HK1207626B - Optically pure benzyl-4-chlorophenyl c-glucoside derivative - Google Patents

Description

Optically pure benzyl-4-chlorophenyl C-glycoside derivatives

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to an optically pure benzyl-4-chlorophenyl C-glycoside derivative or a pharmaceutically acceptable salt thereof, a method for preparing the compounds and intermediates thereof, a pharmaceutical preparation and a pharmaceutical composition containing the compounds, and application of the optically pure benzyl-4-chlorophenyl C-glycoside derivative or the pharmaceutically acceptable salt thereof serving as a sodium-glucose cotransporter (SGLT) inhibitor in preparation of medicines for treating and/or preventing various diabetes (including insulin-dependent diabetes and non-insulin-dependent diabetes) or various diabetes-related diseases (including insulin resistance diseases and obesity).

Background

Approximately 1 million people worldwide suffer from type II diabetes, which is characterized by hyperglycemia due to excessive hepatic glucose production and peripheral insulin resistance. Hyperglycemia is considered to be a major risk factor for developing diabetic complications and may be directly associated with impaired insulin secretion in late stage type II diabetes. Normalization of insulin can therefore be expected to improve blood glucose in type II diabetic patients. Most of the existing diabetes drugs are insulinotropic drugs or insulin sensitizers, such as sulfonylureas, glinides, thiazolidinediones, metformin and the like, and have potential side effects, such as easy weight gain, hypoglycemia, lactic acidosis and the like, so that the development of antidiabetic drugs with novel, safe and effective action mechanisms is urgently needed.

In the kidney, glucose can freely filter from the glomerulus (about 180 g/day), but is almost actively transported in the proximal convoluted tubule and reabsorbed. Two sodium-glucose transporters play an important role in glucose reabsorption, namely SGLT-1 and SGLT-2, and the SGLT-2 plays an especially prominent role. SGLT-2 is a transmembrane protein specifically expressed only in segment S1 of the proximal tubule, one of the most important physiological effects is absorption of sugar in blood flowing through the renal tubules, accounting for 90% of the absorption effect, SGLT-2 is transported at a sodium-glucose 1: 1 ratio, and SGLT-2 inhibitor inhibits the absorption of blood sugar in the renal tubules, resulting in a large amount of sugar being excreted from urine. While SGLT-1 is mainly expressed in the distal convoluted tubule and accounts for 10% of the absorption, SGLT-1 is transported in a ratio of sodium to glucose of 2: 1. SGLT-1 is also found in the intestinal tract and other tissues. These transporters function via the Na +/ATPase pump and are transported back into the blood by the glucose transporter 2(GLUT 2). This indicates that the SGLT-2 transporter, which is most likely to develop as a target for drug action, is on the one hand its absolute reabsorption of glucose and on the other hand it is only expressed in the kidney. The feasibility of the pathway is also proved in the research of the urine glucose of the familial nephropathy. Familial nephropathy urinary glucose is predominantly expressed as variable amounts of urinary sugar (about 10-120 g/day), but patients are generally in good condition and no long term adverse health effects are found. This benign urinary glucose is mainly due to mutations in the SGLT-2 transporter gene, suggesting that selective pharmacological inhibition of SGLT-2 has no adverse consequences other than the induction of diabetes. Evidence has shown that an important clinical advantage of SGLT-2 inhibitors is that they are less likely to cause hypoglycemia. While inhibition of SGLT-1 causes sugar-galactose malabsorption syndrome, which may lead to dehydration, there is evidence that SGLT-1 inhibitors will delay carbohydrate absorption and cause gastrointestinal symptoms that are intolerable to individuals, while selection of high SGLT-2 inhibitors will not block the glucose absorption and transport action of SGLT-1 in the intestinal tract, and thus are not likely to cause gastrointestinal symptoms. In addition, SGLT-1 is also highly expressed in human myocardial tissues, and blocking thereof may cause new or organic cardiac function. Therefore, the development of a compound having high selectivity for SGLT-2 is of great significance for the research of drugs for treating diabetes.

The SGLT-2 inhibitor can be used for treating hyperglycemia by acting on an SGLT-2 transporter to inhibit reabsorption of renal sugar, and provides a new way for treating diabetes. Although this pathway does not directly act on the pathophysiology of type II diabetes, lowering blood glucose by increasing renal glucose excretion causes a net energy deficit, promotes weight loss and indirectly ameliorates obesity symptoms. The research finds that the medicines are combined with the existing hypoglycemic medicines or insulin, the risk of hypoglycemia is lower, and the medicines have the potential weight reduction effect. The medicines do not depend on the function of beta-cells and insulin resistance, so the SGLT-2 inhibitor has good curative effect on common diabetic patients and also on diabetic patients who fail to treat biguanide and DPP-4 inhibitor medicines. Therefore, the medicine can be combined with hypoglycemic agents such as biguanides, DPP-4 inhibitors and the like for use in the future.

Among them, patent documents such as WO0127128, US2005209166 and the like disclose a series of compounds as SGLT-2 inhibitors.

The applicant also discloses a series of C-glycoside SGLT-2 inhibitor compounds in a patent WO2013/000275A1, wherein a compound 4 has a good inhibition effect and good selectivity on SGLT-2 and has a structural formula shown in the specification

The compound is a mixture of stereoisomers, which have asymmetric centers, with multiple optical isomers. In consideration of the potential problems that a plurality of chiral mixture drugs in the prior art are easy to generate unknown toxic and side effects, the drug effect is reduced, the quality control is difficult and the like, the research and development risks are greatly increased, and the optically pure stereoisomer has the advantages of higher safety, lower probability of generating toxic and side effects, higher stability and easier quality control compared with the chiral mixture, and also has potential improvement characteristics in pharmacodynamics, pharmacokinetics and toxicology, so that the development of a single stereoisomer which has high selectivity, quick response, high efficiency, safety and good stability on SGLT-2 has important significance on the subsequent drug research and development and the quality control in the drug production after marketing.

Disclosure of Invention

The technical scheme of the invention is as follows:

1. a stereoisomer compound of a compound of formula (I) or a pharmaceutically acceptable salt thereof, selected from the group consisting of formulae (II), (III), (IV), and (V):

its name is (2S,3R,4R,5S,6R) -2- (3- (4- (((1R,3S,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol,

its name is (2S,3R,4R,5S,6R) -2- (3- (4- (((1R,3R,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol,

its name is (2R,3R,4R, 5S,6R) -2- (3- (4- (((1R,3S,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol,

its name is (2R,3R,4R, 5S,6R) -2- (3- (4- (((1R,3R,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol.

2. The present invention further claims a process for the preparation of a compound of formula (II) as described in 1 above, which process comprises the reaction scheme:

wherein X represents fluorine, chlorine, bromine or iodine,

g represents a hydroxyl protecting group selected from the group consisting of trimethylsilyl, triethylsilyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, pivaloyl, allyl, methoxymethyl, benzyloxymethyl or trimethylsilylethyl, preferably trimethylsilyl.

The preparation process comprises the following steps:

reacting a compound of formula b, i.e. (1R,3R,5S) -bicyclo [3.1.0]Dissolving hexane-3-yl methanesulfonate in organic solvent (the organic solvent can be selected from N-methylpyrrolidone, N-dimethylformamide, tetrahydrofuran, dioxane and acetonitrile, preferably N-methylpyrrolidone), adding formula a, controlling temperature to react at 0-70 ℃ to obtain formula c, and reacting formula c with formula cReacting to obtain a formula d-1, deprotecting the formula d-1 to obtain a formula d-2, reacting the formula d-2 at the temperature of-78 ℃ to 30 ℃ to obtain a formula e, and purifying the formula e to obtain a compound of a formula (II).

The compound of formula (II) purified by the above formula e can be purified by the following purification method, but is not limited to the following method.

The purification method comprises the following steps: and (3) carrying out hydroxyl protection reaction on the formula e to generate a formula f, and carrying out deprotection reaction on the formula f to generate a compound of a formula (II).

Wherein G' represents a hydroxyl-protecting group selected from acetyl, trimethylsilyl, triethylsilyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, pivaloyl, allyl, methoxymethyl, benzyloxymethyl, trimethylsilylethyl, propionyl, isobutyryl or benzoyl, etc., preferably acetyl, pivaloyl, propionyl, isobutyryl or benzoyl.

The compounds of formula (ii) of the present invention may be synthesized using the methods described in the schemes above and/or other techniques known to those of ordinary skill in the art, but are not limited to the methods described above.

3. The present invention further claims a process for the preparation of a compound of formula (III) as described in 1 above, which process comprises the reaction scheme:

wherein X represents fluorine, chlorine, bromine or iodine,

g represents a hydroxyl protecting group selected from the group consisting of trimethylsilyl, triethylsilyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, pivaloyl, allyl, methoxymethyl, benzyloxymethyl or trimethylsilylethyl, preferably trimethylsilyl.

The preparation process comprises the following steps:

dissolving formula a in an organic solvent (the organic solvent can be selected from toluene, N-dimethylformamide, tetrahydrofuran, dioxane and acetonitrile, preferably toluene), adding formula b, and reacting at 0-70 deg.C to obtain formula c ', formula c' andthe reaction is carried out to obtain a formula d '-1, the deprotection is carried out on the formula d' -1 to obtain a formula d '-2, the formula d' -2 is reacted at the temperature ranging from-78 ℃ to 30 ℃ to obtain a formula e ', and the formula e' is purified to obtain the compound shown in the formula (III).

The compound of formula (III) purified by the above formula e' can be obtained by the following purification method, but is not limited thereto.

The purification method comprises the following steps: and carrying out hydroxyl protection reaction on the formula e ' to generate a formula f ', and carrying out deprotection reaction on the formula f ' to generate a compound of a formula (III).

Wherein G' represents a hydroxyl-protecting group selected from acetyl, trimethylsilyl, triethylsilyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, pivaloyl, allyl, methoxymethyl, benzyloxymethyl, trimethylsilylethyl, propionyl, isobutyryl or benzoyl, etc., preferably acetyl, pivaloyl, propionyl, isobutyryl or benzoyl.

The compounds of formula (III) of the present invention may be synthesized using the methods described in the schemes above and/or other techniques known to those of ordinary skill in the art, but are not limited to the methods described above.

4. The invention further claims intermediates of the compounds of formula (II) shown below,

5. the invention further claims intermediates of the compounds of formula (II) as shown below,

wherein X represents bromine or iodine.

6. The invention further claims intermediates of the compounds of formula (IIl) as shown below,

7. the invention further claims intermediates of the compounds of formula (III) as shown below,

wherein X represents bromine or iodine.

The "pharmaceutically acceptable salt" includes alkali metal salts such as sodium salt, potassium salt, lithium salt and the like; alkaline earth metal salts such as calcium salts, magnesium salts, and the like; other metal salts such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts, etc.; inorganic base salts such as ammonium salts; organic base salts such as t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N' -dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, piperazine salt, tetramethylamine salt, tris (hydroxymethyl) aminomethane salt, and the like; hydrohalic acid salts such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide and the like; inorganic acid salts such as nitrate, perchlorate, sulfate, phosphate and the like; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate and the like; aryl sulfonates such as benzenesulfonate, p-benzenesulfonate and the like; organic acid salts such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalate, maleate, etc.; amino acid salts such as glycinate, trimethylglycinate, arginate, ornithine, glutamate, aspartate and the like.

The invention also claims a pharmaceutical composition comprising the compound of formula (II) and/or formula (III) or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers and/or diluents, which can be prepared into any pharmaceutically acceptable dosage form. Administered to a patient in need thereof by oral, parenteral, rectal or pulmonary administration, and the like. For oral administration, it can be made into conventional solid preparations such as tablet, capsule, pill, granule, etc.; it can also be made into oral liquid, such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. For parenteral administration, it can be made into injection, including injection solution, sterile powder for injection and concentrated solution for injection. The injection can be prepared by conventional method in the existing pharmaceutical field, and can be prepared without adding additives or adding appropriate additives according to the properties of the medicine. For rectal administration, it can be made into suppository, etc. For pulmonary administration, it can be made into inhalant or spray. Each unit preparation contains 0.005g to 10g of the compound represented by the formula (I), which may be 0.005g, 0.01g, 0.05g, 0.1g, 0.125g, 0.2g, 0.25g, 0.3g, 0.4g, 0.5g, 0.6g, 0.75g, 1g, 1.25g, 1.5g, 1.75g, 2g, 2.5g, 3g, 4g, 5g, 10g, etc., in a physiologically effective amount.

The invention further claims a pharmaceutical composition of the compound of formula (II) and/or formula (III) or pharmaceutically acceptable salt thereof and other pharmaceutically active ingredients, wherein the other pharmaceutically active ingredients can be one or more hypoglycemic drugs selected from sitagliptin phosphate, vildagliptin, saxagliptin, alogliptin benzoate, linagliptin, tegagliptin, gemagliptin, metformin, phenformin, exenatide or liraglutide.

The invention also claims application of the compound of formula (II) and/or formula (III) or pharmaceutically acceptable salt thereof in preparing medicines for treating and/or preventing various diabetes or various diabetes-related diseases. The diabetes includes insulin-dependent diabetes (type I diabetes) and non-insulin-dependent diabetes (type II diabetes), and the diabetes-related diseases include insulin-resistant diseases, obesity, and the like.

The present invention further claims a method for treating and/or preventing various diabetes mellitus (including insulin-dependent diabetes mellitus and non-insulin-dependent diabetes mellitus) or various diabetes-related diseases (including insulin-resistant diseases and obesity), which comprises administering an effective dose of a compound of formula (II) and/or formula (III) or a pharmaceutically acceptable salt thereof of the present invention to a mammal including a human in need thereof.

The compound of the invention has the following characteristics:

(1) the compounds of the present invention have high selectivity for SGLT-2, and can be safely used for the treatment and/or prevention of diabetes mellitus in various mammals (including human beings) and various diseases caused by diabetes mellitus.

(2) The compound has high-efficiency inhibition effect on SGLT-2, obvious blood sugar reducing effect, quick response, small toxic and side effect and high safety.

(3) The compound of the invention has good physicochemical properties, high purity, good stability and easily controlled quality, and is suitable for large-scale industrial production.

4. Detailed description of the preferred embodiments

For convenience, well-known abbreviations used herein include, but are not limited to:

me: a methyl group;

et: an ethyl group;

ms: a methylsulfonyl group;

ac: acetyl;

TBS: tert-butyldimethylsilyl group;

THF: tetrahydrofuran;

DMAP: 4-dimethylaminopyridine;

DIPEA: n, N-diisopropylethylamine;

n-BuLi: n-butyl lithium;

TMS: a trimethylsilyl group.

In the present invention, room temperature means 10 ℃ to 30 ℃.

The advantageous effects of the compounds of the present invention are further illustrated below by pharmacological experiments, but this should not be construed as the compounds of the present invention having only the following advantageous effects.

Experimental example 1 in vitro Activity experiment of the Compound of the present invention

And (3) testing the sample: the chemical names and preparation methods of the compounds of formula (II), formula (III), formula (IV) and formula (V) of the present invention are shown in the preparation examples of each compound.

Control 1: compound 4 in WO2013/000275A1, self-made (see WO2013/000275A1 for a preparation method), has the following structural formula:

compound 4, a compound of formula (I).

The abbreviations used in the following experiments have the following meanings:

NMG N-methylglucamine (N-methyl-glucosamine)

KRH Krebs-Ringer-Henseleit

The experimental method comprises the following steps: the human SGLT-2 and SGLT-1 sequences are transfected into Chinese hamster ovary cells for stable expression by inhibiting the cell pair¹⁴C]-sodium-dependent absorption of the label-R-methyl-D-glucopyranoside (AMG), determination of the semi-inhibitory concentration IC50, and determination of the activity.

Buffer A(KRH-Na⁺)：120mM NaCl，4.7mM KCl，1.2mM MgCl₂，2.2mMCaCl₂，10mMHEPES(PH7.4with1mM Tris)。

Buffer A-(KRH-NMG)：120mM NMG，4.7mM KCl，1.2mM MgCl₂，2.2mM CaCl₂，10mMHEPES(PH74with1mM Tris)。

Buffer D：120mM NaCl，4.7mM KCl，1.2mM MgCl₂，2.2mM CaCl₂，10mM HEPES，0.5mMphlorizin(PH7.4with1mM Tris)。

The experimental method comprises the following steps: human SGLT-2 and SGLT-1 sequences were stably expressed in CHO cells by cell culture in 96-well plates for 12 hours using KRH-Na⁺Buffer A or KRH-NMG (Buffer A-) Buffer solution 200. mu.L/well, washed 3 times. Then adding the Buffer A or Buffer A-plus [ alpha ], [ beta ] -a¹⁴C]AMG (10. mu. Ci/mL) in 100. mu.L/well buffer, incubated at 37 ℃ for 1 hour. Then, 100. mu.L of a Buffer solution (Buffer D) pre-cooled with ice was added to stop the test, and washed 5 times. Then 20. mu.L/well of ice-cold lysis buffer (100mM NaOH) was added and centrifuged at 600rpm for 5 minutes, and 80. mu.L/well of Microscint40 was added and centrifuged at 600rpm for 5 minutes. Finally, the value was detected by scintillation counting using a Microbeta Trilux (available from PerkinElmer Co., Ltd.)¹⁴C]Radioactivity of AMG, half inhibitory concentration IC50 was calculated.

Experimental results and conclusions:

TABLE 1 evaluation results of inhibitory Effect of the Compound of the present invention

As shown in Table 1, the compound of formula (II) of the present invention has better inhibitory effect and better selectivity to SGLT-2, and shows obvious advantages compared with the control drug 1.

Experimental example 2 rat in vivo pharmacokinetic experiment of the Compound of the present invention

The test animals were: male SD rats (purchased from Beijing Wittingle laboratory animal technology Co., Ltd.) 6-8 weeks old, 3 per compound, weighing 200-.

And (3) testing the sample: the chemical name and preparation method of the compound of formula (II) of the present invention are shown in example 1 below.

Control 1: compound 4 in WO2013/000275A1, self-made (see WO2013/000275A1 for a preparation method), has the following structural formula:

compound 4, a compound of formula (I).

Control 2: compound 22 in WO2013/000275A1, self-made (see WO2013/000275A1 for a preparation method), has the following structural formula:

compound 22.

Solvent: 0.5% MC (methyl cellulose) solution + 0.1% SDS (sodium dodecyl sulfate).

The experimental method comprises the following steps:

the methods of intragastric administration (PO) are detailed in Table 2

Rat PK (pharmacokinetic) dosing method for compounds in Table 2

Blood collection: 0.17 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours, 30 hours, 48 hours, 54 hours, 72 hours, about 200. mu.L of whole blood was collected at each time point, and plasma was separated by centrifugation at 8000 rpm for 6 minutes in a low-temperature high-speed centrifuge (5415R, Eppendorf) at 4 ℃ and stored in a refrigerator at-80 ℃.

Plasma sample analysis: mu.L of plasma was removed with precision, 600. mu.L of internal standard MTBE (methyl tert-butyl ether) solution (containing the internal standard dapagliflozin 25ng/mL) was added, vortexed at 1500 rpm for 10min, centrifuged for 5min (12000 rpm), 400. mu.L of supernatant was dried with nitrogen, reconstituted with 200. mu.L of reconstitution solution (acetonitrile: water = 7: 3), vortexed for 10min, and analyzed using LC-MS/MS (API4000, aplied Biosystems).

Table 3 rat PK (pharmacokinetic) evaluation results (PO) of Compounds

T_1/2Represents the half-life

Tmax represents the peak time of the drug in plasma

Plasma drug concentration at Cmax passage expression peak

AUC_lastArea under curve 0 → t when representing drug

AUC_infArea 0 → ∞ under curve when drug is represented

And (4) conclusion: as can be seen from the experimental results in Table 3, the compound of formula (II) of the present invention has short peak reaching time in rat blood concentration, rapid onset of action, and higher exposure and significant difference compared with the control drug 1 and the control drug 2, which indicates that the compound of formula (II) of the present invention has significant progress.

The present invention will be described in further detail with reference to the following examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples.

In the examples, the raw material compounds used were commercially available from companies such as African chemical Co., Ltd, national drug group chemical reagent Co., Ltd, Fuyu fine chemical Co., Ltd, Shanghai Banghu chemical Co., Ltd, Guangdi chemical reagent Co., Ltd, Guangdi fine chemical Co., Ltd, and Kemiou chemical reagent Co., Ltd.

Example 1(2S,3R,4R,5S,6R) -2- (3- (4- (((1R,3S,5S) -bicyclo [ 3.1.0)]Hexane-3-yl) oxy Preparation of yl) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) -tetrahydro-2H-pyran-3, 4, 5-triol (compound of formula (II)

(1) Preparation of 5-bromo-2-chlorobenzoyl chloride

5-bromo-2-chlorobenzoic acid (270g, 1.15mol) was suspended in dichloromethane (2700mL), N-dimethylformamide (1mL) was added, and oxalyl chloride (288mL, 3.46mol) was added dropwise at 0 ℃. After the dropwise addition, the reaction solution is moved to 20 ℃ for reaction for 3 hours, the reaction solution becomes clear, TLC (thin layer chromatography) shows that the reaction is finished, and the product is obtained by rotary evaporation at 30-35 ℃ and is directly used for the next reaction.

(2) Preparation of (5-bromo-2-chlorophenyl) (4-methoxyphenyl) methanone

Under the protection of nitrogen, anhydrous aluminum trichloride (155g, 1.16mol) is suspended in dichloromethane (2050mL), anisole (125mL, 1.15mol) is added at one time at the temperature of-5 ℃, after stirring for 20min, a dichloromethane solution (300mL) of 5-bromo-2-chlorobenzoyl chloride is added dropwise, and reaction is carried out for 3h at the temperature of-5 ℃. TLC showed the reaction was complete, poured into 2N hydrochloric acid and the layers separated. And (3) taking the organic phase, washing twice with a saturated sodium bicarbonate solution, then washing with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, and performing rotary evaporation to obtain a solid. Ethanol (150mL) was added and the mixture was slurry washed for 30min, filtered and the filter cake was dried to give the product (265g, 71% yield).

(3) Preparation of 4-bromo-1-chloro-2- (4-methoxybenzyl) benzene

(5-bromo-2-chlorophenyl) (4-methoxyphenyl) methanone (265g, 0.81mol) was dissolved in dichloromethane (515mL) and acetonitrile (1030mL), and triethylsilane (352mL, 2.22mol) was added. Boron trifluoride diethyl etherate (273mL, 2.22mol) was added dropwise at 0 ℃ under nitrogen. After the dropwise addition, the mixture is stirred for 20min and moved to room temperature for reaction for 2 h. TLC indicated completion of the reaction, added methyl tert-butyl ether (1.5L) and saturated sodium bicarbonate solution (1.5L), stirred for 30min, the organic phase separated, washed four times with saturated sodium bicarbonate solution, once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, rotary evaporated to give an oil, added ethanol, stirred at room temperature for 30min, stirred in ice bath for 30min, precipitated a large amount of solid, filtered, and the filter cake dried to give the product (226g, 89% yield).

(4) Preparation of 4- (5-bromo-2-chlorobenzyl) phenol

Under nitrogen protection and with the exclusion of light, 4-bromo-1-chloro-2- (4-methoxybenzyl) benzene (226g, 0.73mol) was dissolved in dichloromethane (2240mL) and a solution of boron tribromide (357g, 1.42mol) in dichloromethane (1416mL) was slowly added dropwise at-78 ℃. After the dropwise addition, the reaction solution is transferred to room temperature for reaction for 2 hours. TLC showed the reaction was complete, water was slowly added dropwise under ice-water bath conditions, the dichloromethane phase was taken, the remaining aqueous phase was extracted twice with dichloromethane (1L), the organic phases were combined, washed twice with water, once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and rotary evaporated to give the product (210g, 97% yield).

(5) Preparation of (1R,3R,5S) -bicyclo [3.1.0] hexan-3-ol

Diethyl zinc (7.16L, 7.14mol) was added dropwise to dichloromethane (9L) at 0 deg.C, and when the addition was complete, a solution of trifluoroacetic acid (816g, 7.16mol) in dichloromethane (1L) was slowly added dropwise until there was no white smoke in the flask. After completion of the dropwise addition, stirring was carried out for 30min, and then a methylene chloride solution (1L) of diiodomethane (1918g, 7.14mol) was added dropwise. After the completion of the dropwise addition, after stirring for 30min, a methylene chloride solution (800mL) of cyclopentane-3-en-1-ol (200g, 2.38mol) was added dropwise, and after the completion of the dropwise addition, the reaction mixture was warmed to room temperature to react for 30 min. TLC showed complete reaction, poured into saturated ammonium chloride, stirred for 10min, separated, extracted the aqueous phase once with dichloromethane (2L), the organic phase washed with saturated sodium sulfite, saturated sodium bicarbonate, saturated sodium chloride, dried over anhydrous sodium sulfate, and the residue chromatographed to give the product (112g, 48% yield).

(6) Preparation of (1R,3R,5S) -bicyclo [3.1.0] hex-3-yl methanesulfonate

(1R,3R,5S) -bicyclo [3.1.0] hexan-3-ol (112g, 1.14mol) was dissolved in dichloromethane (1250mL) under ice-water bath conditions, triethylamine (174g, 1.69mol) was added, and methanesulfonyl chloride (197g, 1.72mol) was slowly added dropwise. After the dropwise addition, the reaction was carried out at 0 ℃ for 30 min. TLC showed complete reaction, the reaction solution was poured into water, separated, the organic phase was washed once with dilute hydrochloric acid, twice with water and then with saturated sodium chloride, dried over anhydrous sodium sulfate and rotary evaporated to give the product (138g, 68% yield).

(7) Preparation of (1R,3S,5S) -3- (4- (5-bromo-2-chlorobenzyl) phenoxy) bicyclo [3.1.0] hexane

(1R,3R,5S) -bicyclo [3.1.0] hex-3-yl methanesulfonate (138g, 0.78mol) was dissolved in N-methylpyrrolidone (2.1L), and 4- (5-bromo-2-chlorobenzyl) phenol (210g, 0.71mol), cesium carbonate (462g, 1.42mol), benzyltriethylammonium chloride (5.46g, 24mmol) were further added. After stirring at room temperature for 10min, the reaction mixture was transferred to 50 ℃ for overnight reaction. TLC showed completion of the reaction, after addition of water, extracted twice with a mixed solution of petroleum ether and methyl tert-butyl ether (petroleum ether: methyl tert-butyl ether = 1: 1), the organic phases were combined, washed twice with saturated sodium bicarbonate solution, twice with saturated sodium chloride, dried over anhydrous sodium sulfate, rotary evaporated, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate = 50: 1) to give the product (135g, 50% yield).

The molecular formula is as follows: c₁₉H₁₈BrClO molecular weight: 377.71

¹H-NMR(400MHz，CDCl₃)：7.28-7.21(m，3H)，7.07-7.05(d，2H)，6.82-6.78(m，2H)，4.42-4.35(m，1H)，3.98(s，2H)，2.36-2.31(m，2H)，1.96-1.90(m，2H)，1.40-1.33(m，2H)，0.47-0.44(m，1H)，0.07-0.02(m，1H).

(8) Preparation of (3R,4S, 5R,6R) -3,4, 5-tris ((trimethylsilyl) oxy) -6- (((trimethylsilyl) oxy) methyl) tetrahydro-2H-pyran-2-one

Suspending (D) - (+) -gluconic acid-1, 5-lactone (85g, 0.47mol) in THF (tetrahydrofuran) (932mL), adding N-methylmorpholine (405mL, 4.78mol), cooling to-5 ℃ under the protection of nitrogen, adding TMSCl (trimethylchlorosilane) (360mL, 4.78mol), stirring for 1h at room temperature after finishing dropping, stirring for 5h at 35 ℃, maintaining the stirring at 25 ℃ for overnight, and detecting by TLC that the reaction is finished. Toluene (200mL) was added, water (1L) was added dropwise in an ice-water bath, and the organic phase was washed once with sodium dihydrogen phosphate, once with water, once with a saturated sodium chloride solution, dried and concentrated to give the product (218g, 100% yield).

(9) Preparation of (3R,4S,5S, 6R) -2- (3- (4- (((1R,3S,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3, 4, 5-triol

(1R,3S,5S) -3- (4- (5-bromo-2-chlorobenzyl) phenoxy) bicyclo [3.1.0] hexane (135g, 0.358mol) was dissolved in tetrahydrofuran (813mL) and toluene (813mL) under nitrogen, and after cooling to-78 ℃, n-butyllithium (194mL, 0.465mol) was added dropwise, and the mixture was stirred for 2 hours. The reaction mixture was removed by syringe and added to a solution of (3R,4S, 5R,6R) -3,4, 5-tris ((trimethylsilyl) oxy) -6- (((trimethylsilyl) oxy) methyl) tetrahydro-2H-pyran-2-one (218g, 0.47mol) in toluene (950mL) and after stirring for 1H, a solution of methanesulfonic acid (44.9mL, 2.15mol) in methanol (1.2L) was added and stirred at-78 ℃ for 1H and allowed to warm to room temperature for overnight. TLC detection reaction is complete, saturated sodium bicarbonate solution is added for quenching, ethyl acetate (2L) is used for extraction, organic phase is taken and washed by water, saturated sodium chloride solution is washed, anhydrous sodium sulfate is dried, and rotary evaporation is carried out to obtain the product (173g, yield 98%).

(10) Preparation of (3R,4R,5S, 6R) -2- (3- (4- (((1R,3S,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol

(3R,4S,5S, 6R) -2- (3- (4- (((1R,3S,5S) -bicyclo [3.1.0] hexan-3-yl) oxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3, 4, 5-triol (173g, 0.352mol) and triethylsilane (180mL, 1.05mol) were dissolved in dichloromethane (2L) at-78 ℃ under a nitrogen blanket, boron trifluoride diethyl ether (134mL, 1.05mol) was slowly added dropwise, and the reaction was carried out at-78 ℃ for 1H and slowly warmed to room temperature for 1H. HPLC detection reaction is complete, saturated sodium bicarbonate solution is dropped, ethyl acetate (1L) is extracted, organic phase is washed by water and saturated sodium chloride solution, dried by anhydrous sodium sulfate, and rotary evaporation is carried out to obtain the product (143g, yield 88%).

(11) Preparation of (2R,3R,4R, 5S, 6S) -2- (acetoxymethyl) -6- (3- (4- (((1R,3S,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) tetrahydro-2H-pyran-3, 4, 5-triyltriacetate

(3R,4R,5S, 6R) -2- (3- (4- (((1R,3S,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (143g, 0.311mol) was dissolved in dichloromethane (720mL), pyridine (252mL, 3.11mol) and DMAP (4-dimethylaminopyridine) (1.9g, 15.6mmol) were added, and acetic anhydride (292mL, 3.11mol) was added dropwise in an ice-water bath and stirred at room temperature for 3 hours. Adding water to quench the reaction, extracting with ethyl acetate (1.5L), collecting the organic layer, washing with dilute hydrochloric acid for three times, washing with saturated sodium bicarbonate for one time, washing with water, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, rotary evaporating, and recrystallizing the residue with ethanol to obtain the product (81g, 42% yield).

(12) Preparation of (2S,3R,4R,5S,6R) -2- (3- (4- (((1R,3S,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol

Mixing (2R,3R,4R, 5S, 6S) -2- (acetoxymethyl) -6- (3- (4- (((1R,3S,5S) -bicyclo [ 3.1.0)]Hexane-3-yl) oxy) benzyl) -4-chlorophenyl) tetrahydro-2H-pyran-3, 4, 5-triyltriacetate (81g, 0.129mol) was dissolved in a mixed solvent of tetrahydrofuran (313mL), methanol (470mL) and water (156mL), and lithium hydroxide monohydrate (6.32g, 150mmol) was added and stirred at room temperature overnight. TLC showed complete reaction, solvent was removed by rotary evaporation, ethyl acetate (400mL) was added and dissolved, and the organic phase was washed with saturated aqueous sodium chloride, KHSO₄Washed twice with water, dried over anhydrous sodium sulfate, rotary evaporated and the residue chromatographed on C18 reverse phase preparative chromatography to give the final product (54.2g, 91% yield).

The molecular formula is as follows: c₂₅H₂₉ClO₆Molecular weight: 460.95 LC-MS (m/z): 478.3[ M + NH₄]⁺

¹H-NMR(400MHz，MeOD)：7.35-7.26(m，3H)，7.08-7.06(d，2H)，6.76-6.74(d，2H)，4.45-4.41(m，1H)，4.10-4.00(m，3H)，3.89-3.88(d，1H)，3.71-3.69(m，1H)，3.45-3.38(m，3H)，3.31-3.26(m，1H)，2.34-2.29(m，2H)，1.87-1.81(m，2H)，1.37-1.33(m，2H)，0.43-0.42(m，1H)，0.11-0.10(m，1H).

Example 2: (2S,3R,4R,5S,6R) -2- (3- (4- (((1R,3R,5S) -bicyclo [ 3.1.0)]Hexane-3-yl) oxy Yl) benzyl) -4-chlorophenyl) -6- (hydroxymethyl-tetrahydro-2H-pyran-3, 4, 5-triol (Compound of formula (III))Preparation of

(1) Preparation of (1R,3R,5S) -3- (4- (5-bromo-2-chlorobenzyl) phenoxy) bicyclo [3.1.0] hexane

4- (5-bromo-2-chlorobenzyl) phenol (29.7g, 0.10mol) prepared according to the procedures of steps (1) to (4) of example 1 was dissolved in toluene (450mL), and sodium hydroxide (8g, 0.20mol), water (27mL), and (1R,3R,5S) -bicyclo [3.1.0] hex-3-ylmethanesulfonate (17.6g, 0.10mol) prepared according to the procedures of steps (5) to (6) of example 1, benzyltriethylammonium chloride (1.05g, 4.61mmol) were added in this order. The reaction is carried out for 2h at 70 ℃. TLC showed complete reaction, 500mL of ethyl acetate was added for extraction, the organic phase was dried, the solvent was removed by rotary evaporation, and the residue was chromatographed on silica gel (petroleum ether: ethyl acetate = 50: 1) to give the product (10.1g, 27% yield).

The molecular formula is as follows: c₁₉H₁₈BrClO molecular weight: 377.71

¹H-NMR(400MHz，CDCl₃)：7.28-7.21(m，3H)，7.07-7.05(d，2H)，6.76-6.72(d，2H)，4.79-4.76(m，1H)，3.98(s，2H)，2.22-2.16(m，2H)，2.05-2.01(m，2H)，1.35-1.31(m，2H)，0.62-0.58(m，1H)，0.51-0.46(m，1H).

(2) Preparation of (3R,4S,5S, 6R) -2- (3- (4- (((1R,3R,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3, 4, 5-triol

(1R,3R,5S) -3- (4- (5-bromo-2-chlorobenzyl) phenoxy) bicyclo [3.1.0] hexane (1.5g, 3.97mmol) was dissolved in tetrahydrofuran (100mL) and cooled to-78 ℃ under nitrogen. N-butyllithium (2mL, 4.8mmol) was added dropwise, and after completion of the addition, the mixture was stirred at-78 ℃ for 1 hour. A solution of (3R,4S, 5R,6R) -3,4, 5-tris ((trimethylsilyl) oxy) -6- (((trimethylsilyl) oxy) methyl) tetrahydro-2H-pyran-2-one (3.0g, 6.4mmol) in toluene (25mL) was added dropwise and the reaction was maintained at-78 deg.C for 1H. Then, a solution of methanesulfonic acid (3.8g, 39.6mmol) in methanol (50mL) was added thereto, and the mixture was reacted at-78 ℃ for 0.5 hour and then at room temperature for 18 hours. The reaction solution was quenched with saturated aqueous sodium bicarbonate (100mL), extracted with ethyl acetate (100 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to give the product (1.5g, 77% yield).

(3) Preparation of (3R,4R,5S, 6R) -2- (3- (4- (((1R,3R,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol

((3R,4S,5S, 6R) -2- (3- (4- (((1R,3R,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3, 4, 5-triol (1.40g, 2.86mmol) was dissolved in a mixed solution of dichloromethane (40mL) and acetonitrile (40mL), triethylsilane (1.0g, 8.6mmol) was added, boron ethyl ether (1.2g, 8.45mmol) was added dropwise with stirring at room temperature, after completion of the addition, the reaction was reacted at room temperature for 16 hours, a saturated aqueous sodium hydrogen carbonate solution (100mL) was added to the reaction system, ethyl acetate (100 mL. times.3) was added, the organic phases were combined, dried over anhydrous sodium sulfate, filtration was carried out, and the filtrate was concentrated under reduced pressure to remove the solvent to obtain a crude product (1.0g, yield 76%).

(4) Preparation of (2R,3R,4R, 5S, 6S) -2- (acetoxymethyl) -6- (3- (4- ((1R,3R,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) tetrahydro-2H-pyran-3, 4, 5-triyltriacetate

((3R,4R,5S, 6R) -2- (3- (4- (((1R,3R,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (1.0g, 2.2mmol) was dissolved in dichloromethane (40mL), pyridine (1.76mL) and DMAP (13mg) were added, acetic anhydride (2.07mL) was added dropwise under ice bath conditions, stirred at room temperature for 3H, water (10mL) was added to quench the reaction, the organic phases were separated, the aqueous phase was extracted with ethyl acetate (50mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain a product (400mg, yield 29%).

(5) Preparation of (2S,3R,4R,5S,6R) -2- (3- (4- (((1R,3R,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol

(2R,3R,4R, 5S, 6S) -2- (acetoxymethyl) -6- (3- (4- ((1R,3R,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) tetrahydro-2H-pyran-3, 4, 5-triyltriacetate (400mg, 0.64mmol) was dissolved in a mixed solvent of tetrahydrofuran (5mL), water (5mL) and methanol (5mL), lithium hydroxide monohydrate (107.5mg, 2.56mmol) was added, and the reaction was stirred at room temperature for 2H, TLC showed completion. After removal of the solvent by rotary evaporation, the residue was subjected to silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain a final product (200mg, yield 68%).

The molecular formula is as follows: c₂₅H₂₉ClO₆Molecular weight: 460.95

¹H-NMR(400MHz，MeOD)d:7.23-7.38(m，3H)，7.07(m，2H)，6.69(m，2H)，4.79(m，1H)，4.06-4.11(m，1H)，3.94-4.05(m，2H)，3.87(m，1H)，3.64-3.73(m，1H)，3.36-3.24(m，4H)，2.19(m，2H)，1.88-2.02(m，2H)，1.26-1.41(m，2H)，0.52-0.60(m，1H)，0.39-0.50(m，1H).

Example 3: (2R,3R,4R, 5S,6R) -2- (3- (4- (((1R,3S,5S) -bicyclo [ 3.1.0)]Hexane-3-yl) oxy Preparation of yl) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) -tetrahydro-2H-pyran-3, 4, 5-triol (compound of formula (IV)

(1) Preparation of (3R,4S,5S, 6R) -2- (3- (4- (((1R,3S,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3, 4, 5-triol

(1R,3S,5S) -3- (4- (5-bromo-2-chlorobenzyl) phenoxy) bicyclo [3.1.0] hexane (5g, 13.3mmol) was dissolved in tetrahydrofuran (100mL) and cooled to-78 ℃ under nitrogen. n-BuLi (6.7mL, 15.8mmol) was added dropwise, and the reaction was stirred at-78 ℃ for 1 hour after the addition. (3R,4S, 5R,6R) -3,4, 5-tris ((trimethylsilyl) oxy) -6- (((trimethylsilyl) oxy) methyl) tetrahydro-2H-pyran-2-one (10g, 21.4mmol) was dissolved in toluene (50mL), added dropwise to the reaction system, and reacted at-78 ℃ for 1 hour. Further, methanesulfonic acid (12.7g, 132mmol) dissolved in methanol (60mL) was added and the reaction was carried out at room temperature for 18 hours. The reaction solution was quenched with saturated aqueous sodium bicarbonate (100mL), extracted with ethyl acetate (100 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to give the product (4.5g, 69% yield).

(2) Preparation of (3R,4R,5S, 6R) -2- (3- (4- (((1R,3S,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol

(3R,4S,5S, 6R) -2- (3- (4- (((1R,3S,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3, 4, 5-triol (4g, 8.16mmol) was dissolved in a mixed solution of dichloromethane (30mL) and acetonitrile (30mL), triethylsilane (2.86g, 24.6mmol) was added, boron trifluoride ether (3.43g, 24.2mmol) was added dropwise with stirring at room temperature, and after completion of the addition, the reaction was carried out at room temperature for 16 hours. To the reaction system was added saturated aqueous sodium bicarbonate (50mL), followed by extraction with ethyl acetate (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, and the resulting crude product was purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain a product (2mg, yield 53%).

(3) Preparation of (2R,3R,4R, 5S,6R) -2- (acetoxymethyl) -6- (3- (4- (((1R,3S,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) tetrahydro-2H-pyran-3, 4, 5-triyltriacetate

(3R,4R,5S, 6R) -2- (3- (4- (((1R,3S,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (1.0g, 2.17mmol) was dissolved in dichloromethane (20mL), and N, N-diisopropylethylamine (2.8g, 21.7mmol), acetic anhydride (2.2g, 21.7mmol) and a catalytic amount of 4-dimethylaminopyridine (25mg) were added. After stirring at room temperature for 2h, the reaction mixture was washed with 1N hydrochloric acid (15mL), the layers were separated to give an organic phase, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to give the product (0.55g, 40% yield).

(4) Preparation of (2R,3R,4R, 5S,6R) -2- (3- (4- (((1R,3S,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol

(2R,3R,4R, 5S,6R) -2- (acetoxymethyl) -6- (3- (4- (((1R,3S,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) tetrahydro-2H-pyran-3, 4, 5-triyltriacetate (0.55g, 0.87mmol) was dissolved in a mixed solvent (25mL, 2: 1) of water, methanol and tetrahydrofuran, and lithium hydroxide monohydrate (0.37g, 8.7mmol) was added and stirred at room temperature overnight. After removing the solvent by rotary evaporation, ethyl acetate (10mL × 3) was added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain a final product (0.27mg, yield 67.5%).

The molecular formula is as follows: c₂₅H₂₉ClO₆Molecular weight: 460.95

¹H-NMR(400MHz，MeOD)d：7.21-7.31(m，3H)，6.93-7.09(m，2H)，6.74-6.79(m，2H)，4.53-4.63(m，1H)，4.39-4.48(m，1H)，4.14-4.20(m，1H)，3.89-4.11(m，5H)，3.82(m，1H)，3.67(m，1H)，2.32(m，2H)，1.84(m，2H)，1.34(m，2H)，0.43(m，1H)，0.10(m，1H).

Example 4: (2R,3R,4R, 5S,6R) -2- (3- (4- (((1R,3R,5S) -bicyclo [ 3.1.0)]Hexane-3-yl) oxy Preparation of yl) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) -tetrahydro-2H-pyran-3, 4, 5-triol (Compound of formula (V)

(1) Preparation of 2-chloro-5-iodobenzoyl chloride

2-chloro-5-iodobenzoic acid (10.0g, 35.5mmol) was suspended in dichloromethane (200mL), N-dimethylformamide (0.05mL) was added, oxalyl chloride (11.3g, 89.0mmol) was added dropwise at 0 ℃ and, after completion of the addition, the mixture was warmed to room temperature and stirred for 4 hours. The resulting clear solution was rotary evaporated to remove the solvent to give the product (10.7g, 100% yield) which was used in the next reaction without purification.

(2) Preparation of (2-chloro-5-iodophenyl) (4-methoxyphenyl) methanone

2-chloro-5-iodobenzoyl chloride (10.7g, 35.5mmol) was dissolved in dichloromethane (200mL), cooled in an ice-water bath, and aluminum trichloride (10.4g, 78.2mmol) was added. A solution of anisole (4.2g, 38.9mmol) in dichloromethane (50mL) was added dropwise, and after completion of the addition, the mixture was warmed to room temperature and stirred for 3 hours. The reaction solution was quenched by pouring into ice water, 3mol/L hydrochloric acid was added, liquid separation was performed, the aqueous phase was extracted with dichloromethane (150mL × 2), the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 0-1: 100) to obtain a product (12.0g, yield 91%).

(3) Preparation of 1-chloro-4-iodo-2- (4-methoxybenzyl) benzene

(2-chloro-5-iodophenyl) (4-methoxyphenyl) methanone (12.0g, 32.2mmol) and triethylsilane (9.86g, 84.8mmol) were dissolved in acetonitrile (200mL), and boron trifluoride etherate (13.7g, 96.5mmol) was added at 0 ℃ and, after completion of the dropwise addition, the mixture was heated to 70 ℃ and stirred for 3 hours. Cooling to room temperature, adding saturated sodium bicarbonate solution for quenching, extracting with ethyl acetate (200mL × 3), combining organic phases, washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and purifying the crude product by silica gel column chromatography (ethyl acetate: petroleum ether ═ 0-1: 100) to obtain the product (10.0g, 87% yield).

(4) Preparation of 4- (2-chloro-5-iodobenzyl) phenol

Dissolving 1-chloro-4-iodo-2- (4-methoxybenzyl) benzene (10.0g, 27.9mmol) in dichloromethane (150mL), cooling in an ice-water bath, dropwise adding boron tribromide (21g, 83.7mmol), heating to room temperature after dropwise addition, and stirring for 3 hours. After quenching with saturated sodium bicarbonate solution, separation of the phases, extraction of the aqueous phase with dichloromethane (150mL × 2), combination of the organic phases, washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, concentration under reduced pressure and purification of the crude product by silica gel column chromatography (ethyl acetate: petroleum ether ═ 0 to 1: 20) gave the product (8.5g, 88% yield).

(5) Preparation of (4- (2-chloro-5-iodobenzyl) phenoxy) tert-butyldimethylsilane

4- (2-chloro-5-iodobenzyl) phenol (8.5g, 24.7mmol) and triethylamine (5.0g, 49.5mmol) were dissolved in dichloromethane (200mL), tert-butyldimethylchlorosilane (5.6g, 37.1mmol) and 4- (dimethylamino) pyridine (305mg, 2.5mmol) were added at 0 deg.C, and after completion of addition, the mixture was warmed to room temperature and stirred for 18 hours. Water (100mL) was added, the layers were separated, the aqueous layer was extracted with dichloromethane (100 mL. times.2), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-1: 100) to give the product (10.0g, 88% yield).

(6) Preparation of (3R,4S,5S, 6R) -2- (3- (4- ((tert-butyldimethylsilyl) oxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3, 4, 5-triol

(4- (2-chloro-5-iodobenzyl) phenyloxy) tert-butyldimethylsilane (10.0g, 21.8mmol) was dissolved in a mixed solution of anhydrous tetrahydrofuran (80mL) and toluene (80mL), cooled to-78 ℃, n-butyllithium (2.4mol/L n-hexane solution) (13.6mL, 32.6mmol) was slowly added dropwise thereto, reacted at-78 ℃ for 2 hours, warmed to-60 ℃, and a toluene (60mL) solution in which (3R,4S, 5R,6R) -3,4, 5-tris ((trimethylsilyl) oxy) -6- (((trimethylsilyl) oxy) methyl) tetrahydro-2H-pyran-2-one (15.3g, 32.7mmol) was dissolved was added to the reaction solution all at once, and reacted at-60 ℃ for 2 hours. A solution of methanesulfonic acid (14.6g, 152.1mmol) in methanol (50mL) was added dropwise thereto, and after completion of the addition, the reaction was stirred at room temperature for 17 hours. After quenching with saturated sodium bicarbonate solution, separation of the liquids, extraction of the aqueous phase with ethyl acetate (200 mL. times.3), combination of the organic phases, washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, concentration under reduced pressure to give the crude product (9.0g), which was used in the next reaction without purification.

(7) Preparation of (3R,4S,5S, 6R) -2- (4-chloro-3- (4-hydroxybenzyl) phenyl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3, 4, 5-triol

The crude (3R,4S,5S, 6R) -2- (3- (4- ((tert-butyldimethylsilyl) oxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3, 4, 5-triol (9.0g) was dissolved in tetrahydrofuran (70mL), tetrabutylammonium fluoride trihydrate (22.1g, 70mmol) was added, stirring was carried out at room temperature for 2 hours, concentration was carried out under reduced pressure, ethyl acetate (400mL) and water (200mL) were added, liquid separation was carried out, the organic phase was washed with water (200 mL. times.3) in succession, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude (6.5g) which was used in the next reaction without purification.

(8) Preparation of (3R,4R,5S, 6R) -2- (4-chloro-3- (4-hydroxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol

Crude (3R,4S,5S, 6R) -2- (4-chloro-3- (4-hydroxybenzyl) phenyl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3, 4, 5-triol (6.5g) and triethylsilane (4.03g, 34.7mmol) were dissolved in a mixed solvent of dichloromethane (100mL) and acetonitrile (100mL), and boron trifluoride etherate (5.6g, 39.5mmol) was added dropwise at 0 ℃ and then warmed to room temperature and stirred for 16 hours. Quenching with saturated sodium bicarbonate solution, extracting with ethyl acetate (250mL × 3), combining the organic phases, washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and purifying the crude product by silica gel column chromatography (methanol: dichloromethane = 0-1: 15) to give the product (3.8g, 46% yield over 3 steps).

(9) Preparation of (3R,4R,5S, 6R) -2- (3- (4- (((1R,3R,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol

Suspending (3R,4R,5S, 6R) -2- (4-chloro-3- (4-hydroxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (3.8g, 10mmol) and (1R,3R,5S) -bicyclo [3.1.0] hex-3-yl methanesulfonate (3.5g, 20mmol) in toluene (100mL) and water (10mL), adding sodium hydroxide (1.0g, 25mmol) and benzyltriethylammonium chloride (114mg, 0.5mmol) in this order, heating to 80 ℃ for reaction for 16 hours, cooling to room temperature, adding water (50mL), separating, extracting the aqueous phase with ethyl acetate (50 mL. times.3), combining the organic phases, washing with a saturated sodium chloride solution, drying with sodium sulfate, concentrating under reduced pressure to obtain an anhydrous crude product (5.0g), the reaction mixture was used in the next reaction without further purification.

(10) Preparation of (2R,3R,4R, 5S,6R) -2- (acetoxymethyl) -6- (3- (4- (((1R,3R,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) tetrahydro-2H-pyran-3, 4, 5-triyltriacetate

Dissolving crude (3R,4R,5S, 6R) -2- (3- (4- (((1R,3R,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (5.0g) in dichloromethane (50mL), adding pyridine (7.9g, 100mmol) and 4- (dimethylamino) pyridine (122mg, 1mmol), adding acetic anhydride (10.2g, 100mmol) under ice bath, warming to room temperature, stirring for 4 hours, adding water, extracting with ethyl acetate (150 mL. times.3), combining the organic phases, washing sequentially with 1mol/L hydrochloric acid (150 mL. times.3), a saturated sodium bicarbonate solution (150mL), a saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 0-1: 4) to give the product (350mg, 5.6% yield over 2 steps).

(11) Preparation of (2R,3R,4R, 5S,6R) -2- (3- (4- (((1R,3R,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol

Mixing (2R,3R,4R, 5S,6R) -2- (acetoxymethyl) -6- (3- (4- (((1R,3R,5S) -bicyclo [ 3.1.0)]Hexane-3-yl) oxy) benzyl) -4-chlorophenyl) tetrahydro-2H-pyran-3, 4, 5-triyltriacetate (350mg, 0.56mmol) was dissolved in a mixed solvent of water, methanol and tetrahydrofuran (1: 2) (25mL), and LiOH. H.₂O (118mg, 2.8mmol), stirred at rt for 16h, concentrated under reduced pressure, extracted with water (20mL), ethyl acetate (30mL × 3), the organic phases combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product purified by silica gel column chromatography (methanol: dichloromethane = 0-1: 15) to give the product (140mg, 54.7% yield).

The molecular formula is as follows: c₂₅H₂₉ClO₆Molecular weight: 460.95

¹H-NMR(400MHz，MeOD):7.29-7.31(m，3H)，7.04-7.07(m，2H)，6.68-6.71(m，2H)，4.77-4.81(m，1H)，4.57-4.61(m，1H)，4.15-4.19(m，1H)，3.98-4.05(4H，m)，3.92-3.93(m，1H)，3.80-3.83(m，1H)，3.63-3.68(m，1H)，2.16-2.21(m，2H)，1.94-1.97(m，2H)，1.24-1.34(m，2H)，0.54-0.56(m，1H)，0.39-0.49(m，1H).

Claims (13)

1. A compound of formula (II):

its name is (2S,3R,4R,5S,6R) -2- (3- (4- (((1R,3S,5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol.

2. A compound of formula (ii) as defined in claim 1A process for preparing a compound of formula (c) which comprises dissolving formula (b) in an organic solvent, adding formula (a), reacting at a temperature of 0 ℃ to 70 ℃ to obtain formula (c), and reacting formula (c) withReacting to obtain a formula d-1, reacting the formula d-1 to obtain a formula d-2, reacting the formula d-2 at the temperature of between 78 ℃ below zero and 30 ℃ to obtain a formula e, purifying the formula e to obtain a compound of a formula (II),

wherein X represents fluorine, chlorine, bromine or iodine,

g represents a hydroxyl protecting group selected from trimethylsilyl, triethylsilyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, pivaloyl, allyl, methoxymethyl, benzyloxymethyl or trimethylsilylethyl.

3. The process for preparing a compound of formula (ii) according to claim 2, wherein G is selected from trimethylsilyl.

4. The process for preparing a compound of formula (ii) according to claim 2, wherein the organic solvent is selected from the group consisting of N-methylpyrrolidone, N-dimethylformamide, tetrahydrofuran, dioxane and acetonitrile.

5. The process for the preparation of the compound of formula (ii) as claimed in claim 4, wherein the organic solvent is selected from N-methylpyrrolidone.

6. A process for the preparation of a compound of formula (ii) as claimed in claim 2, wherein the purification of formula e to give a compound of formula (ii) is by: carrying out hydroxyl protection reaction on the formula e to generate a formula f, carrying out deprotection reaction on the formula f to generate a compound of a formula (II),

wherein G' represents a hydroxyl protecting group selected from acetyl, trimethylsilyl, triethylsilyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, pivaloyl, allyl, methoxymethyl, benzyloxymethyl, trimethylsilylethyl, propionyl, isobutyryl or benzoyl.

7. The process for preparing a compound of formula (ii) according to claim 6, wherein G' is selected from acetyl, pivaloyl, propionyl, isobutyryl or benzoyl.

8. An intermediate of a compound of formula (II) shown below,

9. a pharmaceutical composition comprising a compound of formula (ii) as claimed in claim 1 in association with one or more pharmaceutically acceptable carriers and/or diluents, in any pharmaceutically acceptable dosage form.

10. The pharmaceutical composition of claim 9, further comprising one or more hypoglycemic agents selected from sitagliptin phosphate, vildagliptin, saxagliptin, alogliptin benzoate, linagliptin, tegagliptin, gemagliptin, metformin, phenformin, exenatide, or liraglutide.

11. Use of a compound of formula (ii) according to claim 1 as a sodium-glucose cotransporter inhibitor for the preparation of a medicament for the treatment and/or prevention of diabetes or diabetes-related diseases.

12. Use of a compound of formula (ii) according to claim 11 as a sodium-glucose cotransporter inhibitor for the preparation of a medicament for the treatment and/or prevention of diabetes mellitus or a diabetes-related disease selected from the group consisting of insulin-dependent diabetes mellitus and non-insulin-dependent diabetes mellitus.

13. Use of a compound of formula (ii) according to claim 11 as a sodium-glucose cotransporter inhibitor for the preparation of a medicament for the treatment and/or prevention of diabetes or diabetes-related diseases selected from insulin resistance diseases and obesity.