Preparation method of an irinotecan derivative and intermediate thereof

Abstract

The present invention discloses a preparation method of an irinotecan derivative and an intermediate thereof. The method includes a preparation method of a compound of formula (I), which comprises the following steps: in a solvent, subjecting the compound of formula (II) to the following deprotection reaction under the action of a deprotecting reagent to obtain the compound of formula I; wherein, PG is a silyl-based protecting group or a benzyl-based protecting group. Using the synthetic route and intermediate of the present invention, the target product with high purity can be prepared in high yield, and the target product involved will not racemize and the purification process is easy to operate, thus being suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of drug synthesis, and particularly relates to a preparation method of an irinotecan derivative and an intermediate thereof. Background Art

[0002] Antibody-drug conjugates (ADCs) have been one of the hotspots in the pharmaceutical industry in recent years. Since the clinical efficacy of many antibody drugs is not satisfactory, many industry giants have increasingly turned their attention to ADC drugs. The basic modules of ADC drugs include antibodies, linkers, and effector molecules. Antibodies are used to transport effector molecules to tumor sites for enrichment, thereby killing tumor cells. Traditional effector molecules are mostly highly active tubulin inhibitors, usually with large toxic and side effects, which limit the application of ADCs. Recently, Immunomedics invented a new ADC drug IMMU-132 (ZL200980156218) using a camptothecin compound as an effector molecule, showing good anti-tumor effects. Daiichi Sankyo invented another ADC drug DS-8201a (ZL201380053256.2) using a camptothecin compound as an effector molecule, also showing good anti-tumor effects.

[0003] DS-8201a is composed of a "humanized HER2 antibody" and a "novel topoisomerase I inhibitor irinotecan derivative Dxd" conjugated through a cleavable tetrapeptide GGFG linker. Compared with the marketed T-DM1, although both are HER2-targeted, DS-8201a has the characteristics of a high DAR value (close to 8:1) and high plasma stability, and its cytotoxic small molecule Dxd has strong membrane permeability and can produce a strong bystander effect. Currently, this drug has been launched overseas. Relying on its own design advantages, it is expected to achieve remarkable results in the treatment fields of HER2-mutated cancer types including breast cancer, gastric cancer, colorectal cancer, and lung cancer.

[0004] The excellent performance of DS-8201a has made the research and development of ADC drugs using Dxd (the structure is shown in Formula I) as a cytotoxic small molecule a hot topic of concern for many pharmaceutical companies. The preparation of Dxd has also become an important link in the research and development of such ADC drugs. The synthetic routes of Dxd that have been disclosed currently are Synthetic Route 1 (Example 75 of ZL201380053256.2 and Example 12 of WO2019236954A1) and Synthetic Route 2 (Example 76 of ZL201380053256.2) as shown below:

[0005] Synthetic Route 1:

[0006]

[0007] The synthesis method of Route 1 includes: reacting irinotecan mesylate with chloroacetate to obtain an acetate intermediate, and removing the acetyl group of the acetate intermediate under alkaline conditions to obtain the target product Dxd. There is racemization in the deacetylation of this method, resulting in impurities that are difficult to remove.

[0008] Synthesis Route 2:

[0009]

[0010] The synthesis method of Route 2 includes: condensing irinotecan mesylate with glycolic acid in the presence of a condensing reagent to obtain the target product Dxd. This method requires column chromatography purification for Dxd, and Dxd has poor solubility in the eluent, making it difficult to scale up and not suitable for industrial production.

[0011] Therefore, it is necessary to explore a synthesis route suitable for industrial production with high yield, no racemization of the product, and easy operation in the product purification process. Summary of the Invention

[0012] To overcome the defects existing in the above-mentioned prior art, the present invention provides a preparation method of a compound of Formula I and its intermediate. The product of the synthesis route provided by the present invention does not undergo racemization, has a high yield, and the product purification process is easy to operate, which can reduce production costs, improve product purity, and is more suitable for industrial production.

[0013]

[0014] The present invention provides a preparation method of a compound of Formula I, which includes the following steps: in a solvent, reacting a compound of Formula II under the action of a protecting group removing reagent to carry out the following protecting group removal reaction to obtain a compound of Formula I,

[0015]

[0016] wherein, PG is a silyl-based protecting group or a benzyl-based protecting group.

[0017] In the preparation method of the compound of Formula I, the conditions of the reaction can be the conventional conditions of this type of reaction in the art, and the present invention preferably adopts the following conditions.

[0018] In a preferred embodiment of the present invention, in the preparation method of the compound of Formula I, when PG is a silyl-based protecting group, the silyl-based protecting group can be a conventional silyl-based protecting group used for hydroxyl protection in the art, such as tert-butyldiphenylsilyl, tris(tert-butyl)silyl, tert-butyldimethylsilyl, or triisopropylsilyl, preferably tert-butyldiphenylsilyl or tert-butyldimethylsilyl, and further preferably tert-butyldiphenylsilyl

[0019] In a preferred embodiment of the present invention, in the preparation method of the compound of formula I, when PG is a benzyl-type protecting group, the benzyl-type protecting group can be a conventional benzyl-type protecting group used in the art for hydroxyl protection, such as benzyl or p-methoxybenzyl, preferably benzyl.

[0020] In a preferred embodiment of the present invention, in the preparation method of the compound of formula I, PG is preferably a silyl-type protecting group, more preferably tert-butyldiphenylsilyl or tert-butyldimethylsilyl, and most preferably tert-butyldiphenylsilyl.

[0021] In a preferred embodiment of the present invention, in the preparation method of the compound of formula I, the reagent for removing the protecting group can be tetraalkylammonium fluoride and acetic acid; wherein, the tetraalkylammonium fluoride can be tetrabutylammonium fluoride, tetraethylammonium fluoride or tetramethylammonium fluoride, preferably tetrabutylammonium fluoride; the molar ratio of the tetraalkylammonium fluoride to the compound of formula II can be 1-5, preferably 2-4, more preferably 2; the molar ratio of acetic acid to the compound of formula II can be 1-5, preferably 2-4, more preferably 2.

[0022] In a preferred embodiment of the present invention, in the preparation method of the compound of formula I, the solvent can be a mixed solvent of a chloroalkane solvent and an alcohol solvent. The chloroalkane solvent can be dichloromethane and / or dichloroethane, preferably dichloromethane; the alcohol solvent can be methanol and / or ethanol, preferably methanol; in the solvent, the volume ratio of the chloroalkane solvent to the alcohol solvent can be 50∶1-10∶1, preferably 20∶1-15∶1, more preferably 20∶1.

[0023] In a preferred embodiment of the present invention, in the preparation method of the compound of formula I, the temperature of the reaction for removing the protecting group can be a conventional temperature for such reactions in the art, such as 20-30 °C, preferably 20-25 °C, more preferably 25 °C.

[0024] In a preferred embodiment of the present invention, in the preparation method of the compound of formula I, the progress of the reaction for removing the protecting group can be monitored by conventional testing methods in the art (such as TLC, GC, HPLC or NMR, etc.), and generally the reaction end point is taken when the compound of formula II is no longer detected. The reaction time of the deprotection reaction can be 12-24 hours, preferably 16-20 hours, more preferably 16 hours.

[0025] In the preparation method of the compound of formula I according to the present invention, it may further include the preparation method of the compound of formula II, which includes the following steps: in a solvent, the compound of formula III and the compound of formula IV are subjected to the following condensation reaction in the presence of a condensing agent and a base to obtain the compound of formula II.

[0026]

[0027] Among them, the definition of PG is as described above.

[0028] In the preparation method of the compound of formula II, the conditions of the reaction can be the conventional conditions for this type of reaction in the art, and the present invention preferably adopts the following conditions.

[0029] In a preferred embodiment of the present invention, in the preparation method of the compound of formula II, in the condensation reaction, the compound of formula IV can be 2-((tert-butyldiphenylsilyl)oxy)acetic acid, 2-((tri-tert-butylsilyl)oxy)acetic acid, 2-((tert-butyldimethylsilyl)oxy)acetic acid or 2-((triisopropylsilyl)oxy)acetic acid, preferably 2-((tert-butyldiphenylsilyl)oxy)acetic acid or 2-((tert-butyldimethylsilyl)oxy)acetic acid, and more preferably 2-((tert-butyldiphenylsilyl)oxy)acetic acid.

[0030] In a preferred embodiment of the present invention, in the preparation method of the compound of formula II, in the condensation reaction, the molar ratio of the compound of formula IV to the compound of formula III in the feed can be 1.0 - 3.0, preferably 1.5 - 2.0, and more preferably 2.0.

[0031] In a preferred embodiment of the present invention, in the preparation method of the compound of formula II, in the condensation reaction, the condensing agent can be a conventional condensing agent in the art, such as 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride, N,N′-dicyclohexylcarbodiimide, the combination of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 1-hydroxybenzotriazole, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate, and 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate (the same hereinafter), preferably one or more of 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate, and 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate, and more preferably 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride.

[0032] In a preferred embodiment of the present invention, in the preparation method of the compound of formula II, in the condensation reaction, the molar ratio of the condensing agent to the compound of formula III in the feed can be 1.2 - 3.0, preferably 1.5 - 2.0, and more preferably 1.5.

[0033] In a preferred embodiment of the present invention, in the method for preparing the compound of formula II, in the condensation reaction, the base can be a conventional base in the art, such as one or more of N,N - diisopropylethylamine, triethylamine, and 4 - dimethylaminopyridine, preferably N,N - diisopropylethylamine and / or 4 - dimethylaminopyridine, and more preferably N,N - diisopropylethylamine.

[0034] In a preferred embodiment of the present invention, in the method for preparing the compound of formula II, in the condensation reaction, the molar ratio of the base to the compound of formula III in the feed can be 2.0 - 4.0, preferably 2.5 - 3.0, and more preferably 2.5.

[0035] In a preferred embodiment of the present invention, in the method for preparing the compound of formula II, in the condensation reaction, the feeding mode of the base can be a conventional feeding mode for such reactions in the art, such as adding all at once, adding in batches, or drop - wise addition, preferably drop - wise addition.

[0036] In a preferred embodiment of the present invention, in the method for preparing the compound of formula II, in the condensation reaction, the solvent can be a conventional solvent for such reactions in the art, such as one or more of dichloromethane, dimethyl sulfoxide, N,N - dimethylformamide, chloroform, and toluene, preferably dichloromethane and / or N,N - dimethylformamide, and more preferably dichloromethane.

[0037] In a preferred embodiment of the present invention, in the method for preparing the compound of formula II, in the condensation reaction, the reaction temperature can be a conventional temperature for such reactions in the art, for example, 20 - 30 °C, preferably 20 - 25 °C, and more preferably 25 °C.

[0038] In a preferred embodiment of the present invention, in the method for preparing the compound of formula II, the progress of the condensation reaction can be monitored by a conventional testing method in the art (such as TLC, GC, HPLC, or NMR, etc.), and generally, the reaction end point is when the compound of formula III is no longer detected. The reaction time of the condensation reaction can be 12 - 24 hours, preferably 16 - 20 hours, and more preferably 16 hours.

[0039] In a preferred embodiment of the present invention, the method for preparing the compound of formula II may include the following steps: adding the base to a mixed system of the compound of formula III, the compound of formula IV, the condensing agent, and the solvent, and carrying out the reaction.

[0040] In the preparation method of the compound of formula I according to the present invention, the preparation method of the compound of formula IV may further be included, which comprises the following steps: In a solvent, glycolic acid and the compound of formula VI are reacted in the presence of a base to obtain the compound of formula IV,

[0041]

[0042] wherein, PG is as described above; X is chlorine, bromine or iodine.

[0043] In the preparation method of the compound of formula IV, the reaction conditions may be the conventional conditions for this type of reaction in the art, and the following conditions are preferred in the present invention.

[0044] In a preferred embodiment of the present invention, in the preparation method of the compound of formula IV, X may be chlorine.

[0045] In a preferred embodiment of the present invention, in the preparation method of the compound of formula IV, the compound of formula VI may be tert-butyldiphenylchlorosilane, tris(tert-butyl)chlorosilane, tert-butyldimethylchlorosilane, benzyl bromide or p-methoxybenzyl bromide, preferably tert-butyldiphenylchlorosilane or tris(tert-butyl)chlorosilane, and more preferably tert-butyldiphenylchlorosilane.

[0046] In a preferred embodiment of the present invention, in the preparation method of the compound of formula IV, the molar ratio of the compound of formula VI to glycolic acid in the feed may be 2.0 - 4.0, preferably 2.2 - 2.5, and more preferably 2.2.

[0047] In a preferred embodiment of the present invention, in the preparation method of the compound of formula IV, the base used may be a conventional base in the art, such as one or more of diisopropylethylamine, triethylamine and 4-dimethylaminopyridine, preferably diisopropylethylamine and / or 4-dimethylaminopyridine, and more preferably diisopropylethylamine.

[0048] In a preferred embodiment of the present invention, in the preparation method of the compound of formula IV, the molar ratio of the base used to glycolic acid in the feed may be 2.0 - 6.0, preferably 3.0 - 4.0, and more preferably 3.5.

[0049] In a preferred embodiment of the present invention, in the preparation method of the compound of formula IV, the solvent used may be a conventional solvent for this type of reaction in the art, such as one or more of dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide and chloroform, preferably dichloromethane and / or N,N-dimethylformamide, and more preferably N,N-dimethylformamide.

[0050] In a preferred embodiment of the present invention, in the preparation method of the compound of formula IV, the temperature of the reaction between the compound of formula VI and glycolic acid can be the conventional temperature for such reactions in the art, for example, 10 - 30 °C, preferably 15 - 30 °C.

[0051] In a preferred embodiment of the present invention, in the preparation method of the compound of formula IV, the progress of the reaction between the compound of formula VI and glycolic acid can be monitored by conventional testing methods in the art (such as TLC, GC, HPLC or NMR, etc.), and generally, the reaction end point is when the compound of formula VI is no longer detected. The reaction time of the reaction can be 1 - 10 hours, preferably 2 - 5 hours, and more preferably 2 hours.

[0052] In a preferred embodiment of the present invention, the preparation method of the compound of formula IV may include the following steps: in a mixed system of glycolic acid and the solvent, the base and the compound of formula VI are added in sequence for reaction. Among them, the feeding temperature and feeding mode of the compound of formula VI are in accordance with the conventional operations for such reactions in the art. For example, the feeding temperature can be controlled at 0 - 15 °C, preferably 0 - 10 °C, more preferably 0 - 5 °C or 5 - 10 °C; the feeding mode can be batch feeding or dropping, and preferably dropping.

[0053] In a preferred embodiment of the present invention, in the preparation method of the compound of formula IV, after the reaction, it further includes the step of acidifying the reaction solution with an acid. The acid can be a conventional acid used in this type of operation in the art, such as hydrochloric acid and / or sulfuric acid, preferably hydrochloric acid; the concentration of the acid can be the conventional concentration of the acid in this type of operation in the art, such as 0.5 - 2 mol / L, preferably 1 - 2 mol / L, more preferably 1 mol / L; the amount of the acid used can adjust the pH value of the reaction solution to 3 - 5, preferably 3 - 4, more preferably 3.

[0054] In a preferred embodiment of the present invention, in the preparation method of the compound of formula IV, after the reaction, before acidifying the reaction solution with an acid, it further includes the step of diluting the reaction solution with a solvent. The solvent is a mixed solvent of water and an organic solvent; the organic solvent can be ethyl acetate and / or dichloromethane, preferably ethyl acetate; the volume ratio of water to the organic solvent can be 1 - 5, preferably 2.

[0055] The present invention also provides a compound of formula II:

[0056]

[0057] Wherein, the definition of PG is as described above.

[0058] In a preferred embodiment of the present invention, the compound of formula II is

[0059]

[0060] The present invention also provides a method for preparing the compound of II, which comprises the following steps: in a solvent, condensing the compound of formula III and the compound of formula IV in the presence of a condensing agent and a base to obtain the compound of formula II through the following condensation reaction.

[0061]

[0062] Wherein, the definition of PG and the reaction conditions of the condensation reaction are as described above.

[0063] In a preferred embodiment of the present invention, the synthetic route of the method for preparing the compound of formula I is as follows:

[0064]

[0065] Wherein, the definitions of R and X and the reaction conditions of each step of the reaction are as described above.

[0066] On the basis of not violating the common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention.

[0067] The reagents and raw materials used in the present invention are all commercially available.

[0068] The positive and progressive effects of the present invention are as follows: using the synthetic route and intermediates of the present invention, the target product with high purity can be prepared in high yield, and the target product involved will not racemize and the purification process is easy to operate, so it is suitable for industrial production. Detailed Description of the Invention

[0069] The present invention will be further illustrated below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods without specific conditions noted in the following examples are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0070] In the following examples, mass spectrometry was performed using a Waters Acquity Xevo G2-XS QTof UPLC / MS ultra-high performance liquid chromatography high-resolution mass spectrometry combined system, 1 1H-NMR was performed using a Bruker AVANCE III 400MHz nuclear magnetic resonance spectrometer or a Bruker AVANCE III HD 300MHz nuclear magnetic resonance spectrometer, and HPLC was performed using an Agilent 1260 high performance liquid chromatography instrument.

[0071] In the following examples, "room temperature / ambient temperature" refers to 20 - 25 °C. "Overnight" refers to 16 - 20 hours.

[0072] Example 1: Synthesis of Compound 1 by the method of the present invention

[0073] Step 1: Synthesis of Compound of Formula 4

[0074]

[0075] Glycolic acid (24 g, 0.316 mol) was dissolved in N,N-dimethylformamide (480 mL), and then diisopropylethylamine (143 g, 1.105 mol) was added. The resulting mixture was cooled to 0 - 5 °C. While maintaining the internal temperature at 5 - 10 °C and under stirring conditions, tert-butyldiphenylchlorosilane (192 g, 0.694 mol) was added dropwise to the mixture. After the dropwise addition, the resulting reaction solution was heated to 15 - 30 °C and stirred for another 2 hours. The reaction was detected to be complete by TLC (developing agent: dichloromethane∶methanol = 5∶1, volume ratio), and potassium permanganate was used for color development). After the resulting reaction solution was cooled to 10 °C, 1 L of water was added for dilution, and then 500 mL of ethyl acetate was added. The resulting mixed system was adjusted to pH 3 with about 1 N hydrochloric acid (480 mL) under stirring conditions, and then extracted twice with ethyl acetate (500 mL each). The combined organic phases were washed three times with 1.5 L of saturated brine, then dried over sodium sulfate, and finally filtered and concentrated to obtain a colorless liquid (210 g, yield 120%, containing residues). MS: m / z = 315.1 (M + H).

[0076] Step 2: Synthesis of Compound of Formula 2

[0077]

[0078] Under nitrogen protection, irinotecan mesylate (18.7 g, 35.2 mmol), 2-((tert-butyldiphenylsilyl)oxy)acetic acid (22 g, 70.4 mmol), and 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (15.6 g, 52.8 mmol) were dispersed in anhydrous dichloromethane (400 mL). N,N-Diisopropylethylamine (14.5 mL, 88 mmol) was added dropwise at room temperature. After the addition, the reaction solution was stirred overnight at room temperature. The resulting reaction solution was concentrated under reduced pressure to remove the solvent, and the resulting crude product was purified by column chromatography (dichloromethane∶methanol = 40∶1) to obtain a light yellow solid of Compound of Formula 2 (25 g, yield 97%). ESI-MS m / z: 732.3 (M + H).

[0079] Step 3: Synthesis of Compound of Formula 1

[0080]

[0081] Under nitrogen protection, compound 2 (25 g, 34.2 mmol) was dissolved in a mixed solvent of dichloromethane / methanol (150 mL, volume ratio 20:1). At room temperature, acetic acid (4 mL, 68.4 mmol) and tetrabutylammonium fluoride (17.9 g, 68.4 mmol) were successively added to the solution. After addition, the resulting mixture was stirred overnight at room temperature, and a white solid precipitated in the solution. The resulting reaction solution was filtered, and the obtained filter cake was washed twice with dichloromethane and then dried in vacuo to obtain the white solid of formula 1 compound (16 g, yield 95%). ESI-MS m / z: 494.2 (M+H), 1 1H NMR (400 MHz, DMSO) δ 8.39 (d, J = 8.9 Hz, 1H), 7.77 (d, J = 11.0 Hz, 1H), 7.30 (s, 1H), 6.50 (s, 1H), 5.62 - 5.55 (m, 1H), 5.47 (t, J = 5.8 Hz, 1H), 5.42 (s, 2H), 5.26 - 5.09 (m, 2H), 3.96 (d, J = 5.8 Hz, 2H), 3.26 - 3.05 (m, 2H), 2.39 (s, 3H), 2.26 - 2.07 (m, 2H), 1.93 - 1.78 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H).

[0082] Comparative Example 1: The compound of formula 1 was synthesized according to the method of Synthetic Route 1 in the background technology.

[0083] Step 1: Synthesis of acetate intermediate

[0084]

[0085] Irinotecan mesylate (350 mg, 0.66 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (350 μL, 1.98 mmol) and acetoxyacetyl chloride (0.1 mL, 0.79 mmol) were added, and the resulting reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and the resulting residual solid was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain a brown solid (0.35 g, yield 99%).

[0086] Step 2: Removal of acetyl group to obtain the compound of formula 1

[0087]

[0088] The intermediate obtained in Step 1 was dissolved in a mixed solvent of methanol (20 mL) and tetrahydrofuran (10 mL), and 1 mol / L sodium hydroxide solution (4 mL) was added dropwise. The resulting reaction solution was stirred at room temperature for 2 hours, and TLC monitoring showed that the reaction was complete. 1 mol / L hydrochloric acid (4 mL) was added dropwise to the resulting reaction solution, and a solid precipitated. The solid was filtered by suction to obtain a pale yellow solid (70 mg, yield 22%).

[0089] Example 2: Purity test of the target compound (Compound of Formula 1)

[0090] The purity of the products obtained in Example 1 and Comparative Example 1 was detected by high performance liquid chromatography. It was found that the ratio of the Compound of Formula 1 to the diastereoisomer with a configuration inversion at the NH in the structure of the Compound of Formula 1 in the product obtained in Comparative Example 1 (shown in the following Formula 5, the impurity at this position is the product with a configuration inversion at NH and was confirmed by comparison with the reference substance of Compound 5, which was purchased from Shanghai Xiyao Pharmaceutical Technology Co., Ltd.) was 1:1, while the proportion of Compound 5 in the product obtained in Example 1 was less than 0.1%.

[0091]

[0092] The liquid phase conditions used were as follows: Mobile phase A was 0.1% formic acid aqueous solution, mobile phase B was 0.1% formic acid acetonitrile solution, the chromatographic column was Agilent ZORBAX Eclipse Plus C18, 3.5 μm, 4.6×100 mm, the detection wavelength was 370 nm, and the gradient was set as shown in Table 1 below.

[0093] Table 1: Mobile phase gradient setting

[0094] Time (min) Mobile phase A % Mobile phase B % 0.00 90.0 10.0 1.70 90.0 10.0 11.70 30.0 70.0 11.80 0.0 100.0 15.70 0.0 100.0

[0095] 15.80 90.0 10.0 20.00 90.0 10.0

Claims

1. A method for preparing a compound of formula I, which comprises the following steps: in a solvent, reacting a compound of formula II with a deprotecting reagent to carry out the following deprotection reaction to obtain a compound of formula I, Among them, PG is tert-butyldiphenylsilyl.

2. The method for preparing a compound of formula I according to claim 1, wherein, in the method for preparing a compound of formula I, the deprotecting reagent is tetraalkylammonium fluoride and acetic acid; and / or, in the method for preparing a compound of formula I, the solvent is a mixed solvent of a chloroalkane solvent and an alcohol solvent; and / or, in the method for preparing a compound of formula I, the temperature of the deprotection reaction is 20-30 °C; and / or, in the method for preparing a compound of formula I, the reaction time of the deprotection reaction is 12-24 hours.

3. The method for preparing a compound of formula I according to claim 2, wherein, in the deprotecting reagent in the method for preparing a compound of formula I, the tetraalkylammonium fluoride is tetrabutylammonium fluoride, tetraethylammonium fluoride or tetramethylammonium fluoride; and / or, in the deprotecting reagent in the method for preparing a compound of formula I, the molar ratio of the tetraalkylammonium fluoride to the compound of formula II is 1-5; and / or, in the deprotecting reagent in the method for preparing a compound of formula I, the molar ratio of acetic acid to the compound of formula II is 1-5; and / or, in the solvent in the method for preparing a compound of formula I, the chloroalkane solvent is dichloromethane and / or dichloroethane; and / or, in the solvent in the method for preparing a compound of formula I, the alcohol solvent is methanol and / or ethanol; and / or, in the solvent, the volume ratio of the chloroalkane solvent to the alcohol solvent is 50:1-10:1; and / or, in the method for preparing a compound of formula I, the temperature of the deprotection reaction is 20-25 °C; and / or, in the method for preparing a compound of formula I, the reaction time of the deprotection reaction is 16-20 hours.

4. The method for preparing a compound of formula I according to claim 3, wherein, in the deprotecting reagent in the method for preparing a compound of formula I, the tetraalkylammonium fluoride is tetrabutylammonium fluoride; and / or, in the deprotecting reagent in the method for preparing a compound of formula I, the molar ratio of the tetraalkylammonium fluoride to the compound of formula II is 2-4; and / or, in the deprotecting reagent in the method for preparing a compound of formula I, the molar ratio of acetic acid to the compound of formula II is 2-4; and / or, in the solvent in the method for preparing a compound of formula I, the chloroalkane solvent is dichloromethane; and / or, in the solvent in the method for preparing a compound of formula I, the alcohol solvent is methanol; and / or, in the solvent, the volume ratio of the chloroalkane solvent to the alcohol solvent is 20:1-15:1; and / or, in the method for preparing a compound of formula I, the temperature of the deprotection reaction is 25 °C; And / or, in the method for preparing the compound of formula I, the reaction time of the deprotection reaction is 16 hours.

5. The method for preparing the compound of formula I according to claim 4, wherein in the method for preparing the compound of formula I, in the deprotecting reagent, the molar ratio of the tetraalkylammonium fluoride to the compound of formula II is 2; and / or, in the method for preparing the compound of formula I, in the deprotecting reagent, the molar ratio of acetic acid to the compound of formula II is 2; and / or, in the solvent, the volume ratio of the chloroalkane solvent to the alcohol solvent is 20:

1.

6. The method for preparing the compound of formula I according to any one of claims 1 to 5, characterized in that, It further comprises a method for preparing the compound of formula II, which comprises the following steps: in a solvent, condensing the compound of formula III and the compound of formula IV in the presence of a condensing agent and a base to obtain the compound of formula II, wherein, the definition of PG is as described in claim 1.

7. The method for preparing the compound of formula I according to claim 6, wherein in the method for preparing the compound of formula II, in the condensation reaction, the feeding molar ratio of the compound of formula IV to the compound of formula III is 1.0 - 3.0; and / or, in the method for preparing the compound of formula II, in the condensation reaction, the condensing agent is one or more of 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride, N,N'-dicyclohexylcarbodiimide, the combination of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 1-hydroxybenzotriazole, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate, and 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate; and / or, in the method for preparing the compound of formula II, in the condensation reaction, the feeding molar ratio of the condensing agent to the compound of formula III is 1.2 - 3.0; and / or, in the method for preparing the compound of formula II, in the condensation reaction, the base is one or more of N,N-diisopropylethylamine, triethylamine, and 4-dimethylaminopyridine; and / or, in the method for preparing the compound of formula II, in the condensation reaction, the feeding molar ratio of the base to the compound of formula III is 2.0 - 4.0; and / or, in the method for preparing the compound of formula II, in the condensation reaction, the feeding mode of the base is one-time addition, batch addition, or dropwise addition; and / or, in the method for preparing the compound of formula II, in the condensation reaction, the solvent is one or more of dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide, chloroform, and toluene; and / or, in the method for preparing the compound of formula II, the temperature of the condensation reaction is 20 - 30 °C; and / or, in the method for preparing the compound of formula II, the reaction time of the condensation reaction is 12 - 24 hours; and / or, the method for preparing the compound of formula II comprises the following steps: adding the base to a mixed system of the compound of formula III, the compound of formula IV, the condensing agent, and the solvent for reaction.

8. The preparation method of the compound of formula I as claimed in claim 7, wherein in the preparation method of the compound of formula II, in the condensation reaction, the molar ratio of the compound of formula IV to the compound of formula III in the feed is 1.5 - 2.0; and / or, in the preparation method of the compound of formula II, in the condensation reaction, the condensing agent is 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride; and / or, in the preparation method of the compound of formula II, in the condensation reaction, the molar ratio of the condensing agent to the compound of formula III in the feed is 1.5 - 2.0; and / or, in the preparation method of the compound of formula II, in the condensation reaction, the base is N,N-diisopropylethylamine; and / or, in the preparation method of the compound of formula II, in the condensation reaction, the molar ratio of the base to the compound of formula III in the feed is 2.5 - 3.0; and / or, in the preparation method of the compound of formula II, in the condensation reaction, the feeding mode of the base is dropwise addition; and / or, in the preparation method of the compound of formula II, in the condensation reaction, the solvent is dichloromethane; and / or, in the preparation method of the compound of formula II, the temperature of the condensation reaction is 20 - 25 °C; and / or, in the preparation method of the compound of formula II, the reaction time of the condensation reaction is 16 - 20 hours.

9. The preparation method of the compound of formula I as claimed in claim 8, wherein in the preparation method of the compound of formula II, in the condensation reaction, the molar ratio of the compound of formula IV to the compound of formula III in the feed is 2.0; and / or, in the preparation method of the compound of formula II, in the condensation reaction, the molar ratio of the condensing agent to the compound of formula III in the feed is 1.5; and / or, in the preparation method of the compound of formula II, in the condensation reaction, the molar ratio of the base to the compound of formula III in the feed is 2.5; and / or, in the preparation method of the compound of formula II, the temperature of the condensation reaction is 25 °C; and / or, in the preparation method of the compound of formula II, the reaction time of the condensation reaction is 16 hours.

10. The method for preparing the compound of formula I according to claim 6, characterized in that, It includes the preparation method of the compound of formula IV, which comprises the following steps: in a solvent, glycolic acid and the compound of formula VI are reacted under the condition of the presence of a base to obtain the compound of formula IV, wherein, PG is as claimed in claim 6; X is chlorine, bromine or iodine.

11. The preparation method of the compound of formula I as claimed in claim 10, wherein in the preparation method of the compound of formula IV, X is chlorine; and / or, in the preparation method of the compound of formula IV, the molar ratio of the compound of formula VI to glycolic acid in the feed is 2.0 - 4.0; and / or, in the preparation method of the compound of formula IV, the base used is one or more of diisopropylethylamine, triethylamine and 4-dimethylaminopyridine; and / or, in the preparation method of the compound of formula IV, the molar ratio of the base used to glycolic acid in the feed is 2.0 - 6.0; And / or, in the preparation method of the compound of formula IV, the solvent is one or more of dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide and chloroform; And / or, in the preparation method of the compound of formula IV, the reaction time of the reaction is 1 - 10 hours; And / or, the preparation method of the compound of formula IV comprises the following steps: in a mixed system of glycolic acid and the solvent, the base and the compound of formula VI are added in sequence and reacted; And / or, in the preparation method of the compound of formula IV, after the reaction is completed, it further comprises the step of acidifying the reaction solution with an acid, and the acid is hydrochloric acid and / or sulfuric acid.

12. The preparation method of the compound of formula I according to claim 11, wherein in the preparation method of the compound of formula IV, the molar ratio of the compound of formula VI to glycolic acid in the feed is 2.2 - 2.5; And / or, in the preparation method of the compound of formula IV, the base used is diisopropylethylamine; And / or, in the preparation method of the compound of formula IV, the molar ratio of the base used to glycolic acid in the feed is 3.0 - 4.0; And / or, in the preparation method of the compound of formula IV, the solvent is N,N-dimethylformamide; And / or, in the preparation method of the compound of formula IV, the reaction time of the reaction is 2 - 5 hours; And / or, in the preparation method of the compound of formula IV, the feeding temperature of the compound of formula VI is 0 - 15 °C; And / or, in the preparation method of the compound of formula IV, the feeding mode of the compound of formula VI is batch feeding or dropping; And / or, in the step of acidification treatment, the concentration of the acid is 0.5 - 2 mol / L; And / or, in the step of acidification treatment, the amount of the acid used adjusts the pH value of the reaction solution to 3 - 5; And / or, before the step of acidification treatment, it further comprises the step of diluting the reaction solution with a solvent, wherein the solvent is a mixed solvent of water and an organic solvent.

13. The preparation method of the compound of formula I according to claim 12, wherein in the preparation method of the compound of formula IV, the molar ratio of the compound of formula VI to glycolic acid in the feed is 2.2; And / or, in the preparation method of the compound of formula IV, the molar ratio of the base used to glycolic acid in the feed is 3.5; And / or, in the preparation method of the compound of formula IV, the reaction time of the reaction is 2 hours; And / or, in the preparation method of the compound of formula IV, the feeding temperature of the compound of formula VI is 0 - 10 °C; And / or, in the preparation method of the compound of formula IV, the feeding mode of the compound of formula VI is dropping; And / or, in the step of acidification treatment, the concentration of the acid is 1 - 2 mol / L; And / or, in the step of acidification treatment, the amount of the acid used adjusts the pH value of the reaction solution to 3 - 4; And / or, before the step of acidification treatment, the organic solvent is ethyl acetate and / or dichloromethane; And / or, before the step of acidification treatment, the volume ratio of water to the organic solvent is 1 - 5.

14. The preparation method of the compound of formula I according to claim 13, characterized in that in the preparation method of the compound of formula IV, the feeding temperature of the compound of formula VI is 0-5 °C or 5-10 °C; and / or, in the step of acidification treatment, the concentration of the acid is 1 mol / L; and / or, in the step of acidification treatment, the amount of the acid used adjusts the pH value of the reaction solution to 3; and / or, before the step of acidification treatment, the organic solvent is ethyl acetate; and / or, before the step of acidification treatment, the volume ratio of water to the organic solvent is 2.

15. A compound of formula II: Among them, PG is tert-butyldiphenylsilyl.

16. A preparation method of a compound of II, which comprises the following steps: in a solvent, the compound of formula III and the compound of formula IV are subjected to the following condensation reaction in the presence of a condensing agent and a base to obtain the compound of formula II, Among them, the definition of PG is as described in claim 15, and the reaction conditions of the condensation reaction are as described in any one of claims 6-14.

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