A fully continuous flow chemical synthesis process of an apixaban intermediate, (Z)-2-chloro[(4-methoxyphenyl)hydrazono]acetic acid ethyl ester

Abstract

The application discloses a kind of full continuous flow chemical synthesis methods of apixaban intermediate (Z)-2-chloro [(4-methoxyphenyl) hydrazono] ethyl acetate.The full continuous flow chemical synthesis method includes the following steps: sodium nitrite solution, formula (I) compound solution, acid is passed into dynamic tubular reactor, and diazotization reaction occurs under the condition that temperature is not higher than 0 DEG C;Sodium acetate solution, 2-chloroacetoacetic acid ethyl ester solution is passed into microchannel reactor, and Japp-Klingemann reaction occurs with diazotization reaction liquid mixture under the condition that temperature is-5~2 DEG C, concentration, to obtain apixaban intermediate formula (II) compound.The application provides a kind of full continuous flow chemical synthesis method of apixaban intermediate (Z)-2-chloro [(4-methoxyphenyl) hydrazono] ethyl acetate, can be efficiently, high purity, high yield in a few tens of seconds to prepare target product.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic synthesis, and particularly relates to a full continuous flow chemical synthesis method of an intermediate (Z)-2-chloro[(4-methoxyphenyl)hydrazono]ethyl acetate of apixaban. BACKGROUND

[0002] Apixaban, chemical name: 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, CAS: 503612-47-3, has the structure of:

[0003] .

[0004] Apixaban is an oral anticoagulant drug, which is a direct factor Xa inhibitor, and is jointly developed by Bristol-Myers Squibb and Pfizer, and is used for preventing and treating thrombotic diseases. Compared with other first-line anticoagulant drugs, apixaban has significant advantages in clinical efficacy, safety and use convenience.

[0005] In the synthesis of apixaban, the currently reported methods basically use (Z)-2-chloro[(4-methoxyphenyl)hydrazono]ethyl acetate as a key intermediate. Patent publication CN101967145A discloses that p-methoxyaniline is used as a raw material to form a diazonium salt under acidic conditions, and then reacts with 2-chloroacetoacetic acid ethyl ester to generate the key intermediate (Z)-2-chloro[(4-methoxyphenyl)hydrazono]ethyl acetate. However, the above reaction has the following main problems: (1) when methanol solvent is used as a reaction solvent, the solvent is easy to react with the substrate to generate ester exchange impurities and ether exchange impurities, and these impurities are transferred to the active pharmaceutical ingredient apixaban along with the process flow, which is very difficult to remove due to the very similar structure to the API, thereby affecting the product quality of the API; (2) the product has poor solubility in solvents such as methanol, and the black viscous material obtained after work-up cannot be normally crystallized and is wrapped with a large amount of impurities, so that the purity of the obtained intermediate is low and cannot meet the production requirements; the work-up is very complex, so that the separation yield is less than 80%; (3) the reaction is sensitive to temperature, and in order to control the reaction temperature, the dropping process needs to be prolonged, which basically needs more than 20 hours, and the reaction time is long.

[0006] Therefore, it is urgent to develop a synthesis method of the intermediate (Z)-2-chloro[(4-methoxyphenyl)hydrazono]ethyl acetate of apixaban, which is safe and controllable, has high product purity, high yield, quality up to standard, simple synthesis conditions, short cycle and high efficiency. SUMMARY

[0007] In view of the prior art problems existing above, the primary object of the present application is to provide a full continuous flow chemical synthesis method of an apixaban intermediate (Z)-2-chloro[(4-methoxyphenyl)hydrazono]acetic acid ethyl ester.

[0008] To achieve the above object, the technical scheme adopted by the present application is as follows:

[0009] A full continuous flow chemical synthesis method of an apixaban intermediate (Z)-2-chloro[(4-methoxyphenyl)hydrazono]acetic acid ethyl ester, comprising the following steps:

[0010] S1, a sodium nitrite solution, a solution of a compound of formula (I), and an acid are fed into a dynamic tubular reactor to occur diazotization reaction under the condition that the temperature is not higher than 0℃; wherein the flow rate of the sodium nitrite solution is ≤1.0 mL / min, the flow rate of the solution of the compound of formula (I) is ≤0.8 mL / min, and the flow rate of the acid is ≤0.5 mL / min;

[0011] S2, a sodium acetate solution and a 2-chloroacetoacetic acid ethyl ester solution are fed into a microchannel reactor to mix with the reaction liquid obtained in step S1 to occur Japp-Klingemann reaction under the condition that the temperature is-5~2℃, and then concentrated to obtain the compound of formula (II), an apixaban intermediate (Z)-2-chloro[(4-methoxyphenyl)hydrazono]acetic acid ethyl ester; wherein the flow rate of the sodium acetate solution is ≤0.5 mL / min, and the flow rate of the 2-chloroacetoacetic acid ethyl ester solution is ≤1.2 mL / min;

[0012] The 2-chloroacetoacetic acid ethyl ester solution is a 2-chloroacetoacetic acid ethyl ester tetrahydrofuran solution or a 2-chloroacetoacetic acid ethyl ester 2-methyltetrahydrofuran solution;

[0013] The reaction formula is as follows:

[0014] .

[0015] For the first step diazotization reaction, in the prior art, the diazotization reaction product generated is very unstable, and the longer the time in the system, the faster the degradation; and for the second step Japp-Klingemann reaction, the process is exothermic, which leads to local temperature rise, and the impurities in the system increase significantly, and with the increase of reaction time, the generated impurities increase, and the yield will be significantly reduced.

[0016] The application adopts a full continuous flow chemical synthesis method, and how to maintain the stability of the intermediate product (diazonium salt) in the reaction process is the key to the preparation process. The inventors found that when tetrahydrofuran or 2-methyltetrahydrofuran is used as the reaction solvent, it can better stabilize the intermediate product, so that it is not easy to degrade, and the stability of the intermediate product can be greatly improved. At the same time, because the tetrahydrofuran solvent does not react with the substrate, it will not produce ester exchange impurities and ether exchange impurities, thereby avoiding the generation of impurities. By stabilizing the intermediate product and avoiding the generation of side reactions, a high yield and high purity of the compound of formula (II) is obtained. In addition, the dynamic tubular reactor used in step S1 has a large channel size, which can ensure that the product is obtained from sampling to discharge each time, and only a few seconds are needed to complete the reaction, thereby avoiding heat accumulation, improving reaction efficiency, and improving product stability, which is conducive to the second step reaction. The microchannel reactor used in step S2 can be precisely controlled at the microsecond level, which is conducive to accurately controlling the amount of diazotization product participating in the second step reaction. After the reaction is completed in 10-20s, the product can be separated from the system, thereby effectively avoiding the increase in impurities caused by time extension.

[0017] Further, in the reaction process, the flow rates of the sodium nitrite solution, the compound of formula (I) and the acid in step S1, and the flow rates of the sodium acetate solution and the 2-chloroacetoacetate solution in step S2 need to be strictly controlled, so as to avoid the increase in the reaction temperature of the system caused by the high flow rate of the reaction solution, and to avoid the difficulty in controlling the temperature and the reaction process, thereby causing the degradation of the intermediate product.

[0018] The full continuous flow chemical synthesis method provided by the application can complete the reaction in a few tens of seconds from feeding to obtaining the product by matching specific solvents, thereby avoiding the degradation of the intermediate product and the accumulation of heat. Under the premise of ensuring the yield and purity of the product, the product can be obtained by simple concentration and drying without complex and tedious post-treatment. The application solves the problems of difficult recovery of solvents in each step, high salt, high nitrogen, high chemical oxygen demand (COD) of wastewater, and large environmental pollution and high risk of linear diazotization reaction, and meets the requirements of green and sustainable production.

[0019] Preferably, the size (width x height x depth) of the dynamic tubular reactor is (1300-1600) x (650-850) x (300-400) mm, and the diameter of the microchannel reactor is 500-700 μm; more preferably, the size of the dynamic tubular reactor is 1500 x 750 x 500 mm, and the diameter of the microchannel reactor is 600 μm.

[0020] Preferably, the acid in step S1 is at least one of concentrated hydrochloric acid, concentrated sulfuric acid, and phosphoric acid. More preferably, the acid in step S1 is concentrated hydrochloric acid. It is found in experiments that the use of concentrated hydrochloric acid is more conducive to the formation of stable diazonium salt, thereby improving the purity and yield of the final product.

[0021] Preferably, the reaction temperature in step S1 is -20~0℃. Temperature is a major influencing parameter of the reaction. If the temperature exceeds 0℃, the yield will be greatly reduced, and the impurities of the prepared product will increase, which is not conducive to the preparation of high-yield and high-purity intermediate (Z)-2-chloro[(4-methoxyphenyl)hydrazono]ethyl acetate.

[0022] Preferably, the 2-chloroacetoacetic acid ethyl ester solution in step S2 is a tetrahydrofuran solution of 2-chloroacetoacetic acid ethyl ester. Compared with 2-methyltetrahydrofuran, tetrahydrofuran has a better effect on stabilizing diazonium salt, and can better improve the purity and yield of the product.

[0023] Preferably, the flow rate of the sodium nitrite solution in step S1 is 0.4~1.0 mL / min, the flow rate of the solution of compound of formula (I) is 0.4~0.8 mL / min, and the flow rate of the acid is 0.2~0.5 mL / min. Further preferably, the flow rate of the sodium nitrite solution in step S1 is 0.5~0.7 mL / min, the flow rate of the solution of compound of formula (I) is 0.45~0.6 mL / min, and the flow rate of the acid is 0.25~0.4 mL / min. Under this preferred condition, the (Z)-2-chloro[(4-methoxyphenyl)hydrazono]ethyl acetate prepared has higher yield and purity.

[0024] Preferably, the molar ratio of compound of formula (I) to sodium nitrite in step S1 is 1:(0.4~0.5).

[0025] Preferably, the ratio of compound of formula (I) to acid in step S1 is 1 mmol:(250~400) mL. More preferably, the ratio of compound of formula (I) to acid is 1 mmol:(300~400) mL.

[0026] Preferably, the reaction temperature in step S2 is -5~0℃. This step is an exothermic reaction, and the local temperature rises during the reaction process, and the impurities in the system increase significantly. Therefore, controlling the temperature not higher than 0℃ is helpful to improve the purity of the product.

[0027] Preferably, the flow rate of the sodium acetate solution in step S2 is 0.2-0.5 mL / min; the flow rate of the ethyl 2-chloroacetoacetate solution is 0.8-1.2 mL / min. Further preferably, the flow rate of the sodium acetate solution in step S2 is 0.2-0.4 mL / min; the flow rate of the ethyl 2-chloroacetoacetate solution is 0.8-1.0 mL / min. Under the preferred conditions, the (Z)-ethyl 2-chloro[(4-methoxyphenyl)hydrazono]acetate prepared has higher yield and purity.

[0028] Preferably, the molar ratio of the compound of formula (I) to sodium acetate in step S2 is 1:(2-3).

[0029] Preferably, the volume ratio of the ethyl 2-chloroacetoacetate to tetrahydrofuran or 2-methyltetrahydrofuran in step S2 is 1:(4-5).

[0030] Compared with the prior art, the present application has the following beneficial effects:

[0031] (1) The present application provides a full continuous flow chemical synthesis method of an intermediate (Z)-ethyl 2-chloro[(4-methoxyphenyl)hydrazono]acetate of apixaban, which can efficiently and highly produce the target product in tens of seconds.

[0032] (2) The present application can greatly improve the production efficiency and the precision of process control, and ensure the stable product quality. After the reaction is completed, the target product can be obtained through simple concentration and drying, without complex and tedious post-treatment. The obtained product meets the quality standard, is beneficial to the subsequent drug research and production, so that the final drug product meets the standard and is safe and effective. BRIEF DESCRIPTION OF DRAWINGS

[0033] Figure 1 It is a synthesis route diagram of the intermediate (Z)-ethyl 2-chloro[(4-methoxyphenyl)hydrazono]acetate of apixaban.

[0034] Figure 2 It is a purity and yield diagram of the compound of formula (II) prepared in Example 1.

[0035] Figure 3 and Figure 4 They are the hydrogen spectrum and carbon spectrum of the compound of formula (II) prepared in Example 1, respectively.

[0036] Figure 5 It is a purity diagram of the compound of formula (II) prepared in Example 2.

[0037] Figure 6 It is a purity diagram of the compound of formula (II) prepared in Example 3.

[0038] Figure 7 Purity profile of the compound of formula (II) prepared for Example 4.

[0039] Figure 8 Purity profile of the compound of formula (II) prepared for Example 5.

[0040] Figure 9 Purity profile of the compound of formula (II) prepared for Example 6.

[0041] Figure 10 Purity profile of the compound of formula (II) prepared for Comparative Example 1.

[0042] Figure 11 Purity profile of the compound of formula (II) prepared for Comparative Example 2.

[0043] Figure 12 Purity profile of the compound of formula (II) prepared for Comparative Example 3.

[0044] Figure 13 Purity profile of the compound of formula (II) prepared for Comparative Example 4.

[0045] Figure 14 Purity profile of the compound of formula (II) prepared for Comparative Example 5.

[0046] Figure 15 Purity profile of the compound of formula (II) prepared for Comparative Example 6.

[0047] Figure 16 Purity profile of the compound of formula (II) prepared for Comparative Example 7.

[0048] Figure 17 Purity profile of the compound of formula (II) prepared for Comparative Example 8.

[0049] Figure 18 Purity profile of the compound of formula (II) prepared for Comparative Example 9. DETAILED DESCRIPTION

[0050] The present application is further illustrated by the following description and examples, which are not intended to limit the application in any manner. Unless otherwise indicated, the reagents, methods and apparatus used in the present application are of conventional

[0051] Example 1

[0052] The reaction scheme of the synthesis method is shown below, and the reaction scheme diagram is shown in Figure 1A continuous flow chemical synthesis method of an intermediate of Apixaban, (Z)-2-chloro[(4-methoxyphenyl)hydrazono]acetic acid ethyl ester, is shown. The method comprises the following steps:

[0053]

[0054] S1, 27 g of NaNO2 was dissolved in 105 mL of water at room temperature as feed liquid A, with a concentration of 0.26 g / mL; 100 g of the compound of formula (I) was dissolved in 310 mL of water as feed liquid B, with a concentration of 0.32 g / mL; 240 mL of concentrated hydrochloric acid was used as feed liquid C, with a concentration of 0.43 g / mL. Feed liquid A, feed liquid B and feed liquid C were respectively passed through plunger pumps P1, P2 and P3 at flow rates of 0.6 mL / min, 0.45 mL / min and 0.3 mL / min, and were sequentially fed into a first dynamic tubular reactor (R1, HC-276, Shanghai Yuxuan, size 1500*750*500 mm) to undergo diazotization reaction. During the reaction process, the temperature of the system was controlled to be not more than 0°C. After 8-10 s of incubation, the diazotization product was obtained, and the flow rate was 0.83 mL / min;

[0055] S2, anhydrous sodium acetate solid (146 g) was dissolved in 30 mL of water as feed liquid D, with a concentration of 4.87 g / mL; 2-chloroacetoacetic acid ethyl ester (112 mL) was dissolved in tetrahydrofuran solution (500 mL) as feed liquid E, with a concentration of 0.27 g / mL. Feed liquid D and feed liquid E were sequentially fed into a second microchannel reactor (R2, G5, Corning, diameter 600 μm) through plunger pump P4 at flow rates of 0.22 mL / min and 0.95 mL / min, and were mixed with the reaction liquid from the first dynamic tubular reactor in the second microchannel reactor to undergo Japp-Klingemann reaction. After 16 s of incubation at 0°C, the sample was detected by TLC.

[0056] S3, the reaction liquid was concentrated through an online concentration device at 50°C and a N2 flow rate of 60 mL / min, to obtain the compound of formula (II). The yield (separation yield) of the compound of formula (II) was 98.9% based on the compound of formula (I), and the purity was 99.91% (purity diagram as shown in Figure 2 ).

[0057] Figure 3 and Figure 4 are respectively the hydrogen spectrum and carbon spectrum of the compound of formula (II) prepared in Example 1, and the specific data are shown as follows: 1H NMR (400 MHz, DMSO-d6) δ 10.43 (1H, s), 7.31 (2H, d, J=8.0 Hz), 6.94 (2H, d, J=8.0 Hz), 4.30 (2H, q, J=4.0 Hz), 3.73 (3H, s), 1.31 (3H, t, J=4.0 Hz); 13 C NMR (100.6 MHz, DMSO-d6) δ 159.93, 155.52, 136.76, 116.31, 114.98, 112.71, 62.45, 55.71, 14.60).

[0058] Example 2

[0059] The concentrated hydrochloric acid in step S1 of Example 1 is replaced by concentrated sulfuric acid with a mass fraction of 55%, and other operations remain unchanged.

[0060] The yield (separation yield) of the compound of formula (II) is 91.7%, and the purity is 99.72% (the purity diagram is shown in Figure 5 ).

[0061] Example 3

[0062] The concentrated hydrochloric acid in step S1 of Example 1 is replaced by phosphoric acid with a mass fraction of 45%, and other operations remain unchanged.

[0063] The yield (separation yield) of the compound of formula (II) is 92.9%, and the purity is 99.65% (the purity diagram is shown in Figure 6 ).

[0064] Example 4

[0065] The tetrahydrofuran solution in step S2 of Example 1 is replaced by a 2-methyltetrahydrofuran solution, and other operations remain unchanged.

[0066] The yield (separation yield) of the compound of formula (II) is 90.4%, and the purity is 99.81% (the purity diagram is shown in Figure 7 ).

[0067] Example 5

[0068] In step S1, the flow rate of the sodium nitrite solution is 1.0 mL / min, the flow rate of the solution of the compound of formula (I) is 0.8 mL / min, and the flow rate of the acid is 0.5 mL / min.

[0069] The yield (separation yield) of the compound of formula (II) is 99.2%, and the purity is 99.97% (the purity diagram is shown in Figure 8 ).

[0070] Example 6

[0071] In step S2, the flow rate of sodium acetate solution was 0.5 mL / min; the flow rate of 2-chloroacetoacetate ethyl ester solution was 1.2 mL / min.

[0072] The yield (separation yield) of the compound of formula (II) was 99.4%, and the purity was 100% (the purity diagram is shown in Figure 9 ).

[0073] Comparative Example 1

[0074] The tetrahydrofuran solution in step S2 of Example 1 was replaced with a toluene solution, and other operations were unchanged.

[0075] The yield (separation yield) of the compound of formula (II) was 71.4%, and the purity was 99.83% (the purity diagram is shown in Figure 10 ).

[0076] Comparative Example 2

[0077] The tetrahydrofuran solution in step S2 of Example 1 was replaced with a dichloromethane solution, and other operations were unchanged.

[0078] The yield (separation yield) of the compound of formula (II) was 63.1%, and the purity was 95.82% (the purity diagram is shown in Figure 11 ).

[0079] Comparative Example 3

[0080] The tetrahydrofuran solution in step S2 of Example 1 was replaced with a methanol solution, and other operations were unchanged.

[0081] During the reaction, ester exchange and ether exchange impurities were detected, which were difficult to remove, ultimately leading to the flow to API products that did not meet the requirements, and did not meet the requirements of industrial production and other applications. The yield (separation yield) of the compound of formula (II) was 42.6%, and the purity was 82.06% (the purity diagram is shown in Figure 12 ).

[0082] Comparative Example 4

[0083] The tetrahydrofuran solution in step S2 of Example 1 was replaced with an ethanol solution, and other operations were unchanged.

[0084] During the reaction, ester exchange and ether exchange impurities were detected, which were difficult to remove, ultimately leading to the flow to API products that did not meet the requirements, and did not meet the requirements of industrial production and other applications. The yield (separation yield) of the compound of formula (II) was 58.3%, and the purity was 82.82% (the purity diagram is shown in Figure 13 ).

[0085] Comparative Example 5

[0086] The reaction temperature in step S1 in Example 1 is replaced with 5°C, and other operations remain unchanged.

[0087] The yield (separation yield) of the compound of formula (II) is calculated to be 84.1%, and the purity is 91.85% (the purity diagram is shown in Figure 14 ).

[0088] Comparative Example 6

[0089] The feeding rates of the liquid A, the liquid B and the liquid C in step S1 in Example 1 are each increased by 2 times, and other operations remain unchanged.

[0090] The yield (separation yield) of the compound of formula (II) is calculated to be 66.4%, and the purity is 86.98% (the purity diagram is shown in Figure 15 ). It can be seen that the reaction can be carried out when the feeding rate is increased, but the impurities are obviously increased, which significantly affects the purity and yield of the product.

[0091] Comparative Example 7

[0092] The reaction temperature in step S2 in Example 1 is replaced with 5°C, and other operations remain unchanged.

[0093] The yield (separation yield) of the compound of formula (II) is calculated to be 80.4%, and the purity is 91.95% (the purity diagram is shown in Figure 16 ).

[0094] Comparative Example 8

[0095] The existing synthesis method of (Z)-2-chloro[(4-methoxyphenyl)hydrazono]acetic acid ethyl ester, an intermediate of Apixaban, is used, and the specific operation is as follows:

[0096] Into a reaction kettle, 310 mL of water and 100 g of the compound of formula (I) are added, and the temperature is lowered to 10±5°C. Concentrated hydrochloric acid is added dropwise, and the internal temperature is controlled to be not more than 20°C. After the dropwise addition is completed, the reaction is maintained for 3 h. The temperature of the system is controlled to be -15±5°C, and 20% sodium nitrite aqueous solution is slowly added dropwise into the reaction system (the dropwise addition time is controlled to be not less than 25 h). After the dropwise addition is completed, the stirring is maintained for 5 h. The temperature of the system is controlled to be -15±5°C, and anhydrous sodium acetate solid is added into the reaction system in batches. After the addition is completed, the reaction is maintained for 2 h, the temperature of the system is controlled to be -15±5°C, and the solution of 2-chloroacetic acid ethyl ester in tetrahydrofuran (112 mL of 2-chloroacetic acid ethyl ester is dissolved in 500 mL of tetrahydrofuran) is slowly added dropwise. After the dropwise addition is completed, the reaction is maintained for 24 h at 0°C, and the sample is detected to determine the remaining amount of the raw material. When the raw material is completely consumed, the reaction is considered to be completed.

[0097] The yield (separation yield) of the compound of formula (II) is calculated to be 67.4%, and the purity is 92.31% (the purity diagram is shown inFigure 17 As shown in the figure). It can be seen that when (Z)-2-chloro[(4-methoxyphenyl) hydrazono] ethyl acetate is prepared by using the prior art process, using tetrahydrofuran as the reaction solvent can effectively avoid the generation of the ester exchange impurity, but the product yield of the method is low, the atom economy is poor, and the method is not suitable for mass production of the intermediate.

[0098] Comparative Example 9

[0099] The flow rate of the sodium acetate solution in step S2 of Example 1 was adjusted to 1.0 mL / min; the flow rate of the 2-chloroacetoacetic acid ethyl ester solution was adjusted to 2.4 mL / min, and other operations were unchanged.

[0100] The yield (separation yield) of the compound of formula (II) was 57.1%, and the purity was 81.50% (the purity diagram is shown in the figure). Figure 18

[0101] In summary, the application provides a full continuous flow chemical synthesis method for an intermediate (Z)-2-chloro[(4-methoxyphenyl) hydrazono] ethyl acetate of apixaban, the raw material is easy to obtain, the process is simple, the yield is high, the environmental pollution is small, the impurities are controllable, the solvent and waste water can be recycled and reused, meets the requirements of green and sustainable industrial production in the field of biological medicines, and has good application prospects.

[0102] The foregoing examples are merely illustrative of some features of the method described in the application. The appended claims are intended to claim as broadly as possible consistent with the prior art, and the examples presented herein are intended to demonstrate the application of the principles of the application. Thus, the applicant's intention is not to limit the appended claims to the selection of examples that illustrate some features of the application. Some numerical ranges recited in the claims are inclusive of the endpoints and are also inclusive of sub-ranges within the ranges, and variations of the ranges in the claims should be construed as if individually individually presented.​

Claims

1. A fully continuous flow chemical synthesis process of an apixaban intermediate (Z)-2-chloro[(4-methoxyphenyl)hydrazono]acetic acid ethyl ester, characterized in that, The method comprises the following steps: S1, a sodium nitrite solution, a solution of a compound of formula (I), and an acid are fed into a dynamic tubular reactor to perform a diazotization reaction under a temperature of not higher than 0℃; wherein the flow rate of the sodium nitrite solution is ≤1.0 mL / min, the flow rate of the solution of the compound of formula (I) is ≤0.8 mL / min, and the flow rate of the acid is ≤0.5 mL / min; S2, a sodium acetate solution and a 2-chloroacetoacetic acid ethyl ester solution are fed into a microchannel reactor to mix with the reaction liquid obtained in step S1 to perform a Japp-Klingemann reaction under a temperature of-5-2℃, and then concentrated to obtain a compound of formula (II), (Z)-2-chloro[(4-methoxyphenyl)hydrazono]acetic acid ethyl ester, which is an intermediate of apixaban; wherein the flow rate of the sodium acetate solution is ≤0.5 mL / min, and the flow rate of the 2-chloroacetoacetic acid ethyl ester solution is ≤1.2 mL / min. The 2-chloroacetoacetic acid ethyl ester solution is a tetrahydrofuran solution of 2-chloroacetoacetic acid ethyl ester or a 2-methyltetrahydrofuran solution of 2-chloroacetoacetic acid ethyl ester. The reaction formula is as follows: 。 2. The fully continuous flow chemical synthesis process according to claim 1, wherein, The acid in step S1 is at least one of concentrated hydrochloric acid, concentrated sulfuric acid, and phosphoric acid.

3. The fully continuous flow chemical synthesis process of claim 2, wherein, The acid in step S1 is concentrated hydrochloric acid.

4. The fully continuous flow chemical synthesis process of claim 1, wherein, The reaction temperature in step S1 is-20-0℃.

5. The fully continuous flow chemical synthesis process of claim 1, wherein, The flow rate of the sodium nitrite solution in step S1 is 0.4-1.0 mL / min, the flow rate of the solution of the compound of formula (I) is 0.4-0.8 mL / min, and the flow rate of the acid is 0.2-0.5 mL / min.

6. The fully continuous flow chemical synthesis process of claim 1, wherein, The 2-chloroacetoacetic acid ethyl ester solution in step S2 is a tetrahydrofuran solution of 2-chloroacetoacetic acid ethyl ester.

7. The fully continuous flow chemical synthesis process of claim 1, wherein, The molar ratio of the compound of formula (I) to sodium nitrite in step S1 is 1:(0.4-0.5).

8. The fully continuous flow chemical synthesis process of claim 1, wherein, The flow rate of the sodium acetate solution in step S2 is 0.2-0.5 mL / min, and the flow rate of the 2-chloroacetoacetic acid ethyl ester solution is 0.8-1.2 mL / min.

9. The fully continuous flow chemical synthesis process of claim 1, wherein, The molar ratio of the compound of formula (I) to sodium acetate is 1:(2-3).

10. The fully continuous flow chemical synthesis process of claim 1, wherein, The volume ratio of 2-chloroacetoacetic acid ethyl ester to tetrahydrofuran or 2-methyltetrahydrofuran in step S2 is 1:(4-5).

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