A process for the preparation of (2R,5S)-1-Boc-5-aminopiperidine-2-carboxylate

Abstract

This invention relates to a method for preparing (2R,5S)-1-Boc-5-aminopiperidine-2-carboxylic acid ethyl ester, which uses a fixed-bed reduction method with isopropanol as a solvent, extending catalyst lifetime and stability, and simplifying post-processing, making it suitable for industrial-scale production.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis, specifically to a method for preparing (2R,5S)-1-Boc-5-aminopiperidine-2-carboxylic acid ethyl ester. Background Technology

[0002] (2R,5S)-1-Boc-5-aminopiperidine-2-carboxylate plays a crucial role in the pharmaceutical industry and is a very important pharmaceutical intermediate. For example, WO2023028534A1 discloses the use of this compound in the preparation of NLRP3 inhibitors, while WO2020216766A1 and WO2022084447A1 disclose its use in the preparation of modulators of integrated stress response (ISR). Integrated stress response (ISR) is a cellular stress response common to all eukaryotes. Dysregulation of ISR signaling has important pathological consequences, especially associated with inflammation, viral infections, diabetes, cancer, and neurodegenerative diseases. (2R,5S)-1-Boc-5-aminopiperidine-2-carboxylic acid ethyl ester has been widely used to prepare a new class of modulators that can serve as integrated stress response pathway modulators, effectively treating diseases associated with integrated stress response pathways and exhibiting improved pharmaceutically relevant properties, including activity, solubility, selectivity, ADMET properties, and / or reduced side effects.

[0003]

[0004] WO2022084447A1 discloses a method for preparing ethyl (2R,5S)-1-Boc-5-aminopiperidine-2-carboxylate:

[0005]

[0006] This method uses palladium on carbon as a catalyst and ethanol as a solvent for catalytic hydrogenation, with reaction quantities on the gram scale, which cannot meet the requirements for large-scale industrial production. Research results obtained from chemical process experiments using small-scale equipment often differ significantly from those obtained from large-scale production facilities under the same operating conditions; the influence of these differences is called the scale-up effect. This is because the temperature, concentration, and material residence time distribution differ between small-scale and large-scale equipment. Therefore, equipment scale-up in chemical engineering is a challenging and urgent problem to solve. In industrial production, high-pressure hydrogenation reactor processes suffer from poor safety, low efficiency, large catalyst consumption, and high costs. In contrast, fixed-bed reduction uses hydrogen as a green, environmentally friendly, safe, and reliable reducing agent, has simple post-treatment, and offers high selectivity for certain reduction reactions. Summary of the Invention

[0007] This invention addresses the synthesis of debenzyl alcohol reactions, such as 1-(tert-butyl)-2-ethyl(2R,5S)-5-(benzyloxy)amino)piperidine-1,2-dicarboxylate. Through the development and optimization of a fixed-bed process using Pd(OH)₂ / Al₂O₃, it achieves a step-by-step scale-up from pilot-scale to production. Compared to batch reactors, this method is safer and more controllable, significantly reducing catalyst usage and meeting the requirements for industrial-scale production. Fixed-bed hydrogenation, as a safe, efficient, and green hydrogenation technology, has attracted widespread attention due to its advantages, including faster reaction rates, reduced reactor volume, improved reaction selectivity, avoidance of catalyst separation, enhanced safety, and continuous automated production.

[0008] This invention provides a method for preparing ethyl (2R,5S)-1-Boc-5-aminopiperidine-2-carboxylate, comprising the following steps:

[0009]

[0010] Compound II is dissolved in an organic solvent and then reduced with hydrogen in a fixed-bed reactor under the action of a catalyst to produce compound I.

[0011] Preferably, the catalyst is selected from palladium on carbon or Pd(OH)2 / Al2O3.

[0012] Preferably, the organic solvent is selected from one or more of methanol, ethanol, isopropanol, and tetrahydrofuran.

[0013] More preferably, the organic solvent is selected from isopropanol.

[0014] Preferably, the reaction pressure is 2-3 MPa.

[0015] Preferably, the reaction temperature is 50–70°C.

[0016] Beneficial effects

[0017] Fixed-bed hydrogenation, as a safe, efficient, and green hydrogenation technology, has attracted widespread attention. It offers advantages such as accelerated reaction rates, reduced reactor volume, improved reaction selectivity, avoidance of catalyst separation, enhanced safety, and continuous automated production. It holds the promise of revolutionizing the current extensive production methods of fine chemicals and achieving a leapfrog improvement in production technology. This invention utilizes a fixed-bed reduction process, employing hydrogen as the reducing agent—a green, environmentally friendly, safe, and reliable process with simple post-treatment. Fixed-bed hydrogenation technology exhibits high selectivity for certain reduction reactions. Detailed Implementation

[0018] The present invention will be further illustrated below with reference to specific embodiments. These embodiments are implemented under the premise of the technical solution of the present invention. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0019] Example 1

[0020]

[0021] Preparation of raw material solution A: Add 258.647 kg, 653 mol, 1 eq. of isopropanol solution of compound II to isopropanol (2327.4 kg) to prepare a 10% wt solution. Add 10% wt activated carbon and silica gel, stir at room temperature for 1 h, and then filter for later use.

[0022] Reaction: The pre-weighed volume and mass of 5% Pd(OH)₂ / Al₂O₃ catalyst are slowly poured into the reaction tube. The system's airtightness is checked. The N₂ pressure is set to 0.5 MPa. The entire system is purged with nitrogen for 15-20 minutes through the N₂ bypass to remove all air. The preheater's integrated heating and cooling unit is set to 75℃, and the reactor's initial jacket temperature is set to 20-30℃. The feed pump is primed with the reaction liquid. Back pressure is applied to the system through the nitrogen bypass, set to 2.5 MPa. After back pressure is established, the feed rate is set to 0.1 L / min, and the air intake rate is set to 3 L / min. The system maintained a stable feed rate of 0.4–0.8 L / min and an intake gas rate of 10–20 L / min. After stabilizing the feed, the reaction parameters were adjusted. Throughout the production process, the preheater temperature increased from an initial 80°C to a final temperature of 83°C. The catalyst bed temperature ranged from 68–80°C in the upper layer, 66–77°C in the middle layer, and 64–77°C in the lower layer. After the system stabilized, the interlock control was activated, and the feed was stopped when the hydrogen flow rate dropped below 10 L / min. After passing the central control test, the product was transferred to the qualified product container, yielding 137.8 kg of compound I, with a yield of 74%.

[0023] Comparative Example 1

[0024]

[0025] Following the method in Example 1, screening tests were conducted on the reaction reagents and reaction conditions, and the results are shown in Tables 1-3.

[0026] Table 1 Reaction Time and Solvent Screening

[0027]

[0028] Experiments on solvent and reaction time show that as reaction time increases, the catalyst is significantly poisoned by the benzyl alcohol produced in the reaction, leading to a decrease in its activity and a reduction in the intermediate purity of the product. When isopropanol is used as the solvent, the intermediate purity can still be maintained above 95% even after 22 hours of reaction. Therefore, isopropanol is selected as the solvent for this reaction.

[0029] Table 2. Screening of reaction temperatures (reaction solvent is isopropanol)

[0030] test batch Reaction time (h) Reaction temperature (°C) Central Purity (IPC) 1 1.0 50 96.3 2 2.0 60 97.2 3 50.5 73 94.5 4 70.5 78 89.8

[0031] The temperature test results show that the catalyst is not resistant to high temperatures. The catalyst deactivation will be accelerated when the reaction temperature exceeds 80℃. Therefore, the reaction temperature should be controlled between 50 and 70℃.

[0032] Table 3. Reaction pressure screening (reaction solvent is isopropanol)

[0033] test batch Reaction pressure (MPa) Reaction temperature (°C) Central Purity (IPC) 1 1.5 60 90.8 2 2.0 60 95.0 3 2.5 60 97.2 4 3.0 60 96.5

[0034] The pressure test results show that the reaction is not effective at low pressures. Below 2.5 MPa, the purity decreases. Therefore, the reaction pressure should be controlled at 2.5 MPa.

[0035] While the specific embodiments of the present invention have been described above, they are not intended to limit the scope of protection of the present invention. For those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing ethyl (2R,5S)-1-Boc-5-aminopiperidine-2-carboxylate, characterized in that... It includes the following steps: Compound II is dissolved in an organic solvent and then reduced with hydrogen in a fixed-bed reactor under the action of a catalyst to produce compound I.

2. The preparation method according to claim 1, characterized in that: The catalyst is selected from palladium on carbon or Pd(OH)2 / Al2O3.

3. The preparation method according to claim 1, characterized in that: The organic solvent is selected from one or more of methanol, ethanol, isopropanol, and tetrahydrofuran.

4. The preparation method according to claim 1, characterized in that: The organic solvent is isopropanol.

5. The preparation method according to claim 1, characterized in that: The reaction is carried out at a pressure of 2–3 MPa.

6. The preparation method according to claim 1, characterized in that: The reaction was carried out at a pressure of 2.5 MPa.

7. The preparation method according to claim 1, characterized in that: The reaction temperature is 50–70°C.

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