A method and apparatus for continuous flow synthesis of the key intermediate MMPE, etoposide.

Abstract

This invention provides a method and apparatus for continuous flow synthesis of the key intermediate MMPE, etocoxib. The method includes the following steps: First, a 4-methanesulfonylphenylacetic acid solution and a first stream of tert-butylmagnesium chloride solution are subjected to a first-step continuous flow synthesis to obtain reaction solution A; then, reaction solution A and a methyl 6-methylnicotinate solution are subjected to a second-step continuous flow synthesis to obtain reaction solution B; next, reaction solution B and a second stream of tert-butylmagnesium chloride solution are combined to obtain the final reaction solution C; the obtained reaction solution C is post-processed to obtain the desired MMPE product. A microreactor is selected as the reactor for the reaction. The method provided by this invention significantly simplifies the preparation process, greatly shortens the reaction time, and achieves excellent yield and purity, while also exhibiting excellent reproducibility.

Description

Technical Field

[0001] This invention belongs to the field of chemical engineering technology, specifically relating to a method and apparatus for continuous flow synthesis of the key intermediate MMPE, etocoxib. Background Technology

[0002] Etoricoxib, a nonsteroidal anti-inflammatory drug, is widely used in clinical treatment. The initial and most widely used synthetic routes for etoricoxib both involve the compound 1-(6-methyl-3-pyridyl)-2-(4-methylsulfonylphenyl)ethyl ketone, also known as the key intermediate (MMPE) of etoricoxib, with the following molecular formula: The widely used and documented synthetic route of MMPE is to use 4-methanesulfonylphenylacetic acid and 6-methylnicotinic acid methyl ester as raw materials, and to prepare MMPE by condensation reaction in the presence of Grignard reagent tert-butylmagnesium chloride.

[0003] Chinese patent application CN102898357A discloses a novel method for preparing the intermediate 1-(6-methylpyridin-3-yl)-2-[4-(methanesulfonyl)phenyl]ethyl ketone, which can achieve a molar yield of 78%-88%. However, according to the specific embodiments of this patent, if 4-methanesulfonylphenylacetic acid is used as a raw material, a high purity product cannot be obtained. Therefore, this technical solution requires the prior preparation of a basic salt of 4-methanesulfonylphenylacetic acid. However, the background technology of Chinese patent application CN104045596A mentions that through multiple verifications of the technical solution in patent application CN102898357A, the maximum yield reached was 58%, which does not meet the reported value. This means that the method provided by the aforementioned patent has the problem of being difficult to reproduce. Furthermore, actual analysis of the reaction mechanism shows that this reaction is complex and involves many variables. In batch operation, the actual yield is often affected by the external environment, resulting in unstable yield and making scale-up quite difficult. In addition, current technologies for preparing etoricoxib intermediates all involve multiple batches of material feeding during the reaction process, which is cumbersome in actual production and the reaction time is as long as 7 to 9 hours. Summary of the Invention

[0004] To address the issues of yield stability and ease of operation, and to simplify the operation as much as possible while significantly reducing reaction time, this invention provides a method and apparatus for continuous flow synthesis of the key intermediate MMPE, etocoxib.

[0005] To achieve the above objectives, the technical solution provided by the present invention is as follows: A method for continuous-flow synthesis of the key intermediate MMPE, derived from diococci, includes the following steps: (1) A first-step continuous flow synthesis was carried out between a 4-methanesulfonylphenylacetic acid solution and a first stream of tert-butylmagnesium chloride solution to obtain reaction solution A; (2) The reaction solution A and the methyl 6-methylnicotinate solution were subjected to a second-step continuous flow synthesis to obtain the reaction solution B; (3) Combine reaction solution B with the second strand of tert-butylmagnesium chloride solution to obtain the final reaction solution C; (4) The obtained reaction solution C is subjected to post-treatment including quenching reaction, washing and drying to obtain the desired MMPE product.

[0006] The present invention is further configured such that the molar ratio of 4-methanesulfonylphenylacetic acid solution to the first strand of tert-butyl magnesium chloride is 1:(1~3), and the molar ratio of 4-methanesulfonylphenylacetic acid solution to the second strand of tert-butyl magnesium chloride is 1:(0.5~1.5).

[0007] The present invention is further configured such that the concentration of the 4-methanesulfonylphenylacetic acid solution is 0.8 mol / L-1.2 mol / L, the concentration of the 6-methylnicotinic acid methyl ester solution is 0.50 mol / L-3.0 mol / L, and the concentration of the tert-butylmagnesium chloride is 0.5 mol / L-1 mol / L.

[0008] The present invention is further configured such that the reaction time of step (1) is 1.0 min-1.5 min, the reaction time of step (2) is 0.01 min-0.1 min, and the reaction time of step (3) is 1.8 min-3.0 min.

[0009] The present invention is further configured such that the reaction time of step (1) is 1.10 min to 1.35 min, the reaction time of step (2) is 0.01 min to 0.1 min, and the reaction time of step (3) is 2.0 min to 2.8 min.

[0010] The present invention is further configured such that the reaction temperature of steps (1) to (3) is 45 to 65°C.

[0011] The present invention is further configured such that the post-processing in step (4) includes the following process: the reaction solution is added dropwise to the hydrochloric acid solution under ice bath conditions and stirred, then extracted with methyl tert-butyl ether, the aqueous phase is taken and ammonia is added to adjust the pH to 7-9, a suspension is obtained and stirred, and the suspension is filtered, washed and dried to obtain the MMPE product.

[0012] The present invention is further configured such that, based on 1 eq of 4-methanesulfonylphenylacetic acid, the amount of hydrochloric acid used is 8 eq-10 eq, the stirring time is 0.8 h-1.2 h; the stirring time of the suspension is 0.4 h-1 h; and the washing liquid is water or ethanol.

[0013] The present invention further specifies that the concentration of the hydrochloric acid solution is 1~3 mol / L.

[0014] The present invention also provides an apparatus for continuous flow synthesis of the key intermediate MMPE, etocoxib, for implementing the above-described method, comprising a first microreactor, a second microreactor, and a third microreactor for carrying out the reaction, and a first injection pump, a second injection pump, a third injection pump, and a fourth injection pump; the first injection pump and the second injection pump are connected to the inlet end of the first microreactor, the outlet end of the first microreactor and the third injection pump are connected to the inlet end of the second microreactor, and the outlet end of the second microreactor and the fourth injection pump are connected to the third microreactor.

[0015] The present invention is further configured such that the first microreactor, the second microreactor and the third microreactor are all selected as capillary microreactors, and the inner diameter of the capillary microreactor is 0.6 mm-1.6 mm.

[0016] Compared with the prior art, the present invention has the following effects: (1) The method for continuous flow synthesis of the key intermediate MMPE from etoricoxib provided by the present invention has greatly simplified the process and shortened the reaction time, while achieving better yield and purity.

[0017] (2) The method for continuous flow synthesis of the key intermediate MMPE from etoricoxib provided by the present invention has a stable reaction process and excellent reproducibility. Attached Figure Description

[0018] Figure 1 This is a schematic diagram of a continuous flow synthesis apparatus. Among them, 1, first injection pump, 2, second injection pump, 3, third injection pump, 4, fourth injection pump, 5, first microreactor, 6, second microreactor, and 7, third microreactor.

[0019] Figure 2 This is a schematic diagram of the continuous flow synthesis apparatus for Comparative Example 2. Detailed Implementation

[0020] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0021] Experimental methods in the embodiments of this invention that do not specify specific conditions are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents whose specific sources are not specified are commercially available conventional reagents. The 4:1 hydrochloric acid solution used in subsequent embodiments refers to a hydrochloric acid solution prepared by mixing water and 36% concentrated hydrochloric acid at a volume ratio of 4:1. HPLC determinations were performed using Shimadzu high-performance liquid chromatography with a C18 reversed-phase column and a mobile phase of water and methanol.

[0022] like Figure 1 As shown, the present invention provides an apparatus for continuous flow synthesis of the key intermediate MMPE, etocoxib, comprising a first microreactor 5, a second microreactor 6, and a third microreactor 7, as well as a first injection pump 1, a second injection pump 2, a third injection pump 3, and a fourth injection pump 4; the first injection pump 1 and the second injection pump 2 are connected to the inlet end of the first microreactor 5, the outlet end of the first microreactor 5 and the third injection pump 3 are connected to the inlet end of the second microreactor 6, and the outlet end of the second microreactor 6 and the fourth injection pump 4 are connected to the third microreactor 7.

[0023] The first, second, and third microreactors are all capillary microreactors, and the inner diameter of the capillary microreactors is 0.6 mm to 1.6 mm.

[0024] In this invention, the capillary microreactor used in subsequent embodiments has an inner diameter of 0.8 mm.

[0025] This invention provides a method for continuous-flow synthesis of the key intermediate MMPE, etoposide, using the following method: Figure 1 The apparatus shown specifically includes the following steps: (1) The 4-methanesulfonylphenylacetic acid solution and the first stream of tert-butylmagnesium chloride solution are continuously fed into the first microreactor 5 for the first step of continuous flow synthesis to obtain reaction solution A; (2) The reaction solution A and methyl 6-methylnicotinic acid ester solution output from the first microreactor 5 are continuously fed to the second microreactor 6 for the second step of continuous flow synthesis to obtain reaction solution B; (3) The reaction liquid B output from the second microreactor 5 and the second stream of tert-butyl magnesium chloride solution are continuously fed to the third microreactor 7 for the third step of continuous flow synthesis to obtain the final reaction liquid C; (4) The reaction liquid C output from the third microreactor 7 is purified and dried to obtain the desired MMPE product.

[0026] The technical solution of the present invention will be further described below with reference to specific embodiments.

[0027] Example 1 This embodiment provides a method for continuous-flow synthesis of the key intermediate MMPE, etoposide, using methods such as... Figure 1 The apparatus shown specifically includes the following steps: (1) The first continuous flow synthesis step A is carried out by continuously feeding the 4-methanesulfonylphenylacetic acid solution and the first tert-butylmagnesium chloride solution into the first microreactor 5 using the first injection pump 1 and the second injection pump 2 respectively, to obtain reaction solution A; wherein the concentration of the 4-methanesulfonylphenylacetic acid solution is 1.0 mol / L, the flow rate of the first injection pump 1 is 0.12 mL / min, the concentration of the first tert-butylmagnesium chloride solution is 1.0 mol / L, the flow rate of the second injection pump 2 is 0.24 mL / min, and the residence time of the first microreactor 5 is 1.26 min.

[0028] (2) The reaction solution A and 6-methylnicotinic acid methyl ester solution output from the first microreactor 5 are continuously transported to the second microreactor 6 for the second step of continuous flow synthesis to obtain reaction solution B; wherein, the concentration of 6-methylnicotinic acid methyl ester solution is 2.85 mol / L, and it is transported to the second microreactor 6 at a flow rate of 0.04 mL / min using the third syringe 3, and the residence time of the second microreactor 6 is 0.06 min.

[0029] (3) The reaction solution B output from the second microreactor 5 and the second tert-butyl magnesium chloride solution are continuously fed into the third microreactor 7 for the third step of continuous flow synthesis to obtain the final reaction solution C; wherein, the concentration of the second tert-butyl magnesium chloride solution is 1.0 mol / L, and it is fed into the third microreactor 7 at a flow rate of 0.12 mL / min using the fourth syringe 4, and the residence time of the third microreactor 7 is 2.60 min.

[0030] (4) The reaction solution C output from the third microreactor 7 was directly added dropwise into a 4:1 hydrochloric acid solution to quench the reaction. The concentration of the hydrochloric acid solution was 1 mol / L, and the amount of hydrochloric acid used was 8-10 eq, based on the 4-methanesulfonylphenylacetic acid contained in the sample liquid at that time being 1 eq. The mixture was received and stirred simultaneously. After stirring for 1 h, it was extracted using methyl tert-butyl ether. The aqueous phase was collected, and ammonia was added to adjust the pH to 7-9 while stirring. A solid precipitated out. After filtration, the solid was washed with water and dried at 60 °C for 12 h to obtain the key intermediate of the compound etoricoxib.

[0031] In steps (1) to (3) above, the reaction temperature of each step is 55°C, and the back pressure of each reaction system is set to 0.1 MPa using a back pressure valve.

[0032] The HPLC analysis showed a purity of 96.13% and a yield of 59.68%.

[0033] Examples 2-3 This embodiment provides a method for the continuous flow synthesis of the key intermediate MMPE, etoposide, which follows the same steps as in Example 1. It involves repeating the experiments in Example 1 to obtain the final etoposide intermediate. In Example 2, the HPLC purity was 97.25%, and the yield was 60.08%. In Example 3, the HPLC purity was 97.71%, and the yield was 58.92%.

[0034] The results show that, compared with the prior art, the technical solution of the present invention is simpler to operate, has excellent repeatability, and exhibits less fluctuation.

[0035] Example 4 This embodiment provides a method for continuous-flow synthesis of the key intermediate MMPE, etoposide, using methods such as... Figure 1 The apparatus shown specifically includes the following steps: (1) The first continuous flow synthesis step A is carried out by continuously feeding the 4-methanesulfonylphenylacetic acid solution and the first tert-butylmagnesium chloride solution into the first microreactor 5 using the first injection pump 1 and the second injection pump 2 respectively, to obtain reaction solution A; wherein the concentration of the 4-methanesulfonylphenylacetic acid solution is 1.0 mol / L, the flow rate of the first injection pump 1 is 0.12 mL / min, the concentration of the first tert-butylmagnesium chloride solution is 1.0 mol / L, the flow rate of the second injection pump 2 is 0.24 mL / min, and the residence time of the first microreactor 5 is 1.20 min.

[0036] (2) The reaction solution A and 6-methylnicotinic acid methyl ester solution output from the first microreactor 5 are continuously transported to the second microreactor 6 for the second step of continuous flow synthesis to obtain reaction solution B; wherein, the concentration of 6-methylnicotinic acid methyl ester solution is 2.85 mol / L, and it is transported to the second microreactor 6 at a flow rate of 0.04 mL / min using the third syringe 3, and the residence time of the second microreactor 6 is 0.06 min.

[0037] (3) The reaction solution B output from the second microreactor 5 and the second tert-butyl magnesium chloride solution are continuously transported to the third microreactor 7 for the third step of continuous flow synthesis to obtain the final reaction solution C; wherein, the concentration of the second tert-butyl magnesium chloride solution is 1.0 mol / L, and it is transported to the third microreactor 7 at a flow rate of 0.12 mL / min using the fourth syringe 4, and the residence time of the third microreactor 7 is 2.70 min.

[0038] (4) The reaction solution C output from the third microreactor 7 was directly added dropwise into a 4:1 hydrochloric acid solution to quench the reaction. The concentration of the hydrochloric acid solution was 1 mol / L, and the amount of hydrochloric acid used was 8-10 eq based on the 4-methanesulfonylphenylacetic acid content in the sample liquid at that time. The mixture was stirred while receiving the sample. After stirring for 1 h, it was extracted using methyl tert-butyl ether. The aqueous phase was collected, and ammonia was added to adjust the pH to 7-9 while stirring. A solid precipitated out. The solid was washed with water after filtration and dried at 60 °C for 12 h to obtain the key intermediate of the compound etoricoxib.

[0039] In steps (1) to (3) above, the reaction temperature of each step is 55°C, and the back pressure of each reaction system is set to 0.1 MPa using a back pressure valve.

[0040] The HPLC purity was 96.91% and the yield was 59.22%.

[0041] Example 5 This embodiment provides a method for continuous-flow synthesis of the key intermediate MMPE, etoposide, using methods such as... Figure 1 The apparatus shown differs from that in Example 4 in that the residence time of the reactants in the first microreactor is different. In this example, the residence time of the first microreactor 5 is 0.98 min, while the rest of the operation is the same.

[0042] The HPLC purity of the obtained MMPE product was 97.00%, and the yield was 43.35%.

[0043] Example 6 This embodiment provides a method for continuous-flow synthesis of the key intermediate MMPE, etoposide, using methods such as... Figure 1 The apparatus shown differs from that in Example 4 in that the residence time of the reactants in the first microreactor is different. In this example, the residence time of the first microreactor 5 is 1.5 min, while the rest of the operation is the same.

[0044] The HPLC purity of the obtained MMPE product was 97.05%, and the yield was 42.66%.

[0045] Example 7 This embodiment provides a method for continuous-flow synthesis of the key intermediate MMPE, etoposide, using methods such as... Figure 1 The apparatus shown differs from that in Example 4 in that the concentration of the 6-methylnicotinic acid methyl ester solution in step (2) is 1.425 mol / L, and it is delivered to the second microreactor 6 using a third syringe 3 at a flow rate of 0.08 mL / min. All other conditions are the same. The HPLC purity of the obtained MMPE product was 97.25%, and the yield was 54.74%.

[0046] Example 8 This embodiment provides a method for continuous-flow synthesis of the key intermediate MMPE, etoposide, using methods such as... Figure 1 The apparatus shown differs from that in Example 4 in that the residence times of the reactants in the second and third microreactors are different in step (2). In this example, the residence time in the second microreactor 5 is 0.63 min, and the residence time in the third microreactor 7 is 2.90 min. All other operations are the same. The HPLC purity of the obtained MMPE product was 94.51%, and the yield was 33.94%.

[0047] Example 9 This embodiment provides a method for continuous-flow synthesis of the key intermediate MMPE, etoposide, using methods such as... Figure 1 The apparatus shown differs from that in Example 4 in that the residence times of the reactants in the second and third microreactors are different in step (2). In this example, the residence time in the second microreactor 5 is 0.13 min, and the residence time in the third microreactor 7 is 2.90 min. All other operations are the same. The HPLC purity of the obtained MMPE product was 95.12%, and the yield was 46.32%.

[0048] Example 10 This embodiment provides a method for continuous-flow synthesis of the key intermediate MMPE, etoposide, using methods such as... Figure 1 The apparatus shown differs from that in Example 4 in that the concentration of the second tert-butyl magnesium chloride solution in step (3) is different, being 0.8 mol / L, i.e., the molar ratio of 4-methanesulfonylphenylacetic acid to the second tert-butyl magnesium chloride is 1:0.8. All other operations are the same. The HPLC purity of the obtained MMPE product was 97.70%, and the yield was 57.63%.

[0049] Example 11 This embodiment provides a method for continuous-flow synthesis of the key intermediate MMPE, etoposide, using methods such as... Figure 1 The apparatus shown differs from that in Example 10 in that the reaction residence time in the third microreactor in step (3) is different; in this example, it is 2.08 min. All other operations are the same. The HPLC purity of the obtained MMPE product was 96.26%, and the yield was 55%.

[0050] Example 12 This embodiment provides a method for continuous-flow synthesis of the key intermediate MMPE, etoposide, using methods such as... Figure 1The apparatus shown differs from that in Example 11 in that the concentration of the second tert-butylmagnesium chloride solution in step (3) is different, being 0.5 mol / L; all other operations are the same. The HPLC purity of the obtained MMPE product was 95.87%, and the yield was 45.29%.

[0051] Comparative Example 1 This embodiment provides a method for continuous-stream synthesis of the key intermediate MMPE, etoposide, which specifically includes the following process: (1) Prepare a mixed solution of 4-methanesulfonylphenylacetic acid and 6-methylnicotinic acid methyl ester, wherein the concentration of 4-methanesulfonylphenylacetic acid is 1 mol / L and the concentration of 6-methylnicotinic acid methyl ester is 2.85 mol / L; prepare a 0.36 mol / L tert-butylmagnesium chloride solution.

[0052] (2) The two solutions were continuously fed into the same microreactor as in Example 1 for reaction. The flow rate of the mixed solution of 4-methanesulfonylphenylacetic acid and 6-methylnicotinic acid methyl ester was 0.12 mL / min, the flow rate of the tert-butylmagnesium chloride solution was 0.04 mL / min, and the residence time in the reactor was 2.7 min. The temperature of the reaction system was set at 55 °C and the pressure at 0.1 MPa.

[0053] (3) Quenching the reaction was done by directly adding a 4:1 hydrochloric acid solution to the reaction liquid output from the microreactor. The concentration of the hydrochloric acid solution was 1 mol / L, and the amount of hydrochloric acid used was 8-10 eq based on the amount of 4-methanesulfonylphenylacetic acid contained in the sample liquid at that time. The mixture was stirred while receiving the sample. After stirring for 1 h, it was extracted with methyl tert-butyl ether. The aqueous phase was collected, and ammonia was added to adjust the pH to 7-9 while stirring. A solid precipitated out. The solid was washed with water after filtration and dried at 60 °C for 12 h to obtain the key intermediate of the compound etoricoxib. The HPLC purity was 97.52% and the yield was 18.62%.

[0054] Comparative Example 2 This embodiment provides a method for continuous-flow synthesis of the key intermediate MMPE, etoposide, using methods such as... Figure 2 The apparatus shown specifically includes the following steps: (1) The first injection pump 1 and the second injection pump 2 are used to continuously deliver the 4-methanesulfonylphenylacetic acid solution and the tert-butylmagnesium chloride solution to the first microreactor 5 for the first step of continuous flow synthesis to obtain reaction solution A; wherein the concentration of the 4-methanesulfonylphenylacetic acid solution is 1.0 mol / L, the flow rate of the first injection pump 1 is 0.12 mL / min, the concentration of the tert-butylmagnesium chloride solution is 1.0 mol / L, the flow rate of the second injection pump 2 is 0.36 mL / min, and the residence time of the first microreactor 5 is 1.06 min.

[0055] (2) The reaction solution A and 6-methyl nicotinic acid methyl ester solution output from the first microreactor 5 are continuously transported to the third microreactor 7 for the second step of continuous flow synthesis. The concentration of the 6-methyl nicotinic acid methyl ester solution is 2.85 mol / L. The solution is transported to the third microreactor 7 at a flow rate of 0.04 mL / min using the third syringe 3. The residence time of the third microreactor 7 is 2.18 min.

[0056] (3) The reaction was quenched by directly adding a 4:1 hydrochloric acid solution to the reaction liquid output from the third microreactor 7. The concentration of the hydrochloric acid solution was 1 mol / L, and the amount of hydrochloric acid used was 8-10 eq based on the amount of 4-methanesulfonylphenylacetic acid contained in the sample liquid at that time. The mixture was stirred while receiving the sample. After stirring for 1 h, it was extracted with methyl tert-butyl ether. The aqueous phase was collected, and ammonia was added to adjust the pH to 7-9 while stirring. A solid precipitated out. The solid was washed with water after filtration and dried at 60 °C for 12 h to obtain the key intermediate of the compound etoricoxib.

[0057] The reaction temperature in steps (1) and (2) was 55℃, and the pressure was 0.1MPa. HPLC analysis showed a purity of 28.05% and a yield of 96.99%.

[0058] Comparative Example 3 This embodiment provides a method for continuous-flow synthesis of the key intermediate MMPE, etoposide, using methods such as... Figure 2 The apparatus shown specifically includes the following steps: (1) The first injection pump 1 and the second injection pump 2 are used to continuously deliver the 4-methanesulfonylphenylacetic acid solution and the tert-butylmagnesium chloride solution to the first microreactor 5 for the first step of continuous flow synthesis to obtain reaction solution A; wherein the concentration of the 4-methanesulfonylphenylacetic acid solution is 1.0 mol / L, the flow rate of the first injection pump 1 is 0.12 mL / min, the concentration of the tert-butylmagnesium chloride solution is 1.0 mol / L, the flow rate of the second injection pump 2 is 0.24 mL / min, and the residence time of the first microreactor 5 is 1.44 min.

[0059] (2) The reaction solution A and 6-methylnicotinic acid methyl ester solution output from the first microreactor 5 are continuously transported to the third microreactor 7 for the second step of continuous flow synthesis. The concentration of the 6-methylnicotinic acid methyl ester solution is 2.85 mol / L. The solution is transported to the third microreactor 7 at a flow rate of 0.04 mL / min using the third syringe 3. The residence time of the third microreactor 7 is 2.79 min.

[0060] (3) The reaction was quenched by directly adding a 4:1 hydrochloric acid solution to the reaction liquid output from the third microreactor 7. The concentration of the hydrochloric acid solution was 1 mol / L, and the amount of hydrochloric acid used was 8-10 eq based on the amount of 4-methanesulfonylphenylacetic acid contained in the sample liquid at that time. The mixture was stirred while receiving the sample. After stirring for 1 h, it was extracted with methyl tert-butyl ether. The aqueous phase was collected, and ammonia was added to adjust the pH to 7-9 while stirring. A solid precipitated out. The solid was washed with water after filtration and dried at 60 °C for 12 h to obtain the key intermediate of the compound etoricoxib.

[0061] The reaction temperature in steps (1) and (2) was 55℃, and the pressure was 0.1MPa. HPLC analysis showed a purity of 22.25% and a yield of 98.12%.

[0062] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will be able to make various modifications based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, any modifications derived or inspired therefrom are still within the scope of protection of this invention.

Claims

1. A method for continuous flow synthesis of the key intermediate MMPE, derived from diococcalci, characterized in that, Includes the following steps: (1) A first-step continuous flow synthesis was carried out between a 4-methanesulfonylphenylacetic acid solution and a first stream of tert-butylmagnesium chloride solution to obtain reaction solution A; (2) The reaction solution A and the methyl 6-methylnicotinate solution were subjected to a second-step continuous flow synthesis to obtain the reaction solution B; (3) Combine reaction solution B with the second strand of tert-butylmagnesium chloride solution to obtain the final reaction solution C; (4) The obtained reaction solution C is subjected to post-treatment including quenching reaction, washing and drying to obtain the desired MMPE product.

2. The method for continuous-flow synthesis of the key intermediate MMPE, etocrox, according to claim 1, is characterized in that, The molar ratio of 4-methanesulfonylphenylacetic acid solution to the first strand of tert-butyl magnesium chloride is 1:(1~3), and the molar ratio of 4-methanesulfonylphenylacetic acid solution to the second strand of tert-butyl magnesium chloride is 1:(0.5~1.5).

3. The method for continuous-flow synthesis of the key intermediate MMPE, based on coumarin, according to claim 2, is characterized in that... The concentration of the 4-methanesulfonylphenylacetic acid solution is 0.8 mol / L-1.2 mol / L, the concentration of the 6-methylnicotinic acid methyl ester solution is 0.50 mol / L-3.0 mol / L, and the concentration of the tert-butylmagnesium chloride is 0.5 mol / L-1 mol / L.

4. The method for continuous flow synthesis of the key intermediate MMPE, based on coumarin, according to claim 2, is characterized in that, The reaction time for step (1) is 1.0 min to 1.5 min, the reaction time for step (2) is 0.01 min to 0.1 min, and the reaction time for step (3) is 1.8 min to 3.0 min.

5. The method for continuous-flow synthesis of the key intermediate MMPE, etocrox, according to claim 1, is characterized in that, The reaction temperature for steps (1) to (3) is 45 to 65°C.

6. The method for continuous-flow synthesis of the key intermediate MMPE, etoricoxib, according to claim 1, is characterized in that, The post-processing described in step (4) includes the following steps: the reaction solution is added dropwise to hydrochloric acid solution under ice bath conditions and stirred, then extracted with methyl tert-butyl ether, the aqueous phase is taken and ammonia is added to adjust the pH to 7-9, a suspension is obtained and stirred, and the suspension is filtered, washed and dried to obtain MMPE product.

7. An apparatus for continuous-flow synthesis of the key intermediate MMPE, derived from coxib, for carrying out the method according to any one of claims 1 to 6, characterized in that, It includes a first microreactor, a second microreactor, and a third microreactor for carrying out the reaction, as well as a first injection pump, a second injection pump, a third injection pump, and a fourth injection pump; the first injection pump and the second injection pump are connected to the inlet end of the first microreactor, the outlet end of the first microreactor and the third injection pump are connected to the inlet end of the second microreactor, and the outlet end of the second microreactor and the fourth injection pump are connected to the third microreactor.

8. The apparatus according to claim 7, characterized in that, The first, second, and third microreactors are all capillary microreactors, and the inner diameter of the capillary microreactors is 0.6 mm to 1.6 mm.

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