A method for preparing optically pure 2-methylpiperidin-5-amine

Abstract

The present invention provides a method for preparing optically pure 2-methylpiperidin-5-amine. Using racemic 6-methyl-3-piperidinecarboxylate as a raw material, after reacting with a chiral acid for resolution, an optically pure intermediate of formula III is obtained. Then, through alkalization, amino protection, amidation, and Hofmann rearrangement reactions, optically pure 2-methylpiperidin-5-amine, an important intermediate for synthesizing the drug ritlecitinib, is finally obtained in high yield and high optical purity. The raw materials of the present invention are cheap and easily available, and the conditions of the synthesis route are mild, making it easy to carry out large-scale industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a method for preparing optically pure 2-methylpiperidin-5-amine. Background Art

[0002] Ritlecitinib (PF-06651600) is a new generation of orally administered targeted covalent kinase inhibitor developed by Pfizer. It has high selectivity for Janus kinase 3 (JAK3) and tyrosine kinase members expressed in the tyrosine kinase family of hepatocellular carcinoma (TEC), and can inhibit the signal transduction of interleukin-15 (IL-15) and CD-8 cytokines. These two cytokines are important factors driving the immune system to kill hair follicle cells. Ritlecitinib received Breakthrough Therapy designation from the US FDA for the treatment of alopecia areata in September 2018, and is also being evaluated for the treatment of vitiligo, rheumatoid arthritis, Crohn's disease, ulcerative colitis, etc.

[0003] On June 7, 2022, CDE publicly announced that Pfizer's Ritlecitinib capsules were proposed to be included in breakthrough therapy for the treatment of adult moderate to severe active ulcerative colitis (UC).

[0004]

[0005] Among them, optically pure 2-methylpiperidin-5-amine is a key intermediate for the synthesis of ritlecitinib, and its structural formula is:

[0006]

[0007] P is an amino protecting group.

[0008] The literature J.Med.Chem.2017,60,1971-1993 and the patent WO2015083028 reported the preparation method of this compound. The specific synthesis route related to the present invention is as follows:

[0009]

[0010] The method for obtaining the key intermediate in this route is separation by supercritical fluid chromatography (SFC), and a pair of enantiomer mixtures containing the target compound is obtained. The yield is low and the cost is high, which is not suitable for large-scale preparation.

[0011] In Japanese Patent JP2019017295, a method was disclosed in which enzymatic catalysis was used as a key step to resolve racemic 6-methyl-3-piperidinecarboxamide into chiral amide and its enantiomeric carboxylic acid, and then the key intermediate was obtained through Hofmann degradation. The specific synthesis route is as follows:

[0012]

[0013] However, the biocatalytic conversion efficiency of this method is low and the reaction time is long (5 days at 45 °C), making it impossible to carry out large-scale production.

[0014] The preparation method of this key intermediate was disclosed in the literature Org. Process Res. Dev. 2019, 23, 1872 - 1880 and the patent WO2020084435. The specific synthetic route is as follows:

[0015]

[0016] This method uses (R)-N-3,5-dinitrobenzoyl phenylglycine as a resolving agent for resolution. The resolving agent is expensive, and at the same time, the literature also reports that there is a phenomenon of intense heat release when using this resolving agent, and there are great potential safety hazards if not well controlled during production.

[0017] The preparation method of this key intermediate was disclosed in the Chinese patent CN201911417506. The specific synthetic route is as follows:

[0018]

[0019] This method is similar to the above route, but the resolving agent is relatively easier to obtain. However, the last step of resolution will inevitably cause a large amount of material waste, resulting in too high costs.

[0020] The literature Tetrahedron 2021, 101, 132503 reported that using tert-butoxycarbonyl-protected unnatural D-configured pyroglutamic acid as the starting material, through addition of methylmagnesium reagent, reduction of the ester group, protection with methanesulfonyl group, cyclization with benzylamine, and after removing the tert-butoxycarbonyl protecting group, resolution with N-acetyl-L-leucine to obtain the diastereomeric salt of this key intermediate. The specific synthetic route is as follows:

[0021]

[0022] This route is long and complex, with cumbersome operations. The Grignard reaction requires anhydrous and anaerobic conditions, and the operation requirements are high. Moreover, there is also the last step of resolution, resulting in relatively high costs.

[0023] Therefore, it is necessary to develop a new method for synthesizing optically pure 2-methylpiperidin-5-amine, which requires simple operations, easily available and economical raw materials, high product purity, and high yield to meet the large demand for intermediates of such pharmaceutical compounds. Summary of the Invention

[0024] In order to overcome the lack of an economical and effective synthetic method suitable for large-scale industrial preparation of optically pure 2-methylpiperidin-5-amine in the prior art, the present invention proposes a new synthetic strategy, which is to react a chiral acid with racemic 6-methyl-3-piperidinecarboxylate to obtain the compound of formula III as an intermediate with high purity and high yield in one step, and then the optically pure 2-methylpiperidin-5-amine can be conveniently and efficiently obtained through subsequent reactions.

[0025] To solve the above problems, the present invention provides the following technical solutions:

[0026] A method for preparing optically pure 2-methylpiperidin-5-amine, the synthetic route is as follows:

[0027]

[0028] Wherein A-H represents a chiral acid, -COOR represents an ester group, and P represents an amino protecting group.

[0029] Furthermore, the chiral acid is selected from at least one of D-tartaric acid, D-(+)-dibenzoyl tartaric acid, D-(+)-di-p-toluoyl tartaric acid, L-mandelic acid, and D-camphorsulfonic acid.

[0030] Furthermore, R is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C4-10 heterocyclic group, and the heteroatom in the heterocyclic group is at least one of P, S, O, and N.

[0031] Furthermore, the C1-6 alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl; the C2-6 alkenyl is selected from vinyl, allyl, 1-butenyl, 1-pentenyl, and 1-hexenyl; the C2-6 alkynyl is selected from ethynyl, 1-propynyl, 1-butynyl, 1-pentynyl, and 1-hexynyl; the C6-10 aryl is selected from phenyl and naphthyl; the C4-10 heterocyclic group is selected from tetrahydropyranyl, dioxane group, oxetanyl, benzofuran, benzothiazole, benzothiophene, and pyridyl.

[0032] The H atom in R is optionally substituted by halogen, nitro, cyano, alkoxy, hydroxyl, or amino.

[0033] In a more specific technical solution of the present invention, the method for preparing optically pure 2-methylpiperidin-5-amine includes the following steps:

[0034] (S1) Racemic 6-methyl-3-piperidinecarboxylate, i.e., the compound of formula II, reacts with a chiral acid in a solvent under heating conditions to form a diastereomeric salt, and after cooling, the salt of the compound of formula III with optical purity precipitates from the system;

[0035] (S2) Add a base to alkalize the compound of formula III, liberating the piperidineamine compound, which is the compound of formula IV;

[0036] (S3) Add an amino protecting agent to protect the amino group of the compound of formula IV, obtaining the compound of formula V;

[0037] (S4) React the compound of formula V with an ammonia source to obtain an amide compound, which is the compound of formula VI;

[0038] (S5) Subject the compound of formula VI to Hofmann degradation reaction to obtain the target product optically pure 2-methylpiperidin-5-amine, which is the compound of formula I.

[0039] Preferably, in step (S1), the molar ratio of the compound of formula II to the chiral acid is 1:1 - 1.5. Preferably, the molar ratio of the compound of formula II to the chiral acid is 1:1.1 - 1.3. The chiral acid is in relative excess to ensure that as much of the compound of formula II as possible participates in the reaction.

[0040] Preferably, in step (S1), there is no particular limitation on the temperature increase. Generally, the temperature can be raised to the boiling point of the solvent, i.e., the state of heating under reflux. Depending on the different solvents, there will be different temperature increase values, generally between 60 - 90°C. The temperature decrease is to lower the temperature to -15 to 10°C. Further preferably, the temperature decrease is to lower the temperature to -10 to 5°C.

[0041] Preferably, after obtaining the diastereomeric salt in step (S1), if the optical purity is not reached, recrystallization is carried out to further improve the optical purity. The optical purity reaching means that the e.e. value is greater than 90%, preferably the e.e. value is greater than 95%, and more preferably the e.e. value is greater than 97%.

[0042] Preferably, in step (S1), the solvent for precipitation and / or recrystallization is selected from one or more of toluene, tert-butyl methyl ether, tetrahydrofuran, methyltetrahydrofuran, ethyl acetate, isopropyl acetate, butyl acetate, methanol, ethanol, isopropanol, acetone, 2-butanone, methyl isobutyl ketone, and acetonitrile.

[0043] Furthermore, in step (S1), the amount of the solvent used is such that the concentration of the compound of formula II in the system is 0.5 - 1 M; during recrystallization, the volume-to-mass ratio of the solvent used to the substance to be recrystallized is 6 - 8:1 (mL:g). The amount of the recrystallization solvent should not be too much, otherwise the yield will decrease; nor should it be too little, otherwise the optical purity will not be sufficient.

[0044] Further preferably, the recrystallization solvent is a mixed solvent of isopropyl acetate and a ketone solvent in a volume ratio of 1-2:1-2. The ketone solvent is selected from at least one of acetone, 2-butanone, and methyl isobutyl ketone. The inventors unexpectedly found that the mixed solvent of isopropyl acetate and a ketone solvent as the recrystallization solvent in step (S1) has a higher yield of the product with high optical purity. That is, the optical purity and yield of the product are simultaneously improved through the compounded solvent. The inventors found that after the chiral acid resolving agent is used for resolution in step (S1), the optical purity is still insufficient and further recrystallization is required to improve the optical purity. However, during recrystallization, the loss of the product is often relatively large, which is an important factor restricting the yield of the synthesis route of the present invention. The inventors unexpectedly found that using the mixed solvent of isopropyl acetate and a ketone solvent as the recrystallization solvent can significantly improve the yield while ensuring the optical purity of the product.

[0045] Further, in step (S2), the base is an inorganic base and / or an organic base. The inorganic base is selected from at least one of alkali metal bicarbonates, alkali metal carbonates, alkali metal hydroxides, and ammonia water. The salt is at least one of potassium salts, sodium salts, and ammonium salts; the organic base is an organic amine, specifically selected from at least one of triethylamine, pyridine, and diisopropylethylamine.

[0046] Further, in step (S3), the amino protecting agent is selected from at least one of dimethyl dicarbonate, diethyl dicarbonate, diisopropyl dicarbonate, di-tert-butyl dicarbonate, methyl chloroformate, ethyl chloroformate, benzyl chloroformate, 9-fluorenylmethyl chloroformate, allyl chloroformate, p-toluenesulfonyl chloride, ethyl trifluoroacetate, triphenylmethyl chloride, 2,4-dimethoxybenzaldehyde, p-methoxybenzyl bromide, and benzyl bromide; the amino protecting group P is correspondingly the group after the reaction of the above amino protecting agent; the dosage of the amino protecting agent is 1.1-1.5 times the amount of substance of the compound of formula IV. The reaction temperature of step (S3) is 0-25 °C, preferably 10-15 °C.

[0047] Further, in step (S4), the ammonia source is selected from at least one of ammonia water, ammonia gas, and formamide; the reaction temperature of step (S4) is 60-100 °C.

[0048] Step (S5) is a typical Hofmann degradation reaction (also known as Hofmann rearrangement, Hofmann rearrangement), and its reaction conditions are well known in the art. It is a reaction in which the amide compound of formula VI is heated and reacted in a strong base solution of sodium hypochlorite and / or potassium hypochlorite to remove the carbonyl group to generate a primary amine. When adding sodium hypochlorite and / or potassium hypochlorite, it is slowly added at a low temperature (0-10 °C) (added dropwise within 0.5-1 h), and then the reaction system is heated to 50-70 °C and reacted for 2-3 h to complete.

[0049] Furthermore, in steps (S3), (S4), and (S5), the solvent of the reaction system is not particularly limited as long as it can fully dissolve the materials to enable the reaction to proceed smoothly. In a specific embodiment of the present invention, the solvent in steps (S3), (S4), and (S5) is selected from at least one of toluene, tert-butyl methyl ether, methyl tetrahydrofuran, ethyl acetate, isopropyl acetate, butyl acetate, dichloromethane, dichloroethane, chloroform, isopropanol, acetonitrile, and N,N-dimethylformamide.

[0050] Furthermore, in steps (S2), (S3), (S4), and (S5), the purification means of the product are well-known in the art, such as extraction, recrystallization, column chromatography, etc.

[0051] Furthermore, for extraction, the solvent used for extraction is one or more of toluene, tert-butyl methyl ether, methyl tetrahydrofuran, ethyl acetate, isopropyl acetate, butyl acetate, dichloromethane, dichloroethane, and chloroform. The solvent for crystallization is selected from at least one of methyl tetrahydrofuran, ethyl acetate, butyl acetate, isopropyl acetate, methanol, ethanol, propanol, dichloromethane, dichloroethane, chloroform, and n-heptane.

[0052] Through a new synthetic route, the present invention uses a chiral acid that is easily obtained as a resolving agent, and can simply and efficiently obtain optically pure raw materials, continue the reaction, and finally obtain the product optically pure 2-methylpiperidin-5-amine with high yield and high optical purity. As an important intermediate in the synthesis of ritlecitinib drug, it can reduce the cost of the current synthesis method and has good industrialization prospects. Description of the Drawings

[0053] Figure 1 is the 1 HNMR spectrum of the optically pure 2-methylpiperidin-5-amine (P is Boc) obtained in Example 3;

[0054] Figure 2 is the LC-MS chart of the optically pure 2-methylpiperidin-5-amine (P is Boc) obtained in Example 3. Detailed Embodiments

[0055] The present invention will be further described below in conjunction with specific embodiments, but is not limited to the specific embodiments.

[0056] In the following examples, the experimental methods are conventional methods unless otherwise specified; the reagents and materials can be obtained from commercial sources unless otherwise specified.

[0057] Example 1

[0058]

[0059] Among them, Cbz is benzyloxycarbonyl,.

[0060] (S1) Add racemic methyl 6-methylpiperidine-3-carboxylate, i.e., Compound of Formula II (157.2 g, 1.0 mol) and D-tartaric acid (150.1 g, 1.0 mol) to 1000 mL of methanol, heat up to reflux until the system becomes clear. Slowly cool down to room temperature, and a large amount of solid precipitates in the system. Continue stirring for 1 hour, filter, wash the filter cake with methanol, and dry to obtain Compound of Formula IIIa (146.0 g), with a yield of 47.5% and an e.e. value of 92.6%.

[0061] Recrystallize the obtained solid once with 1168 mL of isopropanol to obtain solid Compound of Formula IIIa (99.7 g), with a yield of 68.3% and an e.e. value of 98.1%.

[0062] (S2) Dissolve Compound of Formula IIIa (100 g, 0.33 mol) in water (300 mL), add sodium bicarbonate powder in portions under ice-water bath cooling, and measure the pH value. After it becomes alkaline, continue stirring for 30 minutes, and extract with ethyl acetate. After separating the organic phase, dry and concentrate under reduced pressure to obtain Compound of Formula IV (51.0 g), with a yield of 99.0%.

[0063] (S3) Add a solution of sodium carbonate (12.7 g, 0.12 mol) in portions to a dioxane solution of Compound of Formula IV (10.0 g, 0.06 mol), cool to below 10 °C under ice-water bath, and dropwise add benzyl chloroformate (11.9 g, 0.07 mol). After the addition is complete, let it warm up to room temperature naturally and continue the reaction for 2 h. Extract with ethyl acetate. After separating the organic phase, dry and concentrate under reduced pressure to obtain Compound of Formula Va (16.0 g), with a yield of 86.3%.

[0064] (S4) Dissolve Compound of Formula Va (10 g, 0.034 mol) in methanol (20 mL), add ammonia water (20 mL). Seal the reactor, heat up to 80 °C and stir overnight. Concentrate a part of the methanol under reduced pressure, cool to below 10 °C, continue stirring for 2 hours, filter, wash the filter cake with ice water and dry to obtain Compound of Formula VIa (8.3 g), with a yield of 87.4%.

[0065] (S5) Add the compound of formula VIa (5.0 g, 18.0 mmol) to 20% sodium hydroxide solution (30 mL). While controlling the temperature at 0 - 5 °C, add sodium hypochlorite solution dropwise. After the addition, stir at the same temperature for 3 h. Then raise the temperature of the reaction system to 50 °C and stir for 2 h. Cool down to 15 - 20 °C, adjust the pH to 9 - 10 with hydrochloric acid, extract with ethyl acetate. After separating the organic phase, dry and concentrate under reduced pressure to obtain the crude product. Recrystallize with n - heptane to obtain the compound of formula Ia (3.5 g), with a yield of 78.3% and an e.e. value of 99.4%; HNMR (600 MHz, DMSO - d6) δ ppm 7.37 (m, 5H), 5.07 (s, 2H), 4.31 (m, 1H), 4.00 (d, J = 9.42 Hz, 1H), 3.19 (m, 2H), 1.81 (m, 2H), 1.57 (m, 2H), 1.10 (d, J = 6.84 Hz, 3H); LC - MS (EI): m / z = 249.16.

[0066] Example 2:

[0067]

[0068] Wherein, Bn is benzyl.

[0069] (S1) While controlling the temperature at 20 - 25 °C, add the solution of mandelic acid (15.2 g, 0.1 mol) dissolved in isopropyl acetate dropwise into the solution of the compound of formula II (15.7 g, 0.1 mol) in isopropyl acetate. Heat up to reflux and stir for 1 h. Slowly cool down to 0 - 10 °C, and a large amount of solid precipitates in the system. Continue to stir for 1 h, filter, wash the filter cake with isopropyl acetate, and dry to obtain the compound of formula IIIb (16.4 g), with a yield of 53.1% and an e.e. value of 86.2%.

[0070] Recrystallize the obtained solid once with 100 mL of isopropyl acetate to obtain the solid compound of formula IIIb (g), with a yield of 68.5% and an e.e. value of 97.5%.

[0071] (S2) Dissolve the compound of formula IIIb (10.0 g, 32.3 mmol) in water (30 mL), add 30% sodium hydroxide solution dropwise under an ice - water bath and measure the pH value. After it becomes alkaline, continue to stir for 30 minutes, then extract with ethyl acetate. After separating the organic phase, dry and concentrate under reduced pressure to obtain the compound of formula IV (5.0 g), with a yield of 98.5%.

[0072] (S3) Potassium carbonate (6.6 g, 47.7 mmol) powder and benzyl bromide (6.5 g, 38.2 mmol) were added to the N,N-dimethylformamide solution of the compound of formula IV (5.0 g, 31.8 mmol). The reaction was continued at room temperature for 12 h. Ethyl acetate and water were added to dilute the reaction system. After separating the organic phase, it was dried and concentrated under reduced pressure to obtain the compound of formula Vb (7.2 g) with a yield of 91.5%.

[0073] (S4) The compound of formula Vb (5.0 g, 20.2 mmol) was dissolved in dioxane (40 mL), and ammonia gas was introduced until saturated. A catalytic amount of sodium methoxide was added, and the temperature was raised to 60 - 65 °C and reacted for 8 hours. Part of the solvent was concentrated under reduced pressure, and solid was precipitated by adding water. It was cooled to below 10 °C and stirred for another 2 hours, then filtered. The filter cake was washed with ice water and dried to obtain the compound of formula Vlb (4.3 g) with a yield of 91.6%.

[0074] (S5) The compound of formula Vlb (3.0 g, 12.9 mmol) was added to 30% sodium hydroxide solution (20 mL). While controlling the temperature at 0 - 5 °C, 11% sodium hypochlorite solution was added dropwise. After dropping, it was stirred at the same temperature for 3 h. The reaction system was heated to 50 °C and stirred for 2 hours. It was cooled to 15 - 20 °C, and the pH was adjusted to 9 - 10 with hydrochloric acid. Then ethyl acetate was added for extraction. After separating the organic phase, it was dried and concentrated under reduced pressure to obtain the crude product of formula Ib. The compound of formula Ib (1.9 g) was obtained by vacuum distillation with a yield of 72.0%. The e.e. value was 99.1%, and LC-MS (EI): m / z = 205.17.

[0075] Example 3

[0076]

[0077] Boc is tert-butoxycarbonyl.

[0078] (S1) While controlling the temperature at 20 - 25 °C, the solution of N-Boc-D-leucine (23.1 g, 0.1 mol) dissolved in tetrahydrofuran was added dropwise to the tetrahydrofuran solution of the compound of formula II (15.7 g, 0.1 mol). The temperature was raised to reflux and stirred for 1 hour. It was slowly cooled to 0 - 10 °C, and a large amount of solid precipitated in the system. Stirring was continued for 1 hour, then filtered. The filter cake was rinsed with tetrahydrofuran and dried to obtain the compound of formula IIIc (21.1 g) with a yield of 54.3%. The e.e. value was 82.7%.

[0079] The obtained solid was recrystallized once with 160 mL of acetone to obtain the solid compound of formula IIIc (14.0 g) with a yield of 66.4%. The e.e. value was 98.3%.

[0080] (S2) Dissolve the compound of formula Ⅲc (10.0 g, 25.7 mmol) in dichloromethane, and add triethylamine (3.1 g, 30.8 mmol) dropwise under cooling in an ice-water bath. Stir at room temperature for 1 hour, filter, and obtain the solution of the compound of formula Ⅳ directly for the next reaction step.

[0081] (S3) Add triethylamine (3.1 g, 30.8 mmol) to the solution of the compound of formula Ⅳ obtained in the previous step. Dropwise add di-tert-butyl dicarbonate (6.2 g, 28.3 mmol) under cooling in an ice-water bath. React at room temperature for 6 h. Wash the reaction solution successively with water and 1% hydrochloric acid, then dry and concentrate under reduced pressure to obtain the compound of formula Ⅴc (6.2 g) with a yield of 93.6%.

[0082] (S4) Add the compound of formula Ⅴc (5.0 g, 19.4 mmol) and formamide (8.6 g, 0.19 mol) to N,N-dimethylformamide (25 mL). Dropwise add 28% sodium methoxide methanol solution (7.5 g, 38.8 mmol) while controlling the temperature below 25 °C. After dropping, raise the temperature to 60 - 65 °C and react for 8 hours. Add water to the reaction system to precipitate a solid. Cool to below 10 °C, continue to stir for 2 hours, filter, wash the filter cake with ice water, and then dry to obtain the compound of formula Ⅵc (4.1 g) with a yield of 87.0%.

[0083] (S5) Add the compound of formula Ⅵc (3.0 g, 12.4 mmol) to 15% sodium hydroxide solution (20 mL). Dropwise add 11% sodium hypochlorite solution while controlling the temperature at 0 - 5 °C. After dropping, keep stirring at the same temperature for 3 h. Raise the temperature of the reaction system to 70 °C and stir for 1 hour. Cool to 15 - 20 °C, adjust the pH to 9 with hydrochloric acid, add dichloromethane for extraction, separate the organic phase, then dry and concentrate under reduced pressure to obtain the crude product of formula Ⅰc. Crystallize with n-heptane to obtain the compound of formula Ⅰc (1.8 g) with a yield of 67.8%; e.e. value 99.6%; HNMR (600 MHz, CD3OD) δ ppm 4.77 (br, 2H), 4.33 (m, 1H), 3.79 (m, 1H), 3.11 (dd, J1 = 13.8 Hz, J2 = 2.7 Hz, 1H), 3.01 (m, 1H), 2.00 (m, 1H), 1.90 (m, 1H), 1.50 (m, 1H), 1.47 (s, 9H), 1.33 (m, 1H), 1.14 (d, J = 6.96 Hz, 3H); LC-MS (EI): m / z = 215.23.

[0084] Figure 1 It is the 1 HNMR spectrum of the optically pure 2-methylpiperidin-5-amine (P is Boc) obtained in Example 3.

[0085] Figure 2It is the LC-MS chart of the optically pure 2-methylpiperidin-5-amine (P is Boc) obtained in Example 3.

[0086] Example 4

[0087] Other conditions and operations are the same as in Example 3, except that the solvent used for recrystallization in step (S1) is replaced with a mixed solvent of acetone and isopropyl acetate in equal volume according to a volume ratio of 1:1. After recrystallization, the yield is 74.7%, and the e.e. value is 99.5%.

[0088] Example 5

[0089] Other conditions and operations are the same as in Example 3, except that the solvent used for recrystallization in step (S1) is replaced with a mixed solvent of acetone and isopropyl acetate in equal volume according to a volume ratio of 1:2. After recrystallization, the yield is 73.4%, and the e.e. value is 99.4%.

[0090] Example 6

[0091] Other conditions and operations are the same as in Example 3, except that the solvent used for recrystallization in step (S1) is replaced with a mixed solvent of acetone and isopropyl acetate in equal volume according to a volume ratio of 2:1. After recrystallization, the yield is 72.9%, and the e.e. value is 99.5%.

[0092] Example 7

[0093] Other conditions and operations are the same as in Example 3, except that the solvent used for recrystallization in step (S1) is replaced with a mixed solvent of acetone and isopropyl alcohol in equal volume according to a volume ratio of 1:1. After recrystallization, the yield is 68.2%, and the e.e. value is 99.4%.

[0094] Example 8

[0095] Other conditions and operations are the same as in Example 3, except that the solvent used for recrystallization in step (S1) is replaced with a mixed solvent of isopropyl acetate and isopropyl alcohol in equal volume according to a volume ratio of 1:1. After recrystallization, the yield is 67.1%, and the e.e. value is 99.2%.

Claims

1. A preparation method of optically pure 2-methylpiperidin-5-amine, characterized in that, The synthesis route is as follows: ； (S1) Control the temperature at 20 - 25 °C, and dropwise add the solution of N-Boc-D-leucine dissolved in tetrahydrofuran into the tetrahydrofuran solution of Compound II. The amount of N-Boc-D-leucine used is 0.1 mol, and the amount of Compound II used is 0.1 mol. Heat up to reflux and stir for 1 hour; Slowly cool down to 0 - 10 °C. A large amount of solid precipitates in the system. Continue to stir for 1 hour, filter, wash the filter cake with tetrahydrofuran, and dry to obtain 21.1 g of Compound IIIc; Recrystallize the obtained solid once with 160 mL of solvent, where the solvent is a mixed solvent of acetone and isopropyl acetate in a volume ratio of 1:1, to obtain solid Compound IIIc; (S2) Dissolve 25.7 mmol of Compound IIIc in dichloromethane, dropwise add 30.8 mmol of triethylamine under ice-water bath cooling, continue to stir at room temperature for 1 hour, filter, and directly use the solution of Compound IV for the next reaction; (S3) Add 30.8 mmol of triethylamine to the solution of Compound IV obtained in the previous step. Under ice-water bath cooling, dropwise add 28.3 mmol of di-tert-butyl dicarbonate, and continue to react at room temperature for 6 h; Wash the reaction solution successively with water and 1% hydrochloric acid, then dry and concentrate under reduced pressure to obtain 6.2 g of Compound Vc; (S4) Add 19.4 mmol of Compound Vc and 0.19 mol of formamide to 25 mL of N,N-dimethylformamide. Control the temperature below 25 °C and dropwise add the methanol solution of 28% sodium methoxide. The amount of sodium methoxide used is 38.8 mmol. After dropping, heat up to 60 - 65 °C and react for 8 hours; Add water to the reaction system to precipitate a solid. Cool to below 10 °C, continue to stir for 2 hours, filter, wash the filter cake with ice water, and dry to obtain 4.1 g of Compound VIc; (S5) Add 12.4 mmol of Compound VIc to 20 mL of 15% sodium hydroxide solution. Control the temperature at 0 - 5 °C and dropwise add 11% sodium hypochlorite solution. After dropping, keep stirring at a constant temperature for 3 h; Heat up the reaction system to 70 °C and stir for 1 hour; Cool down to 15 - 20 °C, adjust the pH to 9 with hydrochloric acid, add dichloromethane for extraction. After separating the organic phase, dry and concentrate under reduced pressure to obtain the crude product of Compound Ic, and crystallize with n-heptane to obtain 1.8 g of Compound Ic.

2. The preparation method according to claim 1, characterized in that, 160 mL of the solvent is a mixed solvent of acetone and isopropyl acetate in a volume ratio of 1:

2.

3. The preparation method according to claim 1, characterized in that, 160 mL of the solvent is a mixed solvent of acetone and isopropyl acetate in a volume ratio of 2:1.

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