A tumor-activated sorafenib prodrug and its preparation method and application

Abstract

The present invention discloses a tumor-activated sorafenib prodrug, its preparation method, and its application, belonging to the field of biomedicine technology. The present invention designs a tumor-activated sorafenib prodrug, composed of sorafenib and ferrocenecarboxylic acid molecules as its main structure. It can specifically activate cytotoxicity at the tumor site, and compared to sorafenib, it is more effective in killing liver cancer cells. Furthermore, it undergoes an in situ Fenton reaction, generating oxygen to alleviate tumor hypoxia and reduce tumor invasion and migration. The Fenton reaction can generate highly toxic hydroxyl radicals, which kill liver cancer cells and provide auxiliary treatment.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and specifically relates to a tumor-activated sorafenib prodrug and a preparation method and application thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance understanding of the overall background of the invention and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to those skilled in the art.

[0003] Sorafenib is an FDA-approved oral medication for the treatment of inoperable hepatocellular carcinoma. Because sorafenib's toxicity lacks cell specificity, it can easily injure normal cells. Additionally, since sorafenib can inhibit angiogenesis in liver cancer tissue, the blood vessels supplying the liver cancer tissue decrease after using sorafenib, and the amount of oxygen the liver cancer tissue receives also decreases. This puts the liver cancer tissue in a state of "hypoxia," and in this state of "hypoxia," the ability of tumor cells to transform into other surrounding cells (i.e., tumor stromal cells) (a phenomenon known as "epithelial-mesenchymal transition," EMT) is enhanced. This enhanced ability will ultimately lead to enhanced tumor migration and invasiveness, which means an increased probability of tumor metastasis. Summary of the Invention

[0004] To address the deficiencies of the prior art, the present invention aims to provide a tumor-activated sorafenib prodrug. Addressing the lack of specificity of sorafenib, a molecular structure is designed for specific activation at the tumor site to avoid accidental damage to normal cells. Addressing sorafenib-induced tumor hypoxia, a molecular structure is designed that can undergo a Fenton reaction at the tumor site, generating oxygen to improve hypoxia and generating highly toxic hydroxyl free radicals for auxiliary treatment. The improvement in tumor hypoxia reduces the tumor's ability to invade and migrate, facilitating better treatment of hepatocellular carcinoma.

[0005] In order to achieve the above object, the technical solution of the present invention is:

[0006] In a first aspect, the present invention provides a tumor-activated sorafenib prodrug, the structure of which is shown in Formula I:

[0007]

[0008] The sorafenib prodrug comprises a sorafenib molecule and a ferrocenecarboxylic acid molecule as a main structure and can specifically activate cytotoxicity at the tumor site.

[0009] In a second aspect, the present invention provides a method for preparing a tumor-activated sorafenib prodrug, comprising the following steps:

[0010] Using an alkaline solution to hydrolyze sorafenib to prepare sorafenib carboxylic acid;

[0011] Preparation of thioketal molecules using 2-mercaptoethylamine hydrochloride;

[0012] An intermediate molecule is prepared using a ferrocenecarboxylic acid molecule and a thioketal molecule;

[0013] The sorafenib carboxylic acid and the intermediate molecule are reacted to prepare a sorafenib prodrug.

[0014] In some embodiments, the specific steps of hydrolyzing sorafenib with an alkaline solution to prepare sorafenib carboxylic acid are: dissolving sorafenib and the alkaline solution in an organic solvent and heating; removing the organic solvent, adjusting the pH to neutralize to acidity, filtering and purifying the precipitated solid to obtain sorafenib carboxylic acid;

[0015] Furthermore, the alkaline solution is sodium hydroxide.

[0016] Furthermore, the molar ratio of sorafenib to alkaline solution is 1-5:25-35, preferably 1:30.

[0017] Furthermore, the organic solvent is anhydrous ethanol.

[0018] Furthermore, the heating is performed at 60-100° C. with stirring for 10-14 h; preferably, the heating is performed at 80° C. with stirring for 12 h.

[0019] Furthermore, the purification is performed using a silica gel column, and the eluent is a mixture of dichloromethane and methanol, with dichloromethane:methanol = 10:1.

[0020] Furthermore, the sorafenib carboxylic acid (C 20 H 13 The structural formula of ClF3N3O4 is shown below:

[0021]

[0022] In some embodiments, the specific steps of using 2-mercaptoethylamine hydrochloride to prepare the thioketal molecule are: dissolving 2-mercaptoethylamine hydrochloride in concentrated hydrochloric acid and stirring, adding acetone and dichloromethane in sequence, continuing to stir until a white solid precipitates, and filtering; stirring the filtered solid precipitate in an alkaline solution for a long time, and obtaining the thioketal molecule after extraction.

[0023] Furthermore, the 2-mercaptoethylamine hydrochloride is dissolved in concentrated hydrochloric acid at low temperature, wherein the low temperature is 0-5°C;

[0024] Furthermore, the long-term stirring has a stirring time of 10-14 hours.

[0025] Furthermore, the thioketal molecule (C7H 18 The structural formula of N2S2 is as follows:

[0026]

[0027] In some embodiments, the specific steps of preparing the intermediate molecule using ferrocenecarboxylic acid and thioacetal molecules are: dissolving ferrocenecarboxylic acid in an organic solvent, adding 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N-diisopropylethylamine, and thioacetal molecules while stirring, reacting at room temperature for a certain time, and purifying to obtain the intermediate molecule.

[0028] Furthermore, the molar ratio of ferrocenecarboxylic acid, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N-diisopropylethylamine, and thioketal is 1-2:1-2:2-3:3-5, preferably 1:1:2:3.

[0029] Furthermore, the reaction time at room temperature is 0.5-1..5h.

[0030] Furthermore, the purification is performed using a silica gel column, and the eluent is a mixture of ethyl acetate and petroleum ether, wherein the ratio of ethyl acetate to petroleum ether is 1:1.

[0031] Furthermore, the intermediate molecule (C 18 H 26 The structural formula of FeN2S2 is as follows:

[0032]

[0033] In some embodiments, the specific steps of reacting the sorafenib carboxylic acid and the intermediate molecule to prepare the sorafenib prodrug are:

[0034] Sorafenib carboxylic acid is dissolved in an organic solvent, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N-diisopropylethylamine and an intermediate molecule are added during stirring. The mixture is reacted at room temperature and purified after the reaction to obtain a sorafenib prodrug.

[0035] Furthermore, the molar ratio of sorafenib carboxylic acid, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N-diisopropylethylamine, and the intermediate molecule is 1-2:1-2:2-3:3-4, preferably 1:1:2:3.

[0036] Furthermore, the reaction is carried out at room temperature and the reaction time is 1-2 hours.

[0037] Furthermore, the purification is performed using a silica gel column, and the eluent is a mixture of dichloromethane and methanol, wherein the ratio of dichloromethane to methanol is 10:1.

[0038] Furthermore, the structure of the sorafenib prodrug is shown in Formula I:

[0039]

[0040] In a third aspect, the tumor-activated sorafenib prodrug obtained by the above preparation method is used in the preparation of drugs for treating liver cancer.

[0041] The present invention is used to treat any form or state of liver cancer, including but not limited to hepatocellular carcinoma (HCC), fibrolamellar carcinoma, hepatobiliary cancer (cholangiocarcinoma), angiosarcoma or hepatoblastoma. Preferably, the liver cancer is hepatocellular carcinoma.

[0042] The drug for treating hepatocellular carcinoma can be taken orally or by intravenous injection. The oral preparation can be tablets, capsules, pills, granules, suspensions or drops.

[0043] The drug for treating hepatocellular carcinoma of the present invention can also be used in combination with other treatments, such as in a single dose, multiple doses, or sequential doses.

[0044] In a fourth aspect, the present invention further provides a pharmaceutical preparation comprising the above-mentioned tumor-activated sorafenib prodrug; preferably, the pharmaceutical preparation further comprises a pharmaceutically acceptable excipient or carrier.

[0045] The pharmaceutically acceptable excipient or carrier is at least one of a diluent, a disintegrant, a precipitation inhibitor, a glidant, a binder, a dispersant, a suspending agent, an isotonic agent, a thickener, an emulsifier, a preservative, a stabilizer, and the like.

[0046] The present invention provides a pharmaceutical formulation as described herein for use in a method of treating a human or animal subject in need thereof, in particular for use in a method of treating liver cancer in a subject.

[0047] In a fifth aspect, the present invention also provides a method for treating liver cancer in a human or animal subject in need thereof, the method comprising administering to the human or animal subject a therapeutically effective amount of a sorafenib prodrug or pharmaceutical formulation as described herein; and use of the sorafenib prodrug or pharmaceutical formulation as described herein in the preparation of a medicament for treating liver cancer in a human or animal subject in need thereof.

[0048] One or more of the above technical solutions have the following advantages or beneficial effects:

[0049] The designed and synthesized sorafenib prodrug consists of sorafenib molecules and ferrocenecarboxylic acid molecules as the main structure. It can specifically activate cytotoxicity at the tumor site and kill liver cancer cells better than sorafenib.

[0050] The designed and synthesized sorafenib prodrug can undergo Fenton reaction in situ, generating oxygen to improve tumor hypoxia and reduce the invasion and migration ability of tumors; the Fenton reaction can generate highly toxic hydroxyl free radicals, kill liver cancer cells and assist in treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] The accompanying drawings, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0052] Figure 1 Mass spectrum of the designed sorafenib prodrug;

[0053] Figure 2 are the NMR images of the intermediate molecule and the sorafenib prodrug, wherein a is the NMR image of the intermediate molecule and b is the NMR image of the sorafenib prodrug;

[0054] Figure 3 The images were taken using the fluorescent probe DCFH-DA (taken using a confocal microscope) for detecting reactive oxygen species. The PBS group was incubated without any material; the Sfb group was incubated with sorafenib in HePa 1-6 liver cancer cells; the Fca group was incubated with ferrocenecarboxylic acid in HePa 1-6 liver cancer cells; and the Sfb-Fca group was incubated with sorafenib prodrug molecules in HePa 1-6 liver cancer cells.

[0055] Figure 4 Images of live and dead cell detection using the fluorescent probe AM / PI (taken using a confocal microscope) are shown. The PBS group was incubated without any material; the Fca group was incubated with ferrocenecarboxylic acid for HePa 1-6 liver cancer cells; the Sfb group was incubated with sorafenib for HePa 1-6 liver cancer cells; and the Sfb-Fca group was incubated with sorafenib prodrug for HePa 1-6 liver cancer cells.

[0056] Figure 5 The tumor volume of mice in different groups was detected during in vivo treatment in the C57 black mouse model. Among them, the PBS group was mice not injected with any material; the Fca group was mice injected with ferrocenecarboxylic acid; the Sfb group was mice injected with sorafenib; the Sfb-Fca group was mice injected with sorafenib prodrug molecules; and the Sfb+Fca group was mice injected with sorafenib and ferrocenecarboxylic acid. DETAILED DESCRIPTION

[0057] It should be noted that the following detailed descriptions are exemplary and intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs.

[0058] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments of the present invention. Experimental steps not described in detail in the present invention were performed according to conventional experimental procedures or according to product instructions.

[0059] Explanation of terms involved:

[0060] Sorafenib is the name of the drug, English name: Sorafenib, CAS number: 284461-73-0, Chinese name: 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-urea]phenoxy}-pyridine-2-carboxylic acid methylamine, its structural formula is as follows:

[0061]

[0062] Prodrugs are inactive drugs.

[0063] 2-Mercaptoethylamine hydrochloride, CAS number: 156-57-0.

[0064] Ferrocenecarboxylic acid, CAS number: 1271-42-7.

[0065] HATU, Chinese name: 2-(7-azabenzotriazole)-N,N,N',N"-tetramethyluronium hexafluorophosphate, CAS number: 148893-10-1.

[0066] DIPEA, Chinese name: N,N-diisopropylethylamine, CAS number: 7087-68-5.

[0067] As introduced in the background technology, the toxicity of sorafenib lacks cell specificity, and excessive use of sorafenib will cause the tumor tissue to become a hypoxic environment. In the "hypoxic" state, the transformation ability of tumor cells and other surrounding cells (i.e., tumor stromal cells) (this phenomenon is called "epithelial-mesenchymal transition", EMT) will be enhanced, thereby causing the tumor's invasion and migration capabilities to increase.

[0068] In order to solve the above technical problems, the present invention provides a tumor-activated sorafenib prodrug.

[0069] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.

[0070] Example 1

[0071] The preparation method of sorafenib prodrug comprises the following steps:

[0072] 1. Sorafenib is hydrolyzed with sodium hydroxide to prepare sorafenib carboxylic acid:

[0073] 1 mol of sorafenib and 30 mol of NaOH were dissolved in 150 mL of anhydrous ethanol and heated at 80° for 12 hours. After the reaction, the ethanol was dried using a rotary evaporator, dissolved in water, and neutralized with 1 M dilute hydrochloric acid to pH = 5, and solid precipitated. After the solid was filtered, it was dissolved in dichloromethane solvent, mixed with silica gel powder, dried using a rotary evaporator, and purified by silica gel column (eluent ratio dichloromethane: methanol = 10:1) to obtain sorafenib carboxylic acid (C 20 H 13 ClF3N3O4), whose structural formula is shown below:

[0074]

[0075] 2. Preparation of thioketal molecules:

[0076] 5.78 g of 2-mercaptoethylamine hydrochloride was dissolved in 4 mL of concentrated hydrochloric acid at 0 °C. After stirring for 10 minutes, 10 mL of acetone and 4 mL of dichloromethane were added in sequence. Stirring was continued for 10 minutes until a white solid (crude product of thioketal molecule) was precipitated. The solid was filtered. The precipitate was dissolved in an appropriate amount of methanol solvent. After it was fully dissolved, 10 mL of 6 M NaOH solution was added. After stirring at room temperature for 12 hours, 50 mL of dichloromethane was added for extraction to obtain the thioketal molecule (C7H 18 N2S2), whose structural formula is shown below:

[0077]

[0078] 3. Use ferrocenecarboxylic acid and thioketal molecules to prepare intermediate molecules:

[0079] 1 mol of ferrocenecarboxylic acid was dissolved in an appropriate amount of dichloromethane solvent, and 1 mol of HATU, 2 mol of DIPEA and 3 mol of the above-prepared thioketal molecule were added during stirring. After reacting at room temperature for 1 hour, the sample was mixed with silica gel powder, dried by rotary evaporation, and purified by silica gel column (eluent ratio ethyl acetate: petroleum ether = 1:1) to obtain the intermediate molecule (C 18 H 26 FeN2S2), the corresponding NMR data are Figure 2 a, whose structural formula is shown below:

[0080]

[0081] 4. Using the sorafenib carboxylic acid (C20 H 13 ClF3N3O4) and the intermediate molecule prepared above (C 18 H 26 FeN2S2) to prepare the sorafenib prodrug molecule:

[0082] 1 mol of sorafenib carboxylic acid was dissolved in an appropriate amount of dichloromethane solvent, and 1 mol of HATU, 2 mol of DIPEA and 3 mol of the intermediate molecule were added during stirring. After reacting at room temperature for 1 hour, the sample was mixed with silica gel powder, dried using a rotary evaporator, and purified by silica gel column (eluent ratio of dichloromethane: methanol = 10:1) to obtain the sorafenib prodrug molecule (C 38 H 37 ClF3FeN5O4S2), the corresponding mass spectrum and NMR data are Figure 1 and Figure 2 b, whose structure is shown in the following formula I:

[0083]

[0084] Example 2

[0085] Sorafenib prodrug (C 38 H 37 ClF3FeN5O4S2) cell experiment 1:

[0086] Experimental principle: The ferrocene group in the sorafenib prodrug can undergo a Fenton reaction under the action of hydrogen peroxide overexpressed in tumor cells, generating hydroxyl radicals (ROS).

[0087] Experimental plan: Hepatocellular carcinoma cells (HePa 1-6) were cultured in a cell confocal culture dish, and incubated with DCFH-DA kit probe (purchased from Beyotime, product number: S0033S) and 0.25mM sorafenib prodrug for 20 minutes. The production of ROS was recorded under an SP8 confocal microscope ( Figure 3 ).

[0088] like Figure 3 As shown in the figure, the experiment used the reactive oxygen species specific fluorescent probe DCFH-DA. The PBS group was incubated without any material; the Sfb group was incubated with sorafenib in the liver cancer cells HePa1-6; the Fca group was incubated with ferrocenecarboxylic acid in the liver cancer cells HePa 1-6; and the Sfb-Fca group was incubated with sorafenib prodrug molecules in the liver cancer cells HePa 1-6. Figure 3 It can be seen that the designed sorafenib prodrug molecule can effectively generate reactive oxygen hydroxyl radicals in liver cancer cell HePa 1-6.

[0089] Example 3

[0090] Sorafenib prodrug (C 38 H 37 ClF3FeN5O4S2) cell experiment 2:

[0091] Experimental Principle: Overexpressed ROS in cancer cells can disrupt the thioketal bond, releasing sorafenib. Furthermore, the ferrocene group of the sorafenib prodrug molecule, under the influence of overexpressed hydrogen peroxide in tumor cells, undergoes a Fenton reaction, generating hydroxyl radicals (ROS), which further damage the thioketal bond and release sorafenib. Sorafenib is effectively cytotoxic to cancer cells, combining chemotherapy with the Fenton reaction to treat cancer.

[0092] Experimental plan: HePa 1-6 cells were cultured in a cell confocal culture dish and incubated with 0.25mM sorafenib prodrug molecules for 24 hours. The culture medium was then aspirated and washed with PBS buffer. Calcein / PI cell viability and cytotoxicity detection kit (purchased from Beyotime, product number: C2015M) was used to incubate for 20 minutes. Cytotoxicity experiments were recorded under an SP8 confocal microscope ( Figure 4 ).

[0093] like Figure 4 As shown in the figure, the live and dead cell detection fluorescent probe AM / PI was used in the experiment. The PBS group was incubated without any material; the Fca group was incubated with ferrocenecarboxylic acid for HePa 1-6 liver cancer cells; the Sfb group was incubated with sorafenib for HePa 1-6 liver cancer cells; and the Sfb-Fca group was incubated with sorafenib prodrug molecules for HePa 1-6 liver cancer cells. Figure 4 It can be seen that the designed sorafenib prodrug molecule can effectively produce cytotoxicity in liver cancer cell HePa 1-6 in vivo.

[0094] Example 4

[0095] Sorafenib prodrug (C 38 H 37 In vivo therapeutic experiment on C57 black mouse model with ClF3FeN5O4S2).

[0096] 4-5 week old C57 mice were randomly divided into 5 groups of 5 mice each to establish a tumor model. The PBS group was not injected with any material; the Fca group was injected with ferrocenecarboxylic acid; the Sfb group was injected with sorafenib; the Sfb-Fca group was injected with sorafenib prodrug; and the Sfb+Fca group was injected with sorafenib and ferrocenecarboxylic acid. After inoculation of HePa 1-6 liver cancer cells, the mice were allowed to grow to 50 mm. 3 After intratumoral injection of the material (2.5 mM, 50 μl PBS), the changes in tumor volume were recorded every 2 days ( Figure 5 ).

[0097] Depend on Figure 5 As shown, the designed sorafenib prodrug significantly inhibited tumor growth and cured the tumor in vivo in the C57 black mouse model.

[0098] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. A tumor-activated sorafenib prodrug, wherein the structure of the sorafenib prodrug is shown in Formula I: Ⅰ。 2. The method for preparing a tumor-activated sorafenib prodrug according to claim 1, wherein: The steps include: Using an alkaline solution to hydrolyze sorafenib to prepare sorafenib carboxylic acid; Preparation of thioketal molecules using 2-mercaptoethylamine hydrochloride; The intermediate molecule is prepared using ferrocenecarboxylic acid and thioketal molecules; The sorafenib carboxylic acid and the intermediate molecule are reacted to prepare a sorafenib prodrug.

3. The preparation method according to claim 2, characterized in that The specific steps of hydrolyzing sorafenib with an alkaline solution to prepare sorafenib carboxylic acid are as follows: dissolving sorafenib and the alkaline solution in an organic solvent and heating the solution, removing the organic solvent, adjusting the pH value to be acidic, filtering and purifying the precipitated solid to obtain sorafenib carboxylic acid; The molar ratio of sorafenib to alkaline solution is 1-5:25-35; The heating is heating and stirring at 60-100° C. for 10-14 hours; The purification is performed using a silica gel column, and the eluent is a mixture of dichloromethane and methanol.

4. The preparation method according to claim 3, characterized in that The heating and stirring is heating and stirring at 80° C. for 12 h.

5. The preparation method according to claim 2, wherein The specific steps of using 2-mercaptoethylamine hydrochloride to prepare the thioketal molecule are as follows: dissolving 2-mercaptoethylamine hydrochloride in concentrated hydrochloric acid and stirring, adding acetone and dichloromethane in sequence, continuing to stir until a white solid precipitates, and filtering; subjecting the filtered solid precipitate to a long-term stirring reaction in an alkaline solution, and extracting to obtain the thioketal molecule; The 2-mercaptoethylamine hydrochloride is dissolved in concentrated hydrochloric acid at low temperature, wherein the low temperature is 0-5°C; The long-term stirring time is 10-14 hours.

6. The preparation method according to claim 2, characterized in that The specific steps of preparing the intermediate molecule using ferrocenecarboxylic acid and thioacetal molecules are: dissolving ferrocenecarboxylic acid in an organic solvent, adding 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N-diisopropylethylamine, and thioacetal molecules while stirring, reacting at room temperature for a certain time, and purifying to obtain the intermediate molecule.

7. The preparation method according to claim 6, characterized in that The molar ratio of ferrocenecarboxylic acid, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N-diisopropylethylamine, and thioketal is 1-2:1-2:2-3:3-5; The reaction time at room temperature is 0.5-1.5h; The purification is performed using a silica gel column, and the eluent is a mixture of ethyl acetate and petroleum ether; The structure of the intermediate molecule is shown below: 。 8. The preparation method according to claim 7, characterized in that The molar ratio of ferrocenecarboxylic acid, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N-diisopropylethylamine and thioketal is 1:1:2:

3.

9. The preparation method according to claim 2, characterized in that The specific steps of reacting the sorafenib carboxylic acid and the intermediate molecule to prepare the sorafenib prodrug are: dissolving the sorafenib carboxylic acid in an organic solvent, adding 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N-diisopropylethylamine and the intermediate molecule while stirring, reacting at room temperature, and purifying after the reaction to obtain the sorafenib prodrug.

10. The preparation method according to claim 9, characterized in that The molar ratio of sorafenib carboxylic acid, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N-diisopropylethylamine, and the intermediate molecule is 1-2:1-2:2-3:3-4; The reaction is carried out at room temperature for 1-2 hours; The purification is performed by using a silica gel column, and the eluent is a mixture of dichloromethane and methanol.

11. The preparation method according to claim 10, characterized in that: The molar ratio of sorafenib carboxylic acid, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N-diisopropylethylamine and the intermediate molecule is 1:1:2:

3.

12. Use of the tumor-activated sorafenib prodrug according to claim 1 or the tumor-activated sorafenib prodrug obtained by the preparation method of any one of claims 2 to 11 in the preparation of a drug for treating liver cancer.

13. The use according to claim 12, characterized in that The liver cancer includes hepatocellular carcinoma, fibrolamellar carcinoma, hepatobiliary carcinoma, angiosarcoma or hepatoblastoma.

14. The use according to claim 13, characterized in that The liver cancer is hepatocellular carcinoma.

15. A pharmaceutical preparation comprising the tumor-activated sorafenib prodrug of claim 1; the pharmaceutical preparation further comprises a pharmaceutically acceptable excipient or carrier.

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