Method for continuously producing N-nitroso-3-azabicyclo (3.3. 0) octane

Abstract

The invention discloses a method for continuously producing N-nitroso-3-azabicyclo [3.3. 0] octane. The method comprises the following steps: (a) mixing an aza aqueous solution and a sodium nitrite solution to obtain a mixed solution; the aza aqueous solution is a 3-aza-bicyclo [3.3. 0] octane hydrochloride solution, and the molar ratio of the 3-aza-bicyclo [3.3. 0] octane hydrochloride to the sodium nitrite is 1: (1.1-1.6); (b) injecting the mixed solution serving as a stream of feed and a hydrochloric acid solution serving as another stream of feed into a column reactor for reaction; the reaction temperature is 30 to 70 DEG C, the retention time is 0.2 to 2 minutes, and the molar ratio of the 3-azabicyclo [3.3. 0] octane hydrochloride to the hydrochloric acid is 1: (0.2 to 0.6). Gas-liquid separation can be rapidly achieved, stable feeding and continuous production are achieved, the heat exchange area is large, a large amount of heat generated by reaction can be rapidly removed, and the temperature control force is high.

Description

Technical Field

[0001] The present invention belongs to the technical field of continuous production, and relates to a method for producing N-nitroso-3-azabicyclo[3.3.0]octane, and in particular to a method for continuous production of N-nitroso-3-azabicyclo[3.3.0]octane. Background Art

[0002] N-nitroso-3-azabicyclo[3.3.0]octane is an impurity in the diabetes drug gliclazide, known as gliclazide impurity B. It is also a raw material for the synthesis of N-amino-3-azabicyclo[3.3.0]octane hydrochloride, a key intermediate of gliclazide. The conventional production method for N-nitroso-3-azabicyclo[3.3.0]octane involves a batch reaction in a kettle using 3-azabicyclo[3.3.0]octane hydrochloride solution, sodium nitrite, and hydrochloric acid. After stratification, N-nitroso-3-azabicyclo[3.3.0]octane is obtained with a purity of 94% and a molar yield of 95%. This method requires high initial investment, high maintenance costs, and a large footprint. Furthermore, the nitrosation reaction is hazardous, with high heat release and large batch reaction liquid holdup, which poses certain risks. This high-risk, high-investment, and low-capacity production process is a challenge. Summary of the Invention

[0003] The present invention aims to overcome the deficiencies of the prior art and to provide a method for the continuous production of N-nitroso-3-azabicyclo[3.3.0]octane, thereby improving the yield and purity of N-nitroso-3-azabicyclo[3.3.0]octane.

[0004] To achieve the above object, the technical solution adopted by the present invention is: a method for continuous production of N-nitroso-3-azabicyclo[3.3.0]octane, comprising the following steps: (a) mixing an aza-aqueous solution and a sodium nitrite solution to obtain a mixed solution; the aza-aqueous solution is a 3-azabicyclo[3.3.0]octane hydrochloride solution, and the molar ratio of the 3-azabicyclo[3.3.0]octane hydrochloride to the sodium nitrite is 1:1.1-1.6; (b) injecting the mixed solution as one feed and the hydrochloric acid solution as another feed into a column reactor for reaction; the reaction temperature is 30-70° C., the residence time is 0.2-2 min, and the molar ratio of the 3-azabicyclo[3.3.0]octane hydrochloride to the hydrochloric acid is 1:0.2-0.6.

[0005] Optimally, in step (b), the column reactor comprises a reactor body, a stirring mechanism and a heat-insulating jacket, The lower portion of the reactor body is provided with a first feed port and a second feed port, and the upper portion thereof is provided with a discharge port; The stirring mechanism includes a stirring shaft disposed in the reactor body and extending outward thereof, a plurality of stirring blades formed on the outer surface of the stirring shaft and located in the reaction tube, and a motor connected to the upper end of the stirring shaft for driving the stirring shaft to rotate; The heat-insulating jacket is formed on the outer surface of the reactor body, and a jacket inlet is provided at the lower portion thereof and a jacket outlet is provided at the upper portion thereof.

[0006] Furthermore, the reactor body has a diameter of 30-50 mm and a height of 100-200 mm.

[0007] Optimally, in step (a), the aqueous nitrogen solution and the sodium nitrite solution are preheated independently of each other before mixing, and the preheating temperature is 30-70°C.

[0008] Furthermore, in step (a), the mass fraction of 3-azabicyclo[3.3.0]octane hydrochloride in the aza aqueous solution is 50-75%, and the mass fraction of sodium nitrite in the sodium nitrite solution is 30-60%.

[0009] Furthermore, in step (b), the mass fraction of the hydrochloric acid solution is 20-40%.

[0010] Furthermore, the flow rate of the nitrogen-containing aqueous solution is 15-25 g / min, the flow rate of the sodium nitrite solution is 15-25 g / min, and the flow rate of the hydrochloric acid solution is 3-5 g / min.

[0011] Due to the application of the above-mentioned technical solution, the present invention has the following advantages over existing technologies: The present method for continuous production of N-nitroso-3-azabicyclo[3.3.0]octane utilizes a column reactor for multi-stream feeding, overcoming the drawbacks of the reaction's large gas evolution and the significant pressure resistance generated by microchannel or tubular reactors, which can lead to feed pump pressure buildup and stalling. This method allows for rapid gas-liquid separation, maintaining the system pressure at atmospheric or slightly positive pressure, enabling stable feeding and continuous production. The large heat exchange area allows for rapid removal of the large amounts of heat generated by the reaction, resulting in high temperature control. The molar yield of N-nitroso-3-azabicyclo[3.3.0]octane can reach 95% and a purity of 96%. Furthermore, compared to kettle-type reactions, the present equipment occupies a smaller footprint, reducing heat loss and maintenance costs. Furthermore, since nitration reactions are inherently hazardous and release significant heat, this method can effectively reduce reactor liquid holdup, mitigating potential risks. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 Schematic diagram of the equipment used in the continuous production of N-nitroso-3-azabicyclo[3.3.0]octane of the present invention. DETAILED DESCRIPTION

[0013] The preferred embodiments of the present invention will be described in detail below. Example 1

[0014] This embodiment provides a device for continuous production of N-nitroso-3-azabicyclo[3.3.0]octane, such as Figure 1 As shown, it mainly includes a column reactor 1, a mixing component 2 and a hydrochloric acid feeding component 3.

[0015] The column reactor 1 includes a reactor body 11, a stirring mechanism 12, and an insulating jacket 13. The specifications of the reactor body 11 are: diameter 30-50 mm, height 100-200 mm (40 mm diameter, 150 mm height is usually selected in actual production). The lower portion of the reactor body 11 is provided with a first feed port 111 and a second feed port 112 (i.e., it can realize two separate feeds), and the upper portion is provided with a discharge port 113, and the upper portion is also provided with an air outlet 114 located above the discharge port 113. The stirring mechanism 12 includes a stirring shaft 21 disposed within the reactor body 11 and extending therefrom, a plurality of stirring blades 22 formed on the outer surface of the stirring shaft 21 and located within the reaction tube 1, and a motor 23 connected to the upper end of the stirring shaft 21 for driving the stirring shaft 21 to rotate. The stirring mechanism 12 can be any conventional one, as long as it can achieve uniform mixing of the materials. The insulation jacket 13 is formed on the outer surface of the reactor body 11, and is provided with a jacket inlet 131 at the lower part and a jacket outlet 132 at the upper part, for ensuring the reaction temperature in the reactor body 11, such as by inputting 55°C hot water.

[0016] The mixing assembly 2 includes a static mixer 21 connected to the second feed port 112 via a pipeline, a first preheater 22 and a second preheater 24 connected to the static mixer 21 via pipelines (the first preheater 22 and the second preheater 24 are both 2m long 1 / 8 PTFE tubes, preheated to 30-70°C (typically 55°C in actual production), heated in a water bath), a first feed pump 23 connected to the first preheater 22 via a pipeline (for supplying an aqueous nitrogen solution to the reactor body 11), and a second feed pump 25 connected to the second preheater 24 via a pipeline (for supplying a sodium nitrite solution to the reactor body 11). The hydrochloric acid delivery assembly 3 (typically a delivery pump) is connected to the first feed port 111 via a pipeline and is used to supply the hydrochloric acid solution to the reactor body 11. This makes the flow rate of the nitrogen-containing aqueous solution 15-25 g / min, the flow rate of the sodium nitrite solution 15-25 g / min, and the flow rate of the hydrochloric acid solution 3-5 g / min (they can fluctuate within the above range in actual production). Example 2

[0017] This embodiment provides a method for continuous production of N-nitroso-3-azabicyclo[3.3.0]octane, using the apparatus in Example 1, comprising the following steps: (a) mixing an aqueous nitrogen solution and a sodium nitrite solution to obtain a mixed solution (the aqueous nitrogen solution is fed using a first feed pump 23, and the sodium nitrite solution is fed using a second feed pump 25, and the mixed solution is fed into a static mixer 21 and fed into a reactor body 11 through a second feed port 112), and preheating the mixed solution to 55° C. using a first preheater 22 and a second preheater 24 before mixing. (b) The mixed liquid was fed as one stream and the hydrochloric acid solution was fed as another stream (into the reactor body 11 through the first feed port 111) into the column reactor for reaction. The reaction temperature was 55°C (the water temperature in the insulation jacket 13 was 55°C) and the reaction pressure was atmospheric pressure (the molar ratio of 3-azabicyclo[3.3.0]octane hydrochloride, sodium nitrite, and hydrochloric acid was 1:1.54:0.49; the hydrochloric acid was fed at a rate of 3-5 g / min and a mass concentration of 30%, and the other two materials were based on this ratio). Note: The timer began after the reaction liquid exited the column reactor 1. After stabilization for 30 minutes, the feed was added and then fed into the liquid-liquid separator. The upper layer yielded 29.28 g of N-nitroso-3-azabicyclo[3.3.0]octane with a purity of 95.54% and a yield of 96%. Example 3

[0018] This example provides a method for continuous production of N-nitroso-3-azabicyclo[3.3.0]octane, which is basically the same as that in Example 2, except that the molar ratio of 3-azabicyclo[3.3.0]octane hydrochloride, sodium nitrite and hydrochloric acid is 1:1.1:0.6. Example 4

[0019] This example provides a method for continuous production of N-nitroso-3-azabicyclo[3.3.0]octane, which is basically the same as that in Example 2, except that the molar ratio of 3-azabicyclo[3.3.0]octane hydrochloride, sodium nitrite and hydrochloric acid is 1:1.6:0.2.

[0020] Comparative Example 1 This example provides a method for the continuous production of N-nitroso-3-azabicyclo[3.3.0]octane, which is basically the same as that in Example 2, except that a conventional microchannel reactor ("heart-shaped" structure, tube diameter 1 mm) is used. After the feed-liquid contact reaction, a very large pressure resistance is generated, causing the feed pump to stop during pressure increase.

[0021] The above embodiments are only for illustrating the technical concept and features of the present invention. Their purpose is to enable people familiar with this technology to understand the content of the present invention and implement it accordingly. They are not intended to limit the scope of protection of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for continuous production of N-nitroso-3-azabicyclo[3.3.0]octane, characterized in that: The following steps are involved: (a) mixing an aza-aqueous solution and a sodium nitrite solution to obtain a mixed solution; the aza-aqueous solution is a 3-azabicyclo[3.3.0]octane hydrochloride solution, and the molar ratio of the 3-azabicyclo[3.3.0]octane hydrochloride to the sodium nitrite is 1:1.1-1.6; (b) injecting the mixed solution as one feed and the hydrochloric acid solution as another feed into a column reactor for reaction; the reaction temperature is 30-70° C., the residence time is 0.2-2 min, and the molar ratio of the 3-azabicyclo[3.3.0]octane hydrochloride to the hydrochloric acid is 1:0.2-0.

6.

2. The method for continuous production of N-nitroso-3-azabicyclo[3.3.0]octane according to claim 1, characterized in that: In step (b), the column reactor (1) comprises a reactor body (11), a stirring mechanism (12) and a heat-insulating jacket (13), The reactor body (11) is provided with a first feed inlet (111) and a second feed inlet (112) at the lower part thereof and a discharge port (113) at the upper part thereof; The stirring mechanism (12) comprises a stirring shaft (21) disposed in the reactor body (11) and extending outside thereof, a plurality of stirring blades (22) formed on the outer surface of the stirring shaft (21) and located in the reaction tube (1), and a motor (23) connected to the upper end of the stirring shaft (21) for driving the stirring shaft to rotate; The heat-insulating jacket (13) is formed on the outer surface of the reactor body (11), and is provided with a jacket inlet (131) at its lower portion and a jacket outlet (132) at its upper portion.

3. The method for continuous production of N-nitroso-3-azabicyclo[3.3.0]octane according to claim 2, characterized in that: The reactor body (11) has a diameter of 30-50 mm and a height of 100-200 mm.

4. The method for continuous production of N-nitroso-3-azabicyclo[3.3.0]octane according to claim 1, characterized in that: In step (a), the aqueous azo solution and the sodium nitrite solution are preheated independently of each other before mixing, and the preheating temperature is 30-70°C.

5. The method for continuous production of N-nitroso-3-azabicyclo[3.3.0]octane according to claim 3, characterized in that: In step (a), the mass fraction of 3-azabicyclo[3.3.0]octane hydrochloride in the aza aqueous solution is 50-75%, and the mass fraction of sodium nitrite in the sodium nitrite solution is 30-60%.

6. The method for continuous production of N-nitroso-3-azabicyclo[3.3.0]octane according to claim 5, characterized in that: In step (b), the mass fraction of the hydrochloric acid solution is 20-40%.

7. The method for continuous production of N-nitroso-3-azabicyclo[3.3.0]octane according to claim 6, characterized in that: The flow rate of the nitrogen aqueous solution is 15-25 g / min, the flow rate of the sodium nitrite solution is 15-25 g / min, and the flow rate of the hydrochloric acid solution is 3-5 g / min.

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