Synthetic method for preparing 3-hydroxypiperidine through continuous flow strategy

Abstract

The invention relates to the technical field of medical intermediates, and discloses a synthetic method for preparing 3-hydroxypiperidine through a continuous flow strategy, 3-hydroxypiperidine is a medical intermediate with a characteristic skeleton structure, the single enantiomer (R)-3-hydroxypiperidine or (S)-3-hydroxypiperidine of 3-hydroxypiperidine widely exists in various natural products, and the synthesis process is simple. The 3-hydroxypiperidine has wide physiological and pharmacological activities such as cancer resistance and inflammation resistance, a safe and efficient method for synthesizing the 3-hydroxypiperidine suitable for industrial production is established, and the 3-hydroxypiperidine has important market significance and is beneficial to application in the pharmaceutical chemical market.

Description

Technical Field

[0001] The invention relates to a preparation technology of 3-hydroxypiperidine, in particular to a method for synthesizing 3-hydroxypiperidine by adopting a continuous flow strategy. Background Art

[0002] There are currently two main methods for synthesizing 3-hydroxypiperidine:

[0003] Method 1: Ellsworth Edmund Lee et al. (WO 2005 / 026145 A2) used benzyl-3-piperidone as the starting material, methanol as the solvent, and sodium borohydride reduction to produce N-benzyl-3-piperidinol. This was then reduced to 3-hydroxypiperidine using tetrahydrofuran:methanol in a 1:1 ratio as the solvent and Pd / C as the catalyst. The two-step yield was 84%. This route involves hazardous processes due to the toxicity of methanol, the low boiling point of tetrahydrofuran, and the high system pressures required. The sodium borohydride and palladium used are expensive, making it unsuitable for industrial production. The synthetic route is as follows:

[0004]

[0005] Method 2: Patent documents such as "CN 104725299 A", "CN 114436944 A", "CN 117024266 A", "CN103304472 A", and "CN 104725299 A." disclose the synthesis of 3-hydroxypiperidine by catalytic hydrogenation at a certain pressure and temperature using 3-hydroxypyridine as raw material, water or alcohols as solvents, Ru / C, Pd / C, Rh / C, Pt / C as catalysts, and hydrogen as a reducing agent. This method has become the mainstream method for industrial production of 3-hydroxypiperidine and has been industrialized. However, the biggest drawbacks of this method are twofold: first, the autoclave reaction is a dangerous process with a low safety factor; second, the catalyst used in this reaction is relatively expensive and cannot be recycled. The synthetic route is as follows:

[0006] Summary of the Invention

[0007] (1) Technical problems solved

[0008] In view of the shortcomings of the existing technology, the present invention provides a synthetic method for preparing 3-hydroxypiperidine using a continuous flow strategy, which is safe, low-cost, and suitable for industrial production.

[0009] (2) Technical solution

[0010] To achieve the above object, the present invention provides the following technical solution: a synthetic method for preparing 3-hydroxypiperidine using a continuous flow strategy, wherein the synthetic method for preparing 3-hydroxypiperidine using a continuous flow strategy is:

[0011] Using homemade Ni / C as a catalyst and a continuous flow reactor as a carrier, a new method for the synthesis of 3-hydroxypiperidine with a high safety factor, catalyst recycling and extremely low cost was established.

[0012]

[0013] As shown in the figure, starting from 3-hydroxypyridine, using homemade Ni / C as a catalyst, a continuous flow reactor as a carrier, and hydrogen as a reducing agent, catalytic hydrogenation is performed at a certain pressure and temperature to synthesize a crude product 3-hydroxypiperidine with a purity of 95-97%;

[0014] The reaction process is to obtain piperidine by hydrogenating pyridine. The product is single, all 3-hydroxypiperidine, and there are no by-products such as piperidone. The only by-product is unreacted 3-hydroxypiperidine, which can be separated and purified by adjusting the pH, greatly reducing the high energy consumption of separation.

[0015] (3) Beneficial technical effects

[0016] The 3-hydroxypiperidine disclosed in the present invention is a pharmaceutical intermediate having a characteristic skeleton structure. Its single enantiomers, (R)-3-hydroxypiperidine or (S)-3-hydroxypiperidine, are widely present in various natural products and exhibit a wide range of physiological and pharmacological activities, such as anti-cancer and anti-inflammatory properties. Establishing a safe, efficient, and industrially suitable method for synthesizing 3-hydroxypiperidine has important market significance and is beneficial for its application in the pharmaceutical chemical market. The present invention has relatively simple procedures, high product quality, low purification costs, minimal equipment investment, and safe production operations, meeting the needs of large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 This is the spectrum of 3-hydroxypiperidine in Example 1.

[0018] Figure 2 This is the 3-hydroxypiperidine spectrum of Example 2.

[0019] Figure 3 This is the 3-hydroxypiperidine spectrum of Example 3. DETAILED DESCRIPTION

[0020] To make the objectives, technical solutions, and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention are clearly and completely described. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. All other embodiments derived by persons of ordinary skill in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

[0021] In order to better understand the above technical solution, the above technical solution will be described in detail below with reference to the accompanying drawings and specific embodiments.

[0022] Example 1

[0023] (1) Preparation of Ni / C catalyst:

[0024] The dried raw bamboo powder was placed in a tube furnace and heated from room temperature to 700°C at 10°C / min under a N2 atmosphere for 1 hour. The carbon support was then cooled to obtain the carbon support. The prepared carbon support was immersed in a 1 mol / L KOH solution at room temperature in a ratio of m(KOH):m(carbon support) = 1:1. After standing for 10 hours, it was placed in an oven at 105°C for 10 hours. The dried sample was placed in a tube furnace under a N2 atmosphere and heated to 850°C at 10°C / min for 2 hours. The activated sample was acid-washed, washed, and filtered until the filtrate was neutral. The solid was dried at 105°C for 10 hours and ground to 60 mesh. The carbon support was weighed and dissolved in an aqueous solution of 2.0g Ni(NO3)2·6H2O, 0.1g Co(NO3)2·6H2O, 0.1g Cu(NO3)2·3H2O, and 0.15g SiO2 to prepare a solution with a Ni mass fraction of 5%. After adding the above carbon support (catalyst), the mixed solution was ultrasonically shaken for 1 hour, then placed in an oven at 105°C for 24 hours, and the dried sample was placed in a tube furnace and heated to 600°C at 10°C / min under N2 atmosphere and maintained for 6 hours. The obtained catalysts were marked as Ni / C catalysts;

[0025] (2) Preparation of 3-hydroxypiperidine:

[0026] 30 g of 3-hydroxypyridine was dissolved in 1 L of water as the reaction solution. 2.9 g of the homemade Ni / C catalyst was weighed and loaded into the catalytic tube. The reaction was carried out under the conditions of a hydrogen flow rate of 40 mL / min, a reaction liquid flow rate of 1 mL / min, a temperature of 110°C, and a hydrogen pressure of 5 MPa. GC detection showed that the purity of 3-hydroxypiperidine was 95%.

[0027] Example 2

[0028] (1) Preparation of Ni / C catalyst:

[0029] The dried raw bamboo powder was placed in a tube furnace and heated from room temperature to 700°C at 10°C / min under a nitrogen atmosphere for 1 hour. The carbon support was then cooled to obtain the carbon support. The prepared carbon support was immersed in a 1 mol / L KOH solution at room temperature at a ratio of m(KOH):m(carbon support) = 1:1, allowed to stand for 10 hours, and then dried in an oven at 105°C for 10 hours. The dried sample was placed in a tube furnace and heated to 850°C at 10°C / min under N2 atmosphere and maintained for 2h. The activated sample was acid-washed, washed, and filtered until the filtrate was neutral. The obtained solid was dried at 105°C for 10h and ground to 60-80 mesh. The carbon support was prepared by weighing 0.8g of Ni(NO3)2·6H2O, 0.1g of Co(NO3)2·6H2O, 0.1g of Cu(NO3)2·3H2O and 0.15g of SiO2 and dissolving them in aqueous solution to prepare a solution with a Ni mass fraction of 2%. After adding the above carbon support (catalyst), the mixed solution was ultrasonically shaken for 1h and then placed in an oven at 105°C for drying for 24h. The dried sample was placed in a tube furnace and heated to 600°C at 10°C / min under N2 atmosphere and maintained for 6h. The obtained catalysts were marked as Ni / C catalysts.

[0030] (2) Preparation of 3-hydroxypiperidine:

[0031] 30 g of 3-hydroxypyridine was dissolved in 1 L of water as the reaction solution. 2.9 g of the homemade 2% Ni / C catalyst was weighed and loaded into the catalytic tube. The reaction was carried out under the conditions of a hydrogen flow rate of 40 mL / min, a reaction liquid flow rate of 1 mL / min, a temperature of 110°C, and a hydrogen pressure of 5 MPa. GC detection showed that the purity of 3-hydroxypiperidine was 67%.

[0032] Example 3

[0033] Preparation of Ni / C catalyst:

[0034] The dried raw bamboo powder was placed in a tube furnace and heated from room temperature to 700°C at 10°C / min under a nitrogen atmosphere for 1 hour. The carbon support was then cooled to obtain the carbon support. The prepared carbon support was immersed in a 1 mol / L KOH solution at room temperature at a ratio of m(KOH):m(carbon support) = 1:1, allowed to stand for 10 hours, and then dried in an oven at 105°C for 10 hours. The dried sample was placed in a tube furnace and heated to 850°C at 10°C / min under N2 atmosphere for 2 hours. The activated sample was acid-washed, washed, and filtered until the filtrate was neutral. The resulting solid was dried at 105°C for 10 hours and ground to 60 mesh for use as a carbon support. 4g of Ni(NO3)2·6H2O, 0.1g of Co(NO3)2·6H2O, 0.1g of Cu(NO3)2·3H2O, and 0.15g of SiO2 were weighed and dissolved in an aqueous solution to prepare a solution with a Ni mass fraction of 10%. After adding the above carbon support (catalyst), the mixed solution was ultrasonically shaken for 1 hour and then placed in an oven at 105°C for 24 hours. The dried sample was placed in a tube furnace and heated to 600°C at 10°C / min under N2 atmosphere and maintained for 6 hours. The resulting catalysts were labeled as Ni / C catalysts;

[0035] Preparation of 3-hydroxypiperidine:

[0036] 30 g of 3-hydroxypyridine was dissolved in 1 L of water as the reaction solution, and 2.9 g of the homemade 10% Ni / C catalyst was weighed and loaded into the catalytic tube. The reaction was carried out under the conditions of a hydrogen flow rate of 40 mL / min, a reaction liquid flow rate of 1 mL / min, a temperature of 110°C, and a hydrogen pressure of 5 MPa. GC detection showed that the purity of 3-hydroxypiperidine was 97%.

[0037] The preferred embodiments of the present invention disclosed above are intended only to help illustrate the present invention. These preferred embodiments do not exhaustively describe all details, nor do they limit the present invention to the specific embodiments described. Obviously, many modifications and variations are possible based on the content of this specification. These embodiments are selected and described in detail in this specification to better explain the principles and practical applications of the present invention, thereby enabling those skilled in the art to better understand and utilize the present invention. The present invention is limited only by the claims and their full scope and equivalents.

Claims

1. A method for preparing 3-hydroxypiperidine by a continuous flow strategy, characterized in that: The synthetic method for preparing 3-hydroxypiperidine using the continuous flow strategy is: Using homemade Ni / C as a catalyst and a continuous flow reactor as a carrier, a new method for the synthesis of 3-hydroxypiperidine with a high safety factor, catalyst recycling and extremely low cost was established. As shown in the figure, starting from 3-hydroxypyridine, using homemade Ni / C as a catalyst, a continuous flow reactor as a carrier, and hydrogen as a reducing agent, catalytic hydrogenation is performed at a certain pressure and temperature to synthesize a crude product 3-hydroxypiperidine with a purity of 95-97%; The reaction process is to obtain piperidine by hydrogenating pyridine. The product is single, all 3-hydroxypiperidine, and there are no by-products such as piperidone. The only by-product is unreacted 3-hydroxypiperidine, which can be separated and purified by adjusting the pH, greatly reducing the high energy consumption of separation.

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