Rebosilil precursor and continuous flow preparation method of rebosilil

Abstract

The invention relates to a ribosilil precursor and a continuous flow preparation method of ribosilil. The continuous flow preparation method of the ribosilil comprises the following steps: S1, providing a reaction solution I; the reaction liquid I contains a ribosilil precursor; s2, reacting the reaction liquid I and the feed liquid C in a second microreactor to obtain a reaction liquid II; the feed liquid C is an acid solution; s3, carrying out a reaction on the reaction liquid II and a feed liquid D; the feed liquid D is an alkali solution. The method is good in yield, the ribosilil with the purity of 99% or above can be obtained by refining and purifying the obtained crude product when the ribosilil is prepared through the method, and the method is easy to operate, high in safety and short in production period.

Description

Technical Field

[0001] This invention relates to a continuous flow preparation method of a ripocidide precursor and ripocidide. Background Technology

[0002] Developed by Novartis International, reboxil was approved by the FDA in 2017 under the brand name Kisqali. When used in combination with letrozole, it is indicated for the treatment of advanced breast cancer. Like other third-generation CDK inhibitors, reboxil is an orally bioavailable small molecule drug that specifically inhibits CDK4 / 6, thereby reducing retinoblastoma protein phosphorylation, blocking cell cycle progression, and arresting the cell cycle in the G1 phase, thus exerting an anti-tumor effect.

[0003] Novartis reported the original route for reboxil (WO2010020675A), which uses palladium acetate as a catalyst, cesium carbonate as a base, and 4-methyl-2-pentanone as a solvent in the critical Buchwald coupling reaction, carried out at 100°C. In this system, cesium carbonate is insoluble, leading to difficulties in subsequent scale-up, uneven reaction, and the potential for localized excessively high reaction temperatures, thus affecting the purity of the final product and increasing its hazard. Furthermore, this reaction requires an anaerobic environment, making it difficult to industrialize. It is also limited by traditional batch reactor processes, resulting in long reaction times, cumbersome operation, and a tendency to generate impurities.

[0004] In summary, existing technologies for synthesizing ripocidide still suffer from technical drawbacks such as low yield, long production cycle, high cost, complex operation, and low safety. Summary of the Invention

[0005] The technical problem this invention aims to solve is to overcome at least one of the shortcomings of existing technologies for synthesizing ripocidide, such as large catalyst usage, low yield, long production cycle, high cost, complex operation, and low safety. This invention provides a continuous flow method for preparing ripocidide precursors and ripocidide. The method of this invention offers excellent yields, and the crude product obtained through this method can be purified to obtain ripocidide with a purity of over 99%. The method is simple to operate, highly safe, and has a short production cycle.

[0006] The present invention solves the above-mentioned technical problems through the following technical solution:

[0007] In a first aspect, the present invention provides a continuous flow preparation method for a reboxil precursor, comprising the following steps:

[0008] Feed liquid A and feed liquid B react in a first microreactor, the residence time of the reaction is 15-90 min, and the temperature of the reaction is 140-200℃;

[0009] The feed solution A includes SMA, SMB, catalyst and ligand, and the feed solution B is an alkaline salt solution.

[0010] In this invention, SMA refers to 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0011] In this invention, SMB refers to tert-butyl 4-(6-amino-3-pyridyl)piperazine-1-carboxylate.

[0012] In this invention, BINAP refers to 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, with the following structural formula:

[0013] .

[0014] In this invention, the residence time of the reaction in the microreactor is calculated by dividing the liquid holding volume of the microreactor by the volumetric flow rate of the feed liquid entering the microreactor.

[0015] Feed liquid A

[0016] In this invention, the concentration of SMA in the feed liquid A can be 0.05-0.5 mol / L, for example 0.1-0.2 mol / L.

[0017] In this invention, the concentration of SMB in the feed liquid A can be 0.05-0.5 mol / L, for example 0.1-0.2 mol / L.

[0018] In this invention, the concentration of active atoms of the catalyst in the feed liquid A can be 0.25-25.5 mmol / L, for example 0.5-5 mol / L.

[0019] In this invention, the concentration of the coordinating atoms of the ligand in the feed solution A can be 2-20 mmol / L, preferably 4-12 mmol / L, for example 4 mmol / L, 4.8 mmol / L, 8 mmol / L or 12 mmol / L.

[0020] In this invention, the residence time of the feed liquid A in the first microreactor can be greater than or equal to 25 min, preferably 25-60 min, more preferably 30-50 min, for example 34.7 min, 37.1 min, 50 min or 52 min.

[0021] In this invention, the flow rate of the feed liquid A can be 1-15 mL / min, preferably 2.5-7.5 mL / min, for example 2.5 mL / min, 5 mL / min, 7.5 mL / min or 10 mL / min.

[0022] In this invention, the solvent of the feed liquid A can be an organic solvent, preferably a water-soluble organic solvent, such as tetrahydrofuran.

[0023] In this invention, the catalyst may be a palladium catalyst. Preferably, the palladium catalyst is palladium acetate.

[0024] In certain specific embodiments of the present invention, the concentration of the palladium catalyst in the feed liquid A, based on palladium atoms, is 0.1-25.5 mmol / L, for example 0.1 mmol / L, 0.5 mmol / L, 1 mmol / L, 2 mmol / L or 5 mmol / L.

[0025] In this invention, the ligand is a ligand whose coordinating atom can be a phosphorus atom, such as BINAP.

[0026] In certain specific embodiments of the present invention, the concentration of BINAP in the feed solution A is 1-10 mmol / L, preferably 2-6 mmol / L, for example 2 mmol / L, 2.4 mmol / L, 4 mmol / L or 6 mmol / L.

[0027] [Feed solution B]

[0028] In this invention, the concentration of the solute in the alkaline salt solution in the feed liquid B can be 0.1-4 mol / L, preferably 0.4-1 mol / L, for example 0.2 mol / L, 0.4 mol / L, 0.8 mol / L, 1 mol / L or 2 mol / L.

[0029] In this invention, the residence time of the feed liquid B in the first microreactor can be greater than or equal to 25 min, preferably 25-120 min, more preferably 30-120 min, for example 34.7 min, 37.1 min, 52 min or 100 min.

[0030] In this invention, the flow rate of the feed liquid B can be 1-15 mL / min, preferably 2.5-7.5 mL / min, for example 2.5 mL / min, 3.5 mL / min, 4 mL / min, 5 mL / min, 6 mL / min, 7.5 mL / min or 10 mL / min.

[0031] In this invention, the solute in the alkaline salt solution can be an alkali metal phosphate or carbonate, such as potassium phosphate or cesium carbonate.

[0032] [Reaction in the first microreactor]

[0033] In this invention, the molar ratio of the SMA and the SMB can be 1: (1-2), preferably 1: (1-1.5), for example 1: 1, 1: 1.1 or 1: 1.5.

[0034] In this invention, the molar ratio of the SMA and the coordinating atoms of the ligand can be 1:(0.04-0.12), for example 1:0.04, 1:0.048, 1:0.08 or 1:0.12.

[0035] In this invention, the molar ratio of the SMA to the solute in the alkaline salt solution can be 1: (1-10), preferably 1: (4-10), more preferably 1: (8-10), for example 1: 2, 1: 4, 1: 8 or 1: 10.

[0036] In this invention, the molar ratio of the active atom of the catalyst to the coordinating atom of the ligand can be 1: (1-40), preferably 1: (2-40), for example 1: 2.4, 1: 4, 1: 4.8, 1: 8 or 1: 40.

[0037] In certain specific embodiments of the present invention, the molar ratio of the SMA and the palladium catalyst, based on palladium atoms, is 1:(0.001-0.05), preferably 1:(0.02-0.05), for example 1:0.001, 1:0.002, 1:0.005, 1:0.01, 1:0.02 or 1:0.05.

[0038] In certain specific embodiments of the present invention, the molar ratio of the palladium catalyst to the BINAP, based on palladium atoms, is 1:(0.5-20), preferably 1:(1-20), for example 1:1.2, 1:2, 1:2.4, 1:4 or 1:20.

[0039] In certain specific embodiments of the present invention, the molar ratio of the SMA and the BINAP is 1:(0.01-0.06), preferably 1:(0.02-0.06), for example 1:0.02, 1:0.024, 1:0.04 or 1:0.06.

[0040] In this invention, the reaction temperature can be 100-200°C, preferably 140-150°C, for example 140°C or 150°C.

[0041] In this invention, the residence time of the reaction can be 15-90 min, preferably 17-40 min, for example 17.3 min, 18.6 min, 24.8 min, 26 min or 34.7 min.

[0042] In this invention, the pressure of the reaction can be 1-10 MPa, for example 2-4 MPa.

[0043] [The First Microreactor]

[0044] In this invention, the liquid holding volume of the first microreactor can be 100-1000 mL, for example 260 mL, 400 mL or 800 mL.

[0045] In this invention, the first microreactor is made of stainless steel or Hastelloy.

[0046] Secondly, the present invention provides a continuous flow preparation method for reboxil, comprising the following steps:

[0047] S1. Provide reaction solution I; said reaction solution I contains ripotassium precursor;

[0048] S2. React the reaction solution I and the feed solution C in a second microreactor to obtain reaction solution II; the feed solution C is an acid solution.

[0049] S3. React the reaction solution II and the feed solution D; the feed solution D is an alkaline solution.

[0050] [Reaction in the first microreactor]

[0051] In this invention, in step S1, the continuous flow preparation method of the reboxil precursor as described above can be used to provide reaction solution I.

[0052] [Feed liquid C]

[0053] In this invention, in step S2, the feed liquid C contains H in the acid solution. + The molar concentration can be 1-10 mol / L, for example 3-6 mol / L.

[0054] In this invention, in step S2, the acid solution can be a strong acid, such as hydrochloric acid.

[0055] In this invention, in step S2, the flow rate of the feed liquid C can be 5-50 mL / min, for example 10 mL / min, 12 mL / min, 15 mL / min, 19 mL / min and 20 mL / min.

[0056] In this invention, in step S2, the residence time of the feed liquid C in the second microreactor is 15-30 min, preferably 15-20 min, for example 16.67 min, 20 min or 23.68 min.

[0057] [Reaction in the second microreactor]

[0058] In this invention, in step S2, the reaction temperature can be 20-40°C, for example 35°C.

[0059] In this invention, in step S2, the residence time of the reaction can be 5-20 min, preferably 8-11 min, for example 9.76 min, 10.26 min or 12.16 min.

[0060] In certain specific embodiments of the present invention, the SMA and the H in the acid solution + The molar ratio is 1:(50-200), for example 1:85.71, 1:95 or 1:144.

[0061] [Second Microreactor]

[0062] In this invention, in step S2, the liquid holding volume of the second microreactor can be 50-500 mL, for example 100 mL, 200 mL, 300 mL or 450 mL.

[0063] In this invention, in step S2, the material of the second microreactor is conventional in the art, such as polytetrafluoroethylene.

[0064] [Feed liquid D]

[0065] In this invention, in step S3, the flow rate of the feed liquid D can be 5-100 mL / min, preferably 8-25 mL / min, for example 8 mL / min, 12 mL / min, 14 mL / min, 17 mL / min, 21 mL / min, 22 mL / min, 50 mL / min or 100 mL / min.

[0066] In this invention, in step S3, the OH in the alkaline solution... - The molar concentration can be 1-10 mol / L, for example 3-6 mol / L.

[0067] In this invention, in step S3, the alkali in the alkaline solution can be a strong alkali, such as NaOH.

[0068] Intermittent reaction

[0069] In this invention, in step S3, the aqueous phase of the reaction solution II and the feed solution D can be reacted. The reaction can be a batch reaction.

[0070] The aqueous phase of reaction solution II can be obtained by extraction. The extractant can be ethyl acetate and / or n-hexane. The extraction temperature can be 25-30℃.

[0071] The reaction temperature can be 0-30℃, for example 0-10℃.

[0072] Wherein, the SMA and the OH in the alkaline solution - The preferred molar ratio is (0.8-1.2): 1000, for example, 5:6000 or 7:6000.

[0073] The reaction time is preferably 60-120 min, for example 90 min, to complete the reaction. After the reaction proceeds until a solid precipitates, the product is filtered, washed with water, and the solvent is removed under reduced pressure to obtain the crude product. Finally, it is recrystallized from ethanol to obtain the pure product, ripocidil.

[0074] [Reaction in the third microreactor]

[0075] In this invention, in step S3, the reaction solution II and the feed solution D are reacted in a third microreactor. The reaction can be a continuous reaction.

[0076] The reaction temperature can be 0-30℃, for example 0-10℃.

[0077] Wherein, the SMA and the OH in the alkaline solution - The molar ratio is preferably 1: (50-200), for example 7: 480, 1: 105 or 1: 168.

[0078] The residence time of the reaction can be 1-5 min, preferably 1.5-2.5 min, for example 1.79 min, 2.11 min or 3.1 min.

[0079] The residence time of the feed liquid D in the third microreactor can be 4-10 min, preferably 4-8 min, for example 4.29 min, 7.5 min or 8.57 min.

[0080] Following the reaction, the product was extracted with ethyl acetate and n-hexane, and the organic phase was collected to obtain a crude product. The crude product was then removed from the extraction solvent and recrystallized from ethanol to obtain pure ripocidil.

[0081] The Third Microreactor

[0082] The liquid holding volume of the third microreactor can be 50-200 mL, for example 60 mL, 65 mL, 100 mL, 150 mL or 180 mL.

[0083] The material of the third microreactor can be polytetrafluoroethylene.

[0084] The positive and progressive effects of this invention are as follows:

[0085] (1) By adopting continuous flow technology, this invention improves the safety of Buchwald-Hartwig coupling, which requires anaerobic and high-temperature reaction, and avoids the problems of difficult temperature control and difficulty in controlling anaerobic conditions in traditional batch reaction, thus shortening the production cycle.

[0086] (2) This invention utilizes continuous flow technology and conditional reaction pressure to enable the reaction to proceed under conditions exceeding the solvent boiling point, thereby improving the reaction efficiency and the purity of the finished product; it is very suitable for industrial production and has significant application value.

[0087] (3) In the preparation of ripocidide from the ripocidide precursor, the present invention can be carried out by batch reaction, which can further improve the reaction yield. Attached Figure Description

[0088] Figure 1 For the example, a schematic diagram of the process flow for preparing the reboxil precursor in a continuous flow is shown;

[0089] Figure 2 The process flow diagrams for the continuous flow preparation of reboxil in Examples 1 to 3 are shown below;

[0090] Figure 3 The process flow diagrams for the continuous flow preparation of reboxil in Examples 4 and 5 are shown below.

[0091] The diagram shows the following labels: Microreactor 1, Microreactor 2, and Microreactor 3. Detailed Implementation

[0092] The present invention will now be described in detail with reference to specific embodiments. These embodiments will help those skilled in the art to further understand the present invention, but do not limit the invention in any way. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention. These all fall within the scope of protection of the present invention.

[0093] Preparation Examples 1 to 20

[0094] The following preparation example illustrates the process flow diagram for the continuous flow preparation of the reboxil precursor. Figure 1 As shown, the process includes the following steps: The reaction system is washed with ethanol and tetrahydrofuran for 10 min respectively, followed by continuous flow preparation of the ripocidide precursor. Feed solution A and feed solution B are simultaneously pumped in, converging at point I, and then flowing into the first microreactor 1 for the first continuous flow reaction. The first microreactor 1 has a stainless steel reaction pipe with an inner diameter of 1 / 8 inch. The outlet of the first microreactor 1 is connected to a back pressure valve. After equilibrium is reached, reaction solution I containing the ripocidide precursor is obtained, as shown in the following reaction formula:

[0095] .

[0096] Preparation Example 1

[0097] A method for preparing reboxil precursor via continuous flow includes the following steps:

[0098] SMA (29.3 g, 100 mmol, 1.0 equiv), SMB (27.9 g, 100 mmol, 1.0 equiv), palladium acetate (1130 mg, 5 mmol, 0.05 equiv), and BINAP (3750 mg, 6.0 mmol, 0.06 equiv) were placed in a 5 L single-necked flask, and tetrahydrofuran was added to bring the total volume to 1000 mL. The mixture was then thoroughly mixed under nitrogen protection and prepared as feed solution A.

[0099] Cesium carbonate (65.2 g, 200 mmol) was placed in a 5 L single-necked flask, and purified water was added to bring the total volume to 500 mL. The mixture was thoroughly mixed and used as feed solution B. The flow rate of feed solution A was 5 mL / min, and the flow rate of feed solution B was 5 mL / min. The temperature of the first microreactor 1 was set at 140℃, the liquid holding volume was 260 mL, and the back pressure was 2.0 MPa.

[0100] Preparation Example 2

[0101] A method for preparing reboxil precursor via continuous flow includes the following steps:

[0102] SMA (29.3 g, 100 mmol, 1.0 equiv), SMB (27.9 g, 100 mmol, 1.0 equiv), palladium acetate (1130 mg, 5 mmol, 0.05 equiv), and BINAP (3750 mg, 6.0 mmol, 0.06 equiv) were placed in a 5 L single-necked flask, and tetrahydrofuran was added to bring the total volume to 1000 mL. The mixture was then thoroughly mixed under nitrogen protection and prepared as feed solution A.

[0103] Cesium carbonate (65.2 g, 200 mmol) was placed in a 5 L single-necked flask, and purified water was added to bring the total volume to 500 mL. The mixture was thoroughly mixed and used as feed solution B. The flow rate of feed solution A was 7.5 mL / min, and the flow rate of feed solution B was 7.5 mL / min. The temperature of the first microreactor 1 was set at 140℃, the liquid holding volume was 260 mL, and the back pressure was 2.0 MPa.

[0104] Preparation Example 3

[0105] A method for preparing reboxil precursor via continuous flow includes the following steps:

[0106] SMA (29.3 g, 100 mmol, 1.0 equiv), SMB (27.9 g, 100 mmol, 1.0 equiv), palladium acetate (1130 mg, 5 mmol, 0.05 equiv), and BINAP (3750 mg, 6.0 mmol, 0.06 equiv) were placed in a 5 L single-necked flask, and tetrahydrofuran was added to bring the total volume to 1000 mL. The mixture was then thoroughly mixed under nitrogen protection and prepared as feed solution A.

[0107] Cesium carbonate (65.2 g, 200 mmol) was placed in a 5 L single-necked flask, and purified water was added to bring the total volume to 500 mL. The mixture was thoroughly mixed and used as feed solution B. The flow rate of feed solution A was 10 mL / min, and the flow rate of feed solution B was 10 mL / min. The temperature of the first microreactor 1 was set at 140℃, the liquid holding volume was 260 mL, and the back pressure was 2.0 MPa.

[0108] Preparation Example 4

[0109] A method for preparing reboxil precursor via continuous flow includes the following steps:

[0110] SMA (29.3 g, 100 mmol, 1.0 equiv), SMB (27.9 g, 100 mmol, 1.0 equiv), palladium acetate (1130 mg, 5 mmol, 0.05 equiv), and BINAP (3750 mg, 6.0 mmol, 0.06 equiv) were placed in a 5 L single-necked flask, and tetrahydrofuran was added to bring the total volume to 1000 mL. The mixture was then thoroughly mixed under nitrogen protection and prepared as feed solution A.

[0111] Cesium carbonate (163.0 g, 500 mmol) was placed in a 5 L single-necked flask, and purified water was added to bring the total volume to 500 mL. The mixture was thoroughly mixed and used as feed solution B. The flow rate of feed solution A was 10 mL / min, and the flow rate of feed solution B was 4 mL / min. The temperature of the first microreactor 1 was set at 140℃, the liquid holding volume was 260 mL, and the back pressure was 2.0 MPa.

[0112] The main reaction conditions and reaction solution I in the above preparation example were used to detect the content of the ripocidide precursor by HPLC. The content calculated by the area normalization method is shown in the table below.

[0113]

[0114] Based on the comparison of the above preparation examples, it can be seen that if the reaction residence time in the first microreactor is too short, the content of ripocidide precursor in reaction solution I will be low, which will affect the overall yield of ripocidide.

[0115] Preparation Example 5

[0116] A method for preparing reboxil precursor via continuous flow includes the following steps:

[0117] SMA (29.3 g, 100 mmol, 1.0 equiv), SMB (27.9 g, 100 mmol, 1.0 equiv), palladium acetate (113 mg, 0.5 mmol, 0.005 equiv), and BINAP (1250 mg, 2.0 mmol, 0.02 equiv) were placed into a 5 L single-necked flask, and tetrahydrofuran was added to bring the total volume to 1000 mL. The mixture was then thoroughly mixed under nitrogen protection and prepared as feed solution A.

[0118] Potassium phosphate (84.8 g, 400 mmol) was placed in a 5 L single-necked flask, and purified water was added to bring the total volume to 500 mL. The mixture was thoroughly mixed and used as feed solution B. The flow rate of feed solution A was 5 mL / min, and the flow rate of feed solution B was 2.5 mL / min. The temperature of the first microreactor 1 was set at 140℃, the liquid holding volume was 260 mL, and the back pressure was 2.0 MPa.

[0119] Preparation Example 6

[0120] A method for preparing reboxil precursor via continuous flow includes the following steps:

[0121] SMA (29.3 g, 100 mmol, 1.0 equiv), SMB (27.9 g, 100 mmol, 1.0 equiv), palladium acetate (113 mg, 0.5 mmol, 0.005 equiv), and BINAP (1250 mg, 2.0 mmol, 0.02 equiv) were placed into a 5 L single-necked flask, and tetrahydrofuran was added to bring the total volume to 1000 mL. The mixture was then thoroughly mixed under nitrogen protection and prepared as feed solution A.

[0122] Potassium phosphate (84.8 g, 400 mmol) was placed in a 5 L single-necked flask, and purified water was added to bring the total volume to 500 mL. The mixture was thoroughly mixed and used as feed solution B. The flow rate of feed solution A was 7.0 mL / min, and the flow rate of feed solution B was 3.5 mL / min. The temperature of the first microreactor 1 was set at 140℃, the liquid holding volume was 260 mL, and the back pressure was 2.0 MPa.

[0123] Preparation Example 7

[0124] A method for preparing reboxil precursor via continuous flow includes the following steps:

[0125] SMA (29.3 g, 100 mmol, 1.0 equiv), SMB (27.9 g, 100 mmol, 1.0 equiv), palladium acetate (113 mg, 0.5 mmol, 0.005 equiv), and BINAP (1250 mg, 2.0 mmol, 0.02 equiv) were placed into a 5 L single-necked flask, and tetrahydrofuran was added to bring the total volume to 1000 mL. The mixture was then thoroughly mixed under nitrogen protection and prepared as feed solution A.

[0126] Potassium phosphate (84.8 g, 400 mmol) was placed in a 5 L single-necked flask, and purified water was added to bring the total volume to 500 mL. The mixture was thoroughly mixed and used as feed solution B. The flow rate of feed solution A was 12.0 mL / min, and the flow rate of feed solution B was 6.0 mL / min. The temperature of the first microreactor 1 was set at 140℃, the liquid holding volume was 260 mL, and the back pressure was 2.0 MPa.

[0127] After equilibration, the reaction solution was collected to obtain a mixture containing ripocidil. HPLC analysis showed that the ripocidil precursor content was 45.7%.

[0128] Preparation Example 8

[0129] A method for preparing reboxil precursor via continuous flow includes the following steps:

[0130] SMA (29.3 g, 100 mmol, 1.0 equiv), SMB (27.9 g, 100 mmol, 1.0 equiv), palladium acetate (113 mg, 0.5 mmol, 0.005 equiv), and BINAP (1250 mg, 2.0 mmol, 0.02 equiv) were placed into a 5 L single-necked flask, and tetrahydrofuran was added to bring the total volume to 1000 mL. The mixture was then thoroughly mixed under nitrogen protection and prepared as feed solution A.

[0131] Potassium phosphate (84.8 g, 400 mmol) was placed in a 5 L single-necked flask, and purified water was added to bring the total volume to 500 mL. The mixture was thoroughly mixed and used as feed solution B. The flow rate of feed solution A was 5 mL / min, and the flow rate of feed solution B was 5 mL / min. The temperature of the first microreactor 1 was set at 150℃, the liquid holding volume was 260 mL, and the back pressure was 2.0 MPa.

[0132] The main reaction conditions and reaction solution I in the above preparation example were used to detect the content of the ripocidide precursor by HPLC. The content calculated by the area normalization method is shown in the table below.

[0133]

[0134] Based on the comparison of the above preparation examples, it can be seen that if the reaction residence time in the first microreactor is too short, the content of ripocidide precursor in reaction solution I will be low, which will affect the overall yield of ripocidide.

[0135] Preparation Example 9

[0136] A method for preparing reboxil precursor via continuous flow includes the following steps:

[0137] SMA (29.3 g, 100 mmol, 1.0 equiv), SMB (27.9 g, 100 mmol, 1.0 equiv), palladium acetate (452 ​​mg, 2 mmol, 0.02 equiv), and BINAP (1500 mg, 2.4 mmol, 0.024 equiv) were placed in a 5 L single-necked flask, and tetrahydrofuran was added to bring the total volume to 1000 mL. The mixture was then thoroughly mixed under nitrogen protection and prepared as feed solution A.

[0138] Cesium carbonate (65.2 g, 200 mmol) was placed in a 5 L single-necked flask, and purified water was added to bring the total volume to 500 mL. The mixture was thoroughly mixed and used as feed solution B. The flow rate of feed solution A was 7.5 mL / min, and the flow rate of feed solution B was 7.5 mL / min. The temperature of the first microreactor 1 was set at 140℃, the liquid holding volume was 260 mL, and the back pressure was 2.0 MPa.

[0139] Preparation Example 10

[0140] A method for preparing reboxil precursor via continuous flow includes the following steps:

[0141] SMA (29.3 g, 100 mmol, 1.0 equiv), SMB (27.9 g, 100 mmol, 1.0 equiv), palladium acetate (226 mg, 1.0 mmol, 0.01 equiv), and BINAP (750 mg, 1.2 mmol, 0.012 equiv) were placed in a 5 L single-necked flask, and tetrahydrofuran was added to bring the total volume to 1000 mL. The mixture was then thoroughly mixed under nitrogen protection and prepared as feed solution A.

[0142] Cesium carbonate (65.2 g, 200 mmol) was placed in a 5 L single-necked flask, and purified water was added to bring the total volume to 500 mL. The mixture was thoroughly mixed and used as feed solution B. The flow rate of feed solution A was 7.5 mL / min, and the flow rate of feed solution B was 7.5 mL / min. The temperature of the first microreactor 1 was set at 140℃, the liquid holding volume was 260 mL, and the back pressure was 2.0 MPa.

[0143] Preparation Example 11

[0144] A method for preparing reboxil precursor via continuous flow includes the following steps:

[0145] SMA (29.3 g, 100 mmol, 1.0 equiv), SMB (27.9 g, 100 mmol, 1.0 equiv), palladium acetate (452 ​​mg, 2 mmol, 0.02 equiv), and BINAP (2500 mg, 4.0 mmol, 0.04 equiv) were placed into a 5 L single-necked flask, and tetrahydrofuran was added to bring the total volume to 1000 mL. The mixture was then thoroughly mixed under nitrogen protection and prepared as feed solution A.

[0146] Cesium carbonate (65.2 g, 200 mmol) was placed in a 5 L single-necked flask, and purified water was added to bring the total volume to 500 mL. The mixture was thoroughly mixed and used as feed solution B. The flow rate of feed solution A was 7.5 mL / min, and the flow rate of feed solution B was 7.5 mL / min. The temperature of the first microreactor 1 was set at 140℃, the liquid holding volume was 260 mL, and the back pressure was 2.0 MPa.

[0147] Preparation Example 12

[0148] A method for preparing reboxil precursor via continuous flow includes the following steps:

[0149] SMA (29.3 g, 100 mmol, 1.0 equiv), SMB (27.9 g, 100 mmol, 1.0 equiv), palladium acetate (452 ​​mg, 2 mmol, 0.02 equiv), and BINAP (750 mg, 1.2 mmol, 0.012 equiv) were placed in a 5 L single-necked flask, and tetrahydrofuran was added to bring the total volume to 1000 mL. The mixture was then thoroughly mixed under nitrogen protection and prepared as feed solution A.

[0150] Cesium carbonate (65.2 g, 200 mmol) was placed in a 5 L single-necked flask, and purified water was added to bring the total volume to 500 mL. The mixture was thoroughly mixed and used as feed solution B. The flow rate of feed solution A was 7.5 mL / min, and the flow rate of feed solution B was 7.5 mL / min. The temperature of the first microreactor 1 was set at 140℃, the liquid holding volume was 260 mL, and the back pressure was 2.0 MPa.

[0151] The main reaction conditions and reaction solution I in the above preparation example were used to detect the content of the ripocidide precursor by HPLC. The content calculated by the area normalization method is shown in the table below.

[0152]

[0153] As can be seen from the comparison of the above preparation examples, when the ligand content is too low, the content of ripocidide precursor in reaction solution I will be less, which will affect the overall yield of ripocidide.

[0154] Preparation Example 13

[0155] A method for preparing reboxil precursor via continuous flow includes the following steps:

[0156] SMA (29.3 g, 100 mmol, 1.0 equiv), SMB (27.9 g, 100 mmol, 1.0 equiv), palladium acetate (452 ​​mg, 2 mmol, 0.02 equiv), and BINAP (2500 mg, 4.0 mmol, 0.04 equiv) were placed into a 5 L single-necked flask, and tetrahydrofuran was added to bring the total volume to 1000 mL. The mixture was then thoroughly mixed under nitrogen protection and prepared as feed solution A.

[0157] Potassium phosphate (42.4 g, 200 mmol) was placed in a 5 L single-necked flask, and purified water was added to bring the total volume to 500 mL. The mixture was thoroughly mixed and used as feed solution B. The flow rate of feed solution A was 5 mL / min, and the flow rate of feed solution B was 5 mL / min. The temperature of the first microreactor 1 was set at 140℃, the liquid holding volume was 260 mL, and the back pressure was 2.0 MPa.

[0158] Preparation Example 14

[0159] A method for preparing reboxil precursor via continuous flow includes the following steps:

[0160] SMA (29.3 g, 100 mmol, 1.0 equiv), SMB (27.9 g, 100 mmol, 1.0 equiv), palladium acetate (452 ​​mg, 2 mmol, 0.02 equiv), and BINAP (1250 mg, 2.0 mmol, 0.02 equiv) were placed into a 5 L single-necked flask, and tetrahydrofuran was added to bring the total volume to 1000 mL. The mixture was then thoroughly mixed under nitrogen protection and prepared as feed solution A.

[0161] Potassium phosphate (42.4 g, 200 mmol) was placed in a 5 L single-necked flask, and purified water was added to bring the total volume to 500 mL. The mixture was thoroughly mixed and used as feed solution B. The flow rate of feed solution A was 5 mL / min, and the flow rate of feed solution B was 5 mL / min. The temperature of the first microreactor 1 was set at 140℃, the liquid holding volume was 260 mL, and the back pressure was 2.0 MPa.

[0162] Preparation Example 15

[0163] A method for preparing reboxil precursor via continuous flow includes the following steps:

[0164] SMA (29.3 g, 100 mmol, 1.0 equiv), SMB (27.9 g, 100 mmol, 1.0 equiv), palladium acetate (113 mg, 0.5 mmol, 0.005 equiv), and BINAP (625 mg, 1.0 mmol, 0.01 equiv) were placed into a 5 L single-necked flask, and tetrahydrofuran was added to bring the total volume to 1000 mL. The mixture was then thoroughly mixed under nitrogen protection and prepared as feed solution A.

[0165] Potassium phosphate (42.4 g, 200 mmol) was placed in a 5 L single-necked flask, and purified water was added to bring the total volume to 500 mL. The mixture was thoroughly mixed and used as feed solution B. The flow rate of feed solution A was 5 mL / min, and the flow rate of feed solution B was 5 mL / min. The temperature of the first microreactor 1 was set at 140℃, the liquid holding volume was 260 mL, and the back pressure was 2.0 MPa.

[0166] Preparation Example 16

[0167] A method for preparing reboxil precursor via continuous flow includes the following steps:

[0168] SMA (29.3 g, 100 mmol, 1.0 equiv), SMB (27.9 g, 100 mmol, 1.0 equiv), palladium acetate (113 mg, 0.5 mmol, 0.005 equiv), and BINAP (1250 mg, 2.0 mmol, 0.02 equiv) were placed into a 5 L single-necked flask, and tetrahydrofuran was added to bring the total volume to 1000 mL. The mixture was then thoroughly mixed under nitrogen protection and prepared as feed solution A.

[0169] Potassium phosphate (42.4 g, 200 mmol) was placed in a 5 L single-necked flask, and purified water was added to bring the total volume to 500 mL. The mixture was thoroughly mixed and used as feed solution B. The flow rate of feed solution A was 5 mL / min, and the flow rate of feed solution B was 5 mL / min. The temperature of the first microreactor 1 was set at 140℃, the liquid holding volume was 260 mL, and the back pressure was 2.0 MPa.

[0170] Preparation Example 17

[0171] A method for preparing reboxil precursor via continuous flow includes the following steps:

[0172] SMA (29.3 g, 100 mmol, 1.0 equiv), SMB (27.9 g, 100 mmol, 1.0 equiv), palladium acetate (22.6 mg, 0.1 mmol, 0.001 equiv), and BINAP (1250 mg, 2.0 mmol, 0.02 equiv) were placed into a 5 L single-necked flask, and tetrahydrofuran was added to bring the total volume to 1000 mL. The mixture was then thoroughly mixed under nitrogen protection and prepared as feed solution A.

[0173] Potassium phosphate (42.4 g, 200 mmol) was placed in a 5 L single-necked flask, and purified water was added to bring the total volume to 500 mL. The mixture was thoroughly mixed and used as feed solution B. The flow rate of feed solution A was 5 mL / min, and the flow rate of feed solution B was 5 mL / min. The temperature of the first microreactor 1 was set at 140℃, the liquid holding volume was 260 mL, and the back pressure was 2.0 MPa.

[0174] Preparation Example 18

[0175] A method for preparing reboxil precursor via continuous flow includes the following steps:

[0176] SMA (29.3 g, 100 mmol, 1.0 equiv), SMB (27.9 g, 100 mmol, 1.0 equiv), palladium acetate (113 mg, 0.5 mmol, 0.005 equiv), and BINAP (1250 mg, 2.0 mmol, 0.02 equiv) were placed into a 5 L single-necked flask, and tetrahydrofuran was added to bring the total volume to 1000 mL. The mixture was then thoroughly mixed under nitrogen protection and prepared as feed solution A.

[0177] Potassium phosphate (84.8 g, 400 mmol) was placed in a 5 L single-necked flask, and purified water was added to bring the total volume to 500 mL. The mixture was thoroughly mixed and used as feed solution B. The flow rate of feed solution A was 5 mL / min, and the flow rate of feed solution B was 5 mL / min. The temperature of the first microreactor 1 was set at 140℃, the liquid holding volume was 260 mL, and the back pressure was 2.0 MPa.

[0178] The main reaction conditions and reaction solution I in the above preparation example were used to detect the content of the ripocidide precursor by HPLC. The content calculated by the area normalization method is shown in the table below.

[0179]

[0180] As can be seen from the comparison of the above preparation examples, when the ligand content is too low, the content of ripocidide precursor in reaction solution I will be less, which will affect the overall yield of ripocidide.

[0181] Preparation Example 19

[0182] A method for preparing reboxil precursor via continuous flow includes the following steps:

[0183] SMA (29.3 g, 100 mmol, 1.0 equiv), SMB (27.9 g, 100 mmol, 1.0 equiv), palladium acetate (452 ​​mg, 2 mmol, 0.02 equiv), and BINAP (1500 mg, 2.4 mmol, 0.024 equiv) were placed in a 5 L single-necked flask, and tetrahydrofuran was added to bring the total volume to 1000 mL. The mixture was then thoroughly mixed under nitrogen protection and prepared as feed solution A.

[0184] Cesium carbonate (65.2 g, 200 mmol) was placed in a 5 L single-necked flask, and purified water was added to bring the total volume to 500 mL. The mixture was thoroughly mixed and used as feed solution B. The flow rate of feed solution A was 5 mL / min, and the flow rate of feed solution B was 5 mL / min. The temperature of the first microreactor 1 was set at 100℃, the liquid holding volume was 260 mL, and the back pressure was 2.0 MPa.

[0185] Preparation Example 20

[0186] A method for preparing reboxil precursor via continuous flow includes the following steps:

[0187] SMA (29.3 g, 100 mmol, 1.0 equiv), SMB (27.9 g, 100 mmol, 1.0 equiv), palladium acetate (452 ​​mg, 2 mmol, 0.02 equiv), and BINAP (1500 mg, 2.4 mmol, 0.024 equiv) were placed in a 5 L single-necked flask, and tetrahydrofuran was added to bring the total volume to 1000 mL. The mixture was then thoroughly mixed under nitrogen protection and prepared as feed solution A.

[0188] Cesium carbonate (65.2 g, 200 mmol) was placed in a 5 L single-necked flask, and purified water was added to bring the total volume to 500 mL. The mixture was thoroughly mixed and used as feed solution B. The flow rate of feed solution A was 5 mL / min, and the flow rate of feed solution B was 5 mL / min. The temperature of the first microreactor 1 was set at 120℃, the liquid holding volume was 260 mL, and the back pressure was 2.0 MPa.

[0189] The main reaction conditions and reaction solution I in the above preparation example were used to detect the content of the ripocidide precursor by HPLC. The content calculated by the area normalization method is shown in the table below.

[0190]

[0191] As can be seen from the comparison of the above preparation examples, when the reaction temperature is too low, the content of ripocidide precursor in reaction solution I will be less, which will affect the overall yield of ripocidide.

[0192] Examples 1 to 3

[0193] The following Examples 1 to 3 illustrate the process flow diagrams for the continuous flow preparation of reboxil. Figure 2 As shown, it includes the following steps:

[0194] After washing the reaction system with ethanol and tetrahydrofuran for 10 min respectively, the ripocidil precursor was prepared by continuous flow.

[0195] Feed liquid A and feed liquid B are pumped in simultaneously and converge at the confluence point I. Then they flow into the first microreactor 1 for the first continuous flow reaction. The first microreactor 1 has a stainless steel reaction pipe with an inner diameter of 1 / 8 inch. The outlet of the first microreactor 1 is connected to a back pressure valve and then to the second microreactor 2. After equilibrium is reached, reaction liquid I containing the ripocidil precursor is obtained.

[0196] Reaction liquid I and the pumped feed liquid C meet at confluence point II, and then simultaneously flow into the second microreactor 2 for a second continuous flow reaction. The second microreactor 2 has a polytetrafluoroethylene reaction pipe with an inner diameter of 1 / 8 inch, producing reaction liquid II. The outlet of the second microreactor 2 is directly connected to the inlet of the third microreactor 3.

[0197] Reaction liquid II and the pumped feed liquid D meet at the confluence point III, and then flow into the third microreactor 3 simultaneously for the third continuous flow reaction. The third microreactor 3 has a polytetrafluoroethylene reaction pipe with an inner diameter of 1 / 8 inch. After equilibrium is reached, the reaction liquid is received at 0°C to obtain reaction liquid III.

[0198] Finally, reaction solution III was extracted with ethyl acetate and n-hexane, and the organic phase was collected to obtain the crude product. The crude product was then removed from the extraction solvent and recrystallized from ethanol to obtain pure reboxil. The reaction formula is as follows:

[0199] .

[0200] .

[0201] Example 1

[0202] A method for preparing reboxil in a continuous flow, based on preparation example 18, includes the following steps:

[0203] SMA (29.3 g, 100 mmol, 1.0 equiv), SMB (27.9 g, 100 mmol, 1.0 equiv), palladium acetate (113 mg, 0.5 mmol, 0.005 equiv), and BINAP (1250 mg, 2.0 mmol, 0.02 equiv) were placed into a 5 L single-necked flask, and tetrahydrofuran was added to bring the total volume to 1000 mL. The mixture was then thoroughly mixed under nitrogen protection and prepared as feed solution A.

[0204] Potassium phosphate (84.8 g, 400 mmol) was placed in a 5 L single-necked flask, purified water was added to make a volume of 500 mL, and the mixture was thoroughly mixed. This is feed solution B. 6 M hydrochloric acid aqueous solution was placed in a 5 L single-necked flask. This is feed solution C. 6 M sodium hydroxide aqueous solution was placed in a 5 L single-necked flask. This is feed solution D.

[0205] The first microreactor was set at 140℃ with a liquid holding volume of 260 mL and a back pressure of 2.0 MPa; the second microreactor was set at 35℃ with a liquid holding volume of 200 mL; and the third microreactor was set at 0℃ with a liquid holding volume of 60 mL. The flow rates of feed liquid A, feed liquid B, feed liquid C, and feed liquid D were 7 mL / min, 3.5 mL / min, 10 mL / min, and 8 mL / min, respectively.

[0206] Example 2

[0207] A method for preparing reboxil in a continuous flow, based on preparation example 19, includes the following steps:

[0208] SMA (29.3 g, 100 mmol, 1.0 equiv), SMB (27.9 g, 100 mmol, 1.0 equiv), palladium acetate (113 mg, 0.5 mmol, 0.005 equiv), and BINAP (1250 mg, 2.0 mmol, 0.02 equiv) were placed into a 5 L single-necked flask, and tetrahydrofuran was added to bring the total volume to 1000 mL. The mixture was then thoroughly mixed under nitrogen protection and prepared as feed solution A.

[0209] Potassium phosphate (84.8 g, 400 mmol) was placed in a 5 L single-necked flask, purified water was added to make a volume of 500 mL, and the mixture was thoroughly mixed. This is feed solution B. 6 M hydrochloric acid aqueous solution was placed in a 5 L single-necked flask. This is feed solution C. 6 M sodium hydroxide aqueous solution was placed in a 5 L single-necked flask. This is feed solution D.

[0210] The first microreactor was set at 140℃ with a liquid holding volume of 600 mL and a back pressure of 2.0 MPa; the second microreactor was set at 35℃ with a liquid holding volume of 450 mL; and the third microreactor was set at 0℃ with a liquid holding volume of 180 mL. The flow rates of feed liquid A, feed liquid B, feed liquid C, and feed liquid D were 12 mL / min, 6 mL / min, 19 mL / min, and 21 mL / min, respectively.

[0211] Example 3

[0212] A method for preparing reboxil in a continuous flow, based on preparation example 17, includes the following steps:

[0213] SMA (29.3 g, 100 mmol, 1.0 equiv), SMB (27.9 g, 100 mmol, 1.0 equiv), palladium acetate (113 mg, 0.5 mmol, 0.005 equiv), and BINAP (1250 mg, 2.0 mmol, 0.02 equiv) were placed into a 5 L single-necked flask, and tetrahydrofuran was added to bring the total volume to 1000 mL. The mixture was then thoroughly mixed under nitrogen protection and prepared as feed solution A.

[0214] Potassium phosphate (84.8 g, 400 mmol) was placed in a 5 L single-necked flask, purified water was added to make a volume of 500 mL, and the mixture was thoroughly mixed. This is feed solution B. 6 M hydrochloric acid aqueous solution was placed in a 5 L single-necked flask. This is feed solution C. 6 M sodium hydroxide aqueous solution was placed in a 5 L single-necked flask. This is feed solution D.

[0215] The first microreactor was set at 140℃ with a liquid holding volume of 260 mL and a back pressure of 2.0 MPa; the second microreactor was set at 35℃ with a liquid holding volume of 200 mL; and the third microreactor was set at 0℃ with a liquid holding volume of 60 mL. The flow rates of feed liquid A, feed liquid B, feed liquid C, and feed liquid D were 5 mL / min, 2.5 mL / min, 12 mL / min, and 14 mL / min, respectively.

[0216] The main reaction conditions and the yield and purity of pure reboxil in Examples 1 to 3 are shown in the table below.

[0217]

[0218] As can be seen from the above embodiments, by carrying out a continuous flow reaction between reaction solution II and feed solution D, pure ripocidil can be obtained with a considerable yield.

[0219] Examples 4 and 5

[0220] The process flow diagrams for the continuous flow preparation of reboxil in Examples 4 and 5 below are shown below. Figure 3 As shown, it includes the following steps:

[0221] After washing the reaction system with ethanol and tetrahydrofuran for 10 min respectively, the ripocidil precursor was prepared by continuous flow.

[0222] Feed liquid A and feed liquid B are pumped in simultaneously and converge at the confluence point I. Then they flow into the first microreactor 1 for the first continuous flow reaction. The first microreactor 1 has a stainless steel reaction pipe with an inner diameter of 1 / 8 inch. The outlet of the first microreactor 1 is connected to a back pressure valve and then to the second microreactor 2. After equilibrium is reached, reaction liquid I containing the ripocidil precursor is obtained.

[0223] Reaction liquid I and the pumped feed liquid C meet at confluence point II, and then simultaneously flow into the second microreactor 2 for a second continuous flow reaction. The second microreactor 2 has a polytetrafluoroethylene reaction pipe with an inner diameter of 1 / 8 inch. After equilibrium is reached, reaction liquid II is obtained. The outlet of the second microreactor 2 is directly connected to the inlet of the third microreactor 3.

[0224] Reaction solution II was extracted with ethyl acetate and n-hexane at 25°C. The collected aqueous phase was transferred to a round-bottom flask placed in a 0°C water bath. Feed solution D was pumped in at 1.2 L per 100 mL / min, and the mixture was stirred for 60 min until solid precipitated. The crude product was then filtered, washed with water, and dried under vacuum. Finally, pure reboxil was obtained by recrystallization with ethanol. The reaction formula is as follows:

[0225] .

[0226] .

[0227] Example 4

[0228] A method for preparing reboxil in a continuous flow, based on preparation example 18, includes the following steps:

[0229] SMA (29.3 g, 100 mmol, 1.0 equiv), SMB (27.9 g, 100 mmol, 1.0 equiv), palladium acetate (113 mg, 0.5 mmol, 0.005 equiv), and BINAP (1250 mg, 2.0 mmol, 0.02 equiv) were placed into a 5 L single-necked flask, and tetrahydrofuran was added to bring the total volume to 1000 mL. The mixture was then thoroughly mixed under nitrogen protection and prepared as feed solution A.

[0230] Potassium phosphate (84.8 g, 400 mmol) was placed in a 5 L single-necked flask, purified water was added to make a volume of 500 mL, and the mixture was thoroughly mixed. This is feed solution B. 6 M hydrochloric acid aqueous solution was placed in a 5 L single-necked flask. This is feed solution C. 6 M sodium hydroxide aqueous solution was placed in a 5 L single-necked flask. This is feed solution D.

[0231] The first microreactor was set at 140℃ with a liquid holding volume of 260 mL and a back pressure of 2.0 MPa; the second microreactor was set at 35℃ with a liquid holding volume of 200 mL. The flow rates of feed liquid A, feed liquid B, and feed liquid C were 7 mL / min, 3.5 mL / min, and 10 mL / min, respectively.

[0232] Example 5

[0233] A method for preparing reboxil in a continuous flow, based on preparation example 17, includes the following steps:

[0234] SMA (29.3 g, 100 mmol, 1.0 equiv), SMB (27.9 g, 100 mmol, 1.0 equiv), palladium acetate (113 mg, 0.5 mmol, 0.005 equiv), and BINAP (1250 mg, 2.0 mmol, 0.02 equiv) were placed into a 5 L single-necked flask, and tetrahydrofuran was added to bring the total volume to 1000 mL. The mixture was then thoroughly mixed under nitrogen protection and prepared as feed solution A.

[0235] Potassium phosphate (84.8 g, 400 mmol) was placed in a 5 L single-necked flask, purified water was added to make a volume of 500 mL, and the mixture was thoroughly mixed. This is feed solution B. 6 M hydrochloric acid aqueous solution was placed in a 5 L single-necked flask. This is feed solution C. 6 M sodium hydroxide aqueous solution was placed in a 5 L single-necked flask. This is feed solution D.

[0236] The first microreactor was set at 140℃ with a liquid holding volume of 260 mL and a back pressure of 2.0 MPa; the second microreactor was set at 35℃ with a liquid holding volume of 200 mL. The flow rates of feed liquid A, feed liquid B, and feed liquid C were 5 mL / min, 2.5 mL / min, and 12 mL / min, respectively.

[0237] The main reaction conditions and the yield and purity of pure reboxil in Examples 4 and 5 are shown in the table below.

[0238]

[0239] As can be seen from the above embodiments, by intermittently reacting reaction solution II with feed solution D, pure ripocidil can be obtained, and the yield can be further improved.

[0240] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and the scope of protection of the present invention is defined by the appended claims. Those skilled in the art can make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but all such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A continuous flow preparation method for a reboxillic acid precursor, characterized in that, It includes the following steps: Feed solution A and feed solution B react in a first microreactor, wherein the residence time of the reaction in the first microreactor is 15-90 min and the reaction temperature is 140-200℃; feed solution A includes SMA, SMB, catalyst and ligand; feed solution B is an alkaline salt solution.

2. The continuous flow preparation method of the reboxillic acid precursor according to claim 1, characterized in that, It meets one or more of the following conditions: (1) In the first microreactor, the molar ratio of the SMA to the SMB is 1: (1-2), preferably 1: (1-1.5), for example 1: 1, 1: 1.1 or 1: 1.5; (2) In the first microreactor, the molar ratio of the SMA and the coordinating atoms of the ligand is 1: (0.04-0.12), for example 1: 0.04, 1: 0.048, 1: 0.08 or 1: 0.12; (3) In the first microreactor, the molar ratio of the SMA to the solute in the alkaline salt solution is 1: (1-10), preferably 1: (4-10), more preferably 1: (8-10), for example 1: 2, 1: 4, 1: 8 or 1: 10; (4) In the first microreactor, the molar ratio of the active atom of the catalyst to the coordinating atom of the ligand is 1: (1-40), preferably 1: (2-40), for example 1: 2.4, 1: 4, 1: 4.8, 1: 8 or 1:

40.

3. The continuous flow preparation method of the reboxillic acid precursor according to claim 1, characterized in that, It meets one or more of the following conditions: (1) The ligand is a ligand with a phosphorus atom as the coordinating atom, such as BINAP; (2) The catalyst is a palladium catalyst; preferably, the palladium catalyst is palladium acetate; (3) The solute in the alkaline salt solution is an alkali metal phosphate or carbonate, such as potassium phosphate or cesium carbonate; (4) The solvent of the feed liquid A is an organic solvent, preferably a water-soluble organic solvent, such as tetrahydrofuran.

4. The continuous flow preparation method of the reboxil precursor according to claim 1, characterized in that, It meets one or more of the following conditions: (1) In the feed solution A, the concentration of SMA is 0.05-0.5 mol / L, for example 0.1-0.2 mol / L; (2) In the feed solution A, the concentration of SMB is 0.05-0.5 mol / L, for example 0.1-0.2 mol / L; (3) In the feed liquid A, the concentration of active atoms of the catalyst is 0.1-25.5 mmol / L, for example 0.1 mmol / L, 0.5 mmol / L, 1 mmol / L, 2 mmol / L or 5 mmol / L; (4) In the feed solution A, the concentration of the coordinating atoms of the ligand is 2-20 mmol / L, preferably 4-12 mmol / L, for example 4 mmol / L, 4.8 mmol / L, 8 mmol / L or 12 mmol / L; (5) In the feed solution B, the concentration of the solute in the alkaline salt solution is 0.1-4 mol / L, preferably 0.4-1 mol / L, for example 0.2 mol / L, 0.4 mol / L, 0.8 mol / L, 1 mol / L or 2 mol / L.

5. The continuous flow preparation method of the reboxillic acid precursor according to claim 1, characterized in that, It meets one or more of the following conditions: (1) In the first microreactor, the reaction temperature is 140-160°C, for example, 140°C or 150°C; (2) In the first microreactor, the residence time of the reaction is 17-40 min, for example 17.3 min, 18.6 min, 24.8 min, 26 min or 34.7 min; (3) In the first microreactor, the reaction pressure is 1-10 MPa, for example 2-4 MPa; (4) The residence time of the feed liquid A in the first microreactor is greater than or equal to 25 min, preferably 25-60 min, more preferably 30-50 min, for example 34.7 min, 37.1 min, 50 min or 52 min; (5) The flow rate of the feed liquid A is 1-15 mL / min, preferably 2.5-7.5 mL / min, for example 2.5 mL / min, 5 mL / min, 7.5 mL / min or 10 mL / min; (6) The residence time of the feed liquid B in the first microreactor is greater than or equal to 25 min, preferably 25-120 min, more preferably 30-120 min, for example 34.7 min, 37.1 min, 52 min or 100 min; (7) The flow rate of the feed liquid B is 1-15 mL / min, preferably 2.5-7.5 mL / min, for example 2.5 mL / min, 3.5 mL / min, 4 mL / min, 5 mL / min, 6 mL / min, 7.5 mL / min or 10 mL / min.

6. A continuous flow preparation method for reboxil, characterized in that, It includes the following steps: S1. Provide reaction solution I; said reaction solution I contains ripotassium precursor; S2. React the reaction solution I and the feed solution C in a second microreactor to obtain reaction solution II; the feed solution C is an acid solution. S3. React the reaction solution II and the feed solution D; the feed solution D is an alkaline solution.

7. The continuous flow preparation method of reboxil according to claim 6, characterized in that, It meets one or more of the following conditions: (1) In step S1, the reaction solution I is provided by the continuous flow preparation method of the ripocidil precursor as described in any one of claims 1-5; (2) In step S2, the feed liquid C contains H in the acid solution. + The molar concentration is 1-10 mol / L, for example 3-6 mol / L; (3) In step S2, the acid solution is a strong acid, such as hydrochloric acid; (4) In step S2, the flow rate of the feed liquid C is 5-50 mL / min, for example 10 mL / min, 12 mL / min, 15 mL / min, 19 mL / min and 20 mL / min; (5) In step S2, the reaction temperature is 20-40℃, for example 35℃; (6) In step S2, the residence time of the reaction is 5-20 min, preferably 8-11 min, for example 9.76 min, 10.26 min or 12.16 min.

8. The continuous flow preparation method of reboxil according to claim 6, characterized in that, It meets one or more of the following conditions: (1) In step S3, the base in the alkaline solution is a strong base, such as NaOH; (2) In step S3, the OH in the alkaline solution - The molar concentration is 1-10 mol / L, for example 3-6 mol / L; (3) In step S3, the flow rate of the feed liquid D is 5-100 mL / min, preferably 8-25 mL / min, for example 8 mL / min, 12 mL / min, 14 mL / min, 17 mL / min, 21 mL / min, 22 mL / min, 50 mL / min or 100 mL / min; (4) In step S3, the temperature of the reaction is 0-30℃, for example 0-10℃.

9. The continuous flow preparation method of reboxil according to claim 6, characterized in that, In step S3, the aqueous phase of the reaction solution II and the feed solution D are reacted; the reaction time is preferably 60-120 min, for example 90 min; Alternatively, in step S3, the reaction solution II and the feed solution D are reacted in a third microreactor; the residence time of the reaction is preferably 1-5 min, more preferably 1.5-2.5 min, for example 1.79 min, 2.11 min or 3.1 min.

10. The continuous flow preparation method of reboxil according to claim 7, characterized in that, When the aqueous phase of reaction solution II reacts with the feed solution D, the SMA and the OH in the alkaline solution... - The molar ratio is (0.8-1.2):1000, for example 5:6000 or 7:6000; When reaction solution II and feed solution D react in the third microreactor, the SMA and the OH in the alkaline solution... - The molar ratio is 1:(50-200), for example 7:480, 1:105 or 1:168.

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