A process for the preparation of a remdesivir intermediate or its hydrochloride salt

Abstract

The application provides a preparation method of remdesivir intermediate or hydrochloride thereof, and comprises the following reaction route and reaction steps: intermediate D is dissolved in dichloromethane, a certain equivalent of a protic solvent or an acid reagent is added, the temperature is reduced to 10-90 DEG C, a dichloromethane solution of BCl3 is added, the reaction is carried out for several hours under the condition of keeping the reaction temperature at 10-90 DEG C, after the reaction is completed, a quenching organic solvent is added, a solid is precipitated, the solid is filtered and dried, and the hydrochloride of intermediate E or the intermediate compound E is obtained by further being separated from the solid. The application also provides a preparation method of remdesivir intermediate or hydrochloride thereof, and comprises the following steps: the hydrochloride of intermediate compound E is beaten in a protic solvent, and the pure product of the hydrochloride of intermediate E is obtained by separation. The application effectively reduces the related impurities in the key intermediate of remdesivir by controlling the reaction conditions and post-treatment purification, and the key intermediate of remdesivir with a purity greater than 99.0% is prepared. The preparation method is simple in operation, can well control the impurity content in the product, and is suitable for industrial scale production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of drug synthesis, and relates to a method for preparing a high-purity remdesivir key intermediate. BACKGROUND

[0002] Remdesivir (GS-5734) is a small molecule monophosphoramidate prodrug of an adenine nucleotide analogue (NUC inhibitor) developed by Gilead Sciences, which is initially used for treating Ebola virus infection and is currently undergoing clinical trials for the new coronavirus 2019-nCov. According to patents WO 2012012776 and WO 2016069826, an important intermediate compound E is used, and the synthesis route of the compound E is as follows:

[0003]

[0004] WO 2016069826 also reports that compound E is protected by a hydroxyl group to obtain compound F, compound F is reacted with compound G to obtain compound H, and compound H is deprotected to obtain remdesivir (GS-5734), and the synthesis route is as follows:

[0005]

[0006] According to the process route reported in the literature, we have systematically studied the impurities generated in each step and the subsequent trend, and found that the maximum impurity in the intermediate E will derive the corresponding impurity in the remdesivir (GS-5734) API, which is difficult to remove, and if it remains in the API, it will have a great impact on the quality of the final yield. Therefore, the corresponding impurities in the intermediate E need to be strictly controlled to obtain high-purity intermediate E, so as to obtain remdesivir drug substances meeting the ICH standard. SUMMARY

[0007] The application provides a preparation method of a remdesivir key intermediate, which specifically prepares a high-purity key intermediate E by controlling the reaction conditions of the de-benzyl reaction or the purification conditions of the post-treatment, thereby providing a guarantee for obtaining high-quality remdesivir drugs.

[0008] In a first aspect, the application provides that the reaction conditions are controlled to control the unknown impurity generated by the reaction, and the purity of the intermediate E is greater than 99.0%.

[0009] The application provides a preparation method of a remdesivir key intermediate E or a hydrochloride thereof, which comprises the following reaction route and reaction steps:

[0010]

[0011] The intermediate D is dissolved in an organic solvent I (eg dichloromethane), a certain equivalent amount of a protic solvent is added, the temperature is lowered to 10-90℃, a solution of BCl3 (eg BCl3 in dichloromethane) is added, the reaction temperature is maintained at 10-90℃ for several hours, after the reaction is completed, an organic solvent II is added for quenching, and the intermediate E hydrochloride is separated, or the intermediate compound E is further isolated.

[0012] The present application can well control the generation of unknown impurities by adding a certain equivalent amount of a protic solvent or an acid reagent in the reaction system and the above-mentioned steps. The protic solvent provided by the present application is one of methanol, ethanol, isopropanol and water or a mixture of two thereof; and the acid reagent is one of formic acid, acetic acid and other organic acids, nitric acid, phosphoric acid, sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen iodide and other inorganic acids or a mixture of two thereof.

[0013] The certain equivalent amount of the protic solvent in the present application is 0.1-10 times the molar equivalent of the protic solvent of the intermediate D, preferably 0.5-4 times, and further preferably 0.5-2 times.

[0014] The temperature for lowering under nitrogen protection and the reaction temperature in the present application are selected from 10-90℃, preferably -40-65℃, and further preferably -58-62℃.

[0015] The quenching organic solvent II in the present application is methanol, ethanol, isopropanol, and preferably methanol.

[0016] The reaction time in the present application is 2-8 hours, preferably 3-4 hours.

[0017] After the quenching organic solvent is added, the temperature is immediately raised to 0-40℃, preferably 10-30℃, and the mixture is stirred for 1-8 hours (preferably 4-6 hours) under heat preservation.

[0018] The separation in the present application can be achieved by precipitation separation (or re-filtration, suction filtration), extraction separation (or re-selective distillation) and the like, and the obtained separation product can be optionally further dried.

[0019] In the second aspect, the present application provides a method for post-treatment purification to reduce the content of the unknown impurities in the intermediate E, so as to obtain the intermediate E with a purity of >99.0%.

[0020] The present application provides a preparation method (or more specifically a post-treatment purification method) of a key intermediate of remdesivir or a hydrochloride salt thereof, which comprises the following steps:

[0021] The intermediate E hydrochloride is beaten in a protic solvent, and the intermediate E hydrochloride is separated or the intermediate E is further isolated.

[0022] The application provides a preparation method of a remdesivir key intermediate or a hydrochloride thereof.

[0023] The intermediate E hydrochloride is added with a protic solvent, stirring is maintained at 0-30 DEG C for 1-6 hours, filtration is performed, the filter cake is dried to obtain the intermediate E hydrochloride or the intermediate E.

[0024] The protic solvent is one or a mixture of two of methanol, ethanol, isopropanol, tert-amyl alcohol and water.

[0025] The volume of the added protic solvent is 1-10 times (mL / g), preferably 1-8 times (mL / g) of the amount of the crude product E hydrochloride.

[0026] The temperature is maintained at 0-30 DEG C, preferably 1-10 DEG C.

[0027] The stirring is maintained for 1-6 hours, further preferably 2-3 hours.

[0028] In a third aspect, the application provides a preparation method of the remdesivir key intermediate E or the hydrochloride thereof and a post-treatment purification method, which simultaneously controls the generation of a single unknown impurity in the intermediate E under reaction conditions, and further controls the impurity through slurry purification in subsequent purification, to obtain the intermediate E with a purity of >99.5%, especially 99.8% or higher.

[0029] The application has the beneficial technical effects that:

[0030] The preparation method can not only well control the generation of a single unknown impurity in the intermediate E from the reaction conditions, but also further control the impurity through slurry purification in subsequent purification, significantly improving the quality of the intermediate E, and finally the purity of the intermediate E is higher than 99.0%, and the single unknown impurity can be controlled to be less than 0.12%. After subsequent reactions, the remdesivir product does not contain a series of unknown impurities derived from the impurity, and the prepared remdesivir meets the ICH quality standard.

[0031] The preparation method is simple to operate, reduces the risk of related impurities in the intermediate compound E to API, well controls the key impurities of the important intermediate compound E to the final remdesivir API, has high product yield and good purity, and is convenient to store. The unknown impurity content in the intermediate compound E is high, not only a large amount of solvent is wasted for purification or column elution, but also research finds that the unknown impurity content of 0.3-0.5% or higher will bring derived impurities into the finished product, which is difficult to remove by the conventional methods such as crystallization or purification. Detailed Implementation

[0032] The present invention will be further illustrated by way of embodiments below, but the present invention is not limited to the scope of the embodiments described herein.

[0033] Comparative Example 1:

[0034] At room temperature, 5.0 g of intermediate D was weighed and dissolved in 50 mL of dichloromethane. Under nitrogen protection, the mixture was stirred and cooled to -60 °C. 44.5 mL of a dichloromethane solution of BCl3 (1 N, 5.0 eq) was slowly added dropwise while maintaining the temperature at -40 to -65 °C. After the addition was complete, the mixture was stirred and kept at this temperature for 3 h. Then, 25 mL of methanol was slowly added dropwise to quench the reaction while maintaining the temperature at -40 to -65 °C. After the addition was complete, the temperature was raised to 0 °C and stirred and kept at this temperature for 4 h. The mixture was then filtered, and the filter cake was dried under reduced pressure to obtain 2.3 g of a yellow solid with a yield of 80.2%. HPLC analysis showed that the purity of intermediate E was 96.54% (retention time RT = 6.9 min) and the purity of the unknown impurity was 0.57% (retention time RT = 15.1 min).

[0035] Example 1:

[0036] At room temperature, 5.0 g of intermediate D was weighed and dissolved in 50 mL of dichloromethane. 569 mg of methanol (2.0 eq) was added, and the mixture was stirred and cooled to -60 °C under nitrogen protection. 44.5 mL of a dichloromethane solution of BCl3 (1N, 5.0 eq) was slowly added dropwise while maintaining the temperature at -40 to -65 °C. After the addition was complete, the mixture was stirred and kept at this temperature for 3-4 h. 25 mL of methanol was slowly added dropwise to quench the reaction while maintaining the temperature at -40 to -65 °C. After the addition was complete, the temperature was raised to 0 °C, stirred and kept at this temperature for 4 h, and then filtered. The filter cake was dried under reduced pressure to obtain 2.2 g of yellow solid, with a yield of 75.9%. HPLC analysis showed that the purity of intermediate E was 99.05% (retention time RT = 6.9 min), and the purity of the unknown impurity was 0.10% (retention time RT = 15.1 min).

[0037] Example 2:

[0038] At room temperature, 5.0 g of intermediate 5.0 g D was dissolved in 50 mL of dichloromethane, 818 mg of ethanol (2.0 eq) was added, and the mixture was stirred under nitrogen protection and cooled to -60 °C. Then 44.5 mL of BC13 solution in dichloromethane (1 N, 5.0 eq) was slowly added dropwise while maintaining the temperature at -40 to -65 °C. After the addition was completed, the mixture was stirred for 3-4 h. Then 25 mL of methanol was slowly added dropwise while maintaining the temperature at -40 to -65 °C. After the addition was completed, the temperature was increased to 0 °C. After stirring for 4 h, the mixture was filtered. The filter cake was dried under reduced pressure to obtain 2.3 g of yellow solid, with a yield of 79.7%. HPLC detection showed that the purity of intermediate E was 99.22% (the retention time of intermediate E was RT = 6.9 min), and the purity of the unknown impurity was 0.11% (the retention time of the unknown impurity was RT = 15.1 min).

[0039] Example 3:

[0040] At room temperature, 5.0 g of intermediate 5.0 g D was dissolved in 50 mL of dichloromethane, 534 mg of isopropanol (1.0 eq) and 160 mg of water (1.0 eq) were added, and the mixture was stirred under nitrogen protection and cooled to -60 °C. Then 44.5 mL of BC13 solution in dichloromethane (1 N, 5.0 eq) was slowly added dropwise while maintaining the temperature at -40 to -65 °C. After the addition was completed, the mixture was stirred for 3-4 h. Then 25 mL of methanol was slowly added dropwise while maintaining the temperature at -40 to -65 °C. After the addition was completed, the temperature was increased to 0 °C. After stirring for 4 h, the mixture was filtered. The filter cake was dried under reduced pressure to obtain 2.4 g of yellow solid, with a yield of 82.8%. HPLC detection showed that the purity of intermediate E was 99.10% (the retention time of intermediate E was RT = 6.9 min), and the purity of the unknown impurity was 0.08% (the retention time of the unknown impurity was RT = 15.1 min).

[0041] Example 4:

[0042] At room temperature, 5.0 g of intermediate 5.0 g D was dissolved in 50 mL of dichloromethane, 284.5 mg of methanol (1.0 eq) and 80-640 mg of water (0.5-4 eq) were added, and the mixture was stirred under nitrogen protection and cooled to -60 °C. Then 44.5 mL of BC13 solution in dichloromethane (1 N, 5.0 eq) was slowly added dropwise while maintaining the temperature at -40 to -65 °C. After the addition was completed, the mixture was stirred for 3-4 h. Then 25 mL of methanol was slowly added dropwise while maintaining the temperature at -40 to -65 °C. After the addition was completed, the temperature was increased to 0 °C. After stirring for 4 h, the mixture was filtered. The filter cake was dried under reduced pressure to obtain 2.4 g of yellow solid, with a yield of 82.8%. HPLC detection showed that the purity of intermediate E was 99.35% (the retention time of intermediate E was RT = 6.9 min), and the purity of the unknown impurity was 0.07% (the retention time of the unknown impurity was RT = 15.1 min).

[0043] Example 5:

[0044] At room temperature, 5.0 g of intermediate 5.0 g D was dissolved in 50 mL of dichloromethane, 1228 mg of formic acid (3.0 eq) was added, and the mixture was stirred under nitrogen protection and cooled to -60 °C. Then 44.5 mL of BCl3 solution in dichloromethane (1 N, 5.0 eq) was slowly added dropwise while maintaining the temperature at -40 to -65 °C. After the addition was completed, the mixture was stirred for 3-4 h. Then 25 mL of methanol was slowly added dropwise while maintaining the temperature at -40 to -65 °C. After the addition was completed, the temperature was increased to 0 °C. After stirring for 4 h, the mixture was filtered, and the filter cake was dried under reduced pressure to obtain 2.5 g of yellow solid, with a yield of 85.9%. HPLC detection showed that the purity of intermediate E was 99.45% (the retention time of intermediate E was RT = 6.9 min), and the purity of the unknown impurity was 0.03% (the retention time of the unknown impurity was RT = 15.1 min).

[0045] Example 6:

[0046] At room temperature, 5.0 g of intermediate 5.0 g D was dissolved in 50 mL of dichloromethane, 1228 mg of formic acid (3.0 eq) was added, and the mixture was stirred under nitrogen protection and cooled to -60 °C. Then 44.5 mL of BCl3 solution in dichloromethane (1 N, 5.0 eq) was slowly added dropwise while maintaining the temperature at -40 to -65 °C. After the addition was completed, the mixture was stirred for 3-4 h. Then 25 mL of methanol was slowly added dropwise while maintaining the temperature at -40 to -65 °C. After the addition was completed, the temperature was increased to 0 °C. After stirring for 4 h, the mixture was filtered, and the filter cake was dried under reduced pressure to obtain 2.5 g of yellow solid, with a yield of 85.9%. HPLC detection showed that the purity of intermediate E was 99.45% (the retention time of intermediate E was RT = 6.9 min), and the purity of the unknown impurity was 0.03% (the retention time of the unknown impurity was RT = 15.1 min).

[0047] Example 7:

[0048] At room temperature, 5.0 g of intermediate 5.0 g D was dissolved in 50 mL of dichloromethane, 1228 mg of formic acid (3.0 eq) was added, and the mixture was stirred under nitrogen protection and cooled to -60 °C. Then 44.5 mL of BCl3 solution in dichloromethane (1 N, 5.0 eq) was slowly added dropwise while maintaining the temperature at -40 to -65 °C. After the addition was completed, the mixture was stirred for 3-4 h. Then 25 mL of methanol was slowly added dropwise while maintaining the temperature at -40 to -65 °C. After the addition was completed, the temperature was increased to 0 °C. After stirring for 4 h, the mixture was filtered, and the filter cake was dried under reduced pressure to obtain 2.5 g of yellow solid, with a yield of 85.9%. HPLC detection showed that the purity of intermediate E was 99.45% (the retention time of intermediate E was RT = 6.9 min), and the purity of the unknown impurity was 0.03% (the retention time of the unknown impurity was RT = 15.1 min).

[0049] Example 8:

[0050] At room temperature, 5.0 g of intermediate 5.0 g D was dissolved in 50 mL of dichloromethane, 2616 mg of sulfuric acid (3.0 eq) was added, and the system was stirred under nitrogen protection and cooled to -60°C. 44.5 mL of BCl3 solution in dichloromethane (1 N, 5.0 eq) was slowly added dropwise while maintaining the temperature at -40 to -65°C. After the addition was completed, the system was stirred for 3-4 h. 25 mL of methanol was slowly added dropwise to quench the reaction while maintaining the temperature at -40 to -65°C. After the addition was completed, the temperature was raised to 0°C. After stirring for 4 h, the system was filtered. The filter cake was dried under reduced pressure to obtain 1.9 g of yellow solid, with a yield of 65.5%. HPLC detection showed that the purity of intermediate E was 98.01% (the retention time of intermediate E was RT = 6.9 min), and the purity of the unknown impurity was 0.06% (the retention time of the unknown impurity was RT = 15.1 min).

[0051] Example 9:

[0052] At room temperature, 5.0 g of intermediate 5.0 g D was dissolved in 50 mL of dichloromethane, 2616 mg of sulfuric acid (3.0 eq) was added, and the system was stirred under nitrogen protection and cooled to -60°C. 44.5 mL of BCl3 solution in dichloromethane (1 N, 5.0 eq) was slowly added dropwise while maintaining the temperature at -40 to -65°C. After the addition was completed, the system was stirred for 3-4 h. 25 mL of methanol was slowly added dropwise to quench the reaction while maintaining the temperature at -40 to -65°C. After the addition was completed, the temperature was raised to 0°C. After stirring for 4 h, the system was filtered. The filter cake was dried under reduced pressure to obtain 1.9 g of yellow solid, with a yield of 65.5%. HPLC detection showed that the purity of intermediate E was 98.01% (the retention time of intermediate E was RT = 6.9 min), and the purity of the unknown impurity was 0.06% (the retention time of the unknown impurity was RT = 15.1 min).

[0053] Example 10:

[0054] At room temperature, 5.0 g of intermediate 5.0 g D was dissolved in 50 mL of dichloromethane, 2616 mg of sulfuric acid (3.0 eq) was added, and the system was stirred under nitrogen protection and cooled to -60°C. 44.5 mL of BCl3 solution in dichloromethane (1 N, 5.0 eq) was slowly added dropwise while maintaining the temperature at -40 to -65°C. After the addition was completed, the system was stirred for 3-4 h. 25 mL of methanol was slowly added dropwise to quench the reaction while maintaining the temperature at -40 to -65°C. After the addition was completed, the temperature was raised to 0°C. After stirring for 4 h, the system was filtered. The filter cake was dried under reduced pressure to obtain 1.9 g of yellow solid, with a yield of 65.5%. HPLC detection showed that the purity of intermediate E was 98.01% (the retention time of intermediate E was RT = 6.9 min), and the purity of the unknown impurity was 0.06% (the retention time of the unknown impurity was RT = 15.1 min).

[0055] Example 11:

[0056] At room temperature, 5.0 g of intermediate 5.0 g D was weighed and dissolved in 50 mL of dichloromethane, dry hydrogen bromide gas was bubbled into the system, the system increased by 2.2 g (3.1 eq of hydrogen bromide), and the system was stirred under nitrogen protection and cooled to -60 °C. 44.5 mL of BCl3 dichloromethane solution (1 N, 5.0 eq) was slowly added dropwise, the temperature was maintained at -40 to -65 °C, and after the addition was completed, the system was stirred for 3-4 h. 25 mL of methanol was slowly added dropwise to quench, the temperature was maintained at -40 to -65 °C, and after the addition was completed, the temperature was increased to 0 °C. After stirring for 4 h, the system was filtered, the filter cake was dried under reduced pressure, and 2.2 g of yellow solid was obtained, with a yield of 75.92 %, HPLC detection of intermediate E purity 99.16 % (intermediate E retention time RT = 6.9 min), and the unknown impurity purity 0.08 % (unknown impurity retention time RT = 15.1 min).

[0057] Example 12:

[0058] At room temperature, 5.0 g of intermediate 5.0 g D was weighed and dissolved in 50 mL of dichloromethane, dry hydrogen bromide gas was bubbled into the system, the system increased by 2.2 g (3.1 eq of hydrogen bromide), and the system was stirred under nitrogen protection and cooled to -60 °C. 44.5 mL of BCl3 dichloromethane solution (1 N, 5.0 eq) was slowly added dropwise, the temperature was maintained at -40 to -65 °C, and after the addition was completed, the system was stirred for 3-4 h. 25 mL of methanol was slowly added dropwise to quench, the temperature was maintained at -40 to -65 °C, and after the addition was completed, the temperature was increased to 0 °C. After stirring for 4 h, the system was filtered, the filter cake was dried under reduced pressure, and 2.2 g of yellow solid was obtained, with a yield of 75.92 %, HPLC detection of intermediate E purity 99.16 % (intermediate E retention time RT = 6.9 min), and the unknown impurity purity 0.08 % (unknown impurity retention time RT = 15.1 min).

[0059] Beating and purifying example

[0060] The crude intermediate E hydrochloride salt had a purity of 96.54 % and an unknown impurity purity of 0.57 % before beating and purifying solid E.

[0061] Example 13:

[0062] At room temperature, 5.0 g of crude intermediate E hydrochloride salt was weighed and added to 15 mL of methanol. The system was stirred and cooled to 0 °C, and after stirring for 1 h, the system was filtered. The filter cake was dried, and 4.46 g of yellow solid was obtained, with a yield of 89.1 %, HPLC detection of E purity 99.05 % (intermediate E retention time RT = 6.9 min), and the unknown impurity purity 0.12 % (unknown impurity retention time RT = 15.1 min).

[0063] Example 14:

[0064] At room temperature, 5.0 g of the crude intermediate E hydrochloride was weighed, 15 mL of ethanol was added, and the mixture was stirred and cooled to 5°C. After 2 h of stirring at 5°C, the mixture was filtered, and the filter cake was dried to obtain 4.23 g of a yellow solid, with a yield of 84.6%. HPLC detection showed that the purity of E was 99.43% (the retention time of intermediate E was RT = 6.9 min), and the purity of the unknown impurity was 0.06% (the retention time of the unknown impurity was RT = 15.1 min).

[0065] Example 15:

[0066] At room temperature, 5.0 g of the crude intermediate E hydrochloride was weighed, 15 mL of isopropyl alcohol was added, and the mixture was stirred and cooled to 5°C. After 2 h of stirring at 5°C, the mixture was filtered, and the filter cake was dried to obtain 4.30 g of a yellow solid, with a yield of 86.0%. HPLC detection showed that the purity of E was 99.22% (the retention time of intermediate E was RT = 6.9 min), and the purity of the unknown impurity was 0.05% (the retention time of the unknown impurity was RT = 15.1 min).

[0067] Example 16:

[0068] At room temperature, 5.0 g of the crude intermediate E hydrochloride was weighed, 15 mL of isopropyl alcohol was added, and the mixture was stirred and cooled to 5°C. After 2 h of stirring at 5°C, the mixture was filtered, and the filter cake was dried to obtain 4.30 g of a yellow solid, with a yield of 86.0%. HPLC detection showed that the purity of E was 99.22% (the retention time of intermediate E was RT = 6.9 min), and the purity of the unknown impurity was 0.05% (the retention time of the unknown impurity was RT = 15.1 min).

[0069] Example 17:

[0070] At room temperature, 5.0 g of the crude intermediate E hydrochloride was weighed, 15 mL of isopropyl alcohol was added, and the mixture was stirred and cooled to 5°C. After 2 h of stirring at 5°C, the mixture was filtered, and the filter cake was dried to obtain 4.30 g of a yellow solid, with a yield of 86.0%. HPLC detection showed that the purity of E was 99.22% (the retention time of intermediate E was RT = 6.9 min), and the purity of the unknown impurity was 0.05% (the retention time of the unknown impurity was RT = 15.1 min).

[0071] Example 18:

[0072] At room temperature, 5.0 g of the crude intermediate E hydrochloride was weighed, 15 mL of isopropyl alcohol was added, and the mixture was stirred and cooled to 5°C. After 2 h of stirring at 5°C, the mixture was filtered, and the filter cake was dried to obtain 4.30 g of a yellow solid, with a yield of 86.0%. HPLC detection showed that the purity of E was 99.22% (the retention time of intermediate E was RT = 6.9 min), and the purity of the unknown impurity was 0.05% (the retention time of the unknown impurity was RT = 15.1 min).

[0073] Example 19:

[0074] At room temperature, 2.0 g of the hydrochloride salt of intermediate E obtained in example 1 was weighed into 5 mL of methanol and 5 mL of water. The mixture was stirred and cooled to 10 °C and stirred at this temperature for 6 h. The mixture was filtered and the filter cake was dried to give 1.75 g of a yellow solid in 87.7% yield. HPLC analysis showed that the purity of E was 99.89% (retention time of intermediate E, RT = 6.9 min) and the purity of the unknown impurity was 0.02% (retention time of the unknown impurity, RT = 15.1 min).

Claims

1. A method for preparing a remdesivir intermediate or its hydrochloride salt, comprising the following reaction route and reaction steps: Intermediate D is dissolved in an organic solvent I, an equivalent of a protic solvent or an acid reagent, or a mixture of both, is added, a debenzylating reagent is added, and after a number of hours at a certain temperature, the hydrochloride salt of intermediate E is isolated or further freed to give the intermediate compound E; The protic solvent is an alcohol solvent or a mixture of an alcohol solvent and water, the alcohol solvent is methanol, ethanol, isopropanol; the acid reagent is one or a mixture of two of inorganic acid and organic acid, the organic acid is formic acid, acetic acid, and the inorganic acid is nitric acid, phosphoric acid, sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen iodide; The organic solvent I is selected from dichloromethane; the debenzylating reagent is selected from a dichloromethane solution of BCl3; the certain amount of protic solvent or acid reagent is 0.1-10 times the molar amount of the protic solvent of the intermediate D.

2. The method of claim 1, wherein: The separation method is: after the reaction is completed, an organic solvent II is added to quench, and the hydrochloride salt of the intermediate E or the intermediate compound E is further separated.

3. The method of claim 1, wherein: The certain amount of protic solvent or acid reagent is 0.5-4 times the molar amount of the protic solvent of the intermediate D.

4. The method of claim 1, wherein: The certain amount of protic solvent or acid reagent is 0.5-2 times the molar amount of the protic solvent of the intermediate D.

5. The method of claim 1, wherein: The reaction temperature is selected from 10-90℃; the reaction time is 1-8 hours.

6. The method of claim 1, wherein: The reaction temperature is selected from -40-65℃; the reaction time is 3-4 hours.

7. The method of claim 1, wherein: The reaction temperature is selected from -58-62℃.

8. The method of claim 2, wherein: The organic solvent II is methanol, ethanol, isopropanol, after the organic solvent II is added to quench, the temperature is immediately increased to 0-40℃, and the solid is precipitated after stirring for 1-8 hours, and then the solid is filtered or optionally dried.

9. The method of claim 2, wherein: The organic solvent II is methanol, after the organic solvent II is added to quench, the temperature is immediately increased to 10-30℃, and the solid is precipitated after stirring for 4-6 hours, and then the solid is filtered or optionally dried.

10. The method of claim 1, wherein: The preparation method further comprises the following steps: The intermediate E hydrochloride salt is slurried in a protic solvent to separate the pure intermediate E hydrochloride salt or further separate the pure intermediate E.

11. The method of claim 10, wherein: The slurry comprises the following steps: The intermediate E hydrochloride salt is added to a protic solvent, stirred at a temperature of 0-30℃ for 1-6 hours, filtered, and the pure intermediate E hydrochloride salt or the pure intermediate E is further separated.

12. The method of manufacturing according to claim 10 or 11, characterized in that: The protic solvent is one or a mixture of two of methanol, ethanol, isopropanol, tert-amyl alcohol and water.

13. The method of manufacturing according to claim 10 or 11, wherein: The volume of the added protic solvent is 1-10 times the amount of the intermediate E hydrochloride salt in mL / g.

14. The method of claim 10 or 11, wherein: The volume of the added protic solvent is 1-8 times the amount of the intermediate E hydrochloride salt in mL / g.

15. The method of claim 11, wherein: The temperature is 1-10℃; the stirring time is 2-3 hours.

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