. Filter and dry the filter cake to obtain a white solid with a yield of 82%, a liquid phase purity of 99.5%, and 0.12% diastereomers.

[0072] Example 10

[0073] Take 10g of crude product and add 100ml of isopropanol. Heat to reflux at 90℃, add 2.8g of acetic acid and 0.05g of benzylamine. Keep warm and stir for 30min, then cool to 5℃ in an ice water bath. Filter and dry the filter cake to obtain a white solid with a yield of 79%, a liquid phase purity of 99.6%, and 0.15% diastereomers.

[0074] Example 11

[0075] Take 10g of crude product and add 100ml of isopropanol. Heat to reflux at 90℃, add 4.5g of methanesulfonic acid and 0.05g of benzylamine. Keep warm and stir for 30min, then cool to 5℃ in an ice water bath. Filter and dry the filter cake to obtain a white solid with a yield of 82%, a liquid phase purity of 99.8%, and 0.10% diastereomers.

[0076] Example 12

[0077] Take 10g of crude product and add 100ml of isopropanol. Heat to reflux at 90℃, add 8.0g of p-toluenesulfonic acid and 0.05g of benzylamine. Keep warm and stir for 30min, then cool to 5℃ in an ice water bath. Filter and dry the filter cake to obtain a white solid with a yield of 80%, a liquid phase purity of 99.8%, and 0.11% diastereomers.

[0078] Example 13

[0079] Take 10g of crude product and add 100ml of isopropanol. Heat to reflux at 90℃, add 5.5g of succinic acid and 0.05g of benzylamine. Keep warm and stir for 30min, then cool to 5℃ in an ice water bath. Filter and dry the filter cake to obtain a white solid with a yield of 83%, a liquid phase purity of 99.7%, and 0.11% diastereomers.

[0080] Example 14

[0081] Take 10g of crude product and add 100ml of isopropanol. Heat to reflux at 90℃, add 1g of oxalic acid and 0.05g of benzylamine. Keep warm and stir for 30min. Cool to 5℃ in an ice water bath to crystallize. Filter and dry the filter cake to obtain a white solid with a yield of 51%, a liquid phase purity of 99.8%, and 0.03% diastereomers.

[0082] Example 15

[0083] Take 10g of crude product and add 100ml of isopropanol. Heat to reflux at 90℃, add 10g of oxalic acid and 0.05g of benzylamine. Keep warm and stir for 30min. Cool to 5℃ in an ice water bath to crystallize. Filter and dry the filter cake to obtain a white solid with a yield of 71%, a liquid phase purity of 99.7%, and 0.10% diastereomers.

[0084] Example 16

[0085] Take 10g of crude product and add 100ml of isopropanol. Heat to reflux at 90℃, add 4.2g of oxalic acid and 0.05g of aniline. Keep warm and stir for 30min, then cool to 5℃ in an ice water bath. Filter and dry the filter cake to obtain a white solid with a yield of 84% and a liquid phase purity of 99.8%. No diastereomers were detected (0.04%).

[0086] Example 17

[0087] Take 10g of crude product and add 100ml of isopropanol. Heat to reflux at 90℃, add 4.2g of oxalic acid and 0.05g of ammonia. Keep warm and stir for 30min, then cool to 5℃ in an ice water bath. Filter and dry the filter cake to obtain a white solid with a yield of 80%, a liquid phase purity of 99.7%, and 0.14% diastereomers.

[0088] Example 18

[0089] Take 10g of crude product and add 100ml of isopropanol. Heat to reflux at 90℃, add 4.2g of oxalic acid and 0.05g of ethylamine. Keep warm and stir for 30min, then cool to 5℃ in an ice water bath. Filter and dry the filter cake to obtain a white solid with a yield of 80%, a liquid phase purity of 99.8%, and 0.15% diastereomers.

[0090] Example 19

[0091] Take 10g of crude product and add 100ml of isopropanol. Heat to reflux at 90℃, add 4.2g of oxalic acid and 0.05g of ethylenediamine. Keep warm and stir for 30min, then cool to 5℃ in an ice water bath. Filter and dry the filter cake to obtain a white solid with a yield of 80%, a liquid phase purity of 99.8%, and 0.13% diastereomers.

[0092] Example 20

[0093] Take 10g of crude product and add 100ml of isopropanol. Heat to reflux at 90℃, add 4.2g of oxalic acid and 0.05g of triethylamine. Keep warm and stir for 30min, then cool to 5℃ in an ice water bath. Filter and dry the filter cake to obtain a white solid with a yield of 80%, a liquid phase purity of 99.8%, and 0.14% diastereomers.

[0094] Example 21

[0095] Take 10g of crude product and add 100ml of isopropanol. Heat to reflux at 90℃, add 4.2g of oxalic acid and 0.05g of monoethanolamine. Keep warm and stir for 30min, then cool to 5℃ in an ice water bath. Filter and dry the filter cake to obtain a white solid with a yield of 80%, a liquid phase purity of 99.6%, and 0.12% diastereomers.

[0096] Example 22

[0097] Take 10g of crude product and add 100ml of isopropanol. Heat to reflux at 90℃, add 4.2g of oxalic acid and 0.05g of dimethylformamide. Keep warm and stir for 30min, then cool to 5℃ in an ice water bath. Filter and dry the filter cake to obtain a white solid with a yield of 80%, a liquid phase purity of 99.6%, and 0.15% diastereomers.

[0098] Example 23

[0099] Take 10g of crude product and add 100ml of isopropanol. Heat to reflux at 90℃, add 4.2g of oxalic acid and 0.01g of benzylamine. Keep warm and stir for 30min, cool to 5℃ in an ice water bath, filter, and dry the filter cake to obtain a white solid with a yield of 86%, a liquid phase purity of 99.9%, and 0.03% diastereomers.

[0100] Example 24

[0101] Take 10g of crude product and add 100ml of isopropanol. Heat to reflux at 90℃, add 4.2g of oxalic acid and 0.1g of benzylamine. Keep warm and stir for 30min, then cool to 5℃ in an ice water bath. Filter and dry the filter cake to obtain a white solid with a yield of 84%, a liquid phase purity of 99.9%, and 0.02% diastereomers.

[0102] Example 25

[0103] Take 10g of crude product and add 100ml of isopropanol. Heat to reflux at 90℃, add 4.2g of oxalic acid and 0.001g of benzylamine. Keep warm and stir for 30min, then cool to 5℃ in an ice water bath. Filter and dry the filter cake to obtain a white solid with a yield of 85%, a liquid phase purity of 99.9%, and 0.11% diastereomers.

[0104] Example 26

[0105] Take 10g of crude product and add 100ml of isopropanol. Heat to reflux at 90℃, add 4.2g of oxalic acid and 1g of benzylamine. Keep warm and stir for 30min, then cool to 5℃ in an ice water bath. Filter and dry the filter cake to obtain a white solid with a yield of 65% and a liquid phase purity of 99.6%. No diastereomers were detected.

[0106] Example 27

[0107] Take 10g of crude product and add 100ml of isopropanol. Heat to reflux at 90℃, add 4.2g of oxalic acid and 0.05g of benzylamine. Keep warm and stir for 30min, then cool to 0℃, filter, and dry the filter cake to obtain a white solid with a yield of 86%, a liquid phase purity of 99.9%, and 0.01% diastereomers.

[0108] Example 28

[0109] Take 10g of crude product and add 100ml of isopropanol. Heat to reflux at 90℃, add 4.2g of oxalic acid and 0.05g of benzylamine. Keep warm and stir for 30min, cool to 10℃, filter, and dry the filter cake to obtain a white solid with a yield of 84% and a liquid phase purity of 99.9%. No diastereomers were detected.

[0110] Example 29

[0111] Take 10g of crude product and add 100ml of isopropanol. Heat to reflux at 90℃, add 4.2g of oxalic acid and 0.05g of benzylamine. Keep warm and stir for 30min, then cool to 30℃, filter, and dry the filter cake to obtain a white solid with a yield of 81% and a liquid phase purity of 99.9%. No diastereomers were detected.

[0112] Example 30

[0113] Take 10g of crude product and add 100ml of isopropanol. Heat to reflux at 90℃, add 4.2g of oxalic acid and 0.05g of benzylamine. Keep warm and stir for 30min, then cool to -20℃, filter, and dry the filter cake to obtain a white solid with a yield of 88%, a liquid phase purity of 99.5%, and 0.11% diastereomers.

[0114] Comparative Example 1

[0115] 10g of the crude product was added to 100ml of isopropanol and heated under reflux until dissolved. Then, a solution of 4.2g of oxalic acid in 50ml of isopropanol was added dropwise. After the addition was complete, the mixture was kept at this temperature for 1 hour, then cooled in an ice-water bath. A waxy solid was obtained, with a yield of 81% and a liquid chromatography purity of 88.7%, containing 5.4% diastereomers. The related substances HPLC chromatogram of the product is shown below. Figure 3 .

[0116] Comparative Example 2

[0117] 10g of the crude product was added to 100ml of isopropanol and heated under reflux until dissolved. Then, a solution of 4.2g of oxalic acid in 50ml of isopropanol was added dropwise. After the addition was complete, the mixture was kept at this temperature for 1 hour, then cooled uniformly at a rate of 5℃ / h. The solution was kept at 5℃ for 1 hour, and the mixture was filtered to obtain a white solid with a yield of 75%, a liquid phase purity of 96.4%, and 1.7% diastereomers. The related substances HPLC chromatogram of the product is shown below. Figure 4 .

[0118] As can be seen from the above, compared with the comparative examples, the embodiments of this application use a novel purification method for 3-amino-5-methylpiperidine with amino group protected by Boc, which improves the product properties of 3-amino-5-methylpiperidine with amino group protected by Boc during salting out, and increases the product yield and purity. The purity of 3-amino-5-methylpiperidine with amino group protected by Boc in the product is ≥99.5%, and the content of diastereomer impurities is ≤0.15%. At the same time, the operation steps for salting out 3-amino-5-methylpiperidine with amino group protected by Boc are simplified, the operation time is shortened, and the production cost is reduced. In addition, it can be seen that when the purification parameters are within the preferred range of this application, the product yield and purity are better, and the detection amount of diastereomer impurities is lower.

[0119] The above description is merely a preferred embodiment of this application and is not intended to limit this application. Various modifications and variations can be made to this application by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the protection scope of this application.

Claims

1. A method for salt formation and crystallization of 3-amino-5-methylpiperidine with an amino group protected by Boc as shown in Formula I, characterized in that, Includes the following steps: Formula I Step S1: Add solvent to crude 3-amino-5-methylpiperidine with amino group protected by Boc, heat to dissolve, and obtain a mixture; the crude product contains the (3S,5S) configuration product shown in Formula I(a) and / or the (3R,5R) configuration product shown in Formula I(b). Step S2: Add acid and amine crystallization aid to the mixture, stir and disperse to obtain a dispersion; Step S3: Cool the dispersion to crystallize, separate and dry to obtain 3-amino-5-methylpiperidine salt crystals with amino groups protected by Boc. The solvent is selected from methanol, ethanol, n-propanol and isopropanol; the acid is selected from formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, oxalic acid, succinic acid, lactic acid and tartaric acid; the amine crystallization aid is selected from ammonia, ethylamine, ethylenediamine, triethylamine, benzylamine, aniline, monoethanolamine and dimethylformamide.

2. The salt formation and crystallization method according to claim 1, characterized in that, In step S1, the liquid-to-solid ratio of the solvent to the crude 3-amino-5-methylpiperidine with the amino group protected by Boc is (4~16):

1.

3. The salt formation and crystallization method according to claim 1, characterized in that, In step S1, the heating temperature is 40~100℃.

4. The salt formation and crystallization method according to claim 1, characterized in that, In step S2, the acid is selected from oxalic acid, lactic acid, and tartaric acid.

5. The salt formation and crystallization method according to claim 1, characterized in that, In step S2, 0.001 to 0.01 mol of the acid is added to each gram of crude 3-amino-5-methylpiperidine with amino group protected by Boc in the mixture.

6. The salt formation and crystallization method according to claim 1, characterized in that, In step S2, the amine crystallization aid is benzylamine or aniline.

7. The salt formation and crystallization method according to claim 1, characterized in that, In step S2, the mass ratio of the amine crystallization aid to the crude 3-amino-5-methylpiperidine with Boc-protected amino group in the mixture is (0.0001~0.1):

1.

8. The salt formation and crystallization method according to claim 7, characterized in that, In step S2, the mass ratio of the amine crystallization aid to the crude 3-amino-5-methylpiperidine with its amino group protected by Boc in the mixture is (0.001~0.01):

1.

9. The salt formation and crystallization method according to claim 1, characterized in that, In step S2, the dispersion temperature is 40~100℃.

10. The salt formation and crystallization method according to claim 1, characterized in that, In step S3, the crystallization temperature is -20~30℃.

11. The salt formation and crystallization method according to claim 10, characterized in that, In step S3, the crystallization temperature is 0~10℃.

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