Method for continuously preparing (2R, 4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl) amino]-2-methylpentanoic acid

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a method for continuously preparing (2R, 4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl) amino]-2-methylpentanoic acid, which comprises the following steps: dissolving and mixing, S2, carrying out hydrogenation reaction, S3, quenching and concentrating, S4, crystallizing and filtering, and S5, continuously drying: carrying out vacuum drying on a filter cake to obtain a target product (2R, 4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl) amino]-2-methylpentanoic acid. According to the present invention, the continuous hydrogenation reaction, the crystallization and the drying process are performed on the (4S, 4S)-5-(biphenyl-4-yl)-4-[(t-butoxycarbonyl) amino]-2-methylpentanoic acid, such that the batch interval time of the traditional intermittent production is avoided, the productivity per unit time is significantly improved, the method is suitable for industrial amplification, and the reaction time is shortened due to the use of the fixed bed reactor or the micro-channel mixer.

Description

TECHNICAL FIELD

[0001] The application relates to the technical field of organic synthesis, in particular to a method for continuously preparing (2R, 4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid. BACKGROUND

[0002] The original hydrogenation reduction process uses a kettle reaction, the heat exchange area is small, the reaction time is long, the pressure and the reaction condition control are relatively high, the material residence time is long, impurities are prone to be generated, the micro-reaction hydrogenation reduction technology has the characteristics of fast heat and mass transfer, controllable process, continuous reaction, short material residence time and easy amplification, and the application provides a method for continuously preparing (2R, 4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid, the product can be stably prepared by using a tubular reactor, a micro-channel reactor and a fixed bed reactor, the continuous preparation process is safe and controllable, the conversion efficiency is high, the purity is high, impurities are small and the production capacity is high. SUMMARY

[0003] This section is intended to summarize some aspects of the embodiments of the application and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the abstract and title of the specification of the application in order to avoid obscuring the purpose of this section, the abstract and the title, and such simplifications or omissions cannot be used to limit the scope of the application.

[0004] Therefore, the purpose of the application is to provide a method for continuously preparing (2R, 4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid, which avoids the batch interval time of traditional batch production through continuous hydrogenation reaction, crystallization and drying process, significantly improves the production capacity per unit time, is suitable for industrial amplification, and shortens the reaction time by using a fixed bed reactor or a micro-channel mixer.

[0005] To solve the above technical problems, according to one aspect of the application, the application provides the following technical scheme:

[0006] A method for continuously preparing (2R, 4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid, comprising the following steps:

[0007] S1. Dissolution and mixing: continuously inputting ethanol, (R, E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid and a catalyst into a reactor to form a homogeneous liquid;

[0008] S2. Hydrogenation reaction: continuously mixing the solution of step S1 with hydrogen gas through a delivery pump and a mixer, and then feeding into a fixed bed reactor or a continuous stirred reactor for hydrogenation reaction, and continuously outputting the reaction product to a receiving tank;

[0009] S3. Quenching and concentration: continuously filtering the reaction solution, and then feeding the filtrate into a vacuum concentration device after eluting with ethanol to obtain a concentrated product;

[0010] S4. Crystallization and filtration: dissolving the concentrated product with a solvent, slowly cooling to 10-15℃ and stirring for 1-2 hours, and then continuously filtering to obtain a filter cake;

[0011] S5. Continuous drying: vacuum drying the filter cake to obtain the target product (2R, 4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid.

[0012] As a preferred scheme of the method for continuously preparing (2R, 4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid according to the application, in step S1, the catalyst is palladium on carbon, platinum on carbon or Raney nickel, and the amount used is 1%-10% of the mass of the compound.

[0013] As a preferred scheme of the method for continuously preparing (2R, 4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid according to the application, in step S2, the hydrogenation reaction conditions are: hydrogen gas pressure 0.1-2.0 MPa, reaction temperature 20-80℃, and residence time 10-120 min.

[0014] As a preferred scheme of the method for continuously preparing (2R, 4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid according to the application, in step S2, the fixed bed reactor is loaded with a supported metal catalyst, and the mixer is a static mixer or a microchannel mixer.

[0015] As a preferred scheme of the method for continuously preparing (2R, 4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid according to the application, in step S3, the vacuum concentration temperature is 30-60℃, and the vacuum degree is -0.08--0.1 MPa.

[0016] As a preferred scheme of the method for continuously preparing (2R, 4S)-5-(diphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylvaleric acid, in step S4, the solvent is ethanol, methanol, isopropanol or a mixed solvent of two of them, and the amount of solvent is 2-5 times the volume of the concentrated product.

[0017] As a preferred scheme of the method for continuously preparing (2R, 4S)-5-(diphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylvaleric acid, in step S4, the cooling rate is 0.5-2°C / min.

[0018] As a preferred scheme of the method for continuously preparing (2R, 4S)-5-(diphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylvaleric acid, in step S5, the vacuum drying temperature is 40-60°C, and the drying time is 4-12 hours.

[0019] Compared with the prior art, the present application has the beneficial effects of:

[0020] The continuous preparation process is safe and controllable, has high conversion efficiency, high purity, small impurities and high production capacity.

[0021] The reaction is as follows:

[0022] 1. The isomer content is less than 25% using a Pd catalyst;

[0023] 2. The use of 2% Pd on a silica catalyst support is lower in cost than the traditional 5% Pd / AC and 10% Pd / AC;

[0024] 3. The reaction is complete, with 0-0.2% of the raw material remaining, compared with 1%-2% in traditional tank reactors, which is more complete and has a higher conversion rate;

[0025] 4. The reaction efficiency is improved, and the use of a chiral ligand catalyst has more obvious advantages, with an isomer content of less than 0.5%, no raw material remaining, and a catalyst dosage of only 3.5% of that of a tank reactor. The reaction concentration is doubled compared with the tank reactor, greatly improving production efficiency;

[0026] 5. Through continuous hydrogenation reaction, crystallization and drying processes, the batch interval time of traditional batch production is avoided, the unit time capacity is significantly improved, it is suitable for industrialization, and the use of fixed bed reactors or micro-channel mixers shortens the reaction time;

[0027] 6. Continuous flow reaction systems (such as static mixers + fixed beds) ensure uniform mixing of materials and hydrogen, precise control of reaction temperature and pressure parameters, reduction of side reactions, and programmed cooling crystallization process avoids uneven crystal formation caused by local supersaturation, thereby improving crystal yield and batch consistency. Attached Figure Description

[0028] To more clearly illustrate the technical solutions of the embodiments of the present invention, the present invention will be described in detail below with reference to the accompanying drawings and detailed embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort. Wherein:

[0029] Fig. 1 This is a diagram of the reaction apparatus of the present invention;

[0030] Fig. 2 This is a schematic diagram of the preparation method steps of the present invention. Detailed Implementation

[0031] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the accompanying drawings.

[0032] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0033] Secondly, the present invention is described in detail with reference to the schematic diagrams. When detailing the embodiments of the present invention, for ease of explanation, the cross-sectional views illustrating the device structure may be partially enlarged, not according to the usual scale. Furthermore, the schematic diagrams are merely examples and should not limit the scope of protection of the present invention. In addition, actual fabrication should include three-dimensional spatial dimensions of length, width, and depth.

[0034] To make the objectives, technical solutions, and advantages of the present invention clearer, the embodiments of the present invention will be described in further detail below with reference to the accompanying drawings.

[0035] This invention provides a continuous method for preparing (2R,4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid. Through continuous hydrogenation, crystallization, and drying processes, the batch intervals of traditional intermittent production are avoided, significantly increasing the yield per unit time. This method is suitable for industrial scale-up, and the use of fixed-bed reactors or microchannel mixers further shortens the reaction time. Please refer to [link to relevant documentation]. Figs. 1-2 It includes the following steps:

[0036] S1. Dissolution and mixing: ethanol, (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert- butoxycarbonyl)amino)-2-methyl-2-pentenoic acid and catalyst are continuously input into a reactor, and mixed to form a homogeneous liquid;

[0037] S2. Hydrogenation reaction: the liquid from step S1 is continuously mixed with hydrogen gas by a delivery pump and a mixer, and then input into a fixed bed reactor or a continuous stirred reactor for hydrogenation reaction, and the reaction product is continuously output to a receiving tank;

[0038] S3. Quenching and concentration: the reaction solution is continuously filtered, the filtrate is washed with ethanol and then input into a vacuum concentration device to obtain a concentrated product;

[0039] S4. Crystallization and filtration: the concentrated product is dissolved in a solvent, slowly cooled to 10-15°C and stirred for 1-2 hours, and then continuously filtered to obtain a filter cake;

[0040] S5. Continuous drying: the filter cake is vacuum dried to obtain the target product (2R,4S)-5-(biphenyl-4-yl)-4-[(tert-butoxy carbonyl)amino]-2-methyl pentanoic acid;

[0041] The catalyst is palladium-carbon, platinum-carbon or Raney nickel, and the amount is 1%-10% of the mass of the compound. In step S2, the hydrogenation reaction conditions are: hydrogen pressure 0.1-2.0 MPa, reaction temperature 20-80°C, and residence time 10-120 min. In step S2, the fixed bed reactor is filled with a supported metal catalyst, and the mixer is a static mixer or a microchannel mixer. In step S3, the vacuum concentration temperature is 30-60°C, and the vacuum degree is -0.08--0.1 MPa. In step S4, the solvent is ethanol, methanol, isopropanol or a mixed solvent of two of them, and the amount of solvent is 2-5 times the volume of the concentrated product. In step S4, the cooling rate is 0.5-2°C / min. In step S5, the vacuum drying temperature is 40-60°C, and the drying time is 4-12 hours.

[0042] Example: 1

[0043] Dissolution: 5 g of raw material, 50 g of methanol and 0.15 g of 10% Pd / AC are mixed uniformly and dissolved.

[0044] Hydrogenation reaction: the delivery pump is turned on, the hydrogen flow rate is set to 10 ml / min, the liquid flow rate is set to 0.2 ml / min, the liquid and hydrogen gas are mixed through the mixer, and then pass through the tubular reactor (reactor diameter 0.5 mm, length 25 mm), the reaction temperature is controlled at 70°C, the pressure is controlled at 4 MPa, and the reaction solution is received in the receiving tank. The raw material is completely reacted.

[0045] Quenching and concentration: the reaction solution is filtered, the filter cake is washed with a small amount of methanol, and then vacuum concentrated.

[0046] Crystallization filtration: add isopropyl acetate to dissolve, add n-heptane after dissolution, cool to 10-15°C, stir for 1-2h.

[0047] Drying: vacuum dry the filter cake, set the temperature to 55-65°C, obtain 2.3g of product, yield 46%, purity 99.9%, isomer 0.04%.

[0048] Example: 2

[0049] Dissolution: dissolve 10g of raw material, 0.2g in 100g of methanol, mix well.

[0050] Hydrogenation reaction: start the delivery pump, set the hydrogen flow rate to 10ml / min, the feed flow rate to 0.2ml / min, mix the feed and hydrogen in a mixer, pass through a microchannel reactor (microchannel residence 5ml, add 2% Pd / SiO2), control the reaction temperature to 60°C, the pressure to 5Mpa, receive the reaction solution in a receiving tank. The raw material is completely reacted.

[0051] Quenching and concentration: filter the reaction solution, rinse the filter cake with a small amount of methanol, concentrate under reduced pressure.

[0052] Crystallization filtration: add ethanol to dissolve, add n-heptane after dissolution, cool to 10-15°C, stir for 1-2h.

[0053] Drying: vacuum dry the filter cake, set the temperature to 55-65°C, obtain 4.8g of product, yield 48%, purity 99.9%, isomer 0.02%.

[0054] Example: 3

[0055] Dissolution: dissolve 5g of raw material, 50g of methanol, mix well.

[0056] Hydrogenation reaction: start the delivery pump, set the hydrogen flow rate to 100ml / min, the feed flow rate to 2ml / min, mix the feed and hydrogen in a mixer, pass through a fixed bed reactor (diameter 40mm, height 165mm, catalyst 2% Pd / Pd / SiO2 225ml), control the reaction temperature to 50°C, the pressure to 4Mpa, receive the reaction solution in a receiving tank. The raw material is completely reacted.

[0057] Quenching and concentration: filter the reaction solution, rinse the filter cake with a small amount of methanol, concentrate under reduced pressure.

[0058] Crystallization filtration: cool to 20±10°C, stir for 1-2h, filter, rinse the filter cake with water 100ml

[0059] Drying: The filter cake was vacuum dried at a temperature of 55-65 °C to obtain 4.8 g of product at a yield of 48% and a purity of 99.9% with 0.05% isomer.

[0060] Example: 4

[0061] Dissolution: The raw material 5 g, methanol 50 g, and metal ruthenium chiral ligand catalyst 1 mg were mixed uniformly and dissolved.

[0062] Hydrogenation reaction: The delivery pump was turned on, the hydrogen flow rate was set to 10 ml / min, the feed flow rate was set to 0.2 ml / min, the feed solution and hydrogen were mixed in a mixer, and then passed through a tubular reactor (reactor diameter 0.5 mm, length 25 mm), the reaction temperature was controlled at 60 °C, the pressure was controlled at 5 Mpa, and the reaction solution was received in a receiving tank. The raw material was completely reacted.

[0063] Quenching and concentration: The reaction solution was filtered, the filter cake was washed with a small amount of methanol, and then concentrated under reduced pressure.

[0064] Crystallization and filtration: Isopropyl acetate was added to dissolve, n-heptane was added after the solution was clear, the temperature was lowered to 10-15 °C, and stirring was performed for 1-2 h.

[0065] Drying: The filter cake was vacuum dried at a temperature of 55-65 °C to obtain 9.2 g of product at a yield of 92% and a purity of 99.9% with 0.02% isomer.

[0066] Example: 5

[0067] Dissolution: The raw material 5 g, methanol 50 g, and metal ruthenium chiral ligand catalyst 1.5 mg were mixed uniformly and dissolved.

[0068] Hydrogenation reaction: The delivery pump was turned on, the hydrogen flow rate was set to 10 ml / min, the feed flow rate was set to 0.2 ml / min, the feed solution and hydrogen were mixed in a mixer, and then passed through a tubular reactor (reactor diameter 0.5 mm, length 25 mm), the reaction temperature was controlled at 60 °C, the pressure was controlled at 0.5 Mpa, and the reaction solution was received in a receiving tank. The raw material was completely reacted.

[0069] Quenching and concentration: The reaction solution was filtered, the filter cake was washed with a small amount of methanol, and then concentrated under reduced pressure.

[0070] Crystallization and filtration: Ethanol was added to dissolve, n-heptane was added after the solution was clear, the temperature was lowered to 10-15 °C, and stirring was performed for 1-2 h.

[0071] Drying: The filter cake was vacuum dried at a temperature of 55-65 °C to obtain 9.5 g of product at a yield of 95% and a purity of 99.9% with 0.02% isomer.

[0072] Working principle: the invention in use, through the continuous hydrogenation reaction, crystallization and drying process, avoids the batch interval time of traditional batch production, significantly improves the production capacity per unit time, is suitable for industrialization amplification, and shortens the reaction time by using the fixed bed reactor or the micro channel mixer, and the continuous flow reaction system (such as static mixer + fixed bed) ensures that the material and hydrogen are mixed uniformly, the reaction temperature and pressure parameters are accurately controlled, the side reaction is reduced, and the programmed cooling crystallization process avoids the uneven crystal form caused by local supersaturation, improves the crystal yield and batch consistency.

[0073] Although the present application has been described with reference to the embodiments above, various improvements can be made thereto and equivalents can be substituted therefor without departing from the scope of the present application. In particular, features of the disclosed embodiments can be combined together in any manner provided that there is no structural conflict, and the combinations are not exhaustively described in the specification only for the purpose of omitting the length and saving resources. Therefore, the present application is not limited to the specific embodiments disclosed herein, but includes all technical solutions falling within the scope of the claims.

Claims

1. A process for the continuous preparation of (2R,4S)-5-(diphenyl-4-yl)-4-[(tert- butoxycarbonyl)amino]-2-methylpentanoic acid, characterized in that, The method comprises the following steps: S1. Dissolving and mixing: continuously inputting ethanol, (R, E)-5-([1, 1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid and a catalyst into a reactor to form a homogeneous liquid; S2. Hydrogenation reaction: continuously mixing the liquid from step S1 and hydrogen gas through a delivery pump and a mixer, and then inputting into a fixed bed reactor or a continuous stirring reactor to perform hydrogenation reaction, and continuously outputting the reaction product to a receiving tank; S3. Quenching and concentration: continuously filtering the reaction liquid, and then inputting the filtrate into a vacuum concentration device after elution with ethanol to obtain a concentrated product; S4. Crystallization and filtration: dissolving the concentrated product in a solvent, slowly cooling to 10-15°C and stirring for 1-2 hours, and then continuously filtering to obtain a filter cake; S5. Continuous drying: vacuum drying the filter cake to obtain the target product (2R, 4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid.

2. A process for the continuous preparation of (2R, 4S)-5-(diphenyl-4-yl)-4-[(tert- butoxycarbonyl)amino]-2-methylpentanoic acid according to claim 1, characterized in that, In the step S1, the catalyst is palladium-carbon, platinum-carbon or Raney nickel, and the amount is 1%-10% of the mass of the compound.

3. A process for the continuous preparation of (2R, 4S)-5-(diphenyl-4-yl)-4-[(tert- butoxycarbonyl)amino]-2-methylpentanoic acid according to claim 1, characterized in that, In the step S2, the hydrogenation reaction conditions are as follows: hydrogen pressure is 0.1-2.0 MPa, reaction temperature is 20-80°C, and residence time is 10-120 min.

4. The process for the continuous preparation of (2R, 4S)-5-(diphenyl-4-yl)-4-[(tert- butoxycarbonyl)amino]-2-methylpentanoic acid according to claim 1, characterized in that, In the step S2, the fixed bed reactor is filled with a supported metal catalyst, and the mixer is a static mixer or a microchannel mixer.

5. A process for the continuous preparation of (2R, 4S)-5-(diphenyl-4-yl)-4-[(tert- butoxycarbonyl)amino]-2-methylpentanoic acid according to claim 1, characterized in that, In the step S3, the vacuum concentration temperature is 30-60°C, and the vacuum degree is -0.08--0.1 MPa.

6. A process for the continuous preparation of (2R, 4S)-5-(diphenyl-4-yl)-4-[(tert- butoxycarbonyl)amino]-2-methylpentanoic acid according to claim 1, characterized in that, In the step S4, the solvent is ethanol, methanol, isopropanol or a mixed solvent of two of them, and the amount of the solvent is 2-5 times the volume of the concentrated product.

7. A process for the continuous preparation of (2R, 4S)-5-(diphenyl-4-yl)-4-[(tert- butoxycarbonyl)amino]-2-methylpentanoic acid according to claim 1, characterized in that, In the step S4, the cooling rate is 0.5-2°C / min.

8. A process for the continuous preparation of (2R, 4S)-5-(diphenyl-4-yl)-4-[(tert- butoxycarbonyl)amino]-2-methylpentanoic acid according to claim 1, characterized in that, In the step S5, the vacuum drying temperature is 40-60°C, and the drying time is 4-12 hours.

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