A process for the preparation of a high purity intermediate of edoxaban

Abstract

The application belongs to the technical field of medicine purification, and particularly discloses a preparation method of a high-purity edoxaban intermediate. The preparation method comprises the following steps: a synthesis process: raw materials EDB070, triethylamine and a solvent are mixed, first-time heating is performed to dissolve and clear, second-time heating is performed to react, and a product EDB080 is obtained; pyridine and water are added, third-time heating is performed to react, and a product EDB090 is obtained; a purification process: NaCl solution is added to EDB090 to break emulsion, and then NaOH solution is added; extraction and concentration are performed, and then toluene is added to dissolve and clear; finally, normal heptane is added dropwise to perform crystallization, and after filtration, the purified EDB090 is obtained. In the post-treatment and purification process, the system of toluene / normal heptane is used for crystallization, good impurity removal effect is achieved, the purity of the edoxaban intermediate EDB090 is 92.21-93.69%, and the yield can reach 70-78%.

Description

Technical Field

[0001] This invention belongs to the field of drug purification technology, specifically relating to a method for preparing a high-purity edoxaban intermediate. Background Technology

[0002] Idusaban, English name is

[0003] N-(5-chloropyridin-2-yl)-N'-[(1S,2R,4S)-4-(N,N-dimethylcarbamoyl)-2-(5-methyl

[0004] -4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamido)cyclohexyl]oxamide; its structural formula is shown in formula (1).

[0005]

[0006] This drug is mainly used to treat stroke, pulmonary vascular obstruction, deep vein thrombosis, stroke and systemic embolism, venous thromboembolism, and ischemic stroke.

[0007] Currently, the edoxaban intermediate EDB090 is mainly obtained through the following synthetic route:

[0008]

[0009] In the above synthetic route, EDOX009 is used as the raw material, ethanol (EtOH) is used as the solvent, and ethyl acetate (EtOAC) and catalyst (Pd / C) are added. Hydrogen gas is passed through to synthesize EDB090 by catalytic hydrogenation. This synthetic method requires catalytic hydrogenation, which has high equipment requirements and high cost. Moreover, the synthesized EDB090 is a diazo compound, which is highly dangerous.

[0010] Therefore, there is an urgent need to develop a green, efficient, and safe method for synthesizing edoxaban intermediates, and to further improve the purity and yield of the product. Summary of the Invention

[0011] This invention aims to solve at least one of the technical problems existing in the prior art. To this end, this invention proposes a method for preparing a high-purity edoxaban intermediate. The edoxaban intermediate of this invention uses EDB070 as a raw material, first synthesizing EDB080 with triethylamine, and then reacting it with pyridine to obtain EDB090. Simultaneously, in the post-processing purification process, on the one hand, moisture is controlled to promote crystallization; on the other hand, a toluene / n-heptane crystallization system is used, which has a good impurity removal effect, resulting in a high-purity and stable edoxaban intermediate EDB090.

[0012] To overcome the above-mentioned technical problems, the first aspect of the present invention provides a method for preparing an edoxaban intermediate.

[0013] Specifically, a method for preparing an edoxaban intermediate includes the following steps:

[0014] (1) Synthesis process: The raw material EDB070, triethylamine and solvent are mixed, and the mixture is heated to dissolve the solvent in the first heating, and then heated to react in the second heating to obtain product EDB080; then pyridine and water are added, and the mixture is heated to react in the third heating to obtain product EDB090; the chemical structural formulas of EDB070, EDB080 and EDB090 are as follows:

[0015]

[0016] (2) Purification process: NaCl solution is first added to the EDB090 obtained in step (1) to break the emulsion, and then NaOH solution is added; then extraction and concentration are carried out, and after evaporation, toluene is added to dissolve it; finally, n-heptane is added dropwise to crystallize, and after filtration, purified EDB090 is obtained.

[0017] The edoxaban intermediate of this invention mainly includes a synthesis process and a purification process in its preparation. Specifically, the synthesis process uses EDB070 as a raw material. EDB07 is first reacted with triethylamine (TEA) at a certain temperature to obtain product EDB080; EDB080 is then reacted with pyridine (Py) at a certain temperature to obtain product EDB090. The synthetic route is as follows:

[0018]

[0019] To obtain EDB090 with higher purity and yield, this invention also includes a post-processing purification process for EDB090. In the purification process, EDB090 is first extracted, concentrated, and dried. Moisture content is controlled to promote the precipitation of EDB090 crystals. Then, crystallization is carried out in a toluene / n-heptane system, which has a good impurity removal effect, thereby obtaining a high-purity, high-yield, and stable edoxaban intermediate, EDB090. The purification process route is as follows:

[0020]

[0021] As a further improvement to the above scheme, in steps (1) and (2), the solvent includes acetonitrile or a mixed solution of acetonitrile and water. Acetonitrile has good solvent properties and can fully dissolve the raw materials EDB070 and triethylamine.

[0022] Preferably, the solvent is acetonitrile.

[0023] As a further improvement to the above scheme, in step (1), the molar ratio of EDB070, triethylamine and pyridine is 1:(1.0-1.2):(5.0-5.5).

[0024] Preferably, in step (1), the molar ratio of EDB070, triethylamine and pyridine is 1:(1.05-1.15):(5.3-5.5).

[0025] As a further improvement to the above scheme, in step (1), the mass ratio of EDB070, the solvent, and the water is 1:(1.8-2.2):(0.3-0.6).

[0026] Preferably, in step (1), the mass ratio of EDB070, the solvent and the water is 1:(1.9-2.0):(0.4-0.5).

[0027] As a further improvement to the above scheme, in step (1), the temperature is first raised to 40-60℃; the second temperature is raised to 65-70℃; and the third temperature is raised to 75-85℃.

[0028] Preferably, in step (1), the temperature is raised to 40-45℃ for the first time; to 65-68℃ for the second time; and to 75-80℃ for the third time.

[0029] Preferably, the reaction time for the second heating is 2.5-3.5 hours.

[0030] Preferably, the reaction time for the third heating is 2.5-3.5 hours.

[0031] As a further improvement to the above scheme, the mass ratio of EDB070, toluene, and n-heptane is 1:

[0032] (0.9-1.2): (1.9-2.2).

[0033] Preferably, the mass ratio of EDB070, toluene, and n-heptane is 1:(1.0-1.1):(2.0-2.1).

[0034] As a further improvement to the above scheme, the concentration of the NaCl solution is 20-25 wt%; the mass ratio of the NaCl solution to the EDB070 is (2.0-3.0):1.

[0035] Preferably, the concentration of the NaCl solution is 22-25 wt%; the mass ratio of the NaCl solution to the EDB070 is (2.5-3.0):1.

[0036] Preferably, the NaCl solution is added at 25-35°C to break the emulsion.

[0037] As a further improvement to the above scheme, the concentration of the NaOH solution is 40-50 wt%; the mass ratio of the NaOH solution to the EDB070 is (1.0-1.4):1.

[0038] Preferably, the concentration of the NaOH solution is 45-50 wt%; the mass ratio of the NaOH solution to the EDB070 is (1.1-1.2):1.

[0039] Preferably, the NaOH solution is added at 40-50°C.

[0040] As a further improvement to the above scheme, in step (2), the extraction process is as follows: first, ethyl acrylate is added for extraction for 10-30 minutes, and after standing for 10-30 minutes, the liquid is separated; then, ethyl acrylate and NaOH solution are added for secondary extraction, and the liquid is separated.

[0041] Preferably, during the secondary extraction, the concentration of the added NaOH solution is 20-25%, and the mass ratio of the NaOH solution to the EDB070 is (2.5-2.6):1.

[0042] Preferably, the concentration temperature is 40-50°C.

[0043] Preferably, the n-heptane is added dropwise at 50-55°C.

[0044] As a further improvement to the above scheme, in step (2), the crystallization temperature is -5 to 0°C and the time is 4.5 to 5.5 hours.

[0045] Preferably, in step (2), the filtration specifically includes the steps of first performing vacuum filtration; then rinsing with n-heptane; and finally drying.

[0046] A second aspect of the present invention provides an edoxaban intermediate.

[0047] Specifically, an edoxaban intermediate is provided, wherein the edoxaban intermediate is prepared by the purification method described in the first aspect of the present invention, and the purity of the edoxaban intermediate is 92-95%.

[0048] As a further improvement to the above scheme, the yield of the edoxaban intermediate is 72-78%.

[0049] Compared with the prior art, the above-described technical solution of the present invention has at least the following technical effects or advantages:

[0050] (1) The preparation of the edoxaban intermediate of the present invention includes a synthesis process and a purification process. In the synthesis process, EDB070 is used as a raw material. EDB07 is first reacted with triethylamine at a certain temperature to obtain EDB080; EDB080 is then reacted with pyridine to obtain EDB090. In the purification process of the present invention, on the one hand, the moisture content is controlled to promote crystallization; on the other hand, a toluene / n-heptane system is used for crystallization, which has a good impurity removal effect, thereby obtaining a high-purity and stable edoxaban intermediate EDB090.

[0051] (2) The preparation method of the edoxaban intermediate of the present invention is simple to operate, the reaction conditions are mild, the reagents used are readily available, and it will not cause pollution to the environment. The edoxaban intermediate EDB090 obtained has a purity of 92.21-93.69% and a yield of 70-78%. Attached Figure Description

[0052] Figure 1 The 1H NMR spectrum of the EDB090 sample prepared in Example 1;

[0053] Figure 2 The high-performance liquid chromatogram of the EDB090 sample prepared in Example 1;

[0054] Figure 3 The high-performance liquid chromatogram of the EDB090 sample prepared in Example 2;

[0055] Figure 4 The high-performance liquid chromatogram of the EDB090 sample prepared in Example 3;

[0056] Figure 5 The high-performance liquid chromatogram of the EDB090 sample prepared in Comparative Example 1 is shown.

[0057] Figure 6 The high-performance liquid chromatogram of the EDB090 sample prepared in Comparative Example 2 is shown.

[0058] Figure 7 The image shows the high-performance liquid chromatogram of the EDB090 sample prepared in Comparative Example 3. Detailed Implementation

[0059] The present invention will now be described in detail with reference to embodiments to facilitate understanding of the invention by those skilled in the art. It is particularly important to note that the embodiments are merely illustrative of the invention and should not be construed as limiting the scope of protection of the invention. Non-essential improvements and adjustments made to the invention by those skilled in the art based on the above description should still fall within the scope of protection of the invention. Furthermore, all raw materials mentioned below, unless otherwise specified, are commercially available products; and all process steps or preparation methods not mentioned in detail are process steps or preparation methods known to those skilled in the art.

[0060] Example 1

[0061] A method for preparing an edoxaban intermediate includes the following steps:

[0062] (1) Synthesis process: 26.4 kg of raw material EDB070, 6.6 kg of triethylamine and 51.0 kg of acetonitrile were mixed. The mixture was first heated to 40 °C to dissolve the raw material, and then heated to 65 °C for 3 hours to obtain product EDB080. Then 25.5 kg of pyridine and 13.2 kg of water were added, and the mixture was heated to 80 °C for 3 hours to obtain product EDB090.

[0063] (2) Purification process: At 30°C, 69.0 kg of 22 wt% NaCl solution was first added to the EDB090 obtained in step (1) to break the emulsion; then the temperature was raised to 40°C and 30 kg of 48 wt% NaOH solution was added; then 38.5 kg of ethyl acrylate was added for a first extraction, stirred for 15 minutes, allowed to stand for 15 minutes, and separated; 38.5 kg of ethyl acrylate and 68.7 kg of 20 wt% NaOH solution were added for a second extraction, and separated; the above-mentioned phases were combined and concentrated at 50°C, evaporated to dryness, and then 26.4 kg of toluene was added to dissolve the solids; finally, 52.8 kg of n-heptane was added dropwise at 50°C, the temperature was lowered to -5°C, and stirred to crystallize for 5 hours; the mixture was filtered, and the filter cake was washed with 26.4 kg of n-heptane; finally, the mixture was vacuum dried at 55°C for 24 hours to obtain the EDB090 sample of this embodiment.

[0064] Figure 2 This is a high-performance liquid chromatogram of the EDB090 sample prepared in Example 1. The vertical axis, Absorbance, represents absorbance. Figure 2 Peak 14 corresponds to EDB090, with a relative area of ​​93.69%. Peaks marked 1-13 and 15-19 correspond to different impurities, and the relative area of ​​each individual impurity does not exceed 2.12%. Figure 2It can be seen that the EDB090 obtained in Example 1 has a purity of 93.69%, and the content of any single impurity does not exceed 2.12%. Meanwhile, the yield of EDB090 obtained in Example 1 is 72%.

[0065] Example 2

[0066] A method for preparing an edoxaban intermediate includes the following steps:

[0067] (1) Synthesis process: 2.0 kg of raw material EDB070, 0.5 kg of triethylamine and 3.8 kg of acetonitrile were mixed. The mixture was first heated to 45 °C to dissolve the raw material, and then heated to 68 °C for 3 hours to obtain product EDB080. Then 1.9 kg of pyridine and 1.0 kg of water were added, and the mixture was heated to 80 °C for 3 hours to obtain product EDB090.

[0068] (2) Purification process: At 30°C, 5.2 kg of 22 wt% NaCl solution was added to the EDB090 obtained in step (1) to break the emulsion; then the temperature was raised to 40°C and 2.2 kg of 48 wt% NaOH solution was added; then 2.9 kg of ethyl acrylate was added for a first extraction, stirred for 15 minutes, allowed to stand for 15 minutes, and separated; 2.9 kg of ethyl acrylate and 5.1 kg of 20 wt% NaOH solution were added for a second extraction and separated; the above-mentioned phases were combined and concentrated at 50°C, evaporated to dryness, and then 2.0 kg of toluene was added to dissolve the solids; finally, 4.0 kg of n-heptane was added dropwise at 55°C, the temperature was lowered to 0°C, and the mixture was stirred to crystallize for 5 hours; the mixture was filtered, and the filter cake was washed with 2.0 kg of n-heptane; finally, the mixture was vacuum dried at 55°C for 24 hours to obtain the EDB090 sample of this embodiment.

[0069] Figure 3 This is a high-performance liquid chromatogram of the EDB090 sample prepared in Example 2. The vertical axis, Absorbance, represents absorbance. Figure 3 Peak marked 8 corresponds to EDB090, with a relative area of ​​92.21%. Peaks marked 1-7 and 9-12 correspond to different impurities, and the relative area of ​​each individual impurity does not exceed 3.70%. Figure 3 It is evident that the EDB090 obtained in Example 2 has a purity of 92.21%, and the content of any single impurity does not exceed 3.70%. Furthermore, the yield of the EDB090 obtained in Example 2 is 78%.

[0070] Example 3

[0071] A method for preparing an edoxaban intermediate includes the following steps:

[0072] (1) Synthesis process: 4.0 kg of raw material EDB070, 1.05 kg of triethylamine and 8 kg of acetonitrile were mixed. The mixture was first heated to 42 °C to dissolve the raw material, and then heated to 66 °C for 3 hours to obtain product EDB080. Then 3.9 kg of pyridine and 1.6 kg of water were added, and the mixture was heated to 80 °C for 3 hours to obtain product EDB090.

[0073] (2) Purification process: At 30°C, 12.0 kg of 22 wt% NaCl solution was first added to the EDB090 obtained in step (1) to break the emulsion; then the temperature was raised to 40°C and 4.8 kg of 48 wt% NaOH solution was added; then 5.8 kg of ethyl acrylate was added for a first extraction, stirred for 15 minutes, allowed to stand for 15 minutes, and separated; 5.8 kg of ethyl acrylate and 10.4 kg of 20 wt% NaOH solution were added for a second extraction, and separated; the above-mentioned phases were combined and concentrated at 50°C, evaporated to dryness, and then 4.4 kg of toluene was added to dissolve the solids; finally, 8.4 kg of n-heptane was added dropwise at 50°C, the temperature was lowered to -3°C, and stirred to crystallize for 5 hours; the mixture was filtered, and the filter cake was washed with 4.4 kg of n-heptane; finally, the mixture was vacuum dried at 55°C for 24 hours to obtain the EDB090 sample of this embodiment.

[0074] Figure 4 This is a high-performance liquid chromatogram of the EDB090 sample prepared in Example 3. The vertical axis, Absorbance, represents absorbance. Figure 4 Peak marked 3 corresponds to EDB090, with a relative area of ​​93.60%. Peaks marked 1, 2, 4, and 5 correspond to different impurities, and the relative area of ​​each individual impurity does not exceed 4.11%. Figure 4 It can be seen that the EDB090 obtained in Example 3 has a purity of 93.60%, and no single impurity exceeds 4.11%. Meanwhile, the yield of EDB090 obtained in Example 3 is 70%.

[0075] Comparative Example 1

[0076] A method for preparing an edoxaban intermediate includes the following steps:

[0077] 26.4 kg of raw material EDB070, 6.6 kg of triethylamine and 51.0 kg of acetonitrile were mixed. The mixture was first heated to 40 °C to dissolve the raw material, and then heated to 65 °C for 3 hours to obtain product EDB080. Then 25.5 kg of pyridine and 13.2 kg of water were added, and the mixture was heated to 80 °C for 3 hours to obtain product EDB090 of the comparative example.

[0078] The difference between Comparative Example 1 and Example 1 is that Comparative Example 1 only includes the synthesis process and does not include the purification process.

[0079] Figure 5 The figure shows the high-performance liquid chromatogram of the EDB090 sample prepared in Comparative Example 1. The vertical axis, Absorbance, represents absorbance. Figure 5 Peak marked 5 corresponds to EDB090, with a relative area of ​​82.32%. Peaks marked 1-4 and 6 correspond to different impurities, and the relative area of ​​each individual impurity does not exceed 4.11%. Figure 5 It can be seen that the EDB090 prepared in Comparative Example 1 has a purity of 82.32%, and no single impurity exceeds 4.11%. Meanwhile, the yield of EDB090 prepared in Comparative Example 1 is 76%.

[0080] Comparative Example 2

[0081] A method for preparing an edoxaban intermediate includes the following steps:

[0082] (1) Synthesis process: 26.4 kg of raw material EDB070, 6.6 kg of triethylamine and 51.0 kg of acetonitrile were mixed. The mixture was first heated to 40 °C to dissolve the raw material, and then heated to 65 °C for 3 hours to obtain product EDB080. Then 25.5 kg of pyridine and 13.2 kg of water were added, and the mixture was heated to 80 °C for 3 hours to obtain product EDB090.

[0083] (2) Purification process: At 30°C, 69.0 kg of 22 wt% NaCl solution was first added to the EDB090 obtained in step (1) to break the emulsion; then the temperature was raised to 40°C and 30 kg of 48 wt% NaOH solution was added; then 38.5 kg of ethyl acrylate was added for a first extraction, stirred for 15 minutes, allowed to stand for 15 minutes, and separated; 38.5 kg of ethyl acrylate and 68.7 kg of 20 wt% NaOH solution were added for a second extraction, and separated; the above-mentioned phases were combined and concentrated at 50°C, evaporated to dryness, and then 26.4 kg of toluene was added to dissolve the solids; finally, 52.8 kg of methanol was added dropwise at 50°C, the temperature was lowered to -5°C, and stirred for crystallization for 5 hours; the mixture was filtered, and the filter cake was washed with 26.4 kg of methanol; finally, the mixture was vacuum dried at 55°C for 24 hours to obtain the EDB090 sample of this embodiment.

[0084] The difference between Comparative Example 2 and Example 1 is that Comparative Example 2 uses a different crystallization system, toluene / methanol, instead of the toluene / n-heptane system in Example 1.

[0085] Figure 6 The figure shows the high-performance liquid chromatogram of the EDB090 sample prepared in Comparative Example 2. The vertical axis, Absorbance, represents absorbance. Figure 6Peak 14 corresponds to EDB090, with a relative area of ​​86.23%. Peaks marked 1-13 and 15-20 correspond to different impurities, and the relative area of ​​each individual impurity does not exceed 4.49%. Figure 6 It can be seen that the EDB090 prepared in Comparative Example 2 has a purity of 86.23%, and no single impurity exceeds 4.49%. Meanwhile, the yield of EDB090 prepared in Comparative Example 2 is 65%.

[0086] Comparative Example 3

[0087] A method for preparing an edoxaban intermediate includes the following steps:

[0088] (1) Synthesis process: 26.4 kg of raw material EDB070, 6.6 kg of triethylamine and 51.0 kg of acetonitrile were mixed. The mixture was first heated to 40 °C to dissolve the raw material, and then heated to 65 °C for 3 hours to obtain product EDB080. Then 25.5 kg of pyridine and 13.2 kg of water were added, and the mixture was heated to 80 °C for 3 hours to obtain product EDB090.

[0089] (2) Purification process: At 30°C, 69.0 kg of 22 wt% NaCl solution was first added to the EDB090 obtained in step (1) to break the emulsion; then the temperature was raised to 40°C and 30 kg of 48 wt% NaOH solution was added; then 38.5 kg of ethyl acrylate was added for a first extraction, stirred for 15 minutes, allowed to stand for 15 minutes, and separated; 38.5 kg of ethyl acrylate and 68.7 kg of 20 wt% NaOH solution were added for a second extraction, and separated; the above-mentioned phases were combined and concentrated at 50°C, evaporated to dryness, and then 26.4 kg of acetone was added to dissolve the solids; finally, 52.8 kg of n-heptane was added dropwise at 50°C, the temperature was lowered to -5°C, and stirred to crystallize for 5 hours; the mixture was filtered, and the filter cake was washed with 26.4 kg of n-heptane; finally, the mixture was vacuum dried at 55°C for 24 hours to obtain the EDB090 sample of this embodiment.

[0090] The difference between Comparative Example 3 and Example 1 is that Comparative Example 3 uses an acetone / n-heptane crystallization system instead of the toluene / n-heptane system in Example 1.

[0091] Figure 7 The figure shows the high-performance liquid chromatogram of the EDB090 sample prepared in Comparative Example 3. The vertical axis, Absorbance, represents absorbance. Figure 7 Peak marked 7 corresponds to EDB090, with a relative area of ​​85.27%. Peaks marked 1-6 and 8-12 correspond to different impurities, and the relative area of ​​each individual impurity does not exceed 5.64%. Figure 7It can be seen that the purity of EDB090 obtained in Comparative Example 3 is 85.27%, and the content of any single impurity does not exceed 5.64%. At the same time, the yield of EDB090 obtained in Comparative Example 3 is 69%.

[0092] For those skilled in the art, several simple deductions or substitutions can be made without departing from the inventive concept, without requiring creative effort. Therefore, any simple improvements made to this invention by those skilled in the art based on the disclosure of this invention should be within the scope of protection of this invention. The above embodiments are preferred embodiments of this invention, and all processes similar to this invention and equivalent changes should fall within the scope of protection of this invention.

Claims

1. A method for preparing an edoxaban intermediate, characterized in that, Includes the following steps: (1) Synthesis process: The raw material EDB070, triethylamine and solvent are mixed, and the mixture is heated to dissolve the solvent for the first time, and then heated to react for the second time to obtain product EDB080; then pyridine and water are added, and the mixture is heated to react for the third time to obtain product EDB090; the chemical structural formulas of EDB070, EDB080 and EDB090 are as follows: ； (2) Purification process: NaCl solution is first added to the EDB090 obtained in step (1) to break the emulsion, and then NaOH solution is added; then extraction and concentration are carried out, and after evaporation, toluene is added to dissolve it; finally, n-heptane is added dropwise to crystallize, and after filtration, purified EDB090 is obtained. The mass ratio of EDB070, toluene, and n-heptane is 1:(0.9-1.2):(1.9-2.2). The concentration of the NaOH solution is 40-50 wt%; the mass ratio of the NaOH solution to EDB070 is (1.0-1.4):1; In 25 Add the NaCl solution at 35°C to break the emulsion.

2. The method for preparing the edoxaban intermediate according to claim 1, characterized in that, In step (1), the solvent is acetonitrile or a mixed solution of acetonitrile and water.

3. The method for preparing the edoxaban intermediate according to claim 1, characterized in that, In step (1), the molar ratio of EDB070, triethylamine and pyridine is 1:(1.0-1.2):(5.0-5.5).

4. The method for preparing the edoxaban intermediate according to claim 1 or 3, characterized in that, In step (1), the mass ratio of EDB070, solvent and water is 1:(1.8-2.2):(0.3-0.6).

5. The method for preparing the edoxaban intermediate according to claim 1, characterized in that, In step (1), the temperature is raised to 40-60℃ for the first time; to 65-70℃ for the second time; and to 75-85℃ for the third time.

6. The method for preparing the edoxaban intermediate according to claim 1, characterized in that, The concentration of the NaCl solution is 20-25 wt%; the mass ratio of the NaCl solution to EDB070 is (2.0-3.0):

1.

7. The method for preparing the edoxaban intermediate according to claim 1, characterized in that, In step (2), the crystallization temperature is -5~0℃.

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