A process for the preparation of L-aminoalkyl alcohols

Abstract

The application provides a preparation method of L-aminoalkyl alcohol, which uses L-aminoalkyl ester as raw material and adopts continuous production mode to generate L-aminoalkyl alcohol through catalytic hydrogenation. The method does not need to add acid to promote the reaction, and is superior to kettle production in efficiency, quality, energy consumption, safety and environmental protection. In conclusion, the technical scheme provided by the application has good economic effect, reduces production cost and is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis, and specifically to a method for preparing L-aminoalkyl alcohols. Background Technology

[0002] L-aminoalkyl alcohols are an important component in drug design, and their derivatives possess high biological activity, finding wide applications in chemistry, chemical engineering, and pharmaceuticals. For example, L-aminopropanol is a crucial intermediate in the synthesis of levofloxacin, a third-generation quinolone antibiotic. Levofloxacin exhibits antibacterial activity several times that of its enantiomer, achieving 100% efficacy against intestinal and gonococcal infections. It is one of the most widely used drugs in clinical practice, possessing advantages such as a broad antibacterial spectrum, strong antibacterial activity, low toxicity and side effects, and no cross-resistance with other antibiotics. Furthermore, L-aminopropanol, as a chiral modifier, has extensive applications in the resolution of racemic mixtures, resulting in significant market demand. In recent years, linking L-aminoalkyl alcohols to specific structures to identify highly active screening drugs has become a hot topic in drug discovery research. Therefore, L-aminoalkyl alcohols are highly promising pharmaceutical intermediates.

[0003]

[0004] There are two main synthetic methods for L-aminopropanol: stereoselective synthesis and chemical resolution. However, due to the high difficulty of industrializing chiral resolution, industrial production generally employs another method: reducing the optically active L-alanine or its derivatives to directly prepare L-aminopropanol. The reducing agents used in industrial production mainly include KBH4, LiBH4, NaBH4, or LiAlH4, but these reducing agents are expensive, hazardous, and involve complex post-processing and significant environmental pollution, thus having considerable limitations. In addition, esterification reduction has been reported in the literature, utilizing the reaction of L-alanine with SOCl2 and anhydrous ethanol to form an ester. The ethyl ester of L-alanine is then added dropwise to an aqueous solution of NaBH4 to reduce L-aminopropanol, which is then extracted with ethyl acetate and distilled under reduced pressure, yielding 67%. In the two reduction methods for synthesizing L-aminopropanol mentioned above, although the reaction conditions are relatively mild, the reducing agents NaBH4 and LiAlH4 used in the reduction method are expensive, flammable, highly dangerous, and highly toxic. Moreover, the product separation and purification process is complex, which is not conducive to industrial production. A large amount of organic solvents are used in the synthesis and separation process, and solvent recovery is difficult during the production process. A large amount of pollutants are generated, such as wastewater, waste gas, and solid waste, which is very detrimental to environmental protection.

[0005] In recent years, the country has advocated green chemical technology, focusing on developing technologies in the fine chemical industry to replace highly toxic and harmful raw materials, solvents, and catalysts with non-toxic or low-toxic and low-harm raw materials, solvents, and catalysts, thereby achieving the greening of raw materials, solvents, and catalysts. Currently, several patents have reported on the direct hydrogenation of L-alanine to prepare L-aminopropanol via catalytic hydrogenation, which effectively avoids the aforementioned drawbacks and represents an environmentally friendly green chemical synthesis method.

[0006] For example, Chinese patent CN101298050A discloses a catalyst for the catalytic hydrogenation synthesis of L-aminopropanol. The preparation method involves using copper chloride and ferric chloride as raw materials, and activated carbon as a support to prepare a modified support. The modified support is then suspended in a suspension using a surfactant. Formaldehyde is used as a reducing agent to reduce ruthenium chloride and palladium chloride to obtain the catalyst. Catalytic hydrogenation of this catalyst in an autoclave at 160°C yields L-2-aminopropanol with a GC content of 99.8% and a product yield of 79%.

[0007] CN115888701B discloses a catalyst for the catalytic hydrogenation of L-aminopropanol, its preparation method, and its application. The catalyst involves melting ruthenium metal, an alkali, and an alkali metal nitrate at 600-900℃, cooling, leaching, and then reducing them with a reducing agent, followed by separation and drying. This catalyst is used to catalyze the synthesis of L-aminopropanol from L-alanine under acidic conditions, exhibiting high yield and product purity.

[0008] CN107715870A discloses a method for preparing a ruthenium-carbon catalyst for the preparation of L-aminopropanol from L-aminopropionic acid. The catalyst is characterized by comprising activated carbon and a metal component supported on the activated carbon, wherein the metal component is ruthenium and auxiliary agents (platinum, palladium, rhodium, molybdenum, cobalt, and nickel). This catalyst exhibits stable performance, excellent reproducibility, and a product yield exceeding 90%.

[0009] CN101648879B describes a process for synthesizing L-aminopropanol by catalytic hydrogenation of a mixture of L-aminopropionic acid as the main raw material and sulfuric acid with a mass fraction of 85%, using ruthenium carbon as a catalyst. This process ensures that the product meets quality standards (purity ≥ 99.0%), and the main technical indicator, specific rotation, reaches +17° to +18°.

[0010] The catalysts and additives used in the above-mentioned catalytic hydrogenation are all precious metals such as ruthenium, platinum, and palladium. Although the safety is improved and the yield and purity are guaranteed compared with the traditional reduction method, the catalysts are expensive, and most of the catalytic reductions using L-aminopropionic acid as raw material require an acidic environment, which increases the requirements for production equipment, resulting in higher production costs and the generation of waste such as sulfate and phosphate. The paper "Heterogeneous Catalytic Hydrogenation of Chiral Amino Acid Methyl Esters to Amino Alcohols with Retention of Configuration Over Mg-Modified Cu / ZnO / Al2O3 Catalyst" (Catal Lett (2017) 147:2160–2166) introduces the use of CuZn 0.3 Mg 0.1 AlO x It can be used as a catalyst in a batch reaction for catalytic hydrogenation. However, the selectivity and yield of the product amino alcohol are only 63%, and there is a high incidence of ring-related byproducts.

[0011]

[0012] Therefore, it is of great significance to develop a method for preparing L-aminoalkyl alcohols that can use inexpensive metal catalysts such as copper, zinc, magnesium, and aluminum for high-efficiency, high-yield, and high-selectivity catalytic hydrogenation reactions, while avoiding the use of dangerous production methods such as high-pressure reactors and the generation of waste such as phosphates and sulfates, so as to achieve industrial-scale production of L-aminoalkyl alcohols with low cost, high safety, and environmental friendliness. Summary of the Invention

[0013] Purpose of the Invention: The purpose of this invention is to overcome the problems of low safety and large amounts of waste generated in the existing processes for preparing L-aminoalkyl alcohols, which are unsuitable for industrial production. This invention provides an improved method for preparing L-aminoalkyl alcohols. This new process uses L-aminoalkyl esters as raw materials, employs a continuous production method, uses smaller equipment, saves space, reduces frequent start-up and shutdown operations, reduces non-production time, and improves efficiency. The reaction conditions are more stable, reducing batch-to-batch variations and resulting in more uniform product quality. Energy consumption during heating and cooling processes is reduced, lowering energy consumption per unit product. The degree of automation is higher, reducing manual operation and the risk of human error. It is superior to batch production in terms of efficiency, quality, energy consumption, safety, and environmental protection, and is more suitable for large-scale production.

[0014] This invention provides a method for preparing a compound of formula I, comprising the following steps: dissolving a compound of formula II in methanol to prepare a feed liquid; adding a catalyst to a continuous tubular reactor for pretreatment; and then introducing hydrogen gas and the feed liquid into the tubular reactor to carry out a catalytic hydrogenation reaction to generate the compound of formula I. The catalyst is a low-cost metal catalyst containing copper, manganese, and aluminum; n = 0 or 1.

[0015]

[0016] Preferably, the molar ratio of copper, manganese and aluminum in the inexpensive metal catalyst is in the range of 1:0.05 to 0.5:0.1 to 1.

[0017] More preferably, the inexpensive metal catalyst is CUCAT-2400T (purchased from Shanghai Xunkai New Materials Technology Co., Ltd.).

[0018] Preferably, the pretreatment method of the catalyst is as follows: in a tubular reactor filled with catalyst, the hydrogen flow rate is set to 10-50 mL / min, the temperature is raised to 180-240℃, and held for 600-1200 min; then the temperature is raised to 200-300℃, held for 60-100 min, and cooled by purging with nitrogen.

[0019] More preferably, the catalyst pretreatment method is as follows: in a tubular reactor filled with catalyst, the hydrogen flow rate is set to 30 mL / min, the temperature is raised to 180°C and held for 600 min; then the temperature is raised to 240°C and held for 60 min, and then cooled by nitrogen gas.

[0020] Preferably, the reaction temperature is 40-100℃;

[0021] More preferably, the reaction temperature is 60-100°C.

[0022] Preferably, the reaction solution prepared by the compound of Formula I and the organic solvent has a mass fraction of 5%.

[0023] Preferably, the reaction pressure is 4.0-5.0 MPa.

[0024] Preferably, the feed flow rate of the reaction is 0.2-0.4 mL / min.

[0025] Beneficial effects

[0026] This invention provides a method for preparing L-aminoalkyl alcohols, using L-aminoalkyl esters as raw materials and employing a continuous production process for catalytic hydrogenation to produce L-aminoalkyl alcohols. Compared with existing synthesis processes, the new process uses a continuous flow reaction mode, eliminating the need for acid to promote the reaction, and is superior to batch production in terms of efficiency, quality, energy consumption, safety, and environmental protection. In summary, the technical solution provided by this invention has excellent economic benefits, reduces production costs, and is suitable for industrial production. Detailed Implementation

[0027] 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.

[0028] Example 1

[0029]

[0030] L-alanine methyl ester (15.53 g, 0.15 mol) was added to methanol (295.07 g), shaken well, and prepared into a 5 wt.% feed solution for later use. The catalyst CUCAT-2400T (purchased from Shanghai Xunkai New Material Technology Co., Ltd.) was crushed and sieved. 5 mL of 20-50 mesh catalyst particles were slowly poured into a 5 mL continuous reactor (inner diameter 4.4 mm, length 33 mm, effective volume 5 mL). While filling, the bottom of the reactor was tapped to ensure that the catalyst was packed tightly. The N2 bypass was opened at room temperature to pressurize the system, and the back pressure valve was adjusted to pressurize the system to 2.5 MPa. The airtightness of the device was then checked.

[0031] Depressurize to atmospheric pressure and adjust the N2 flow rate to 50 mL / min. Purge the entire system with nitrogen for 5 min. Switch to hydrogen and set the flow rate to 30 mL / min. Under atmospheric pressure, raise the furnace temperature from room temperature to 180°C over 75 min, hold for 600 min, then raise the temperature to 240°C over 60 min, hold for 60 min, and then switch to nitrogen at 30 mL / min to allow it to cool naturally to 60°C.

[0032] The furnace temperature was set to 60℃, hydrogen flow rate was set to 30mL / min through a hydrogen flow meter, and the material was pumped into the tubular reactor at a flow rate of 0.2mL / min using a plunger pump. The system was pressurized to 5MPa, and the residence time was 25min. The material was discharged after gas-liquid separation at the outlet. After running for 2 hours, an instantaneous sample was taken for testing, and the product yield was 98.6%.

[0033] Example 2

[0034]

[0035] Add 10g (0.09mol) of L-aminobutyric acid methyl ester to 190g of methanol, shake well, and prepare a 5wt.% raw material solution for later use; crush and sieve the CUCAT-2400T catalyst (purchased from Shanghai Xunkai New Material Technology Co., Ltd.), take 5mL of 20-50 mesh catalyst particles, and slowly pour them into a 5mL continuous reactor (inner diameter 4.4mm, length 33mm, effective volume 5mL), tapping the bottom of the reactor while filling to ensure that the catalyst is packed tightly; open the N2 bypass pressurization at room temperature, adjust the back pressure valve opening, pressurize the system to 2.5MPa, and check the airtightness of the device.

[0036] Depressurize to atmospheric pressure and adjust the N2 flow rate to 50 mL / min. Purge the entire system with nitrogen for 5 min. Switch to hydrogen and set the flow rate to 30 mL / min. Under atmospheric pressure, raise the furnace temperature from room temperature to 180°C over 75 min, hold for 600 min, then raise the temperature to 240°C over 60 min, hold for 60 min, and then switch to nitrogen at 30 mL / min to allow it to cool naturally to 60°C.

[0037] The furnace temperature was set to 60℃, hydrogen flow rate was set to 30mL / min through a hydrogen flow meter, and the material was pumped into the tubular reactor at a flow rate of 0.2mL / min using a plunger pump. The system was pressurized to 5MPa, and the residence time was 25min. The material was discharged after gas-liquid separation at the outlet. After running for 2 hours, an instantaneous sample was taken for testing, and the product yield was 98.6%.

[0038] Comparative Experiment Example 1

[0039]

[0040] Following the method in Example 1, screening experiments were conducted on the reaction conditions, and the results are shown in Tables 1-4.

[0041] Table 1 Effect of reaction temperature

[0042]

[0043] Table 2 Effect of reaction pressure

[0044]

[0045]

[0046] Table 3. Effect of feed flow rate on raw liquid

[0047]

[0048] Table 4 Effect of reaction time

[0049]

[0050] As can be seen from the examples, the preferred reaction conditions of this application for the above-mentioned L-aminoalkyl ester (compound of formula I) have high reaction efficiency, low production cost, and are environmentally friendly, making them suitable for industrial production.

[0051] 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 a compound of formula I, characterized in that... It includes the following steps: Step 1: Dissolve the compound of formula II in methanol to prepare a raw material solution; Step 2: Add the catalyst to the continuous tubular reactor for pretreatment; Step 3: Hydrogen gas and raw material liquid are introduced into a tubular reactor to carry out a catalytic hydrogenation reaction to produce compound I. The catalyst is a low-cost metal catalyst containing copper, manganese, and aluminum; n = 0 or 1.

2. The preparation method according to claim 1, characterized in that: The molar ratio of copper, manganese, and aluminum in the low-cost metal catalyst is in the range of 1:0.05 to 0.5:0.1 to 1.

3. The preparation method according to claim 1, characterized in that: The inexpensive metal catalyst is CUCAT-2400.

4. The preparation method according to claim 1, characterized in that: The catalyst pretreatment method is as follows: in a tubular reactor filled with catalyst, the hydrogen flow rate is set to 10-50 mL / min, the temperature is raised to 180-240℃, and held for 600-1200 min; then the temperature is raised to 200-300℃, held for 60-100 min, and cooled by nitrogen gas.

5. The preparation method according to claim 1, characterized in that: The catalyst pretreatment method is as follows: in a tubular reactor filled with catalyst, the hydrogen flow rate is set to 30 mL / min, the temperature is raised to 180℃ and held for 600 min; then the temperature is raised to 240℃ and held for 60 min, and then cooled with nitrogen gas.

6. The preparation method according to claim 1, characterized in that: The reaction temperature is 40-100℃.

7. The preparation method according to claim 1, characterized in that: The reaction temperature is 60-100℃.

8. The preparation method according to claim 1, characterized in that: The reaction solution prepared by compound I with an organic solvent has a mass fraction of 5%.

9. The preparation method according to claim 1, characterized in that: The reaction pressure is 4.0-5.0 MPa.

10. The preparation method according to claim 1, characterized in that: The feed flow rate for the reaction is 0.2-0.4 mL / min.

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