Galactoside anti-tumor prodrug intermediate as well as preparation and application thereof

Abstract

The invention discloses a galactoside anti-tumor prodrug intermediate as well as preparation and application thereof, and belongs to the field of organic chemistry and medicinal chemistry. The invention provides an intermediate compound with a structure as shown in the specification: # imgabs0 #, any one of R3, R4, R5 and R6 is an optical cage group, and the other three are hydroxyl protecting groups. A dual-response beta-galactosidase prodrug can be prepared on the basis of the intermediate compound, so that the space-time controllability of a galactoside single prodrug release drug is further improved, and the toxic and side effects are reduced.

Description

Technical Field

[0001] The invention belongs to the field of organic chemistry and medicinal chemistry, and specifically relates to a galactoside anti-tumor prodrug intermediate, and its preparation and application. Background Art

[0002] β-galactoside prodrugs are oxygen glycoside compounds obtained by coupling the terminal position of β-D-galactose with the active essential group of the drug molecule. The active drug can be released after the β-galactosidase hydrolyzes the β-galactosidase bond. Compared with normal cells, the activity of β-galactosidase in tumor cells such as ovarian cancer, colon cancer, and breast cancer is increased. Therefore, β-galactoside prodrugs are expected to release drugs in tumor cells in a controllable manner and selectively kill tumor cells. In the past three decades, dozens of β-galactoside prodrugs with different structures for anti-tumor have been reported. For example: Huang Gangliang's team at Chongqing Normal University reported the galactoside prodrug of epothilone in 2018; Hou Jingli's team at Tianjin Medical University reported a galactoside prodrug that can release hydrogen sulfide in 2024. These reported β-galactoside prodrugs are all prodrugs activated by a single stimulus condition (β-galactosidase), referred to as "single prodrugs".

[0003] However, in addition to inhibiting certain tumor cells, these reported β-galactosidase single prodrugs also produce certain toxicity in non-tumor cells with high expression of β-galactosidase (such as M2 polarized macrophages, high glucose-induced macrophages, neurons, osteoclasts, etc.) and normal tissues (such as liver, small intestine, placenta, etc.). The uncontrollability of their time and space makes them have the risk of being activated in non-tumor sites to release drugs and produce toxic side effects. Therefore, it is urgent to develop a prodrug compound with higher selectivity and lower risk of toxic side effects. Summary of the invention

[0004]

Technical issues

[0005] The existing prodrug construction method is to couple the terminal position of β-D-galactose with the active essential group of the drug molecule to obtain an oxygen glycoside compound. The prodrug obtained in this way has low selectivity in non-tumor cells and normal tissues with high expression of β-galactosidase and has a high risk of toxic side effects.

[0006]

Technical solution

[0007] The present invention provides an intermediate compound, in the structure of which photocage groups are introduced on the 2, 3, 4, and 6 hydroxyl groups of galactoside. Based on the intermediate compound, the present invention constructs a new dual-activated hydroxyl photocage group-modified galactoside anti-tumor prodrug.

[0008] The present invention constructs a total of four new intermediate compounds and corresponding synthetic routes; the synthetic routes mainly include:

[0009] 1) The orthogonal hydroxyl protection strategy was used to selectively block some hydroxyl groups of galactose, and photocage groups were introduced regioselectively at the 2, 3, 4, and 6 hydroxyl groups;

[0010] 2) A linker is introduced at the end of the galactose through glycosylation reaction and further coupled to a cytotoxic molecule.

[0011] The present invention also provides a method for preparing a prodrug compound based on the intermediate compound, which is to remove the blocking group of the hydroxyl group on the galactose to obtain the final double prodrug.

[0012] The galactoside double prodrug prepared based on the intermediate compound of the present invention does not respond to β-galactosidase by itself, and needs to be converted into a single prodrug after first removing the photocage group through light irradiation, and further responds to β-galactosidase to release the drug. This type of new structure double prodrug has the following advantages: (1) It improves the controllability of drug release and reduces the risk of toxic side effects; (2) Theoretically, all β-galactoside single prodrugs can be constructed into double prodrugs through this method, which has universal applicability; (3) Photocage groups with different optical properties can be introduced on the galactose hydroxyl group, which has high flexibility; (4) The galactoside single prodrug has four exposed hydroxyl groups at positions 2, 3, 4, and 6, which can be introduced with photocage groups, which provides the possibility of constructing galactoside double prodrugs with diverse structures, fully studying the structure-activity relationship, and finding the optimal double prodrug.

[0013] The specific contents of the plan are as follows:

[0014] The first object of the present invention is to provide a prodrug intermediate compound having the structure shown below:

[0015]

[0016] in,

[0017] Z is a vacant bond or an ester group (-CO-O-), and R1 is derived from a cytotoxic drug containing a hydroxyl group or an amino group; or, Z-R1 is a hydroxyl group;

[0018] R2 is selected from hydrogen atom, C 1-6 Alkyl, halogen, nitro, amino, carboxyl, C 1-6 Alkoxy, acylamino R a -CONH-, alkoxyacyl R b OCO-, where R a , R b Independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl, alkenyl, halogenated alkenyl, aromatic group;

[0019] Any one of R3, R4, R5, and R6 is a photocage group that can break the ether bond and release the galactose hydroxyl group after light irradiation, and the other three are hydroxyl protecting groups;

[0020] The photocage group is selected from R c Selected from hydrogen atoms or C 1-6 Alkyl; R d , R e independently selected from hydrogen, halogen, nitro, amino, C 1-6 alkylamino, substituted or unsubstituted five- to six-membered saturated heterocyclic group, substituted or unsubstituted phenyl, substituted or unsubstituted C 1-6 The substituted groups on the alkoxy, saturated heterocyclic group or phenyl group are selected from halogen, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino; C 1-6 The substituted groups on the alkoxy group are selected from halogen, nitro, C 1-6 Alkyl, halogenated C 1-6 alkyl;

[0021] The hydroxyl protecting group is selected from: acetyl (Ac), benzoyl (Bz), tert-butyldimethylsilyl (TBDMS), levulinyl (Lev), pivaloyl (Piv), allyloxycarbonyl (Alloc), chloroacetyl (ClAc), dichloroacetyl (DCA), trichloroacetyl (TCA), 2-naphthylmethyl (Nap), p-methoxybenzyl (PMB), tert-butyldiphenylsilyl (TBDPS), triethylsilyl (TES), benzyl (Bn); or the ortho position (R3, R4, or R4, R5) forms an acetal or ketal structure.

[0022] In one embodiment of the present invention, the acetal and ketal structures can be specifically selected from: benzyl acetal (PhCH), isopropyl ketal ((CH3)2CH).

[0023] In one embodiment of the present invention, the prodrug intermediate compound has the following structure:

[0024]

[0025] In one embodiment of the present invention, when Z is a blank bond, R1 is derived from a cytotoxic drug containing a hydroxyl group, with the hydroxyl oxygen atom as the connection site, and the cytotoxic drug is selected from Compretin (CA4), 8-hydroxyquinoline (HQ), 5-chloro-8-hydroxyquinoline, camptothecin, 7-ethyl-10-hydroxycamptothecin, resorufin, iodoresorufin, duocarmycin MA, duocarmycin MB, duocarmycin GA, duocarmycin TM, chlorambucil, and 5-fluorouridine.

[0026] In one embodiment of the present invention, when Z is an ester group, R1 is derived from a cytotoxic drug containing an amino group, with the amino nitrogen atom as the connection site, and the cytotoxic drug is selected from curcumin analog EF24, amifide, gemcitabine, cytarabine, monomethyl auristatin E (MMAE), methylene blue, cyclophosphamide, linifanib, and doxorubicin.

[0027] Furthermore, C 1-6 The alkylamino group may specifically be a diethylamino group.

[0028] Furthermore, the five- to six-membered saturated heterocyclic group includes at least one heteroatom, and the heteroatom is N, O, or S. The five- to six-membered saturated heterocyclic group specifically includes: morpholinyl, piperidinyl, and piperazinyl.

[0029] Furthermore, C 1-6 Alkoxy groups include: C 1-6 Straight chain alkoxy, C 1-6 of branched alkoxy.

[0030] Furthermore, the photocage group is preferably Where R c is selected from a hydrogen atom or a methyl group; R d , R e independently selected from hydrogen, halogen, nitro, amino, hydroxyl, diethylamino, morpholinyl, piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted phenyl, substituted or unsubstituted C 1-6 Straight chain alkoxy, substituted or unsubstituted C 1-6 of branched alkoxy.

[0031] Further optimization of R c is a hydrogen atom, R d and R e It is a methoxy group.

[0032] Preferably R2 is nitro, and the substitution position of R2 is further preferred as follows:

[0033]

[0034] The present invention also provides a method for preparing an intermediate compound, comprising the following methods:

[0035] Method 1:

[0036] Compound i is then subjected to an etherification reaction to modify the R2 group of the 2-hydroxyl group of galactose to obtain compound ii; compound ii is brominated by iodine monobromide and then reacted with compound iii under the catalysis of silver oxide to obtain compound iv; compound iv is reduced by sodium borohydride to obtain compound v; compound v is reacted with a cytotoxic compound via a Mitsunobu reaction or a Williamson etherification reaction to obtain a final intermediate compound vi, or reacted with p-nitrophenyl chloroformate to form an active intermediate and then reacted with a cytotoxic compound to obtain a final intermediate compound vii;

[0037] Among them, the structure of compound i is The structure of compound ii is

[0038] The structure of compound iii is The structure of compound iv is

[0039] The structure of compound v is The structure of compound vi is The structure of compound vii is

[0040] Method 2:

[0041] Compound viii is modified with the R2 group at the 3-hydroxyl group of galactose by a classical regioselective strategy using dibutyltin oxide as a catalyst to obtain compound ix; then the acetal is removed by acid catalysis and then the exposed hydroxyl group on galactose is acetylated using acetic anhydride with pyridine as a solvent to obtain compound x; compound x is brominated with iodine monobromide and then reacted with compound iii by silver oxide catalysis to obtain compound xi; compound xi is reduced with sodium borohydride to obtain compound xii; compound xii is reacted with a cytotoxic compound by Mitsunobu reaction conditions or Williamson etherification reaction to obtain the final intermediate compound xiii, or reacted with p-nitrophenyl chloroformate to form an active intermediate and then reacted with a cytotoxic compound to obtain the final intermediate compound xiv;

[0042] Among them, the structure of compound viii is The structure of compound ix is The structure of compound x is The structure of compound xi is The structure of compound xii is The structure of compound xiii is The structure of compound xiv is

[0043] Method 3:

[0044] Compound xv is modified with the R2 group at the 4-position hydroxyl group of galactose by a classical regioselective strategy using dibutyltin oxide as a catalyst to obtain compound xvi; compound xvi is then acetylated in an acetic anhydride solution containing concentrated sulfuric acid and all hydroxyl groups are acetylated to obtain compound xvii; compound xvii is brominated with hydrobromic acid and then reacted with compound iii catalyzed by silver oxide to obtain compound xviii; compound xviii is reduced with sodium borohydride to obtain compound xix; compound xix is ​​reacted with a cytotoxic compound through Mitsunobu reaction conditions or Williamson etherification reaction to obtain the final intermediate compound xx, or reacted with p-nitrophenyl chloroformate to form an active intermediate and then reacted with a cytotoxic compound to obtain the final intermediate compound xxi;

[0045] Among them, the structure of compound xv is The structure of compound xvi is The structure of compound xvii is a mixture of α and β configurations The structure of compound xviii is The structure of compound xix is The structure of compound xx is The structure of compound xxi is

[0046] Method 4:

[0047] The hydroxyl group of compound xxii is protected by tert-butyldiphenylsilyl ether to obtain compound xxiii; the acetyl group on the sugar ring is then removed, and the hydroxyl group at position 6 on the sugar is selectively protected by triphenylmethyl to obtain xxiv; the hydroxyl groups at positions 2, 3, and 4 of compound xxiv are replaced by benzoyl groups, and the hydroxyl group at position 6 is removed and protected by triphenylmethyl to obtain compound xxv; compound xxv and compound xxvi are reacted by acid catalysis to obtain compound xxvii; TBDPS is removed by tetrabutylammonium fluoride to expose the hydroxyl group on the connecting arm to obtain compound xxviii; compound xxviii is coupled with a cytotoxic compound containing a hydroxyl group by Mitsunobu reaction or Williamson etherification reaction to synthesize the final intermediate compound xxix; or compound xxviii is coupled with p-nitrophenyl chloroformate to form an active intermediate and then coupled with the residue of an amino-containing cytotoxic compound to synthesize the final intermediate compound xxx;

[0048] The structure of compound xxii is The structure of compound xxiii is The structure of compound xxiv is The structure of compound xxv is The structure of compound xxvi is The structure of compound xxvii is The structure of compound xxviii is The structure of compound xxix is The structure of compound xxx is

[0049] Specifically:

[0050] Method 1:

[0051] In one embodiment of the present invention, the synthesis process of the above compound ii comprises:

[0052] Under the protection of inert gas, compound i was dissolved in dichloromethane, and then added in sequence Molecular sieve, R2-Br, silver oxide and tetrabutylammonium iodide are reacted at room temperature for 12 hours to obtain compound ii; the preferred molar ratio of compound i, R2-Br, silver oxide and tetrabutylammonium iodide is 1:1.5:2:0.5.

[0053] In one embodiment of the present invention, the synthesis process of the above compound iv comprises:

[0054] Compound ii was dissolved in dichloromethane and added Molecular sieve, add iodine monobromide (IBr) under the protection of inert gas at 0℃, return to room temperature and react for 1 hour to obtain a brominated intermediate. After the brominated intermediate is dissolved in acetonitrile, add Molecular sieve, compound iii, silver oxide and tetrabutylammonium iodide are reacted at room temperature for 12 hours to obtain compound iv; the molar ratio of compound ii, iodine monobromide, compound iii, silver oxide and tetrabutylammonium iodide is preferably 1:1:1.2:2:0.5.

[0055] In one embodiment of the present invention, the synthesis process of the above compound v comprises:

[0056] Compound iv is dissolved in a mixture of dichloromethane and isopropanol, sodium borohydride is added at 0°C under the protection of an inert gas, and the mixture is returned to room temperature for reaction for 2 hours to obtain compound v; the molar ratio of compound iv to sodium borohydride is preferably 1:2.

[0057] In one embodiment of the present invention, the synthesis process of the above compound vi comprises:

[0058] The Mitsunobu reaction method is preferred, wherein compound v is dissolved in tetrahydrofuran, and cytotoxic drugs, tributylphosphine and diisopropyl azodicarboxylate are added at 0°C under the protection of an inert gas, and the reaction is restored to room temperature for 2 hours to obtain compound vi; the molar ratio of compound v, cytotoxic drugs, triphenylphosphine and diisopropyl azodicarboxylate is preferably 1:1:1.1:1.

[0059] In one embodiment of the present invention, the synthesis process of the above compound vii comprises:

[0060] Compound vi is dissolved in dichloromethane, and p-nitrophenyl chloroformate, diisopropylethylamine and pyridine are added under the protection of inert gas at 0°C, and the mixture is returned to room temperature and reacted for 1 hour to obtain a carbonate intermediate compound. The molar ratio of compound vi, p-nitrophenyl chloroformate, diisopropylethylamine and pyridine is preferably 1:3:4:0.5;

[0061] The carbonate intermediate is dissolved in dichloromethane, and cytotoxic drugs, diisopropylethylamine and pyridine are added under the protection of inert gas at 0°C. After returning to room temperature, the reaction is carried out for 2 hours to obtain compound vii; the molar ratio of carbonate intermediate, cytotoxic drug, diisopropylethylamine and pyridine is preferably 1:1.5:1.5:0.2.

[0062] Method 2:

[0063] In one embodiment of the present invention, the synthesis process of the above compound ix comprises:

[0064] Toluene and dibutyltin oxide are added to compound viii in sequence under the protection of inert gas, and the solution is heated to reflux. After reflux for 6 hours, the mixture is returned to room temperature and the toluene is evaporated. The evaporated mixture is dissolved in N,N-dimethylformamide, and R2-Br, tetrabutylammonium bromide and cesium fluoride are added in sequence under the protection of inert gas. After reacting at room temperature for 16 hours, compound ix is ​​obtained; the molar ratio of compound viii, dibutyltin oxide, R2-Br, tetrabutylammonium bromide and cesium fluoride is preferably 1:1.2:1:1.1:1.1.

[0065] In one embodiment of the present invention, the synthesis process of the above compound x comprises:

[0066] Add 80% acetic acid aqueous solution to compound ix, stir at 50°C for 4 hours, and after the reaction, directly spin-dry the solvent to obtain a compound with the benzyl group removed and co-evaporate with toluene twice. Then, under the protection of an inert gas, the compound is dissolved in pyridine, and acetic anhydride and 4-dimethylaminopyridine are added in sequence. After reacting at room temperature for 4 hours, compound x is obtained; the preferred molar ratio of compound ix, acetic anhydride and 4-dimethylaminopyridine is 1:4.5:0.5.

[0067] In one embodiment of the present invention, the synthesis process of the above compound xi comprises:

[0068] Dissolve compound x in dichloromethane and add Molecular sieve, add iodine monobromide (IBr) under the protection of inert gas at 0℃, return to room temperature and react for 1 hour to obtain a brominated intermediate. After the brominated intermediate is dissolved in acetonitrile, add Molecular sieve, compound iv, silver oxide and tetrabutylammonium iodide are reacted at room temperature for 12 hours to obtain compound xi; the molar ratio of compound x, iodine monobromide, compound iv, silver oxide and tetrabutylammonium iodide is preferably 1:1:1.2:2.1:0.5.

[0069] In one embodiment of the present invention, the synthesis process of the above compound xii comprises:

[0070] Compound xi is dissolved in a mixture of dichloromethane and isopropanol, sodium borohydride is added at 0°C under the protection of an inert gas, and the mixture is returned to room temperature for reaction for 2 hours to obtain compound xii; the molar ratio of compound xi to sodium borohydride is preferably 1:2.

[0071] In one embodiment of the present invention, the synthesis process of the above compound xiii comprises:

[0072] The preferred method is the Mitsunobu reaction, wherein compound xii is dissolved in tetrahydrofuran, and cytotoxic drugs, tributylphosphine and diisopropyl azodicarboxylate are added under the protection of an inert gas at 0°C, and the reaction is restored to room temperature for 2 hours to obtain compound xiii. The molar ratio of compound xii, cytotoxic drugs, triphenylphosphine and diisopropyl azodicarboxylate is preferably 1:1:1.1:1;

[0073] In one embodiment of the present invention, the synthesis process of the above compound xiv comprises:

[0074] Compound xii is dissolved in dichloromethane, and p-nitrophenyl chloroformate, diisopropylethylamine and pyridine are added under the protection of inert gas at 0°C, and the mixture is returned to room temperature and reacted for 1 hour to obtain a carbonate intermediate compound. The molar ratio of compound xii, p-nitrophenyl chloroformate, diisopropylethylamine and pyridine is preferably 1:3:4:0.5;

[0075] The carbonate intermediate is dissolved in dichloromethane, and cytotoxic drugs, diisopropylethylamine and pyridine are added at 0°C under the protection of inert gas. After returning to room temperature, the reaction is carried out for 2 hours to obtain compound xiv; the molar ratio of carbonate intermediate, cytotoxic drug, diisopropylethylamine and pyridine is preferably 1:1.5:1.5:0.2.

[0076] Method 3:

[0077] In one embodiment of the present invention, the synthesis process of the above compound xvi comprises:

[0078] Toluene and dibutyltin oxide are added to compound xv in sequence under the protection of inert gas, and the solution is heated to reflux. After reflux for 6 hours, the mixture is returned to room temperature and the toluene is evaporated. The evaporated mixture is dissolved in N,N-dimethylformamide, and R2-Br and tetrabutylammonium bromide are added in sequence under the protection of inert gas. After reacting at room temperature for 16 hours, compound xvi is obtained. The molar ratio of compound xv, dibutyltin oxide, R2-Br and tetrabutylammonium bromide is preferably 1:1.2:1:1.1;

[0079] In one embodiment of the present invention, the synthesis process of the above compound xvii comprises:

[0080] Add acetic anhydride solution containing preferably 2% by volume of concentrated sulfuric acid to compound xvi under inert gas protection at 0°C, stir at 0°C for 20 minutes, and then return to room temperature for reaction for 2 hours to obtain compound xvii;

[0081] In one embodiment of the present invention, the synthesis process of the above compound xviii comprises:

[0082] Compound xvii was dissolved in dichloromethane, and 33% hydrogen bromide in acetic acid solution was added under inert gas protection at 0°C, and the mixture was stirred at room temperature for 2 hours to obtain a brominated intermediate. The brominated intermediate was dissolved in acetonitrile, and then the following were added in sequence under inert gas protection: Molecular sieve, compound iii, silver oxide and tetrabutylammonium iodide are reacted at room temperature for 12 hours to obtain compound xviii. The molar ratio of compound xvii, hydrogen bromide, compound iii, silver oxide and tetrabutylammonium iodide is preferably 1:7:1.2:2.3:0.5;

[0083] In one embodiment of the present invention, the synthesis process of the above compound xix comprises:

[0084] Dissolve compound xviii in a mixture of dichloromethane and isopropanol, add sodium borohydride at 0°C under inert gas protection, and return to room temperature for 2 hours to obtain compound xix. The molar ratio of compound xviii to sodium borohydride is preferably 1:2;

[0085] In one embodiment of the present invention, the synthesis process of the above compound xx comprises:

[0086] The preferred method is the Mitsunobu reaction, wherein compound xix is ​​dissolved in tetrahydrofuran, cytotoxic drugs, tributylphosphine and diisopropyl azodicarboxylate are added at 0°C under the protection of an inert gas, and the reaction is restored to room temperature for 2 hours to obtain compound xx. The molar ratio of compound xix, cytotoxic drugs, tributylphosphine and diisopropyl azodicarboxylate is preferably 1:1:1.1:1;

[0087] In one embodiment of the present invention, the synthesis process of the above compound xxi comprises:

[0088] Dissolve compound xix in dichloromethane, add p-nitrophenyl chloroformate, diisopropylethylamine and pyridine at 0°C under inert gas protection, return to room temperature and react for 1 hour to obtain a carbonate intermediate compound, wherein the molar ratio of compound xix, p-nitrophenyl chloroformate, diisopropylethylamine and pyridine is preferably 1:3:4:0.5;

[0089] The carbonate intermediate is dissolved in dichloromethane, and cytotoxic drugs, diisopropylethylamine and pyridine are added under the protection of inert gas at 0°C. After returning to room temperature, the reaction is carried out for 2 hours to obtain compound xxi; the molar ratio of carbonate intermediate, cytotoxic drug, diisopropylethylamine and pyridine is preferably 1:1.5:1.5:0.2.

[0090] Method 4:

[0091] In one embodiment of the present invention, the synthesis process of the above compound xxiii comprises:

[0092] The compound xxii is dissolved in N,N-dimethylformamide, and imidazole and tert-butyldiphenylsilyl chloride (TBDPSCl) are added in sequence under the protection of inert gas, and the reaction is carried out at room temperature for 2 hours to obtain the compound xxiii, wherein the molar ratio of 4-hydroxymethyl-2-nitrophenyl-tetra-O-acetyl-β-galactoside, imidazole and TBDPSCl is preferably 1:2:1.5.

[0093] In one embodiment of the present invention, the synthesis process of the above compound xxiv comprises:

[0094] Compound xxiii was dissolved in methanol, sodium methoxide was added and reacted at room temperature for 2 hours, and then H + Exchange the resin, filter the resin and directly concentrate it and dissolve it in a pyridine solution. Add triphenylmethane (TrtCl) under inert gas protection at 0°C, add triethylamine dropwise after it is fully dissolved, and react for 14 hours to obtain compound xxiv; the molar ratio of compound xxiii to sodium methoxide, TrtCl and triethylamine is preferably 1:0.5:3:1.4.

[0095] In one embodiment of the present invention, the synthesis process of the above compound xxv comprises:

[0096] Compound xxiv is dissolved in pyridine, and benzoyl chloride (BzCl) is added under inert gas protection at 0°C. After reacting for 6 hours, the reaction solution is directly concentrated under reduced pressure to obtain compound xxv. The molar ratio of compound xxiv to BzCl is preferably 1:4.5.

[0097] In one embodiment of the present invention, the synthesis process of the above compound xxvii comprises:

[0098] Compound v is dissolved in dry dichloromethane, and compound xxvi and trifluoromethanesulfonic acid are added in sequence at 0°C under the protection of inert gas. After reacting at 0°C for 1 hour, compound xxvii is obtained; the molar ratio of compound xxv, compound xxvi and trifluoromethanesulfonic acid is preferably 1:2:0.5.

[0099] In one embodiment of the present invention, the synthesis process of the above compound xxviii comprises:

[0100] Compound vii is dissolved in tetrahydrofuran, and acetic acid and 1 mmol / L tetrabutylammonium fluoride tetrahydrofuran solution are added under inert gas protection at 0°C, and the reaction is carried out for 2 hours to obtain compound xxviii; the molar ratio of compound xxvii, acetic acid and tetrabutylammonium fluoride is preferably 1:0.5:2.

[0101] In one embodiment of the present invention, the synthesis process of the above compound xxix comprises:

[0102] Method 1: Compound xxviii is dissolved in tetrahydrofuran, and cytotoxic drugs, tributylphosphine and diisopropyl azodicarboxylate are added at 0°C under the protection of inert gas. The molar ratio of compound xxviii, cytotoxic drugs, triphenylphosphine and diisopropyl azodicarboxylate is preferably 1:1.2:1.1:1;

[0103] Alternatively, method 2: Compound xxviii is dissolved in dichloromethane, phosphorus tribromide is added at 0°C under inert gas protection, and the brominated intermediate is obtained after reaction for 1 hour. The brominated intermediate is extracted and spin-dried, and then dissolved in acetonitrile, a cytotoxic drug is added, and then silver oxide is added to obtain compound xxix. The preferred molar ratio of compound xxviii, phosphorus tribromide, cytotoxic drug, and silver oxide is 1:0.5:1.2:2.

[0104] In one embodiment of the present invention, the synthesis process of the above compound xxx comprises:

[0105] Compound xxviii is dissolved in dichloromethane, and p-nitrophenyl chloroformate, diisopropylethylamine and pyridine are added under the protection of inert gas at 0°C. After returning to room temperature, the reaction is carried out for 1 hour to obtain a carbonate intermediate compound. The molar ratio of compound xxviii, p-nitrophenyl chloroformate, diisopropylethylamine and pyridine is preferably 1:3:4:0.5;

[0106] The carbonate intermediate is dissolved in dichloromethane, and cytotoxic drugs, diisopropylethylamine and pyridine are added under the protection of inert gas at 0°C. After returning to room temperature, the reaction is carried out for 2 hours to obtain compound x; the molar ratio of carbonate intermediate, cytotoxic drug, diisopropylethylamine and pyridine is preferably 1:1.5:1.5:0.2.

[0107] The present invention also provides the use of the intermediate compound in the preparation of β-galactoside prodrug.

[0108] The application comprises: removing the hydroxyl protecting group of the intermediate compound under acetyl chloride or alkaline environment to obtain the corresponding β-galactoside prodrug.

[0109] There are two specific situations:

[0110] A. In the presence of acetyl chloride, the above compound vi or vii is subjected to the removal of the 6-hydroxyl tert-butyl dimethylsilyl ether of galactose and the acetonide protecting groups of the 3- and 4-hydroxyl groups of galactose to obtain a β-galactoside prodrug;

[0111] B. The above-mentioned compound xiii, compound xiv, compound xx, compound xxi, compound xxix, or compound xxx is subjected to alkaline conditions to remove other hydroxyl protecting groups on galactose except the photocage group to obtain the corresponding β-galactoside prodrug.

[0112] In one embodiment of the present invention, the above method A specifically includes the following process:

[0113] Under the protection of inert gas, compound vi or compound vii is dissolved in a mixture of methanol and dichloromethane, the mixture is cooled to 0°C and acetyl chloride is added, and the mixture is restored to room temperature for reaction for 6 hours to obtain a β-galactoside prodrug; the mixing ratio of methanol and dichloromethane is preferably 1:1, and the molar ratio of compound vi and acetyl chloride is preferably 1:2.

[0114] In one embodiment of the present invention, the above method B specifically includes the following process:

[0115] Under the protection of inert gas, compound xiii or compound xiv is dissolved in a mixture of methanol and dichloromethane, and then sodium methoxide solution is added, and the mixture is reacted at room temperature for 2 hours to obtain a β-galactoside prodrug; the molar ratio of compound xiii or compound xiv to sodium methoxide is preferably 1:0.6;

[0116] Alternatively, compound xx or compound xxi is dissolved in a mixture of methanol and dichloromethane under inert gas protection, and then sodium methoxide solution is added, and the mixture is reacted at room temperature for 2 hours to obtain a β-galactoside prodrug; the volume ratio of methanol to dichloromethane is preferably 4:4, and the molar ratio of compound xx or compound xxi to sodium methoxide is preferably 1:0.6;

[0117] Alternatively, compound xxix or compound xxx is dissolved in methanol, sodium methoxide is added, and then H + Exchange the resin, and filter the resin to obtain the β-galactoside prodrug; the feed ratio of compound xxix to sodium methoxide is preferably 1:1.

[0118] In one embodiment of the present invention, the intermediate compound is specifically:

[0119]

[0120]

[0121] The corresponding prodrug compounds are:

[0122]

[0123] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0124] The present invention aims to provide a new intermediate compound, which can be used to construct an unreported dual-stimulation condition-activated β-galactoside prodrug. The β-galactoside prodrug (also known as a double prodrug) constructed based on the intermediate compound needs to respond to light and β-galactosidase in sequence to release the drug, and the controllability of drug release is improved through the logical construction of the "AND gate". Since β-galactosidase has a high substrate specificity, the introduction of the photocage group makes the double prodrug unable to be hydrolyzed by β-galactosidase, reducing the risk of releasing the mother drug in non-tumor sites. The double prodrug of the present invention is converted into a single prodrug after removing the photocage group by light, and further responds to β-galactosidase to release the drug. Activity tests have shown that the prepared double prodrug does have strong controllability. BRIEF DESCRIPTION OF THE DRAWINGS

[0125] Figure 1 This is the H NMR spectrum of the intermediate compound vi obtained in Example 1.

[0126] Figure 2 This is the NMR carbon spectrum of the intermediate compound vi obtained in Example 1.

[0127] Figure 3 It is the H NMR spectrum of prodrug compound A.

[0128] Figure 4 This is the NMR carbon spectrum of prodrug compound A.

[0129] Figure 5 This is the H NMR spectrum of the intermediate compound xiii obtained in Example 2.

[0130] Figure 6This is the NMR carbon spectrum of the intermediate compound xiii obtained in Example 2.

[0131] Figure 7 It is the H NMR spectrum of prodrug compound B.

[0132] Figure 8 This is the NMR carbon spectrum of prodrug compound B.

[0133] Fig. 9 This is the H NMR spectrum of the intermediate compound xx obtained in Example 3.

[0134] Fig.10 This is the H NMR spectrum of prodrug compound C.

[0135] Fig.11 This is the NMR carbon spectrum of prodrug compound C.

[0136] Fig.12 This is the H NMR spectrum of the intermediate compound xxviii obtained in Example 4.

[0137] Fig.13 This is the NMR carbon spectrum of the intermediate compound xxviii obtained in Example 4.

[0138] Fig.14 It is the H NMR spectrum of prodrug compound D.

[0139] Fig.15 This is the NMR carbon spectrum of prodrug compound D.

[0140] Fig.16 These are the results of cytotoxicity tests of prodrug compounds A, B, C and D on OVCAR3 cells.

[0141] Fig.17 These are the results of cytotoxicity tests of prodrug compounds A, B, C and D on SKOV3 cells. DETAILED DESCRIPTION

[0142] The present invention is further described in detail below in conjunction with embodiments and drawings, but the embodiments of the present invention are not limited thereto.

[0143] In the following examples, compound i can be prepared by referring to the literature (Collins, SL; Saha, J.; Bouchez, LC; Hammond, EM; Conway, SJ Hypoxia-Activated, Small-Molecule-Induced Gene Expression. ACS Chem Biol, 2018, 13 (12), 3354-3360.).

[0144] Compound viii can be prepared by referring to the literature (D'Angelo, KA; Taylor, MS Borinic Acid Catalyzed Stereo-and Regioselective Couplings of Glycosyl Methanesulfonates. J Am Chem Soc, 2016, 138(34), 11058-11066.).

[0145] Compound xv can be prepared by referring to the literature (Liang, C.; Lee, DW; Newton, MG; Chu, CK Synthesis of L-Dioxolane Nucleosides and Related Chemistry. J Org Chem, 1995, 60(6), 1546-1553).

[0146] Compound xxii can be found in the literature (Chauvin, T.; Durand, P.; Bernier, M.; Meudal, H.; Doan, B.-T.; Noury, F.; Badet, B.; Beloeil, J.-C.; Tóth, Detection of Enzymatic Activity by PARACEST MRI: A General Approach to Target a Large Variety of Enzymes. AngewChem IntEdit, 2008, 47(23), 4370-4372.) Homemade.

[0147] Compound xxvi can be found in the literature (Tang, S.; Wan, Z.; Gao, Y.; Zheng, J.-S.; Wang, J.; Si, Y.-Y.; Chen, X.; Qi, H.; Liu, L.; Liu, W. Total chemical synthesis of photoactivatable proteins for light-controlled manipulation of antigen–antibody interactions. Chem Sci,2016,7(3),1891-1895.) Self-made.

[0148] Other reagents used were commercially purchased.

[0149] Embodiment 1:

[0150] (1) Synthesis of compound ii:

[0151]

[0152] Specific operations:

[0153] Under inert gas protection, compound i (1.12 g, 2.17 mmol, 1.0 equiv.) was dissolved in dichloromethane (20 mL), and silver oxide (571 mg, 8.39 mmol, 2.0 equiv.), tetrabutylammonium iodide (402 mg, 1.09 mmol, 0.5 equiv.), and Molecular sieves. After stirring for 10 minutes, 4,5-dimethoxy-2-nitrobenzyl bromide (898 mg, 3.25 mmol, 1.5 equiv.) dissolved in dichloromethane (5 mL) was added, and the reaction solution was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was diluted with dichloromethane and the silver oxide was filtered using diatomaceous earth. The organic phase was washed twice in sequence with water, saturated ammonium chloride and saturated brine, respectively. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated by reduced pressure distillation using a rotary evaporator to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate, 20:1, v / v) to obtain a yellow oil compound ii (649 mg, 0.911 mmol, yield 42%).

[0154] 1 H NMR (400MHz, CDCl3) δ7.72-7.67(m,4H,Ar),7.65(s,1H,Ar(DMNB)),7.50(s,1H,Ar(DMNB)),7.47-7.34(m,6H,Ar),5.29-5.14(m,2H ,ArCH2),4.52(d,J=9.9Hz,1H,1-H),4.28(dd,J=5.5,2.1Hz,1H,4-H),4.22(dd,J=6.8,5.4Hz,1H,3-H),4.03(s,3H,ArOCH3),3.96-3 .89(m,5H,6-H,ArOCH3),3.84(ddd,J=7.1,5.8,2.1Hz,1H,5-H),3.47(dd,J=9.9,6.7Hz,1H,2-H),3.27(hept,J=6.7Hz,1H,SCH),1.3 9(s,3H,CH3(isopropylidene)),1.34-1.27(m,9H,CH3(isopropylidene),CH3(isopropylthio)×2),1.05(s,9H,C(CH3)3(TBDPS)).

[0155] 13C NMR (151MHz, CDCl3) δ153.7,147.6,139.6,135.7,135.6,133.5,133.4,130.7,129.8,127.8,127.7,110.5,11 0.1,107.7,82.6,80.1,79.4,73.7,69.4,63.0,56.6,56.4,34.3,28.0,26.81,26.79,26.4,23.9,23.7,19.2.

[0156] ESI-MS: found 734.20[M+Na] + .

[0157] (2) Synthesis of Compound iv:

[0158]

[0159] Specific operations:

[0160] (a) Under argon protection, compound ii (300 mg, 0.421 mmol, 1.0 equiv.) was dissolved in dry dichloromethane (3 mL). The mixture was cooled to 0° C. in an ice bath and stirred for 10 minutes. Then, Molecular sieves and iodine monobromide (87 mg, 0.421 mmol, 1.0 equiv.). After the reaction is completed, the molecular sieves are removed by filtration, and the organic phase is collected and washed twice in sequence with 10% sodium thiosulfate, saturated sodium bicarbonate and saturated brine. The organic phase is then dried with anhydrous sodium sulfate, filtered, and then concentrated with a rotary evaporator under reduced pressure to obtain a crude bromide, which is directly used in the next step.

[0161] (b) The crude bromide was dissolved in dry acetonitrile (4 mL), and compound iii (85 mg, 0.506 mmol, 1.2 equiv.), silver oxide (195 mg, 0.842 mmol, 2.0 equiv.), tetrabutylammonium iodide (78 mg, 0.211 mmol, 0.5 equiv.) and Molecular sieve. After reacting at room temperature for 12 hours, the silver oxide and molecular sieve were filtered using diatomaceous earth, and the organic phase was washed twice with sodium carbonate, water, saturated sodium bicarbonate and saturated brine in sequence. The organic phase was collected and dehydrated with anhydrous sodium sulfate, and the solvent was concentrated after filtering out the sodium sulfate solid to obtain a crude mixture. The crude product was separated and purified using a silica gel column (petroleum ether: ethyl acetate, 7:3, v / v) to obtain a light yellow oily compound iv (142 mg, 0.180 mmol, yield 42%).

[0162] 1H NMR (400MHz, CDCl3) δ9.89(s,1H,ArCHO),8.31(t,J=1.6Hz,1H,Ar),7.79(dt,J=8.7,1.6Hz,1H,Ar),7.71-7.60(m,5H, Ar×4,Ar(DMNB)),7.48-7.28(m,8H,Ar×7,Ar(DMNB)),5.24(s,2H,ArCH2),5.13(d,J=7.8Hz,1H,1-H),4.33(t,J=6.1Hz, 1H, 3-H), 4.24 (dd, J=5.6, 1.8Hz, 1H, 4-H), 4.07 (t, J=6.1Hz, 1H, 5-H), 4.03-3.90 (m, 8H, 6-H, ArOCH3×2), 3.77 (t, J=7. 2Hz,1H,2-H),1.40(s,3H,CH3(isopropylidene)),1.31(s,3H,CH3(isopropylidene)),1.07(s,9H,C(CH3)3(TBDPS)).

[0163] 13 C NMR (101MHz, CDCl3) δ188.7,154.1,153.4,147.9,140.7,140.2,135.62,135.56,134.4,133.2,132.9,130.6,130.0,129.9,129.3, 127.84,127.80,126.9,118.0,111.3,110.8,108.1,100.5,79.7,78.5,75.0,73.1,70.6,63.0,56.5,56.4,27.8,26.8,26.3,19.3.

[0164] ESI-MS: found 825.19[M+Na] + .

[0165] (3) Synthesis of Compound V:

[0166]

[0167] Specific operations:

[0168] Under the protection of inert gas, compound iv (130 mg, 0.162 mmol, 1.0 equiv.) was dissolved in a mixed solution of dichloromethane and isopropanol (2 mL), the mixed solution was cooled to 0 ° C in an ice bath, sodium borohydride powder (12 mg, 0.324 mmol, 2.0 equiv.) was added, and the reaction solution was slowly heated from 0 ° C to room temperature and continued to react for 2 hours. After TLC confirmed that the crude raw material reaction was complete. Then the reaction solution was diluted with dichloromethane, and washed twice in sequence with water, saturated ammonium chloride, saturated sodium bicarbonate, and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, and the anhydrous sodium sulfate was filtered off and the organic phase was concentrated by vacuum distillation using a rotary evaporator. After concentration, the crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate, 1: 1, v / v) to obtain a light yellow oily compound v (123 mg, 0.153 mmol, yield 94%).

[0169] 1 H NMR(600MHz,CDCl3)δ7.80(s,J=2.0Hz,1H,Ar),7.72-7.61(m,5H,Ar×4,Ar(DMNB)),7.48-7.24(m,9H,Ar×8,Ar(DMNB) ),5.25(s,2H,ArCH2(DMNB)),5.01(d,J=7.9Hz,1H,1-H),4.68-4.61(m,2H,ArCH2),4.30(dd,J=6.7,5.5Hz,1H,3-H), 4.23(dd,J=5.6,1.9Hz,1H,4-H),4.07-3.89(m,9H,5-H,6-H,ArOCH3),3.73(dd,J=7.9,6.7Hz,1H,2-H),1.79(t,J=5. 8Hz,1H,OH),1.39(s,3H,CH3(isopropylidene)),1.31(s,3H,CH3(isopropylidene)),1.05(s,9H,C(CH3)3(TBDPS)).

[0170] 13 C NMR (151MHz, CDCl3) δ153.5,149.1,147.8,140.9,140.1,135.8,135.7,135.6,133.3,133.2,132.1,129.9,129.83,129.81,1 27.8,123.5,118.9,111.3,110.6,108.1,101.0,79.9,78.8,74.6,73.3,70.5,63.7,63.0,56.5,56.4,27.8,26.9,26.3,19.3.

[0171] ESI-MS: found 827.31[M+Na] + .

[0172] (4) Synthesis of intermediate compound vi:

[0173]

[0174] Specific operations:

[0175] Under the protection of inert gas, compound v (60 mg, 0.074 mmol, 1.0 equiv.) and CA4 (23 mg, 0.074 mmol, 1.0 equiv.) were dissolved in a dry tetrahydrofuran solution (1 mL), the mixture was cooled to 0°C in an ice bath and stirred for 15 minutes, and tributylphosphine (20 μL, 0.081 mmol, 1.1 equiv.) and diisopropyl azodicarboxylate (15 μL, 0.077 mmol, 1.0 equiv.) were added in sequence, and the reaction solution was heated from 0°C to room temperature and continued to react for 1 hour. The reaction solution was diluted with dichloromethane and washed twice with saturated ammonium chloride, saturated sodium bicarbonate, and saturated sodium chloride solutions in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by reduced pressure distillation using a rotary evaporator. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate, 3:2, v / v) to give a light yellow oil vi (49 mg, 0.044 mmol, yield 60%).

[0176] 1H NMR(600MHz,CDCl3)δ7.80(s,1H,Ar),7.71-7.62(m,5H,Ar×4,Ar(DMNB)),7.45-7.29(m,8H,Ar×7,Ar(DMNB)),7.26-7.23(m,1H,Ar),6.90(d,J=8.2Hz,1H,Ar(CA4)),6.84-6.77(m,2H,Ar(CA4)),6.48(s,2H,Ar(CA4)),6.43(s,2H,Ar(CA4)),5.25(s,2H,ArCH2(DMNB)),5.02(d,J=7.8Hz,1H,1-H),4.85(d,J=3.5Hz,2H,ArCH2),4.30(t,J=6.2Hz,1H,3-H),4.24(d,J=5.8Hz,1H,4-H),4.01(t,J=6.61Hz,1H,5-H),3.97(s,3H,ArOCH3(DMNB)),3.96-3.92(m,5H,ArOCH3(DMNB),6-H),3.84(s,3H,ArOCH3(CA4)),3.81(s,3H,ArOCH3(CA4)),3.72(t,J=7.4Hz,1H,2-H),3.67(s,6H,ArOCH3(CA4)),1.40(s,3H,CH3(isopropylidene)),1.31(s,3H,CH3(isopropylidene)),1.04(s,9H,C(CH3)3(TBDPS)).

[0177] 13 C NMR(101MHz,CDCl3)δ153.4,153.1,149.4,149.0,147.7,147.1,140.8,140.0,135.7,135.6,133.2,133.1,132.9,132.6,132.0,129.91,129.89,129.88,129.8,129.5,129.1,127.8,124.0,123.2,118.6,114.9,111.6,111.2,110.5,108.0,106.0,100.9,79.8,78.7,74.4,73.2,70.5,69.4,62.9,60.9,56.5,56.4,55.99,55.97,27.9,26.8,26.3,19.2.

[0178] ESI-MS:found 1125.5[M+Na] + .

[0179] Preparation of prodrug compound A using intermediates:

[0180]

[0181] Specific operations:

[0182] Under argon protection, vi (40 mg, 0.036 mmol, 1.0 equiv.) was dissolved in a mixture of methanol and dichloromethane (1 mL, 4:1, v / v), and acetyl chloride (4.4 μL, 0.061 mmol, 2.0 equiv.) was added. The reaction solution was stirred at room temperature for 6 hours. After the reaction was completed, the reaction solution was directly concentrated, and the crude product was purified by silica gel column chromatography (methanol: dichloromethane, 1:20, v / v) to obtain a white solid compound A (16 mg, 0.019 mmol, yield 54%)

[0183] 1 H NMR (600MHz, (CD3)2SO) δ7.85 (d, J=2.1Hz, 1H, Ar), 7.64 (s, 1H, Ar (DMNB)), 7.60 (dd, J= 8.8,2.2Hz,1H,Ar),7.46(d,J=9.5Hz,2H,Ar,Ar(DMNB)),6.95(d,J=1.9Hz,1H,Ar(CA4) ),6.93(d,J=8.4Hz,1H,Ar(CA4)),6.89(dd,J=8.3,1.9Hz,1H,Ar(CA4)),6.56(s,2H,Ar (CA4)),6.51(d,J=12.2Hz,1H,Ar(CA4)),6.47(d,J=12.2Hz,1H,Ar(CA4)),5.38(d,J=7 .6Hz,1H,1-H),5.14(d,J=15.7Hz,1H,ArCH2(DMNB)),5.06(d,J=15.6Hz,1H,ArCH2(DMN) B)),4.90(s,2H,ArCH2),3.83(s,3H,ArOCH3(CA4)),3.78(s,1H,4-H),3.76-3.72(m,7H ,ArOCH3(DMNB),5-H),3.70-3.68(m,2H,3-H,2-H),3.63(s,3H,ArOCH3(CA4)),3.60(s, 6H, ArOCH3(CA4)), 3.57(dd,J=11.0,5.9Hz,1H,6-H), 3.51(dd,J=10.9,6.6Hz,1H,6-H).

[0184] 13C NMR (151MHz, (CD3)2SO) δ153.3,152.6,148.9,148.6,147.1,147.0,139.3,138.5,136.8,133.4,132.4,131.0,130.7,129.3,129.2,128.7, 123.9,122.2,116.9,114.5,112.0,110.2,107.8,106.0,100.1,79.9, 75.8,72.4,70.5,68.5,68.1,60.04,60.02,56.0,55.8,55.63,55.61.

[0185] HRMS: m / z calculated [M+Na] + =847.2532, found 847.2536.

[0186] Embodiment 2:

[0187] (1) Synthesis of compound ix:

[0188]

[0189] Specific operations:

[0190] (a) To compound viii (600 mg, 1.84 mmol, 1.0 equiv.) were added toluene (20 mL) and dibutyltin oxide (550 mg, 2.21 mmol, 1.2 equiv.) in sequence under inert gas protection, and the solution was heated to reflux. After reflux for 6 hours, the mixture was returned to room temperature and the toluene was evaporated to dryness.

[0191] (b) The mixture after evaporation was dissolved in N,N-dimethylformamide (15 mL), and cesium fluoride (307 mg, 2.02 mmol, 1.1 equiv.), tetrabutylammonium bromide (652 mg, 2.02 mmol, 1.1 equiv.) and 4,5-dimethoxy-2-nitrobenzyl bromide (508 mg, 1.84 mmol, 1.0 equiv.) were added in sequence under the protection of inert gas. After stirring at 60°C for 16 hours, the N,N-dimethylformamide in the reaction solution was removed by reduced pressure distillation, and then dissolved in dichloromethane and washed twice with water, saturated ammonium chloride and saturated brine in sequence, and the organic phase was placed on anhydrous sodium sulfate for drying. After filtering off anhydrous sodium sulfate, the organic phase was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate, 3:1, v / v) to obtain yellow solid compound ix (451 mg, 0.846 mmol, yield 46%).

[0192] 1H NMR (400MHz, CDCl3) δ7.69(s,1H,Ar(DMNB)),7.54(s,1H,Ar(DMNB)),7.52-7.45(m,2H,Ar),7.37-7.30(m,3H,Ar),5.52(s,1H,P hCH),5.19(d,J=15.9Hz,1H,ArCH2),5.12(d,J=15.9Hz,1H,ArCH2),4.45(d,J=9.7Hz,1H,1-H),4.41(dd,J=3.6,1.1Hz,1H,4-H), 4.35(dd,J=12.5,1.6Hz,1H,6-H),4.12-4.01(m,2H,2-H,6-H),3.94(s,3H,ArOCH3),3.74(s,3H,ArOCH3),3.64(dd,J=9.2,3.5H z,1H,3-H),3.49(q,J=1.5Hz,1H,5-H),3.32(hept,J=6.7Hz,1H,SCH),2.57(s,1H,OH),1.45-1.33(m,6H,CH3(isopropylthio)).

[0193] 13 C NMR (151MHz, CDCl3) δ154.0,147.6,139.0,137.9,131.1,129.1,128.2,126.5,110.3, 107.8,101.5,86.1,81.4,73.2,70.2,69.5,68.5,67.9,56.4,56.3,35.0,24.6,24.1.

[0194] ESI-MS: found 544.5[M+Na] + .

[0195] (2) Synthesis of compound x:

[0196]

[0197] Specific operations:

[0198] (a) Under inert gas protection, 80% acetic acid aqueous solution (5 mL, v / v) was added to compound ix (220 mg, 0.421 mmol, 1.0 equiv) and stirred at 60° C. for 12 hours. After the reaction, the reaction solution was dried by vacuum distillation to obtain a crude product after the benzylidene ketal was removed.

[0199] (b) After the crude product was co-evaporated with toluene twice, pyridine (5 mL), 4-dimethylaminopyridine (26 mg, 0.211 mmol, 0.5 equiv.) and acetic anhydride (0.18 mL, 1.90 mmol, 4.5 equiv.) were added to the dry crude product under inert gas protection at 0°C. The reaction was returned to room temperature and the reaction was continued for 12 hours. The reaction solution was diluted with EA and washed twice with water, 1M hydrochloric acid, saturated sodium bicarbonate and saturated brine in sequence. The organic phase was collected and dried over anhydrous sodium sulfate. After filtering off anhydrous sodium sulfate, the organic phase was concentrated and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate, 2:1, v / v) to obtain yellow foam compound x (201 mg, 0.358 mmol, yield 85%).

[0200] 1 H NMR (400MHz, CDCl3) δ7.70(s,1H,Ar(DMNB)),7.18(s,1H,Ar(DMNB)),5.63(dd,J=3.4,1.1Hz,1H,4-H),5.25(t,J=9.8Hz,1H,2-H) ,5.10(dd,J=14.5,0.9Hz,1H,ArCH2),4.91(dd,J=14.6,0.8Hz,1H,ArCH2),4.58(d,J=10.1Hz,1H,1-H),4.17(qd,J=11.4,6.7Hz,2 H,6-H),3.99(s,3H,ArOCH3),3.94(s,3H,ArOCH3),3.90(td,J=6.6,1.1Hz,1H,5-H),3.76(dd,J=9.4,3.4Hz,1H,3-H),3.20(hept ,J=6.8Hz,1H,SCH),2.11(s,3H,CH3(Ac)),2.07(s,3H,CH3(Ac)),2.06(s,3H,CH3(Ac)),1.44-1.33(m,6H,CH3(isopropylthio)).

[0201] 13 C NMR (101MHz, CDCl3) δ170.5,170.2,169.8,154.1,147.7,138.8,130.1,109.6,107.8, 83.7,80.0,74.5,69.4,66.7,61.9,56.7,56.4,35.6,24.1,23.8,21.1,20.81,20.77.

[0202] ESI-MS: found 582.6[M+Na] + .

[0203] (3) Synthesis of compound xi:

[0204]

[0205] Specific operations:

[0206] (a) Under inert gas protection, compound x (150 mg, 0.268 mmol, 1.0 equiv.) was dissolved in dry dichloromethane (3 mL). The mixture was cooled to 0°C in an ice bath and stirred for 10 minutes. Then, Molecular sieves and iodine monobromide (56 mg, 0.268 mmol, 1.0 equiv.). After the reaction is completed, the molecular sieves are filtered off, and the organic phase is collected and washed twice in sequence with 10% sodium thiosulfate, saturated sodium bicarbonate and saturated brine. The organic phase is then dried with anhydrous sodium sulfate, filtered, and then concentrated with a rotary evaporator under reduced pressure to obtain a crude bromide, which is directly used in the next step.

[0207] (b) The crude bromide was dissolved in dry acetonitrile (2.5 mL), and then 4-hydroxy-3-nitrobenzaldehyde (54 mg, 0.322 mmol, 1.2 equiv.), silver oxide (130 mg, 0.563 mmol, 2.1 equiv.), tetrabutylammonium iodide (50 mg, 0.134 mmol, 0.5 equiv.) and Molecular sieve. After 8 hours of reaction at room temperature, the silver oxide and molecular sieve were filtered using diatomaceous earth and the filter cake was washed with dichloromethane. The organic phase was washed twice in sequence with sodium carbonate, water, saturated sodium bicarbonate and saturated brine. The organic phase was collected and dehydrated with anhydrous sodium sulfate. After filtering out the sodium sulfate solid, the solvent was concentrated to obtain a crude mixture. The crude product was separated and purified using a silica gel column (petroleum ether: ethyl acetate, 2: 1, v / v) to obtain a light yellow solid compound xi (85 mg, 0.131 mmol, yield 49%).

[0208] 1H NMR(600MHz,CDCl3)δ9.98(s,1H,ArCHO),8.30(d,J=1.9Hz,1H,Ar),8.07(dd,J=8.6,1.9Hz,1H,Ar),7.71(s,1H,Ar(DMNB)),7.50(d,J=8.6H z,1H,Ar),7.20(s,1H,Ar(DMNB)),5.68(d,J=3.3Hz,1H,4-H),5.61(dd,J=9.9,7.9Hz,1H,2-H),5.22(d,J=7.9Hz,1H,1-H),5.14(d,J=14.4H z,1H,ArCH2(DMNB)),4.92(d,J=14.3Hz,1H,ArCH2(DMNB)),4.29(dd,J=11.6,7.0Hz,1H,6-H),4.23(dd,J=11.6,6.0Hz,1H,6-H),4.13(t,J= 6.6Hz,1H,5-H),4.00(s,3H,ArOCH3),3.95(s,3H,ArOCH3),3.86(dd,J=10.2,3.4Hz,1H,3-H),2.15(s,3H,CH3(Ac)),2.11(s,6H,CH3(Ac)).

[0209] 13 C NMR (151MHz, CDCl3) δ188.6,170.4,170.0,169.5,154.2,153.7,147.9,138.8,133.9,131.5,129.7 ,126.9,118.8,109.6,108.0,100.1,78.5,72.0,69.5,65.9,61.7,56.7,56.4,20.8,20.73,20.68.

[0210] ESI-MS: found 673.2[M+Na] + .

[0211] (4) Synthesis of Compound xii:

[0212]

[0213] Specific operations:

[0214] Under the protection of inert gas, compound xi (80 mg, 0.123 mmol, 1.0 equiv.) was dissolved in a mixed solution of dichloromethane and isopropanol (2 mL), the mixed solution was cooled to 0°C in an ice bath, sodium borohydride powder (9 mg, 0.246 mmol, 2.0 equiv.) was added, the reaction solution was slowly heated from 0°C to room temperature and continued to react for 2 hours. After TLC confirmed that the crude raw material reaction was complete. Then the reaction solution was diluted with dichloromethane, and washed twice in sequence with water, saturated ammonium chloride, saturated sodium bicarbonate, and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, and the anhydrous sodium sulfate was filtered off and the organic phase was concentrated by vacuum distillation using a rotary evaporator. After concentration, the crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate, 1:1, v / v) to obtain a light yellow oily compound xii (74 mg, 0.114 mmol, yield 93%).

[0215] 1 H NMR (600MHz, CDCl3) δ7.81(d,J=2.1Hz,1H,Ar),7.71(s,1H,Ar(DMNB)),7.53(dd,J=8.7,2.1Hz,1H,Ar),7.37(d,J=8.6Hz,1H,Ar),7.21 (s,1H,Ar(DMNB)),5.66(d,J=3.3Hz,1H,4-H),5.57(dd,J=9.9,8.0Hz,1H,2-H),5.14(d,J=14.6Hz,1H,ArCH2(DMNB)),5.07(d,J=8.0Hz, 1H,1-H),4.91(d,J=14.5Hz,1H,ArCH2(DMNB)),4.73(s,2H,ArCH2),4.29(dd,J=11.4,6.9Hz,1H,6-H),4.21(dd,J=11.4,6.2Hz,1H,6-H ),4.05(t,J=6.6Hz,1H,5-H),4.00(s,3H,ArOCH3),3.95(s,3H,ArOCH3),3.83(dd,J=10.0,3.3Hz,1H,3-H),2.18-2.09(m,9H,CH3(Ac)).

[0216] 13C NMR (151MHz, CDCl3) δ170.4,170.1,169.7,154.2,148.7,147.8,141.5,138.8,137.0,131.7,129.9,123 .3,120.0,109.6,107.9,100.9,78.7,71.6,69.8,69.4,66.1,63.6,61.7,56.7,56.4,20.9,20.8,20.7.

[0217] ESI-MS: found 675.5[M+Na] + .

[0218] (5) Synthesis of intermediate compound xiii:

[0219]

[0220] Specific operations:

[0221] Under inert gas protection, compound xii (35 mg, 0.054 mmol, 1.0 equiv.) and CA4 (17 mg, 0.054 mmol, 1.0 equiv.) were dissolved in a dry tetrahydrofuran solution (1 mL), the mixture was cooled to 0°C in an ice bath and stirred for 15 minutes, and tributylphosphine (15 μL, 0.060 mmol, 1.1 equiv.) and diisopropyl azodicarboxylate (11 μL, 0.054 mmol, 1.0 equiv.) were added in sequence, and the reaction solution was heated from 0°C to room temperature and continued to react for 1 hour. The reaction solution was diluted with dichloromethane and washed twice with saturated ammonium chloride, saturated sodium bicarbonate, and saturated sodium chloride solutions in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by reduced pressure distillation using a rotary evaporator. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate, 3:2, v / v) to give a light yellow oil xiii (42 mg, 0.044 mmol, yield 83%).

[0222] 1H NMR (400MHz, CDCl3) δ7.80 (d, J=2.3Hz, 1H, Ar), 7.72 (s, 1H, Ar (DMNB)), 7.44 (dd, J= 8.6,2.2Hz,1H,Ar),7.32(d,J=8.6Hz,1H,Ar),7.22(s,1H,Ar(DMNB)),6.91(dd,J=8 .3,2.0Hz,1H,Ar(CA4)),6.81(m,J=8.6Hz,2H,Ar(CA4)),6.50-6.42(m,4H,Ar(CA4) ),5.66(dd,J=3.4,1.1Hz,1H,4-H),5.57(dd,J=10.0,8.0Hz,1H,2-H),5.15(d,J=15 .1Hz,1H,ArCH2(DMNB)),5.09(d,J=8.0Hz,1H,1-H),4.96-4.87(m,3H,ArCH2(DMNB) ,ArCH2),4.25(qd,J=11.3,6.4Hz,2H,6-H),4.07(t,J=6.7Hz,1H,5-H),4.00(s,3H, ArOCH3(DMNB)),3.95(s,3H,ArOCH3(DMNB)),3.87(s,3H,ArOCH3(CA4)),3.88-3.81 (m,4H,3-H,ArOCH3(CA4)),3.69(s,6H,ArOCH3(CA4)),2.15-2.10(m,9H,CH3(Ac)).

[0223] 13 C NMR (101MHz, CDCl3) δ170.5,170.1,169.7,154.2,153.1,149.02,149.01,147. 7,147.1,141.3,138.7,133.1,133.0,132.5,132.2,130.0,129.9,129.5,129. 1,125.1,123.8,119.7,114.8,111.6,109.5,107.8,105.9,100.7,100.6,78.7,71.6,69.7,69.5,66.1,62.3,61.0,56.6,56.3,56.0,55.9,20.9,20.8,20.7.

[0224] ESI-MS: found 973.5[M+Na] + .

[0225] Use the intermediate to prepare the prodrug compound B:

[0226]

[0227] Specific operations:

[0228] Under inert gas protection, compound xiii (42 mg, 0.044 mmol, 1.0 equiv.) was dissolved in methanol (1 mL), followed by the addition of 5 mol / L sodium methoxide methanol solution (5 μL, 0.025 mmol, 0.6 equiv.) and stirring at room temperature for 2 hours. The reaction was terminated when TLC detected that all the raw materials had reacted and a single main point was generated. H + The reaction solution was neutralized with ion exchange resin, and after the pH of the solution was detected to be neutral to slightly acidic, the resin was filtered off and washed with a mixture of methanol and methanol-dichloromethane (2:1, v / v). The crude product was concentrated by vacuum distillation using a rotary evaporator, and the crude product was purified using a silica gel column (methanol: dichloromethane, 1:25, v / v) to obtain a white solid compound B (24 mg, 0.030 mmol, yield 68%).

[0229] 1H NMR(600MHz,(CD3)2SO)δ7.86(d,J=2.2Hz,1H,Ar),7.80(s,1H,Ar(DMNB)),7.69(s,1H,Ar(DMNB)),7.58(dd,J=8.8,2.2Hz,1H,Ar),7.43(d,J=8.8Hz,1H,Ar),6.96(d,J=2.0Hz,1H,Ar(CA4)),6.93(d,J=8.4Hz,1H,Ar(CA4)),6.89(dd,J=8.4,1.9Hz,1H,Ar(CA4)),6.56(s,2H,Ar(CA4)),6.53-6.44(m,2H,Ar(CA4)),5.75(d,J=7.6Hz,1H,OH),5.13(d,J=7.7Hz,1H,1-H),5.06(d,J=16.4Hz,1H,ArCH2),4.95(d,J=16.4Hz,1H,ArCH2),4.93-4.86(m,3H,ArCH2(DMNB),OH),4.74(t,J=5.4Hz,1H,OH),4.12-4.03(m,1H,4-H),3.92(s,3H,ArOCH3(DMNB)),3.89-3.82(m,4H,ArOCH3(DMNB),2-H),3.74(s,3H,ArOCH3(CA4)),3.66-3.61(m,4H,ArOCH3(CA4),5-H),3.61-3.57(m,7H,ArOCH3(CA4)×2,6-H),3.52(dt,J=11.1,5.5Hz,1H,6-H),3.43(dd,J=9.6,3.1Hz,1H,3-H).

[0230] 13 C NMR(151MHz,(CD3)2SO)δ153.8,152.6,149.2,148.6,147.1,147.0,139.8,138.6,136.7,133.3,132.4,131.5,130.7,129.3,128.8,123.9,122.2,117.1,114.4,112.0,110.4,107.8,105.9,100.7,81.4,75.5,68.8,68.5,66.0,63.8,60.09,60.06,56.3,56.0,55.64,55.60.

[0231] HRMS:m / z calculated[M+Na] + =847.2532,found 847.2536.

[0232] Embodiment 3:

[0233] (1) Synthesis of compound xvi:

[0234]

[0235] Specific operations:

[0236] Toluene (7 mL) and dibutyltin oxide (225 mg, 0.901 mmol, 1.2 equiv.) were added to compound xv (200 mg, 0.751 mmol, 1.0 equiv.) in sequence under inert gas protection, and the solution was heated to reflux. After 6 hours of reflux, the mixture was returned to room temperature and the toluene was evaporated. The evaporated mixture was dissolved in N, N-dimethylformamide (7 mL), and tetrabutylammonium bromide (266 mg, 0.826 mmol, 1.1 equiv.) and 4,5-dimethoxy-2-nitrobenzyl bromide (207 mg, 0.751 mmol, 1.0 equiv.) were added in sequence under inert gas protection. After stirring at 60°C for 12 hours, N, N-dimethylformamide in the reaction solution was removed by reduced pressure distillation, and then diluted with dichloromethane and washed twice with water, saturated ammonium chloride and saturated brine in sequence, and the organic phase was dried over anhydrous sodium sulfate. After filtering off anhydrous sodium sulfate, the organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate, 7:3, v / v) to obtain yellow oily compound xvi (194 mg, 0.421 mmol, yield 56%).

[0237] 1 H NMR(400MHz, CDCl3)δ8.08-7.98(m,2H,Ar),7.69(s,1H,Ar(DMNB)),7.63-7.53(m,1H,Ar),7.45(t,J=7.8Hz ,2H,Ar),7.18(s,1H,Ar(DMNB)),5.57(t,J=1.5Hz,1H,1-H),5.14-5.12(m,1H,2-H),5.09-5.07(m,2H,ArCH 2),4.66(td,J=4.6,1.3Hz,1H,5-H),4.45(d,J=7.4Hz,1H,6-H),4.32-4.26(m,1H,3-H),4.01(t,J=4.6Hz,1 H,4-H),3.98(s,3H,ArOCH3),3.95(s,3H,ArOCH3),3.76(ddd,J=7.4,5.2,1.0Hz,1H,6-H),2.83(s,1H,OH).

[0238] ESI-MS: found 484.1 [M+Na] + .

[0239] (2) Synthesis of compound xvii:

[0240]

[0241] Specific operations:

[0242] Under the protection of inert gas at 0°C, compound xvi was dissolved in acetic anhydride solution (2 mL) containing 2% concentrated sulfuric acid. After the reaction was restored to room temperature for 2 hours, TLC detected that the reaction was complete, and the mixture was poured into stirred ice water and neutralized with solid sodium bicarbonate, and extracted with dichloromethane 2-3 times. The dichloromethane phase was then washed twice with water, saturated sodium bicarbonate and saturated brine in sequence, and dried over anhydrous sodium sulfate. After filtering off anhydrous sodium sulfate, the organic phase was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate, 1: 1, v / v) to obtain yellow foam compound xvii (165 mg, 0.273 mmol, yield 84%, α: β = 5: 1)

[0243] ESI-MS: found 628.2[M+Na] + .

[0244] (3) Synthesis of compound xviii:

[0245]

[0246] Specific operations:

[0247] (a) Compound xvii (200 mg, 0.330 mmol, 1.0 equiv.) was dissolved in dichloromethane (3 mL) at 0°C under inert gas protection. 33% hydrobromic acid acetic acid solution (0.24 mL, 2.31 mmol, 7.0 equiv.) was added dropwise to the mixture at 0°C under inert gas protection. The mixture was allowed to react for 2 hours at room temperature. When TLC showed that the reaction of the raw material was complete, the reaction solution was diluted with dichloromethane and washed twice with saturated sodium bicarbonate and saturated sodium chloride solutions in sequence. The organic phase was collected, dried over anhydrous sodium sulfate, the anhydrous sodium sulfate was filtered, and concentrated by reduced pressure distillation using a rotary evaporator to obtain a crude bromide.

[0248] (b) Under inert gas protection, the crude bromide was dissolved in acetonitrile, and then 4-hydroxy-3-nitrobenzaldehyde (66 mg, 0.396 mmol, 1.2 equiv.), silver oxide (162 mg, 0.759 mmol, 2.3 equiv.), tetrabutylammonium iodide (61 mg, 0.165 mmol, 0.5 equiv.) and Molecular sieve. After reacting at room temperature for 12 hours, the silver oxide and molecular sieve were filtered using diatomaceous earth and the filter cake was washed with dichloromethane. The organic phase was washed twice with sodium carbonate, water and saturated brine in sequence. The organic phase was collected and dehydrated with anhydrous sodium sulfate. After filtering out the sodium sulfate solid, the solvent was concentrated to obtain a crude mixture. The crude product was separated and purified using a silica gel column (petroleum ether: ethyl acetate, 2: 1, v / v) to obtain a light yellow oily compound xviii (111 mg, 0.155 mmol, yield 47%).

[0249] 1 H NMR(600MHz,CDCl3)δ9.94(s,1H,ArCHO),8.24(d,J=2.0Hz,1H,Ar),8.05(dd,J=8.7,2.0Hz,1H,Ar),8.03-7.98(m,2H,Ar),7.73(s,1H,Ar(DMNB)),7 .60-7.55(m,1H,Ar),7.52-7.41(m,4H,Ar(DMNB),Ar×3),6.02(dd,J=10.2,7.5Hz,1H,2-H),5.43(d,J=7.5Hz,1H,1-H),5.39(dd,J=10.2,2.9Hz,1H,3 -H),5.23(d,J=14.9Hz,1H,ArCH2),5.13(d,J=15.1Hz,1H,ArCH2),4.52(dd,J=11.4,7.1Hz,1H,6-H),4.28(dd,J=11.4,5.9Hz,1H,6-H),4.24(dd,J= 3.0,1.4Hz,1H,4-H),4.19(ddd,J=7.2,5.9,1.4Hz,1H,5-H),4.12(s,3H,ArOCH3),3.97(s,3H,ArOCH3),2.10(s,3H,CH3(Ac)),1.97(s,3H,CH3(Ac)).

[0250] 13 C NMR (151MHz, CDCl3) δ188.6,170.4,170.2,164.9,154.3,153.5,147.9,141.2,138.6,133.9,133.5,131.3,130.0, 129.9,129.1,128.5,127.0,118.4,109.6,107.9,99.7,75.5,73.2,72.5,72.2,68.8,62.1,56.8,56.4,20.8,20.7.

[0251] ESI-MS: found 735.2[M+Na]+ .

[0252] (4) Synthesis of compound xix:

[0253]

[0254] Specific operations:

[0255] Under the protection of inert gas, compound xviii (100 mg, 0.140 mmol, 1.0 equiv.) was dissolved in a mixed solution of dichloromethane and isopropanol (2 mL), the mixed solution was cooled to 0°C in an ice bath, sodium borohydride powder (11 mg, 0.280 mmol, 2.0 equiv.) was added, the reaction solution was slowly heated from 0°C to room temperature and the reaction was continued for 2 hours. After TLC confirmed that the crude raw material had completed the reaction. Then the reaction solution was diluted with dichloromethane, and washed twice in sequence with water, saturated ammonium chloride, saturated sodium bicarbonate, and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, and the anhydrous sodium sulfate was filtered off and the organic phase was concentrated by vacuum distillation using a rotary evaporator. After concentration, the crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate, 3:2, v / v) to obtain a light yellow oil xix (89 mg, 0.125 mmol, yield 89%).

[0256] 1H NMR(600MHz,CDCl3)δ8.02(dd,J=8.2,1.4Hz,2H,Ar),7.74-7.69(m,2H,Ar(DMNB),Ar),7.59-7.54(m,1H,Ar),7.54(s,1H,Ar(DMNB)),7.50(dd,J=8.7,2.2Hz, 1H,Ar),7.43(t,J=7.8Hz,2H,Ar),7.31(d,J=8.6Hz,1H,Ar),5.98(dd,J=10.4, 7.7Hz,1H,2-H),5.34(dd,J=10.4,2.9Hz,1H,3-H),5.27(d,J=7.7Hz,1H,1-H),5 .22(d,J=15.2Hz,1H,ArCH2),5.11(d,J=15.3Hz,1H,ArCH2),4.68(s,2H,ArCH2 (DMNB)),4.50(dd,J=11.3,6.9Hz,1H,6-H),4.25(dd,J=11.3,6.3Hz,1H,6-H),4 .20(dd,J=3.0,1.2Hz,1H,4-H),4.13(s,3H,ArOCH3),4.09(td,J=7.9,7.2,1.9 Hz,1H,5-H),3.97(s,3H,ArOCH3),2.09(s,3H,CH3(Ac)),1.95(s,3H,CH3(Ac)).

[0257] 13 C NMR (151MHz, CDCl3) δ170.4,170.3,165.1,154.4,148.4,147.8,141.5,138.4,136.9,133.4,131.7,130.3,129.9, 129.3,128.5,123.4,119.6,109.6,107.8,100.6,75.7,72.9,72.8,72.2,69.1,63.5,62.1,56.9,56.4,20.8,20.7.

[0258] ESI-MS: found 737.2[M+Na] + .

[0259] (5) Synthesis of intermediate compound xx:

[0260]

[0261] Specific operations:

[0262] Under the protection of inert gas, compound xix (35 mg, 0.049 mmol, 1.0 equiv.) and CA4 (15 mg, 0.049 mmol, 1.0 equiv.) were dissolved in a dry tetrahydrofuran solution (1 mL), the mixture was cooled to 0°C in an ice bath and stirred for 15 minutes, and tributylphosphine (13 μL, 0.054 mmol, 1.1 equiv.) and diisopropyl azodicarboxylate (10 μL, 0.049 mmol, 1.0 equiv.) were added in sequence, and the reaction solution was heated from 0°C to room temperature and continued to react for 1 hour. The reaction solution was diluted with dichloromethane and washed twice with saturated ammonium chloride, saturated sodium bicarbonate, and saturated sodium chloride solutions in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by reduced pressure distillation using a rotary evaporator. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate, 3:2, v / v) to give a light yellow oily compound xx (35 mg, 0.034 mmol, yield 70%).

[0263] 1H NMR(600MHz, CDCl3)δ8.06-8.00(m,2H,Ar),7.75-7.71(m,2H,Ar(DMNB),Ar),7.59-7.54(m,2 H,Ar(DMNB),Ar),7.47-7.38(m,3H,Ar),7.29-7.26(m,1H,Ar),6.89(dd,J=8.3,2.0Hz,1H,Ar( CA4)),6.82-6.76(m,2H,Ar(CA4)),6.51-6.38(m,4H,Ar(CA4)),5.99(dd,J=10.4,7.7Hz,1H,2 -H),5.37(dd,J=10.4,3.0Hz,1H,3-H),5.33(d,J=7.7Hz,1H,1-H),5.23(d,J=15.3Hz,1H,ArCH 2(DMNB)),5.12(d,J=15.3Hz,1H,ArCH2(DMNB)),4.87(s,2H,ArCH2),4.49(dd,J=11.2,6.9Hz ,1H,6-H),4.27(dd,J=11.3,6.3Hz,1H,6-H),4.22(dd,J=3.0,1.3Hz,1H,4-H),4.14(s,3H,ArO CH3(DMNB)),3.97(s,3H,ArOCH3(DMNB)),3.84(s,3H,ArOCH3(CA4)),3.82(s,3H,ArOCH3(CA4) ),3.65(s,6H,ArOCH3(CA4)),2.10(d,J=1.2Hz,3H,CH3(Ac)),1.96(d,J=1.1Hz,3H,CH3(Ac)).

[0264] ESI-MS: found 1035.7[M+Na] + .

[0265] Use the intermediate to prepare the prodrug compound C:

[0266]

[0267] Specific operations:

[0268] Under inert gas protection, compound xx (35 mg, 0.034 mmol, 1.0 equiv.) was dissolved in a mixture of methanol and dichloromethane (1 mL), followed by the addition of 5 mol / L sodium methoxide methanol solution (4 μL, 0.021 mmol, 0.6 equiv.) and stirring at room temperature for 2 hours. The reaction was terminated when all the raw materials were reacted and a single main point was generated by TLC. H +The reaction solution was neutralized with ion exchange resin, and after the pH of the solution was detected to be neutral to slightly acidic, the resin was filtered off and washed with a mixture of methanol and methanol-dichloromethane (2:1, v / v). The crude product was concentrated by vacuum distillation using a rotary evaporator, and the crude product was purified using a silica gel column (methanol: dichloromethane, 1:25, v / v) to obtain a white solid compound C (23 mg, 0.028 mmol, yield 81%).

[0269] 1 H NMR(600MHz,(CD3)2SO)δ7.85(d,J=2.1Hz,1H,Ar),7.67(s,1H,Ar(DMNB)),7.61-7.56(m,2 H,Ar,Ar(DMNB)),7.45(d,J=8.8Hz,1H,Ar),6.96(d,J=1.9Hz,1H,Ar(CA4)),6.93(d,J=8.3 Hz,1H,Ar(CA4)),6.89(dd,J=8.3,1.9Hz,1H,Ar(CA4)),6.56(s,2H,Ar(CA4)),6.49(q,J=1 2.2Hz,2H,Ar(CA4)),5.39(d,J=5.2Hz,1H,OH),5.35(d,J=4.8Hz,1H,OH),5.21(d,J=15.4Hz ,1H,ArCH2(DMNB)),5.15(d,J=7.5Hz,1H,1-H),5.00(d,J=15.5Hz,1H,ArCH2(DMNB)),4.91 (s,2H,ArCH2),4.86(t,J=5.4Hz,1H,OH),3.91(s,3H,ArOCH3(DMNB)),3.88-3.85(m,4H,ArO CH3(DMNB),4-H),3.78(t,J=6.7Hz,1H,5-H),3.74(s,3H,ArOCH3),3.69(ddd,J=9.7,7.5,5 .2Hz,1H,2-H),3.64-3.59(m,10H,3-H,ArOCH3×3),3.52(ddd,J=10.8,7.1,4.4Hz,2H,6-H).

[0270] 13C NMR (151MHz, (CD3)2SO) δ153.4,152.6,149.1,148.6,147.1,147.0,140.1,138.5,136.7,133.3,132.4,131.3,130.9,129.3,128.8,123 .8,122.2,117.3,114.4,112.0,110.4,107.7,105.9,100.8,77.3,75.3,73.7,70.6,68.6,60.1,59.7,56.02,55.98,55.64,55.60,54.9.

[0271] HRMS: m / z calculated [M+Na] + =847.2532, found 847.2540.

[0272] Embodiment 4:

[0273] (1) Synthesis of compound xxiii:

[0274]

[0275] Specific operations:

[0276] Under the protection of inert gas, compound xxii (4.01 g, 8.04 mol, 1.0 equiv.) (see non-patent literature: Liang, C.; Lee, DW; Newton, MG; Chu, CK Synthesis of L-Dioxolane Nucleosides and Related Chemistry. J Org Chem, 1995, 60 (6), 1546-1553.) was dissolved in N, N-dimethylformamide, and then imidazole (1093 mg, 16.08 mol, 2.0 equiv.) was added to the mixed solution system, and the mixed solution was ice-bathed to 0°C, and then TBDPSCl (3.13 mL, 12.06 mol, 1.5 equiv.) was added dropwise to the solution system. After the addition was completed, the reaction solution was heated to room temperature and reacted for 2 hours. TLC detected that the raw materials were completely reacted to generate a main product point, and the reaction solution was cooled to 0°C and sodium bicarbonate solution was added to the reaction solution system to terminate the reaction. The mixture was diluted with dichloromethane, washed twice with saturated sodium bicarbonate and saturated sodium chloride solutions in sequence, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated by reduced pressure distillation on a rotary evaporator. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate, 10: 1, v / v) to give white foam xxiii (5.63 g, 7.64 mmol, yield 95%).

[0277] 1 H NMR(600MHz,CDCl3)δ7.72(d,J=2.1Hz,1H,Ar),7.68-7.60(m,4H,Ar),7.50-7.41(m,3H,Ar),7.39(td,J=7.2,1.5Hz,4H,Ar),7.3 2(d,J=8.6Hz,1H,Ar),5.55(dd,J=10.5,7.9Hz,1H,2-H),5.47(dd,J=3.4,1.1Hz,1H,4-H),5.11(dd,J=10.5,3.4Hz,1H,3-H),5.0 5(d,J=7.9Hz,1H,1-H),4.73(s,2H,ArCH2),4.27(dd,J=11.4,7.0Hz,1H,6-H),4.17(dd,J=11.4,6.3Hz,1H,6-H),4.10-3.99(m,1 H,5-H),2.19(s,3H,CH3(Ac)),2.14(s,3H,CH3(Ac)),2.06(s,3H,CH3(Ac)),2.02(s,3H,CH3(Ac)),1.10(s,9H,C(CH3)3(TBDPS)).

[0278] 13 C NMR (151MHz, CDCl3) δ170.3,170.2,170.2,169.5,148.1,141.3,137.4,135.5,132.8,131.0,130.0,1 27.9,122.6,119.9,100.9,71.4,70.6,67.9,66.7,64.1,61.3,26.8,20.7,20.66,20.65,20.6,19.3.

[0279] ESI-MS: found 760.2[M+Na] + .

[0280] (2) Synthesis of compound xxiii:

[0281]

[0282] Specific operations:

[0283] (a) Under inert gas protection, compound xxiii (5.5 g, 7.45 mmol, 1.0 equiv.) was dissolved in methanol (40 mL), followed by the addition of 5 mol / L sodium methoxide methanol solution (745 μL, 3.73 mmol, 0.5 equiv.) and stirring at room temperature for 2 hours. The reaction was terminated when all the raw materials were reacted and only one main point was generated according to TLC. H + The reaction solution was neutralized with ion exchange resin, and after the pH of the solution was tested to be neutral to slightly acidic, the resin was filtered off and washed with a mixture of methanol and methanol-dichloromethane (2:1, v / v). The solution was concentrated by vacuum distillation using a rotary evaporator to obtain a crude product of 3-nitrobenzyl tert-butyl diphenyl chlorosilyl ether β-D-galactopyranoside, which was directly used in the next step.

[0284] (b) The crude product was dissolved in dry pyridine. After the reactants were fully dissolved, the reaction system was cooled to 0°C and stirred for 15 minutes. Triphenylmethane (6.23 g, 22.35 mmol, 3.0 equiv.) was then added. After stirring at room temperature for 1 hour, 1.5 mL of triethylamine was added dropwise to the solution. After stirring at room temperature for 5 hours, TLC showed no significant changes in the reactants and products, and the reaction was terminated. The reaction solution was diluted with dichloromethane, washed twice with 1 mol / L hydrochloric acid, saturated sodium bicarbonate, and saturated saline solution in sequence, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated by reduced pressure distillation on a rotary evaporator. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: methanol, 1:2:0.05, v / v / v) to finally obtain a transparent flaky solid xxiv (3.75 g, 4.62 mmol, yield 62%).

[0285] 1H NMR(600MHz,DMSO-d6)δ7.80(d,J=2.0Hz,1H,Ar),7.68-7.56(m,6H,Ar),7.48-7.32(m,12H,Ar),7.26(t,J=7.7Hz,6H ,Ar),7.21-7.14(m,3H,Ar),5.24(d,J=5.2Hz,1H,OH),5.17(d,J=7.7Hz,1H,1-H),4.95(d,J=5.8Hz,1H,OH),4.76(s,2 H,ArCH2),4.63(d,J=4.6Hz,1H,OH),3.98(dd,J=8.3,3.2Hz,1H,5-H),3.62-3.53(m,2H,4-H,6-H),3.43(ddd,J=9.3,5 .7,3.2Hz,1H,6-H),3.29(dd,J=9.8,8.1Hz,1H,2-H),2.96(dd,J=9.9,3.1Hz,1H,3-H),1.00(s,9H,C(CH3)3(TBDPS)).

[0286] 13 C NMR (151MHz, DMSO) δ148.6,143.8,139.8,134.98,134.96,134.3,132.6,132.5,131.0,130.0,128. 3,128.0,127.8,126.9,122.0,117.0,100.6,85.8,74.5,73.2,69.9,68.9,63.9,63.7,26.6,18.8.

[0287] ESI-MS: found 834.6[M+Na] + .

[0288] (3) Synthesis of compound xxv:

[0289]

[0290] Specific operation: Under the protection of inert gas, compound xxiv (3.60 g, 4.43 mmol, 1.0 equiv.) was dissolved in pyridine (25 mL), and the reaction system was cooled to 0°C, and then benzoyl chloride (2.32 mL, 20 mmol, 4.5 equiv.) was added dropwise to the solution system. After the addition was complete, the solution was returned to room temperature and stirred for 6 hours. TLC detected that all the raw materials were consumed, and the reaction was terminated. The mixture was concentrated by reduced pressure distillation using a rotary evaporator, and the crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate, 1:1.5, v / v) to finally obtain white foam xxv (yield 85%). <h2 style=";text-align:left;direction:ltr">

[0291] <h2 style=";text-align:left;direction:ltr"> 1 <h2 style=";text-align:left;direction:ltr"> HNMR (400MHz,CDCl3)δ8.12(ddd,J=11.5,8.4,1.4Hz,2H,Ar),8.04-7.96(m,2H,Ar),7.86-7.77(m,2H,Ar),7.68-7.57(m,6H,Ar),7.56-7.30(m,14H,Ar),7.28(d,J=8.0Hz,2H,Ar),6.17(dd,J=10.4,7.9Hz,1H,2-H),5.95-5 .86(m,1H,4-H),5.68(dd,J=10.5,3.4Hz,1H,3-H),5.42(d,J=7.9Hz,1H,1-H),4.71(s,2H,ArCH2),4.23-4.16( m,1H,5-H),3.89(dd,J=12.0,6.7Hz,1H,6-H),3.72(dd,J=12.0,6.5Hz,1H,6-H),1.08(s,9H,C(CH3)3(TBDPS)).<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0292] <h2 style=";text-align:left;direction:ltr"> 13 <h2 style=";text-align:left;direction:ltr"> C NMR(151MHz,CDCl3)δ166.7,165.6,165.2,148.0,141.5,137.3,135.5,134.0,133.5,133.2,132.9,131.2,130.2,130.1,130.0,129.83.1 29.82,129.3,128.8,128.59,128.56,128.44,128.40,128.3,127.9, 122.7,119.4,101.1,74.8,71.6,69.1,68.5,64.1,60.6,26.8,19.3.<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0293] <h2 style=";text-align:left;direction:ltr"> ESI-MS:found 904.3[M+Na]<h2 style=";text-align:left;direction:ltr"> + <h2 style=";text-align:left;direction:ltr"> .<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0294] <h2 style=";text-align:left;direction:ltr"> (4)More<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0295] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0296] Specific operation: Compound xxv (100 mg, 0.113 mmol, 1.0 equiv.) and xxvi (61 mg, 0.170 mmol, 1.5 equiv.) were dissolved in dichloromethane (1 mL) under inert gas protection. The reaction system was cooled to 0°C and trifluoromethanesulfonic acid (5 μL, 0.056 mmol, 0.5 equiv.) was added to the solution system using a microsyringe. The temperature was slowly raised to room temperature after the addition. TLC detected that the raw material of compound xxvi was completely consumed and a new spot was generated. The temperature was cooled to 0°C and saturated sodium bicarbonate was added to terminate the reaction. The reaction solution was diluted with dichloromethane, and washed twice with saturated sodium bicarbonate and saturated saline solution in sequence. The organic phase was collected and dried with anhydrous sodium sulfate, filtered, and then concentrated by reduced pressure distillation using a rotary evaporator. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate, 3:2, v / v) to finally obtain a light yellow transparent oil xxvii (54.8 mg, 0.051 mmol, yield 45%).

[0297] 1 H NMR (400MHz, CDCl3) δ8.10-7.93(m,4H,Ar),7.85-7.77(m,2H,Ar),7.72-7.56(m,7H,Ar×6,Ar(DMNB)),7 .54-7.34(m,14H,Ar),7.28-7.24(m,3H,Ar×2,Ar(DMNB)),6.18-6.05(m,2H,2-H,4-H),5.66(dd,J=10.5 ,3.4Hz,1H,3-H),5.46(d,J=8.0Hz,1H,1-H),5.01-4.85(m,2H,ArCH2),4.71(s,2H,ArCH2'),4.49-4.36 (m,1H,5-H),4.03-3.95(m,2H,6-H),3.91(d,J=6.5Hz,7H,ArOCH3,6-H),1.08(s,9H,C(CH3)3(TBDPS)).

[0298] 13C NMR (101MHz, CDCl3) δ165.7,165.5,165.2,154.1,148.1,147.7,141.3,139.0 ,137.2,135.5,133.7,133.4,133.2,132.9,131.1,130.0,129.9,129.84,129 .79,129.4,128.9,128.7,128.4,128.3,127.9,122.8,119.3,109.7,107.8,101.1,73.1,71.7,70.3,69.0,68.5,67.9,64.1,56.6,56.4,56.3,26.8,19.3.

[0299] ESI-MS: found 1099.3[M+Na] + .

[0300] (5) Synthesis of intermediate compound xxviii:

[0301]

[0302] Specific operation: Compound xxvii (128.29 mg, 0.12 mmol, 1.0 equiv.) was added to dry tetrahydrofuran (1 mL) under inert gas protection, and a tetrahydrofuran solution containing 1 M tetrabutylammonium fluoride (0.15 ml, 0.30 mmol, 1.2 equiv.) was added under nitrogen protection at 0°C, and reacted at 0°C for 3 hours. After the reaction was terminated by TLC monitoring, the organic phase was extracted with dichloromethane (4×10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. Compound xxviii (84.06 mg, yield 83.3%) was obtained by column chromatography purification (methanol: dichloromethane = 4:100) as a light yellow foam.

[0303] 1H NMR (400MHz, CDCl3) δ8.09-8.02(m,2H,Ar),8.00-7.94(m,2H,Ar),7.83-7.76(m,2H,Ar),7.74(d,J=2.0Hz,1H,Ar),7.65(s ,1H,Ar(DMNB)),7.64-7.57(m,1H,Ar),7.51-7.40(m,6H,Ar),7.35(t,J=7.8Hz,2H,Ar),7.28-7.21(m,3H,Ar×2,Ar(DMNB)) ,6.12(dd,J=10.5,7.9Hz,1H,2-H),6.08(dd,J=3.4,1.1Hz,1H,4-H),5.68(dd,J=10.5,3.4Hz,1H,3-H),5.49(d,J=7.9Hz,1 H,1-H),4.98-4.83(m,2H,ArCH2),4.66(s,2H,ArCH2),4.42(td,J=6.3,1.2Hz,1H,5-H),3.91(d,J=1.7Hz,8H,ArOCH3,6-H).

[0304] 13 C NMR (101MHz, CDCl3) δ165.7,165.6,165.2,154.0,148.4,147.7,141.3,139. 0,137.2,137.2,133.7,133.4,133.2,131.9,130.0,129.9,129.82,129.77, 129.3,128.9,128.72,128.67,128.4,128.3,123.4,119.52,119.49,109.8,107.9,100.9,73.3,71.7,70.3,69.1,68.7,68.0,63.39,63.37,56.6,56.3.

[0305] ESI-MS: found 861.2[M+Na] + .

[0306] Preparation of prodrug compound D using intermediates:

[0307]

[0308] Specific operations:

[0309] (a) Under the protection of inert gas, compound xxviii (50 mg, 0.077 mmol, 1.0 equiv.) and Compretin (29 mg, 0.092 mmol, 1.2 equiv.) were dissolved in a dry tetrahydrofuran solution (1 mL), the mixture was cooled to 0°C in an ice bath and stirred for 15 minutes, and triphenylphosphine (22 mg, 0.0847 mmol, 1.1 equiv.) and diisopropyl azodicarboxylate (15 μL, 0.077 mmol, 1.0 equiv.) were added in sequence, and the reaction solution was heated from 0°C to room temperature and continued to react for 1 hour. The reaction solution was diluted with dichloromethane and washed twice with saturated ammonium chloride, saturated sodium bicarbonate, and saturated sodium chloride solutions in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by reduced pressure distillation using a rotary evaporator. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate, 5:2, v / v) to give a light yellow oil xxix (51 mg, 0.054 mmol, yield 70%).

[0310] (b) Under the protection of inert gas, compound xxix (50 mg, 0.053 mmol, 1.0 equiv.) was dissolved in a mixture of methanol and dichloromethane (2:1, v / v) (1.5 mL), and a 5 mol / L sodium methoxide methanol solution (5 μL, 0.025 mmol, 0.5 equiv.) was added, and the mixture was stirred at room temperature for 12 hours. After the reaction of the raw material was completed as monitored by TLC, a hydrogen ion exchange resin was added to neutralize the reaction solution, the resin was filtered, and the resin was washed with a mixture of methanol and dichloromethane (2:1, v / v), and concentrated by reduced pressure distillation using a rotary evaporator. The crude product was separated and purified by silica gel column chromatography (dichloromethane: methanol, 9:1, v / v) to obtain compound D (32 mg, 0.039 mmol, yield 73%).

[0311] 1H NMR(600MHz,(CD3)2SO)δ7.84(d,J=2.1Hz,1H,Ar),7.66(s,1H,Ar(DMNB)),7.48(dd,J=8.8,2.1Hz,1H,Ar),7.41(d,J=8.8Hz,1H,Ar),7.22(s,1H,Ar(DMNB)), 6.95-6.89(m,2H,Ar(CA4)),6.87(dd,J=8.4,1.9Hz,1H,Ar(CA4)),6.54(s,2H, Ar(CA4)),6.46(q,J=12.2Hz,2H,Ar(CA4)),5.23(d,J=5.1Hz,1H,OH),5.13(d,J =7.7Hz,1H,1-H),5.02(s,1H,OH),4.92-4.80(m,4H,ArCH2),4.77(d,J=4.5Hz, 1H,OH),4.01(dd,J=7.5,4.4Hz,1H,5-H),3.83(s,3H,ArOCH3),3.74-3.71(m,4 H,4-H,ArOCH3),3.71-3.67(m,4H,6-H,ArOCH3(CA4)),3.65-3.61(m,4H,6-H,A rOCH3(CA4)),3.61-3.57(m,7H,2-H,ArOCH3(CA4)),3.47(d,J=9.6Hz,1H,3-H).

[0312] 13 C NMR (151MHz, (CD3)2SO) δ153.9,153.1,149.6,149.1,147.8,147.5,140.3,139.6,137.3,133.5,132.9,131.2,130.4,129.8,129.7,129 .2,124.3,122.8,117.3,115.2,112.6,110.3,108.6,106.5,101.3,74.4,73.7,70.4,69.4,69.1,69.0,60.5,56.5,56.4,56.14,56.11.

[0313] HRMS: m / z calculated [M+Na] + =847.2532, found 847.2532.

[0314] Example 5

[0315] MTT cytotoxicity assay of prodrug compounds A, B, C or D:

[0316] OVCAR3 cells (3000 cells per well) or SKOV3 cells (2000 cells per well) were planted in the wells of a 96-well plate and incubated for 24 hours to allow the cells to grow stably. The culture medium was aspirated, and a DMEM culture medium solution containing 5% DMSO was added according to the concentration gradient. After incubation in a 37°C incubator containing 5% carbon dioxide for 3 hours, the illumination group was illuminated for 3 minutes, and other groups were not treated. For the double prodrug A culture medium, Cu (II) with a final concentration of 20 μM was also added. After continuing to incubate with the drug for 24 hours, the culture medium was washed out and the cells were washed 2-3 times with PBS buffer. After replacing the new culture medium, a DMEM solution containing 10% MTT solution (5 mg / mL PBS solution) was added to each well. The well plate was placed in a 37°C incubator containing 5% carbon dioxide for incubation for 3 hours. Finally, the culture medium was carefully aspirated and DMSO was added. After shaking on a shaker at 100 rpm for 10 minutes, the absorbance intensity at 490 nm of the well plate was detected, and the cell survival rate was calculated according to the formula:

[0317]

[0318] Among them, OD + OD is the absorbance value of the wells with MTT reagent, cells and drugs. control OD is the absorbance value of the wells with only MTT reagent added. - is the absorbance of the wells added with only MTT reagent and cells.

[0319] The experimental results are attached. Fig.16 , Fig.17 And Table 1.

[0320] Table 1 IC of drugs against OVCAR3 cells 50 (nM)

[0321]

[0322] Compounds A, B, C and D can activate and controllably eliminate β-galactosidase-overexpressing OVCAR3 or SKOV3 cells under light control, while their corresponding single prodrugs are highly toxic and uncontrollable to β-galactosidase-overexpressing cells, indicating that compounds A, B, C and D have stronger controllability and lower toxic side effects than their corresponding single prodrugs. It can also be seen that compound A has stronger selectivity.

[0323] The MTT colorimetric method was used to verify that the present invention improves the controllability of drug release. In galactose-overexpressing OVCAR3 and SKOV3 cells, the toxicity of the double prodrugs A, B, C, and D was significantly reduced compared with the single prodrug compounds of the corresponding structures. In addition, the toxicity of the double prodrugs after light activation was improved compared with that before activation.

[0324] The embodiments provided above are not intended to limit the scope of the present invention, and the steps described are not intended to limit the execution order thereof. Those skilled in the art may make obvious improvements to the present invention in combination with existing common knowledge, which also fall within the scope of protection defined by the claims of the present invention.

Claims

1. An intermediate compound having the structure shown below: in, Z is a vacant bond or an ester group, and R1 is derived from a cytotoxic drug containing a hydroxyl group or an amino group; or, Z-R1 is a hydroxyl group; R2 is selected from hydrogen atom, C 1-6 Alkyl, halogen, nitro, amino, carboxyl, C 1-6 Alkoxy, acylamino R a -CONH-, alkoxyacyl R b OCO-, where R a , R b Independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl, alkenyl, halogenated alkenyl, aromatic group; Any one of R3, R4, R5, and R6 is a photocage group that can break the ether bond and release the galactose hydroxyl group after light irradiation, and the other three are hydroxyl protecting groups; The photocage group is selected from R c Selected from hydrogen atoms or C 1-6 Alkyl; R d , R e independently selected from hydrogen, halogen, nitro, amino, C 1-6 alkylamino, substituted or unsubstituted five- to six-membered saturated heterocyclic group, substituted or unsubstituted phenyl, substituted or unsubstituted C 1-6 The substituted groups on the alkoxy, saturated heterocyclic group or phenyl group are selected from halogen, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino; C 1-6 The substituted groups on the alkoxy group are selected from halogen, nitro, C 1-6 Alkyl, halogenated C 1-6 alkyl; The hydroxy protecting group is selected from: acetyl, benzoyl, tert-butyldimethylsilyl, levulinyl, pivaloyl, allyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, 2-naphthylmethyl, p-methoxybenzyl, tert-butyldiphenylsilyl, triethylsilyl, benzyl; or an acetal or ketal structure is formed at the ortho position.

2. The intermediate compound according to claim 1, characterized in that Has the following structure:

3. The intermediate compound according to claim 1, characterized in that When Z is a blank bond, R1 is derived from a cytotoxic drug containing a hydroxyl group, with the hydroxyl oxygen atom as the connection site, and the cytotoxic drug is selected from Compretin, 8-hydroxyquinoline, 5-chloro-8-hydroxyquinoline, camptothecin, 7-ethyl-10-hydroxycamptothecin, resorufin, iodoresorufin, duocarmycin MA, duocarmycin MB, duocarmycin GA, duocarmycin TM, chlorambucil, and 5-fluorouridine.

4. The intermediate compound according to claim 1, characterized in that When Z is an ester group, R1 is derived from a cytotoxic drug containing an amino group, with the amino nitrogen atom as the connection site, and the cytotoxic drug is selected from curcumin analog EF24, amifide, gemcitabine, cytarabine, monomethyl auristatin E, methylene blue, cyclophosphamide, linifanib, and doxorubicin.

5. The intermediate compound according to claim 1, characterized in that The structure of the intermediate compound is specifically selected from:

6. A method for preparing the intermediate compound according to any one of claims 1 to 5, characterized in that: The process includes the following: Compound i is then subjected to an etherification reaction to modify the photocage group of the 2-hydroxyl group of galactose to obtain compound ii; compound ii is brominated with iodine monobromide and then reacted with compound iii under the catalysis of silver oxide to obtain compound iv; compound iv is reduced with sodium borohydride to obtain the target intermediate compound v; Compound v reacts with a cytotoxic compound via Mitsunobu reaction or Williamson etherification reaction to obtain a target intermediate compound vi, or reacts with p-nitrophenyl chloroformate to form an active intermediate and then reacts with a cytotoxic compound to obtain a target intermediate compound vii; Among them, the structure of compound i is The structure of compound ii is The structure of compound iii is The structure of compound iv is The structure of compound v is The structure of compound vi is The structure of compound vii is 7. A method for preparing the intermediate compound according to any one of claims 1 to 5, characterized in that: The process includes the following: Compound viii is modified with a photocage group at the 3-hydroxyl group of galactose by a classical regioselective strategy using dibutyltin oxide as a catalyst to obtain compound ix; then the acetal is removed by acid catalysis and then the exposed hydroxyl group on galactose is acetylated using acetic anhydride with pyridine as a solvent to obtain compound x; compound x is brominated with iodine monobromide and then reacted with compound iii by silver oxide catalysis to obtain compound xi; compound xi is reduced with sodium borohydride to obtain intermediate compound xii; Compound xii is reacted with a cytotoxic compound through Mitsunobu reaction conditions or Williamson etherification reaction to obtain the target intermediate compound xiii, or reacted with p-nitrophenyl chloroformate to form an active intermediate and then reacted with a cytotoxic compound to obtain the target intermediate compound xiv; Among them, the structure of compound viii is The structure of compound ix is The structure of compound x is The structure of compound xi is The structure of compound xii is The structure of compound xiii is The structure of compound xiv is 8. A method for preparing the intermediate compound according to any one of claims 1 to 5, characterized in that: The process includes the following: Compound xv is modified with a photocage group at the 4-hydroxyl group of galactose by a classical regioselective strategy using dibutyltin oxide as a catalyst to obtain compound xvi; compound xvi is then acetylated in an acetic anhydride solution containing concentrated sulfuric acid and all hydroxyl groups are acetylated to obtain compound xvii; compound xvii is brominated with hydrobromic acid and then reacted with compound iii under the catalysis of silver oxide to obtain compound xviii; compound xviii is reduced with sodium borohydride to obtain intermediate compound xix; Compound xix is ​​reacted with a cytotoxic compound through Mitsunobu reaction conditions or Williamson etherification reaction to obtain the target intermediate compound xx, or reacted with p-nitrophenyl chloroformate to form an active intermediate and then reacted with a cytotoxic compound to obtain the target intermediate compound xxi; Among them, the structure of compound xv is The structure of compound xvi is The structure of compound xvii is a mixture of α and β configurations The structure of compound xviii is The structure of compound xix is The structure of compound xx is The structure of compound xxi is 9. A method for preparing the intermediate compound according to any one of claims 1 to 5, characterized in that: The process includes the following: The hydroxyl group of compound xxii is protected by tert-butyl diphenylsilyl ether to obtain compound xxiii; the acetyl group on the sugar ring is then removed, and the 6-hydroxyl group on the sugar is selectively protected by triphenylmethyl to obtain xxiv; the 2, 3, and 4-hydroxyl groups of compound xxiv are replaced by benzoyl groups, and the 6-hydroxyl group is removed and protected by triphenylmethyl to obtain compound xxv; compound xxv and compound xxvi are reacted by acid catalysis to obtain compound xxvii; TBDPS is removed by tetrabutylammonium fluoride to expose the hydroxyl group on the connecting arm to obtain intermediate compound xxviii; Compound xxviii is coupled with a cytotoxic compound containing a hydroxyl group through Mitsunobu reaction or Williamson etherification reaction to synthesize a target intermediate compound xxix; or compound xxviii is coupled with p-nitrophenyl chloroformate to form an active intermediate and then coupled with a residue of a cytotoxic compound containing an amino group to synthesize a target intermediate compound xxx; The structure of compound xxii is The structure of compound xxiii is The structure of compound xxiv is The structure of compound xxv is The structure of compound xxvi is The structure of compound xxvii is The structure of compound xxviii is The structure of compound xxix is The structure of compound xxx is 10. Use of the intermediate compound according to any one of claims 1 to 5 in the preparation of β-galactoside prodrugs.

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