Parallel micro-channel reaction system

Abstract

The utility model provides a parallel micro-channel reaction system which comprises a feeding pump A, a feeding pump B, an ultrasonic flowmeter A, an ultrasonic flowmeter B, a check valve, a feeding pipe A, a feeding pipe B, a micro-channel reactor A, a micro-channel reactor B, a high-low temperature integrated circulator, a discharging pipe A, a discharging pipe B, a combined pipeline and a reaction tank, the high-low temperature integrated circulator is connected with the micro-channel reactor A and the micro-channel reactor B through a circulating freezing liquid pipe A and a circulating freezing liquid pipe B, and the reaction tank is used for containing a reaction solution. The parallel micro-channel reaction system not only improves the yield of the sacubitril valsartan sodium intermediate, but also fills the technical blank that the micro-channel reactors are not used in commercial mass production in the market and no double-plate parallel micro-channel reactor exists, is suitable for capacity expansion of all micro-channel reactors, and has no amplification effect.

Description

TECHNICAL FIELD

[0001] The utility model belongs to the technical field of continuous production equipment of chemical industry, medicine and the like, and particularly relates to a parallel microchannel reaction system. BACKGROUND

[0002] Sacubitril / valsartan is the first angiotensin-receptor-neprilysin inhibitor (ARNI) drug in the world, mainly used for treating heart failure and hypertension. At present, researches at home and abroad have focused on the step-by-step construction of the intermediate by asymmetric hydrogenation catalyzed by transition metals and reductive amination reaction catalyzed by transaminase, which needs separation and purification, and there are problems such as transition metal waste treatment and harsh reaction conditions. Therefore, it is of great significance to construct a green and efficient synthesis method of the sacubitril / valsartan intermediate.

[0003] The microchannel reactor is commonly used as a reaction container for synthesizing the sacubitril / valsartan intermediate by the oxidation method. The microchannel reactor is a new type of micro-sized continuous-flow pipeline reactor, which has the advantages of small reaction volume, reduced material consumption, reduced cost, high-speed mixing, high-efficiency heat transfer, good repeatability, and easy operation. The microchannel reactor in the prior art is commonly used for synthesizing the sacubitril / valsartan intermediate by the oxidation method, which greatly improves the yield. However, the liquid holding capacity of a single microchannel reactor is limited, the oxidation reaction time is long, and the batch time single consumption is large, which cannot meet the production capacity demand of the pharmaceutical enterprises for the sacubitril / valsartan intermediate SKB-8. At present, there is no double-plate parallel microchannel reactor, and the mature overall equipment on the market is expensive and has a long procurement cycle. The commonly used catalyst for the reaction from the synthesis of the sacubitril / valsartan intermediate SKB-7 to SKB-8 is TEMPO reagent. TEMPO can selectively catalyze the oxidation of alcohol to rapidly become the corresponding aldehyde or ketone. However, it is difficult to separate TEMPO from the product, the residual TEMPO affects the purity of the product, column chromatography can be used for purification in the laboratory, but it is difficult to implement in large-scale industrial production, and TEMPO also has the disadvantages of high price and cannot be recycled. In recent years, 2-azadamantan-nitroxyl radical (AZADO) and its derivatives have been synthesized and widely concerned and researched in alcohol oxidation reactions. Compared with TEMPO, the active center of AZADO has smaller steric hindrance, better catalytic oxidation effect on alcohol, wider range, and higher oxidation.

[0004] This invention addresses the aforementioned technological gap by proposing a parallel microchannel reaction system, applicable to a green and efficient method for synthesizing sacubitril / valsartan sodium intermediates. It utilizes AZADO as a catalyst in the oxidation reaction of sacubitril / valsartan sodium intermediate SKB-7 to SKB-8, meeting the formulation needs of pharmaceutical companies within the expected timeframe. It fills the technological gap in the market where microchannel reactors are not widely used in large-scale commercial production and where dual-plate parallel microchannel reactors are unavailable. Furthermore, it is applicable to capacity expansion of all microchannel reactors without scale-up effects. Utility Model Content

[0005] This invention addresses the shortcomings of existing technologies by providing a parallel microchannel reaction system. By rationally connecting two microchannel reactors in parallel, it achieves the goal of increasing the monthly production of sacubitril / valsartan sodium intermediate SKB-8, meeting the formulation needs of pharmaceutical companies within the expected timeframe. It fills the technological gap in the market where microchannel reactors are not widely used in large-scale commercial production and where there are no dual-plate parallel microchannel reactors. Furthermore, it is applicable to the capacity expansion of all microchannel reactors without scale-up effects.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] A parallel microchannel reaction system includes a feed pump A, a feed pump B, an ultrasonic flow meter A, an ultrasonic flow meter B, a check valve, a feed pipe A, a feed pipe B, a microchannel reactor A, a microchannel reactor B, a high-low temperature integrated circulator, a discharge pipe A, a discharge pipe B, a merging pipeline, and a reaction vessel. The microchannel reactor A and microchannel reactor B are connected in parallel. The high-low temperature integrated circulator is connected to microchannel reactor A and microchannel reactor B through circulating cryogenic liquid pipe A and circulating cryogenic liquid pipe B. The reaction vessel is used to hold an oxidation reaction solution.

[0008] Furthermore, ultrasonic flow meter A and ultrasonic flow meter B are respectively installed on feed pipe A and feed pipe B, respectively. A check valve is also installed on feed pipe A. The material flows through ultrasonic flow meter A and then enters the check valve to prevent material backflow caused by feed pump A stopping.

[0009] Furthermore, the high and low temperature integrated circulation machine is connected to both microchannel reactor A and microchannel reactor B. The circulating refrigerant flows from the high and low temperature integrated circulation machine through circulating refrigerant pipe A to microchannel reactor A and microchannel reactor B, and then flows back to the high and low temperature integrated circulation machine through circulating refrigerant pipe B.

[0010] The beneficial effects of this utility model are as follows:

[0011] The target of improving the single-month production of the intermediate SKB-8 of sacubitril sodium is achieved, the preparation demand of the pharmaceutical enterprises is met within the expected time, the technical blank of the market that the micro-channel reactor is not used much in commercial large production and there is no double-plate parallel micro-channel reactor is filled, and the capacity expansion suitable for all micro-channel reactors has no amplification effect. BRIEF DESCRIPTION OF DRAWINGS

[0012] Figure 1 The flowchart of the utility model.

[0013] Among them: 1 - feed pump A, 2 - feed pump B, 3 - ultrasonic flowmeter A, 4 - ultrasonic flowmeter B, 5 - check valve, 6 - feed pipe A, 7 - feed pipe B, 8 - micro-channel reactor A, 9 - micro-channel reactor B, 10 - high-low temperature integrated circulating machine, 11 - discharge pipe A, 12 - discharge pipe B, 13 - combined pipeline, 14 - reaction tank, 15 - circulating refrigerant pipe A, 16 - circulating refrigerant pipe B. DETAILED DESCRIPTION

[0014] The utility model will be described more specifically below by referring to the specific embodiments shown in the drawings. Various advantages and benefits of the utility model will become apparent to one of ordinary skill in the art upon reading the following detailed description of the utility model in conjunction with the accompanying drawings. It is to be understood, however, that the utility model can be carried out in various forms and should not be limited by the embodiments set forth herein. The following embodiments are provided so that the utility model can be more thoroughly and completely understood. Unless otherwise defined, the technical terms or scientific terms used in this application should be understood as the usual meanings understood by those skilled in the art to which the utility model belongs.

[0015] As Figure 1As shown, a parallel micro-channel reaction system includes a feed pump A 1, a feed pump B 2, an ultrasonic flow meter A 3, an ultrasonic flow meter B 4, a check valve 5, a feed pipe A 6, a feed pipe B 7, a micro-channel reactor A 8, a micro-channel reactor B 9, a high-low temperature integrated circulating machine 10, a discharge pipe A 11, a discharge pipe B 12, a merging pipeline 13, and a reaction tank 14. The micro-channel reactor A 8 and the micro-channel reactor B 9 are connected in parallel. The high-low temperature integrated circulating machine 10 is connected to the micro-channel reactor A 8 and the micro-channel reactor B 9 through a circulating refrigerant pipe A 15 and a circulating refrigerant pipe B 16. The reaction tank 14 is used to hold an oxidation reaction solution. The micro-channel reactor A 8 and the micro-channel reactor B 9 are connected in parallel. The ultrasonic flow meter A 3 and the ultrasonic flow meter B 4 are arranged on the feed pipe A 6 and the feed pipe B 7, respectively. The check valve 5 is arranged on the feed pipe A 6. The material flows through the ultrasonic flow meter A 3 and then enters the check valve 5. The check valve 5 can prevent the backflow of the material caused by the stop of the feed pump A 1. The high-low temperature integrated circulating machine 10 is connected to the micro-channel reactor A 8 and the micro-channel reactor B 9. The circulating refrigerant flows out from the high-low temperature integrated circulating machine 10 to the micro-channel reactor A 8 and the micro-channel reactor B 9 through the circulating refrigerant pipe A 15, and then flows back to the high-low temperature integrated circulating machine 10 through the circulating refrigerant pipe B 16.

[0016] Example: (double-plate parallel connection, yield 45 kg)

[0017] Preparation of the oxidation reagent: 132.2 kg of an aqueous sodium hypochlorite solution and 6.6 kg of sodium bicarbonate were added to an oxidation reagent kettle, and then 112.2 kg of drinking water was added. The system was cooled to 5-10°C to obtain the oxidation reagent, which was kept warm for standby use.

[0018] Preparation of the material solution: 50.0 kg of SKB-7, 1000 L of ethyl acetate, 0.5 kg of AZADO (or 1-Me-AZADO) reagent, 12.5 kg of sodium bicarbonate, 12.5 kg of sodium bromide, and 500 L of drinking water were added to a material kettle. The system was controlled to have a temperature of -5-5°C and a stirring speed of 45-50 Hz. After stirring and dissolving, an SKB-7 ethyl acetate solution was obtained, which was kept warm for standby use.

[0019] The flow rate of the oxidation reagent was set to be 11 L / h, and the flow rate of the SKB-7 ethyl acetate solution was set to be 70 L / h.

[0020] After the micro-channel reactor A 8, the micro-channel reactor B 9, and the temperature are stabilized at 5±5℃, first, the feed pump B2 is started to pump the oxidizing reagent into the micro-channel reactor B 9, the oxidizing reagent flows through the ultrasonic flow meter B 3, the discharge pipe B 12, and the check valve 5 before entering the micro-channel reactor B 9, the check valve 5 can prevent the backflow of the material when the feed pump B 2 stops working; at the same time, the feed pump A 1 is started to pump the SKB-7 ethyl acetate alkane solution into the micro-channel reactor A 8 for oxidation reaction, the SKB-7 ethyl acetate alkane solution flows through the ultrasonic flow meter A 3 and the discharge pipe A 11 before entering the micro-channel reactor A 8, the high-low temperature integrated circulating machine 10 is connected with the micro-channel reactor A 8 and the micro-channel reactor B 9, the circulating refrigerant flows out from the high-low temperature integrated circulating machine 10 through the circulating refrigerant pipe A 15 to the micro-channel reactor A 8 and the micro-channel reactor B 9, and then flows back to the high-low temperature integrated circulating machine 10 through the circulating refrigerant pipe B 16, and the single batch oxidation reaction time is about 23h.

[0021] The oxidation reaction solution is transferred to the reaction tank 14, stirring is started, cooling is started, and the temperature is controlled at 0-10℃, 30% sodium sulfite solution is slowly added for quenching, and the starch KI reagent does not change color after the reaction is completed.

[0022] After the oxidation reaction is completed, the quenching tank is left to stand for layering, 500L of water and 12.5kg of sodium chloride are added to the upper organic layer, stirring is started for 10min, and the lower water layer is separated.

[0023] 500L of water and 12.5kg of sodium chloride are added to the upper organic layer for the second time, stirring is started for 10min, and the lower water layer is separated.

[0024] The organic layer is the product layer (SKB-8) after oxidation, which is used in subsequent processes.

[0025] The comparative example (single board, yield 45kg)

[0026] On the basis of the above embodiment, the micro-channel reactor B 9 is removed, the feed pump A 1 and the feed pump B 2 are connected with the micro-channel reactor A 8, the flow rate of the oxidizing reagent is set to 5.5L / h, the flow rate of the SKB-7 ethyl acetate solution is set to 35L / h, and the remaining conditions are unchanged, and the single batch oxidation reaction time is about 46h.

[0027] The above embodiment is only used to illustrate the technical scheme of the utility model and is not limited, other modifications or equivalent replacements to the technical scheme of the utility model made by the ordinary skilled in the art should be covered in the claim range of the utility model as long as the modifications or equivalent replacements do not deviate from the spirit and range of the technical scheme of the utility model.

Claims

1. A parallel microchannel reactor system, characterized by: It includes feed pump A (1), feed pump B (2), ultrasonic flow meter A (3), ultrasonic flow meter B (4), check valve (5), feed pipe A (6), feed pipe B (7), micro-channel reactor A (8), micro-channel reactor B (9), high and low temperature integrated circulating machine (10), discharge pipe A (11), discharge pipe B (12), combined pipeline (13), reaction tank (14), the micro-channel reactor A (8) and micro-channel reactor B (9) are connected in parallel, the high and low temperature integrated circulating machine (10) is connected with micro-channel reactor A (8) and micro-channel reactor B (9) through circulating refrigerant pipe A (15) and circulating refrigerant pipe B (16), the reaction tank (14) is used for containing reaction solution.

2. A parallel microchannel reactor system according to claim 1, wherein: The feed pipe A (6) and the feed pipe B (7) are respectively provided with ultrasonic flow meter A (3) and ultrasonic flow meter B (4), wherein the feed pipe A (6) is further provided with check valve (5), the material flows through ultrasonic flow meter A (3) and then enters check valve (5), check valve (5) can prevent the backflow of material caused by the stop of feed pump A (1).

3. A parallel microchannel reactor system according to claim 1, wherein: The high and low temperature integrated circulating machine (10) is connected with micro-channel reactor A (8) and micro-channel reactor B (9), circulating refrigerant flows out from high and low temperature integrated circulating machine (10) to micro-channel reactor A (8) and micro-channel reactor B (9) through circulating refrigerant pipe A (15), and then flows back to high and low temperature integrated circulating machine (10) through circulating refrigerant pipe B (16).

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