A preparation method of (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine

Abstract

The invention belongs to the field of chemical synthesis, and discloses a preparation method of (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine, including: (2S, 4S)-2-(tert-butoxycarbonylamino)-4-methylglutaronitrile is dissolved in a solvent, and a base is added to obtain a mixed solution A; a catalyst is loaded into a catalyst bed in a micro-packed bed hydrogenation reactor, a mixed solution A and a hydrogen flow rate are adjusted, and a gas-liquid mixer is entered to mix to obtain a gas-liquid mixed fluid, the gas-liquid mixed fluid is flowed through the catalyst bed and reacted, and the reaction temperature is regulated by a reactor heat exchange chamber; after the reaction is completed, the reaction solution is collected and purified to obtain (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine. The preparation method of the present invention enables a solid catalyst to be fully contacted with the reaction solution, and compared with the preparation method of conventional intermittent hydrogenation, the reaction time is shortened, the efficiency is improved, the safety is high, and it is more beneficial to industrialized amplification production.

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis, and specifically relates to a preparation method of (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine. Background Art

[0002] (3S,5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine (Compound 1 of Formula 1) is an important pharmaceutical intermediate and is used as a main side chain in the synthesis of the non-fluoroquinolone antibacterial drug nemofloxacin.

[0003] , Patent CN102093260A and US20100152452A report (Formula 1), starting from the cheap and readily available raw material L-glutamic acid, a chiral glutaraldehyde intermediate (Compound 3) or a chiral glutaronitrile intermediate (Compound 2) is synthesized through a series of transformations, wherein the chiral glutaraldehyde intermediate is further subjected to a multi-step cascade process of reduction amination, cyclization and deprotection with benzylamine or ammonia under the condition of NaBH4 to generate Compound 1, but the yield is low, only 25% to 30%; while the chiral glutaronitrile (Compound 3) is subjected to a multi-step cascade process of reduction, cyclization and the like with benzylamine or ammonia under the condition of palladium-catalyzed hydrogenation to generate Compound 1, with a crude yield of 99%, an optical purity of >98% after salt purification, and a final yield of more than 75%, but the overall yield from L-glutamic acid to Compound 1 is 30% to 35%. At the same time, this route involves expensive reagents, such as LiHMDS and CH3I, and this step is an ultra-low temperature reaction with high energy consumption, which increases production costs.

[0004] The hydrogenation step in Formula 1 reported in patent IN202121019300 A is cumbersome to operate because it involves multiple serial processes such as monocyano reduction, cyclization, deamination and deprotection, and at the same time, it is necessary to prevent the formation of dimerization by-products and over-hydrogenation impurities, dicyano reduction by-products. Therefore, the hydrogenation process requires multi-stage precise temperature and pressure control, which is cumbersome to operate. At present, this step of hydrogenation adopts an intermittent production method. After the scale is enlarged, the mass transfer between the gas-liquid-solid three phases is further deteriorated, the reaction time is prolonged, and the reaction temperature after enlargement cannot be accurately controlled, which may eventually lead to the risk of reduced yield of this step; in addition, there is a large amount of hydrogen stored in the headspace of intermittent hydrogenation, and operations such as the use of large quantities of Pd catalysts and catalyst filtration and discharge increase the risk of safe production.

[0005] Therefore, the current method for preparing (3S,5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine still has problems such as complicated operation, large amount of catalyst used, long reaction time, low production efficiency and high safety risk. Summary of the invention

[0006] Purpose of the invention: The purpose of the present invention is to overcome the deficiencies of the above-mentioned prior art and provide a method for preparing (3S,5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine.

[0007] To achieve the above purpose, the technical solution provided by the present invention is as follows: The present application provides a method for preparing (3S,5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine, which comprises: Dissolving (2S,4S)-2-(tert-butoxycarbonylamino)-4-methylglutaronitrile in a solvent, and adding a base to mix to obtain a mixed solution A; The catalyst is loaded into a catalyst bed in a micro-packed bed hydrogenation reactor, the flow rates of the mixed liquid A and hydrogen are adjusted, the mixed liquid A and hydrogen are mixed in a gas-liquid mixer at the inlet of the micro-packed bed hydrogenation reactor to obtain a gas-liquid mixed fluid, the gas-liquid mixed fluid is passed through the catalyst bed and reacted, and the reaction temperature is controlled by a reactor heat exchange chamber of the micro-packed bed hydrogenation reactor; After the reaction is completed, the reaction solution is collected and purified to obtain (3S,5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine; After the reaction is finished, the feeding is stopped, the catalyst bed is cleaned with the same solvent, and then the cleaned catalyst bed is blown dry with nitrogen. Under the nitrogen purge state, the catalyst in the reactor is removed and collected in water.

[0008] In some embodiments, the catalyst is a supported metal catalyst, and the carrier of the supported metal catalyst is activated alumina or activated carbon.

[0009] In some embodiments, the metal of the supported metal catalyst is palladium hydroxide, and the metal loading of the supported metal catalyst is 0.1-10 wt %, and preferably the catalyst is spherical palladium hydroxide / alumina with a loading of 5%.

[0010] In some embodiments, the solvent is methanol, ethanol, isopropanol, butanol, ethylene glycol, tetrahydrofuran, dioxane, methyl tert-butyl ether or ethyl acetate, and the preferred solvent is methanol, ethanol, isopropanol.

[0011] In some embodiments, the volume to mass ratio of the solvent to (2S,4S)-2-(tert-butoxycarbonylamino)-4-methylglutaronitrile is 4 to 60:1, and the preferred volume to mass ratio is 5 to 32:1.

[0012] In some embodiments, the base is ammonia gas, an alcoholic ammonia solution or benzylamine, and a preferred base is methanolic ammonia, ethanolic ammonia, isopropyl ammonia or benzylamine.

[0013] In some embodiments, the molar ratio of ammonia to (2S, 4S)-2-(tert-butoxycarbonylamino)-4-methylglutaronitrile in the ammonia gas or the alcoholic ammonia solution is 0.1-20:1, and the molar ratio of benzylamine to (2S, 4S)-2-(tert-butoxycarbonylamino)-4-methylglutaronitrile is 0.1-10:1. Preferably, the molar ratio of ammonia to (2S, 4S)-2-(tert-butoxycarbonylamino)-4-methylglutaronitrile in the ammonia gas or the alcoholic ammonia solution is 5-15:1, and preferably the molar ratio of benzylamine to (2S, 4S)-2-(tert-butoxycarbonylamino)-4-methylglutaronitrile is 0.5-2.5:1.

[0014] In some embodiments, the reaction temperature is 50-150°C, preferably 60-100°C.

[0015] In some embodiments, the reaction pressure is 0.2 to 5 Mpa, and the preferred reaction pressure is 0.5 to 3 Mpa.

[0016] In some embodiments, the flow rate of the mixed solution A is 0.01 to 0.5 mL / (min·mL catalyst bed), for example, the flow rate of the mixed solution A corresponding to 1L of catalyst bed is 10 to 500 mL / min. The preferred flow rate is 0.05 to 0.1 mL / (min·mL catalyst bed).

[0017] In some embodiments, the molar flow rate ratio of the mixed liquid A to the hydrogen is 1:4-50, for example, the molar flow rate of the hydrogen is 4 to 50 times the molar flow rate of the mixed liquid A, and preferably the molar flow rate ratio of the mixed liquid A to the hydrogen is 1:4-10.

[0018] In some embodiments, the purification method is: concentration under reduced pressure, salification with acid, pulping, alkaline release and recrystallization to obtain (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine, the acid used is a tartaric acid derivative, the solvent used for pulping is methyl tert-butyl ether, recrystallization after alkaline release, and the reagent used for recrystallization is methyl tert-butyl ether or n-heptane.

[0019] In some embodiments, the method for preparing (3S,5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine uses a micro-packed bed hydrogenation reactor for reaction, and the micro-packed bed hydrogenation reactor includes a gas-liquid mixer, a reactor heat exchange chamber, and a catalyst bed.

[0020] In some embodiments, standard conditions are standard conditions, ie, conditions at a temperature of 273.15 K (0° C.) and a pressure of 1 atm (101.325 kPa).

[0021] In some embodiments, the gas-liquid mixer of the present invention is a conventional gas-liquid mixer on the market, the purpose of which is to make the gas and liquid contact the catalyst bed uniformly to avoid wall flow. The catalyst after the reaction is dangerous, mainly because it undergoes oxidation reaction in contact with air, which releases a lot of heat or even burns. Therefore, the catalyst after the reaction is introduced into water under the protection of inert gas to avoid contact with air during the process.

[0022] Beneficial effects: The present invention discloses a method for preparing (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine. The present invention uses (2S, 4S)-2-(tert-butoxycarbonylamino)-4-methylglutaronitrile solution as a raw material, adds alkali to mix to obtain a mixed solution A, and reacts with hydrogen through a micro-packed bed hydrogenation reactor to prepare (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine. Compared with the conventional intermittent hydrogenation preparation method, the present method can greatly improve the reaction rate, and the actual reaction time required is less than 10 minutes. In addition, the present method is different from the multi-stage temperature and pressure control and frequent addition of powder catalyst and filtration hazards in the kettle hydrogenation process. Hazardous waste catalysts, solid-supported hydrogenation catalysts are extremely low in danger during loading and unloading, and have lower operating frequencies, small reactor volumes, less online material volume, and higher safety. The reaction conditions for preparing (3S,5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine were studied using a micro-packed bed hydrogenation reactor. The separation yield of the prepared (3S,5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine was as high as 80% compared to conventional reactors. In the central control test, it was found that the use of a micro-packed bed hydrogenation reactor not only improved the conversion rate of (2S,4S)-2-(tert-butoxycarbonylamino)-4-methylglutaronitrile, but also improved the selectivity of the reaction. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The schematic diagram of the process for preparing crude (3S,5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine according to an embodiment of the present invention, in which: 1-mixed liquid A, 2-hydrogen, 3-pump, 4-micro-packed bed hydrogenation reactor, 4-1-gas-liquid mixer, 4-2-reactor heat exchange chamber, 4-3-catalyst bed, 5-back pressure valve, 6-crude product; Figure 2 This is the central control gas chromatogram of (3S,5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine prepared in Example 27. DETAILED DESCRIPTION

[0024] The present invention is further illustrated below in conjunction with specific examples. This example is implemented based on the technical solution of the present invention. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention. The following example routes are as follows: , Example Preparation of crude (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine Figure 1 As shown, hydrogen and mixed liquid A first pass through 4-1-gas-liquid mixer, and then enter 4-3 catalyst bed for uniform contact to prevent wall flow. The temperature and pressure of 4-micro-packed bed hydrogenation reactor can be regulated. After the reaction is completed, the crude product of (3S,5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine is obtained through 5-back pressure valve.

[0025] Examples 1-10 1.5 mL of spherical 5% palladium hydroxide (Pd(OH)2) / alumina (Al2O3) was loaded into a micro-packed bed hydrogenation reactor (2.5 mL). During the loading process, the catalyst was gently tapped to increase the density of the catalyst loading and prevent catalyst bridging. (2S, 4S)-2-(tert-butoxycarbonylamino)-4-methylglutaronitrile (5 g, 1 eq) was dissolved in methanol, the volume of methanol and the mass ratio of (2S, 4S)-2-(tert-butoxycarbonylamino)-4-methylglutaronitrile was 16, and the solution was stirred and dissolved until clear, and then benzylamine (1.0 eq) was added thereto to prepare a methanol solution of (2S, 4S)-2-(tert-butoxycarbonylamino)-4-methylglutaronitrile, which was mixed solution A. The reaction temperature was controlled to be 80°C, the reaction pressure was 2.0 MPa, the flow rate of the mixed liquid A was 0.2 mL / min (i.e., 0.08 mL / (min·mL catalyst bed)), and the flow rate of hydrogen was 30 mL / min (standard condition, 46 times the molar flow rate of (2S, 4S)-2-(tert-butoxycarbonylamino)-4-methylglutaronitrile). Then, the mixed liquid A and hydrogen were first mixed together through the gas-liquid mixer at the inlet of the micro-packed bed hydrogenation reactor and then entered the catalyst bed in the hydrogenation reactor for hydrogenation reaction. After continuous operation for 1-2 h, the reaction was assumed to reach a steady state, 1 mL of the effluent ((3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine crude product solution) was received, 0.1 mL of the reaction solution was taken, diluted to 1 mL with methanol, and then sent to gas chromatography for analysis. The reaction conversion rate was 100%, and the product purity was 95.0% (gas phase (GC) peak area ratio). The crude hydrogenation liquid was concentrated under reduced pressure at 40°C, salified with D-di-p-methylbenzoyltartaric acid (D-DTTA) in isopropanol, and then purified by slurrying with methyl tert-butyl ether (MTBE). Finally, the crude product was alkali-ionized with sodium hydroxide aqueous solution and crystallized with MTBE / n-heptane (n-Heptane) to obtain pure (3S,5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine, with a gas phase purity of >99%. The reaction separation yield was 80%.

[0026] The difference between Example 2-10 and Example 1 lies in the catalyst-loaded carrier, loaded metal, reaction temperature and pressure used in the micro-packed bed hydrogenation reactor. The catalyst and condition parameters of the micro-packed bed hydrogenation reactor in Examples 1-10 and Comparative Examples 1-3 are shown in Table 1 and Table 2: Table 1 Condition parameters of the micro-packed bed hydrogenation reactor in Examples 1 to 10

[0027] Table 2 Condition parameters of the micro-packed bed hydrogenation reactor in Comparative Examples 1 to 3

[0028] From Table 1, Examples 1, 4 to 7, it can be seen that when a micro-packed bed hydrogenation reactor is used and 5% Pd(OH)2 / Al2O3 is used as a catalyst, the more suitable temperature is 80~100°C, with 80°C being the best. If the temperature is too high, some intermediates are not converted into products. When the temperature is too high, trace impurities will be generated, resulting in a decrease in gas phase purity. It can be seen from Examples 1 to 3 that when the reaction pressure is too high or too low, it is not conducive to the reaction. When the pressure is lower than 2MPa, the conversion rate of the intermediate to the product will decrease. When the pressure is too high, because the raw material (2S, 4S)-2-(tert-butoxycarbonylamino)-4-methylglutaronitrile contains two cyano groups, the dicyano reduction product increases, which also leads to a decrease in product selectivity. In addition, the activity of the C carrier in Examples 1, 8 to 9 is lower than that of alumina, and when silica (SiO2) is used as a carrier in Comparative Example 1 in Table 2, the raw material is completely converted and no product is detected. In Example 9, when an attempt is made to reduce the Pd loading to 1%, the gas phase purity of the product decreases, the reducing ability deteriorates, and more intermediate residues occur. In Example 10, when the Pd loading is increased to 10%, the result is similar to that in Example 1. From an economic point of view, a 5% Pd loading is preferred. It can be seen from Comparative Examples 2-3 in Table 2 that when 5% Ru / Al2O3 is used as a catalyst, no product is generated. When 5% Pt / Al2O3 is used as a catalyst, the gas phase purity of the product is only 9.4%. The Pd-based series catalysts are superior.

[0029] Examples 11-17 The difference between Examples 11-17 and Example 1 is that the base and its equivalent number are different. The condition parameters of the micro-packed bed hydrogenation reactor in Examples 1 and 11-17 are shown in Table 3, and the condition parameters of the micro-packed bed hydrogenation reactor in Comparative Example 4 are shown in Table 4.

[0030] Table 3 Condition parameters of micro-packed bed hydrogenation reactor in Example 1, Example 11-Example 17

[0031] Table 4 Condition parameters of the micro-packed bed hydrogenation reactor in Comparative Example 4

[0032] It can be seen from Tables 3 and 4 that when a micro-packed bed hydrogenation reactor is used and 5% Pd(OH)2 / Al2O3 is used as a catalyst, when no base is added, the reaction selectivity is low. The base can inhibit the dimer by-product in the cyanide reduction process. The more suitable base is benzylamine or an alcohol solution of ammonia. When benzylamine is used as an additive, from Examples 1 and 11 to 12, as the benzylamine equivalent increases, the reaction selectivity increases accordingly. When the equivalent number is 1.0eq and 2.5eq, the selectivity is higher, but the difference is not large. For cost considerations, 1.0eq of benzylamine is appropriate. When the equivalent number of an alcohol solution of ammonia is used, it needs to be increased to 5-10eq. The ammonia gas in the alcohol solution of ammonia in the prepared raw material liquid is easy to volatilize.

[0033] Examples 18-24 The difference between Examples 18-24 and Example 1 is that the solvent or the solvent volume used in the micro-packed bed hydrogenation reactor is different. The solvent volume number is the number of the solvent volume to the mass ratio of (2S, 4S)-2-(tert-butoxycarbonylamino)-4-methylglutaronitrile. The condition parameters of the micro-packed bed hydrogenation reactor in Examples 1, 18-24 are shown in Table 5: Table 5 Condition parameters of micro-packed bed hydrogenation reactor in Example 1, Example 18-Example 24

[0034] It can be seen from Table 5 that alcohol solvents have better effects, among which methanol and ethanol have the best effects. Considering the energy consumption during desolventization, methanol is preferred as the solvent. The poor effects of other solvents may be related to their ability to dissolve hydrogen. Among them, oxygen-containing tetrahydrofuran and dioxane are better than ethyl acetate.

[0035] Examples 25-26 The difference between Examples 25-26 and Example 1 is the flow rate of the mixed liquid A in the micro-packed bed hydrogenation reactor. The catalyst and condition parameters of the micro-packed bed hydrogenation reactor in Examples 1, 25-26 are shown in Table 6: Table 6 Condition parameters of micro-packed bed hydrogenation reactor in Example 1, Example 25-Example 26

[0036] It can be seen from Table 6 that when a 2.5mL micro-packed bed reactor is used for hydrogenation, a liquid rate of 0.2mL / min (i.e., 0.08mL / (min·mL catalyst bed)) is more appropriate. When the flow rate is reduced to 0.1mL / min (0.04mL / (min·mL catalyst bed)), although the selectivity is not much different, a flow rate of 0.1mL / min will result in too low a production capacity. When the flow rate is increased to 0.3mL / min (0.2mL / (min·mL catalyst bed)), the raw material conversion is incomplete.

[0037] Embodiment 27 The scaled-up production verification of preparing (3S,5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine was carried out with reference to Example 1: 300 mL of spherical 5% palladium hydroxide / alumina was loaded into a micro-packed bed hydrogenation reactor (500 mL), and the catalyst was gently tapped during the loading process to increase the density of the catalyst loading and prevent catalyst bridging. (2S, 4S)-2-(tert-butoxycarbonylamino)-4-methylglutaronitrile (12.4 kg, 55.6 mol, 1.0 eq) was dissolved in methanol (200 L), stirred and dissolved until clear, and benzylamine (5.9 kg, 55.6 mol, 1.0 eq) was added thereto to prepare a methanol solution of (2S, 4S)-2-(tert-butoxycarbonylamino)-4-methylglutaronitrile, i.e., mixed solution A. The reaction temperature was controlled to be 80°C, the reaction pressure was 2.0 MPa, the flow rate of the mixed liquid A was 40.0 mL / min (i.e., 0.08 mL / min·mL catalyst bed), and the flow rate of hydrogen was 6.0 L / min (standard condition, 46 times the molar flow rate of (2S, 4S)-2-(tert-butoxycarbonylamino)-4-methylglutaronitrile). Then, the mixed liquid A and hydrogen were first mixed together through the gas-liquid mixer at the inlet of the micro-packed bed hydrogenation reactor and then entered the catalyst bed in the hydrogenation reactor for hydrogenation reaction. After continuous operation for 1-2 hours, the reaction was assumed to reach a steady state. 1 mL of the effluent ((3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine crude solution) was received, 0.1 mL of the reaction solution was diluted to 1 mL with methanol and sent to gas chromatography for analysis. The reaction conversion rate was 100%. Figure 2 This is the central control gas chromatogram of (3S,5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine prepared in Example 27. The injection volume is 1 μL. The retention time, type, peak width, peak area, peak height and peak area % of the gas chromatogram are shown in Table 7 below. Table 7

[0038] Type BB: represents a standard peak; VV: refers to a peak that starts and ends at the valley line; BV: represents a peak that starts at the baseline but ends at the valley point of the peak, above the baseline; VB: represents a peak that starts at the valley point of the peak and ends above the baseline. Figure 2 It can be seen that the retention time of (3S,5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine is 8.933min, and the product purity is 94.16% (gas phase (GC) peak area ratio). After the reactor was operated continuously for 5 days, the raw material liquid was consumed, and all the receiving liquid was concentrated under reduced pressure at 40°C, salified with D-di-p-methylbenzoyltartaric acid (D-DTTA) in isopropanol, and purified by slurrying with methyl tert-butyl ether (MTBE), and then alkali-ionized with sodium hydroxide aqueous solution, and finally crystallized with MTBE / n-heptane (n-heptane) to obtain pure (3S,5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine, with a gas phase purity of >99%. The reaction separation yield is 82.1%.

[0039] Comparative Example 5 Conventional intermittent hydrogenation method for preparing (3S,5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine: Methanol (227.0 kg, 12 w / w) and benzylamine (14.0 kg, 131.0 mol, 1.5eq, 0.72 w / w) were added to a 1000L autoclave. (2S,4S)-2-(tert-butoxycarbonylamino)-4-methylglutaronitrile (19.5 kg, 87.3 mol, 1.0 eq) and 10% palladium on carbon (2.5 kg, 0.13 w / w) were added under nitrogen protection. Nitrogen / vacuum replacement was performed 3 times, and hydrogen / vacuum replacement was performed once. Hydrogen was introduced and the pressure was raised to 1 MPa. The temperature was controlled at 20~25℃ and the pressure was controlled at 1Mpa. The reaction was continued for 5 hours. Samples were taken for control and the (2S,4S)-2-(tert-butoxycarbonylamino)-4-methylglutaronitrile disappeared completely. The temperature was raised to 40~45℃ for reaction for 5 hours. Samples were taken for control and the reaction progress was monitored. Heat to 60-65℃ for 5h, sample and control, monitor the reaction progress. Heat to 60-65℃ for 15h, sample and control, monitor the reaction progress, stop the reaction after the reaction is complete, cool to 20-25℃, replace with nitrogen / vacuum 3 times, filter the reaction liquid, and transfer the filtrate to a 1000L reactor. Concentrate at 50-60℃ until no fraction flows out, draw in isopropanol (50 kg, 2.5 w / w), and concentrate again until no fraction flows out. 18.7 kg of crude (3S,5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine was obtained with a yield of 100% and a purity of 86.0%. It was salified with D-di-p-methylbenzoyltartaric acid (D-DTTA) in isopropanol, purified by slurrying with methyl tert-butyl ether (MTBE), and then alkali-ionized with sodium hydroxide aqueous solution. Finally, pure (3S,5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine was obtained by crystallization and drying. The reaction separation yield was 67.0%.

[0040] In summary, according to the process description of Example 1 and Example 27, in a micro-packed bed continuous hydrogenation reactor, after preparing the mixed liquid A, 5% Pd (OH) 2 / Al 2 O 3 is used as a catalyst bed, and the raw material liquid is mixed with hydrogen at a gas-liquid mixer through a feed pump at a specific temperature and pressure and then enters the reaction bed for reaction, (3S, 5S) -3- (tert-butoxycarbonylamino) -5-methylpiperidine can be conveniently and stably prepared, and this continuous process is easy to scale up, and a 500mL reactor can be used to achieve a daily consumption of 2.5kg (2S, 4S) -2- (tert-butoxycarbonylamino) -4-methylglutaronitrile. And by comparing Example 1, Example 27 and Comparative Example 5, the continuous operation is simpler and more efficient than the batch operation of the kettle, involving a smaller reaction volume, and avoiding the operation of filtering the catalyst, which can greatly reduce the danger of the hydrogenation reaction, while the product purity and yield are both improved to a certain extent.

[0041] The above specific implementation methods further illustrate the purpose, technical solutions and beneficial effects of the present application in detail. It should be understood that the above are only specific implementation methods of the present application and are not used to limit the protection scope of the present application. Any modifications, equivalent substitutions, improvements, etc. made on the basis of the technical solutions of the present application should be included in the protection scope of the present application.

Claims

1. A method for preparing (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine, characterized in that: include: Dissolving (2S,4S)-2-(tert-butoxycarbonylamino)-4-methylglutaronitrile in a solvent, and adding a base to mix to obtain a mixed solution A; The catalyst is loaded into a catalyst bed in a micro-packed bed hydrogenation reactor, the flow rates of the mixed liquid A and hydrogen are adjusted, the mixed liquid A and hydrogen are mixed in a gas-liquid mixer at the inlet of the micro-packed bed hydrogenation reactor to obtain a gas-liquid mixed fluid, the gas-liquid mixed fluid is passed through the catalyst bed and reacted, and the reaction temperature is controlled by a reactor heat exchange chamber of the micro-packed bed hydrogenation reactor; After the reaction was completed, the reaction solution was collected and purified to obtain (3S,5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine.

2. The method for preparing (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine according to claim 1, characterized in that: The catalyst is a supported metal catalyst, and the carrier of the supported metal catalyst is activated alumina or activated carbon.

3. The method for preparing (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine according to claim 2, characterized in that: The metal of the supported metal catalyst is palladium hydroxide, and the metal loading amount of the supported metal catalyst is 0.1-10 wt %.

4. The method for preparing (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine according to claim 1, characterized in that: The solvent is methanol, ethanol, isopropanol, butanol, ethylene glycol, tetrahydrofuran, dioxane, methyl tert-butyl ether or ethyl acetate, and the mass ratio of the volume of the solvent to (2S, 4S)-2-(tert-butoxycarbonylamino)-4-methylglutaronitrile is 4 to 60:

1.

5. The method for preparing (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine according to claim 1, characterized in that: The base is ammonia gas, an alcohol solution of ammonia or benzylamine.

6. A method for preparing (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine according to claim 5, characterized in that: The molar ratio of ammonia to (2S, 4S)-2-(tert-butoxycarbonylamino)-4-methylglutaronitrile in the ammonia gas or the alcoholic ammonia solution is 0.1-20:1, and the molar ratio of benzylamine to (2S, 4S)-2-(tert-butoxycarbonylamino)-4-methylglutaronitrile is 0.1-10:

1.

7. The method for preparing (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine according to claim 1, characterized in that: The reaction temperature is 50-150°C, and the reaction pressure is 0.2-5 Mpa.

8. The method for preparing (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine according to claim 1, characterized in that: The flow rate of the mixed solution A is 0.01 to 0.5 mL / (min·mL catalyst bed), and the molar flow rate ratio of (2S,4S)-2-(tert-butoxycarbonylamino)-4-methylglutaronitrile to hydrogen in the mixed solution A is 1:4 to 50.

9. The method for preparing (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine according to claim 1, characterized in that: The purification method comprises: concentrating under reduced pressure, forming salt with acid, beating, freeing with alkali and then recrystallizing to obtain (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine.

10. The method for preparing (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine according to claim 1, characterized in that: The preparation method of (3S, 5S)-3-(tert-butoxycarbonylamino)-5-methylpiperidine adopts a micro-packed bed hydrogenation reactor for reaction, and the micro-packed bed hydrogenation reactor includes a gas-liquid mixer, a reactor heat exchange chamber, and a catalyst bed.

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