Continuous synthesis method and device of MSH

Abstract

The invention discloses a continuous synthesis method and device of MSH.The continuous synthesis method of MSH comprises the steps that 2, 4, 6-trimethylbenzenesulfonyl chloride and an acid binding agent are dissolved in a first solvent to form a first solution, N-hydroxy-acetic acid imino ethyl ester is dissolved in the first solvent to form a second solution, and the second solution is dissolved in a third solvent to form a second solution; respectively pumping the first solution and the second solution into a first reaction container for reaction to obtain a first effluent; the first effluent, perchloric acid and a second solvent respectively flow into a second reaction container for reaction, and second effluent containing MSH is obtained. According to the present invention, the flow chemical design idea is adopted to continuously synthesize MSH, the stability of the raw material is good, the intermediate high-energy product and the high-energy end product can be rapidly utilized, and the accumulation and the long-time retention are effectively avoided so as to effectively avoid the decomposition and reduce the safety risk; the device disclosed by the invention is simple in structure, suitable for being matched with a production line of MSH derivative products, and convenient for synthesizing MSH at present.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of flow chemistry technology, in particular to a continuous synthesis method and device of MSH. BACKGROUND

[0002] MSH (O-trimethylsulfonyl hydroxylamine) is an important chemical reagent with high reactivity, mainly used for amination reaction of organic synthesis, especially widely used in the synthesis of nitrogen-containing heterocyclic compounds, such as pyridine five-membered ring, etc.

[0003] However, MSH has poor room temperature stability and certain explosion risk, and has poor storage safety. Even if stored at 0℃, it will slowly deteriorate. Therefore, MSH is not suitable for long-term storage, and present synthesis is the preferred method for its application. In the prior art, there are two ways to synthesize MSH, one is to react O-(2,4,6-trimethylbenzenesulfonyl) acetyl hydroxamic acid ethyl ester with perchloric acid, and the other is to react N-Boc-O-(2,4,6-trimethylbenzenesulfonyl) hydroxylamine with acid. However, O-(2,4,6-trimethylbenzenesulfonyl) acetyl hydroxamic acid ethyl ester and N-Boc-O-(2,4,6-trimethylbenzenesulfonyl) hydroxylamine also need to be stored at low temperature, and have high energy property. Long-term storage will also cause slow decomposition, which is not conducive to the synthesis of MSH, and the storage safety is also poor.

[0004] In the existing MSH synthesis, mainly with kettle type reaction, the solvent used in the first step is DMF, after the reaction is completed, extraction treatment is needed to remove the TEA hydrochloride and solvent generated in the reaction, then the intermediate is obtained by concentrating and extracting, the second step is to react the intermediate obtained by concentrating and extracting with perchloric acid to obtain MSH, then extract MSH with ether, and the extract is used in the subsequent reaction (Arun babu kumar et al., Synthetic Communications-2018-48-626: Ammonia-free synthesis of 3-trifluoromethyl-3-phenyldiaziridine); in this reaction, at least twice extraction is needed, and the extraction of the intermediate is concentrated extraction, which has safety hazards and other problems due to the poor stability of the intermediate. In addition, in the prior art, O-(2,4,6-trimethylbenzenesulfonyl) acethydroxamic acid ethyl ester is used as the starting material, acetonitrile is used as the solvent, and the generated HSM reaction system is used for the synthesis of subsequent nitrogen-containing heterocyclic compounds after quenching perchloric acid with alkaline solution, but the yield of the final product is low (Cara E. Brocklehurst et al., Synlett: 2017, 28, A-E), and O-(2,4,6-trimethylbenzenesulfonyl) acethydroxamic acid ethyl ester as the starting material has poor stability and safety hazards, even if it is stored at low temperature, it will slowly decompose.

[0005] Therefore, it is a technical problem to be solved in the art to develop a continuous MSH synthesis process which is synthesized on demand, safe and easy to operate. SUMMARY

[0006] The technical problem to be solved by the present application is to provide a continuous synthesis method and device of MSH, which uses the flow chemistry design idea to continuously synthesize MSH, has simple device, high safety, and the synthesized MSH is convenient for direct application in the synthesis of subsequent products.

[0007] In order to solve the above technical problems, the first aspect of the present application provides a continuous synthesis method of MSH, characterized in that it comprises: S1, dissolving 2,4,6-trimethylbenzenesulfonyl chloride and an acid binding agent in a first solvent to form a first solution, dissolving N-hydroxy-acetic acid imidic acid ethyl ester in the first solvent to form a second solution, and pumping the first solution and the second solution into a first reaction container for reaction to obtain a first effluent; S2, flowing the first effluent obtained in S1, perchloric acid and a second solvent into a second reaction container for reaction to obtain a second effluent, wherein the second effluent contains MSH.

[0008] The synthesis route of the present application is as follows:

[0009] In the present application, the starting materials for synthesis are 2,4,6-trimethylbenzenesulfonyl chloride, an acid-binding agent, N-hydroxy-acetic acid imidic acid ethyl ester and perchloric acid, which are safe and stable. O-(2,4,6-trimethylbenzenesulfonyl) acethydroxamic acid ethyl ester is first synthesized, and then quickly reacts with perchloric acid to synthesize MSH, which reduces the accumulation and long-term residence (or storage) of O-(2,4,6-trimethylbenzenesulfonyl) acethydroxamic acid ethyl ester, effectively avoids its decomposition, and reduces the safety risk. The synthesized MSH can be quickly applied to the synthesis of subsequent derivative products, realizing the on-demand synthesis of MSH. For example, the synthesized MSH is directly applied to the synthesis of pyridopyrrolidine compounds, without the need for long-term storage, avoiding safety risks and the influence of decomposition on subsequent reactions.

[0010] In a specific scheme, in S1, the molar ratio of 2,4,6-trimethylbenzenesulfonyl chloride, an acid-binding agent, N-hydroxy-acetic acid imidic acid ethyl ester is 1.05-1.5:1:1.05-1.5; the first solvent is dichloromethane; and the acid-binding agent is triethylamine (TEA). The flow rate ratio of the first solution to the second solution is 1:0.5-0.9.

[0011] In this specific scheme, among the raw materials, N-hydroxy-acetic acid imidic acid ethyl ester is a high-energy compound and has poor stability (but its stability is better than that of O-(2,4,6-trimethylbenzenesulfonyl) acethydroxamic acid ethyl ester and N-Boc-O-(2,4,6-trimethylbenzenesulfonyl) hydroxylamine), so 2,4,6-trimethylbenzenesulfonyl chloride is preferably in excess to as far as possible to improve the conversion rate of N-hydroxy-acetic acid imidic acid ethyl ester and improve the safety of the reaction system; in addition, since continuous synthesis has high requirements for the mobile phase, it is necessary to avoid the precipitation of solids in the fluid, so the selection of the first solvent has certain requirements. For example, it is found that when the first solvent is dioxane, tetrahydrofuran, N,N-dimethylformamide (DMF), acetonitrile (ACN), N,N-dimethylacetamide, methyl tert-butyl ether, ethylene glycol dimethyl ether or toluene, the hydrochloride salt of the acid-binding agent will precipitate in the fluid, affecting the mobile phase of the fluid, while dichloromethane is selected as the first solvent, and almost no hydrochloride salt of the acid-binding agent precipitates, so dichloromethane is preferably selected as the first solvent; in addition, since 2,4,6-trimethylbenzenesulfonyl chloride is preferably in excess, the flow rate of the first solution is preferably greater than that of the second solution.

[0012] In a specific scheme, the first reaction container is a coil reactor, the reaction temperature is 25-35℃, the reaction pressure is 0.1-0.4 MPa, and the reaction time is 8-15 min.

[0013] In this specific scheme, a coil reactor is preferred, which is beneficial to prolong the contact time of the reactants and achieve a full reaction. In addition, regarding the reaction temperature, 31℃~34℃ is preferred, as the reaction is faster and more suitable for continuous reactions. For example, experiments have shown that at 25℃, the reaction takes 30 minutes, while at 33℃, it only takes 10 minutes. Therefore, higher temperatures are beneficial to significantly shorten the reaction time and improve the reaction efficiency. At the same time, a smaller coil reactor can be used, which improves the ease of use of the reaction equipment.

[0014] In one specific scheme, the molar equivalent of perchloric acid in S2 is 2 to 5 times that of N-hydroxy-acetylinyl ethyl ester; The second solvent is selected from one or more of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, and dioxane. The flow rate ratio of the first effluent, perchloric acid, and the second solvent is 10:1.0-1.5:1.5-2.5.

[0015] In this specific scheme, the use of excess perchloric acid is beneficial for the complete conversion of ethyl O-(2,4,6-trimethylbenzenesulfonyl)acetylhydroxamate. Especially when the molar equivalent of perchloric acid is four times that of ethyl O-(2,4,6-trimethylbenzenesulfonyl)acetylhydroxamate, the conversion of ethyl O-(2,4,6-trimethylbenzenesulfonyl)acetylhydroxamate can be almost completely achieved. Furthermore, since perchloric acid is in aqueous solution and is immiscible with the first solvent in the initial reaction, it causes layering, which is detrimental to the reaction. However, it is preferable to add acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, or dioxane as a second solvent. This helps maintain a homogeneous reaction system and improves reaction efficiency; for example, the reaction can be completed in 5 minutes at 25°C.

[0016] In one specific embodiment, the second reaction vessel is a coil reactor, the reaction temperature is 15℃~35℃, and the reaction time is 2-8 min. Understandably, by adding a second solvent to the reaction system, the reaction efficiency is improved; therefore, within the reaction temperature range of 15℃~35℃, the reaction can be completed in 2~8 min.

[0017] In one specific scheme, the first effluent obtained in S1 is washed with a washing solution; the second effluent obtained in S2 is washed with a washing solution.

[0018] In this specific scheme, when using a flow chemistry synthesis route, the first effluent is preferably used directly for subsequent reactions to generate MSH. However, an unknown impurity peak was observed. After washing the first effluent, the unknown impurity peak disappeared. Water is preferred as the washing solution. The washed oil phase continues the subsequent reaction, while the aqueous phase is discharged. It should be noted that a compound of formula I is also generated in the first step of the reaction, but this compound does not affect subsequent derivatives. It is usually removed in subsequent reactions as hydrazine salts, etc., through pulping. It is preferable to control the first effluent after washing. The total content of ethyl O-(2,4,6-trimethylbenzenesulfonyl)acetylhydroxamic acid and compound I in the effluent is not less than 90%. The second effluent is preferably also washed with water to reduce impurities and facilitate subsequent reactions. It should be noted that since the first effluent contains ethyl O-(2,4,6-trimethylbenzenesulfonyl)acetylhydroxamic acid and the second effluent contains MSH, both of which are unstable and easily decomposed, the washing temperature is preferably maintained at around 0°C to improve stability, reduce the possibility of decomposition, and thus increase the yield.

[0019]

[0020] To address the aforementioned technical problems, a second aspect of the present invention is to provide an apparatus for continuous synthesis of MSH, comprising a first reaction vessel, upstream of which a first pump and a second pump are installed. The first pump is used to pump a first solution into the first reaction vessel, and the second pump is used to pump a second solution into the first reaction vessel. The first solution is formed by dissolving 2,4,6-trimethylbenzenesulfonyl chloride and an acid-binding agent in a first solvent, and the second solution is formed by dissolving N-hydroxy-acetylated imine ethyl ester in the first solvent. A back pressure valve, installed downstream of the first reaction vessel, is used to set the pressure of the first reaction vessel; The second reaction vessel is installed downstream of the first reaction vessel. A third, fourth, and fifth pump are installed upstream of the second reaction vessel. The third pump is used to pump the first effluent from the first reaction vessel into the second reaction vessel, the fourth pump is used to pump perchloric acid into the second reaction vessel, and the fifth pump is used to pump the second solvent into the second reaction vessel.

[0021] In this invention, a first reaction vessel and a second reaction vessel are connected in series in a flow chemistry pipeline. The first reaction vessel is used to synthesize ethyl O-(2,4,6-trimethylbenzenesulfonyl)acetylhydroxamic acid, and the second reaction vessel is used to synthesize MSH. The downstream of the second reaction vessel can be directly connected to the production line of the derivative product, realizing the on-demand synthesis of MSH and avoiding the storage of ethyl O-(2,4,6-trimethylbenzenesulfonyl)acetylhydroxamic acid and MSH. The device of this invention has a simple structure, is suitable for matching the production line of MSH derivative products, facilitates the on-demand synthesis of MSH, reduces storage costs and safety hazards, and reduces the impact of MSH decomposition on subsequent reactions during storage.

[0022] In one specific embodiment, both the first and second reaction vessels are coil reactors.

[0023] Preferably, a washing assembly is installed between the back pressure valve and the second reaction vessel, and downstream of the second reaction vessel; The washing assembly includes a mixer, a phase separation container, and a separator connected in series. The washing liquid is mixed with the first or second effluent in the mixer, then separated in the phase separation container, and finally separated in the separator. The washing liquid is pumped into the mixer by a sixth pump.

[0024] More preferably, at least one set of washing components is installed between the first reaction vessel and the second reaction vessel; at least two sets of washing components are installed downstream of the second reaction vessel, and a seventh pump is provided between adjacent washing components.

[0025] In this specific scheme, the washing assembly between the back pressure valve and the second reaction vessel is used to remove unknown impurities in the first effluent, thereby eliminating unknown impurity peaks (unknown impurities) appearing in the second effluent, and is preferably one set; the washing assembly after the second reaction vessel is preferably two sets, controlling the final content of MSH in the oil phase to be higher than 60% and the amount of compound I to be lower than 20%, so as to facilitate subsequent reactions.

[0026] It should be noted that the washing liquid is all water, and the phase separation containers are all coils. Water is pumped into the flow reaction path by the sixth pump (feed pump). When washing the first effluent, for example, a three-way valve is installed downstream of the back pressure valve. The first effluent and water are fed into the two inlets of the three-way valve respectively, and discharged from the outlet of the three-way valve to the mixer for thorough mixing before flowing to the phase separation container. Since the first effluent contains ethyl O-(2,4,6-trimethylbenzenesulfonyl)acetylhydroxamic acid, which has poor stability, the temperature of the phase separation container is preferably set to around 0°C to increase its stability. After phase separation, it flows to the separator. After that, the aqueous phase is discharged, and the oil phase continues to participate in the subsequent reaction, that is, the reaction of mixing with perchloric acid and the second solvent to synthesize MSH. Similarly, when washing the second effluent, since MSH has poor stability, the temperature of the phase separation container is also set to around 0°C. It should also be noted that, in this invention, the first to fifth pumps mainly serve to pump materials and control the flow rate. Pumps used in the prior art for continuous fluid reactions are all applicable to this invention. Attached Figure Description

[0027] To more clearly illustrate the technical solution of the present invention, the accompanying drawings used in the present invention will be briefly introduced below. 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.

[0028] Figure 1 This is a diagram of the apparatus for continuous synthesis of MSH according to the present invention; Figure 2 This is a test spectrum of the first effluent after washing in this invention; Figure 3 This is the test spectrum of the second effluent before washing in this invention; Figure 4 This is a test spectrum of the second effluent from the present invention after two washings.

[0029] Wherein, 1-first reaction vessel; 2-first pump; 3-second pump; 4-back pressure valve; 5-second reaction vessel; 6-third pump; 7-fourth pump; 8-fifth pump; 9-mixer; 10-phase separator; 11-liquid separator; 12-sixth pump; 13-seventh pump. Detailed Implementation

[0030] The technical solutions of the present invention will now be clearly and completely described with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0031] refer to Figure 1 The apparatus for continuous synthesis of MSH according to the present invention is shown, wherein the first effluent is washed once, i.e., a washing assembly is connected in series after the back pressure valve, and the second effluent is washed twice, i.e., two washing assemblies are connected in series after the second reaction vessel; wherein: Both the first reaction vessel and the second reactor are 90 mL disc reactors with an outer diameter of 1 / 8 inch. The phase splitter uses a 30mL coil with an outer diameter of 1 / 8 inch; use Figure 1 The following is a mobile synthetic route for synthesizing MSH using 2,4,6-trimethylbenzenesulfonyl chloride and perchloric acid as raw materials: 1) Raw material preparation: 23.329 g of 2,4,6-trimethylbenzenesulfonyl chloride (1.1 eq) and 11.775 g of triethylamine (1.2 eq) were dissolved in 130 mL of dichloromethane (the first solvent) to form the first solution; Dissolve 10g of N-hydroxy-acetic acid ethyl ester (1eq) in 130mL of dichloromethane (the first solvent) to form a second solution; Prepare 55.664 g of perchloric acid (4 eq, mass concentration of 70%); prepare water as the washing solution; and acetonitrile as the second solvent.

[0032] 2) Flow synthesis circuit: The first solution was delivered using the first pump at a flow rate of 4.275 mL / min; The second solution was delivered using a second pump at a flow rate of 3.69 mL / min; Set the pressure of the back pressure valve to 0.2 MPa; The temperature of the phase separation vessel is set to 0℃; The temperature of the first reaction vessel is set at 33°C. The temperature of the second reaction vessel is set to 25°C; After 11 minutes of operation with the first and second pumps, the sixth pump, used to wash the first effluent, was started to mix the first effluent with the washing liquid (water) in the mixer. The flow rate of the washing liquid was set to 12 mL / min. The mixed reaction system continued to flow to the separator, where the oil phase and aqueous phase were separated. The aqueous phase was discharged. At this point, the oil phase mainly contained ethyl O-(2,4,6-trimethylbenzenesulfonyl)acetylhydroxamic acid, compound I, and dichloromethane. LCMS analysis of the oil phase showed that the content of ethyl O-(2,4,6-trimethylbenzenesulfonyl)acetylhydroxamic acid and compound I was 94.5% (greater than 90%). The chromatogram is shown below. Figure 2 As shown; Further follow-up reactions: The oil phase was delivered using a third pump at a flow rate of 13.5 mL / min; Perchloric acid was delivered using a fourth pump at a flow rate of 1.81 mL / min. Acetonitrile was delivered using the fifth pump at a flow rate of 2.7 mL / min; After pumps three through five were turned on, the first effluent and perchloric acid reacted in the second reaction vessel in the presence of acetonitrile for 5 minutes. The second effluent was measured by LCMS, and the test results are as follows. Figure 3 As shown; simultaneously, the sixth pump of the first washing assembly after the second reaction vessel is turned on, mixing the second effluent with the washing liquid (water) in the mixer. The flow rate of the washing liquid is set to 24 mL / min. The mixed reaction system continues to flow to the separator to separate the oil phase and the water phase. The water phase is discharged, and the oil phase continues to be washed by the next washing assembly. The flow rate of the washing liquid is set to 24 mL / min. The mixed reaction system continues to flow to the separator to separate the oil phase and the water phase again. The water phase is discharged, and the LCMS of the oil phase is measured. The content of MSH is 65.8%, the content of compound I is 16%, and the content of 2,4,6-trimethylbenzenesulfonic acid is 16%. The spectrum is shown in the figure. Figure 4 As shown.

[0033] It can be seen that the changes in MSH, 2,4,6-trimethylbenzenesulfonic acid and compound I before and after washing are not significant, indicating that washing has almost no effect on these three compounds (mainly washing away perchloric acid), especially on MSH, thus indicating that the two washes have almost no effect on the subsequent reaction.

[0034] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A continuous synthesis method for MSH, characterized in that, include: S1. Dissolve 2,4,6-trimethylbenzenesulfonyl chloride and an acid-binding agent in a first solvent to form a first solution, and dissolve N-hydroxy-acetic acid ethyl ester in the first solvent to form a second solution. Pump the first solution and the second solution into a first reaction vessel respectively to react and obtain a first effluent. S2. The first effluent obtained in S1 is reacted with perchloric acid and the second solvent into the second reaction vessel to obtain the second effluent, which contains MSH.

2. The continuous synthesis method of MSH as described in claim 1, characterized in that, In S1, the molar ratio of 2,4,6-trimethylbenzenesulfonyl chloride, acid binder, and N-hydroxy-acetic acid ethyl ester is 1.05–1.5:1:1.05–1.

5. The first solvent is dichloromethane; The acid-binding agent is triethylamine; The flow rate ratio of the first solution to the second solution is 1:0.5 to 0.

9.

3. The continuous synthesis method of MSH as described in claim 2, characterized in that, The first reaction vessel is a coil reactor, with a reaction temperature of 25℃~35℃, a reaction pressure of 0.1~0.4MPa, and a reaction time of 8~15min.

4. The continuous synthesis method of MSH as described in claim 1, characterized in that, In S2, the molar equivalent of perchloric acid is 2 to 5 times that of N-hydroxy-acetylinyl ethyl ester; The second solvent is selected from one or more of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, and dioxane; The flow rate ratio of the first effluent, perchloric acid, and the second solvent is 10: 1.0～1.5：1.5～2.5。 5. The continuous synthesis method of MSH as described in claim 4, characterized in that, The second reaction vessel is a coil reactor, with a reaction temperature of 15℃~35℃ and a reaction time of 2~8min.

6. The continuous synthesis method of MSH as described in claim 1, characterized in that, The first effluent obtained from S1 is washed with washing solution; The second effluent obtained from S2 is washed with washing solution.

7. An apparatus for continuous synthesis of MSH, characterized in that, include: A first reaction vessel is equipped with a first pump and a second pump upstream of it. The first pump is used to pump a first solution into the first reaction vessel, and the second pump is used to pump a second solution into the first reaction vessel. The first solution is formed by dissolving 2,4,6-trimethylbenzenesulfonyl chloride and an acid-binding agent in a first solvent, and the second solution is formed by dissolving N-hydroxy-acetic acid ethyl ester in the first solvent. A back pressure valve, installed downstream of the first reaction vessel, is used to set the pressure of the first reaction vessel; The second reaction vessel is installed downstream of the first reaction vessel. A third, fourth, and fifth pump are installed upstream of the second reaction vessel. The third pump is used to pump the first effluent from the first reaction vessel into the second reaction vessel, the fourth pump is used to pump perchloric acid into the second reaction vessel, and the fifth pump is used to pump the second solvent into the second reaction vessel.

8. The apparatus for continuous synthesis of MSH as described in claim 7, characterized in that, Both the first and second reaction vessels are coil reactors.

9. The apparatus for continuous synthesis of MSH as described in claim 7, characterized in that, A washing assembly is installed between the back pressure valve and the second reaction vessel, as well as downstream of the second reaction vessel; The washing assembly includes a mixer, a phase separation container, and a separator connected in series. The washing liquid is mixed with the first or second effluent in the mixer, then separated in the phase separation container, and finally separated in the separator. The washing liquid is pumped into the mixer by a sixth pump.

10. The apparatus for continuous synthesis of MSH as described in claim 9, characterized in that, At least one set of washing components is installed between the first reaction vessel and the second reaction vessel; At least two sets of washing components are installed downstream of the second reaction vessel, and a seventh pump is installed between adjacent washing components.

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