CN104761522B - C-Glycoside Derivatives of Optically Pure Benzyl-4-Chlorophenyl - Google Patents

Abstract

The invention belongs to the technical field of medicines, and particularly relates to optically pure benzyl-4-chlorphenyl C-glucoside derivatives shown in a formula (II) and a formula (III), 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-chlorphenyl C-glucoside derivatives as a sodium-glucose cotransporter (SGLT) inhibitor in preparation of medicines for treating and/or preventing insulin-dependent diabetes, non-insulin-dependent diabetes, insulin resistance diseases or obesity and other various diabetes and related diseases.

Description

Optically pure C-glycoside derivatives of benzyl-4-chlorophenyl

technical field

The invention belongs to the technical field of medicine, in particular to optically pure benzyl-4-chlorophenyl C-glycoside derivatives or pharmaceutically acceptable salts thereof, methods for preparing these compounds and their intermediates, and medicines containing these compounds Preparations and pharmaceutical compositions, and C-glycoside derivatives of optically pure benzyl-4-chlorophenyl of the present invention or pharmaceutically acceptable salts thereof are used as sodium-glucose cotransporter (SGLT) inhibitors in the preparation of therapeutic And/or application in drugs for preventing various diabetes (including insulin-dependent diabetes and non-insulin-dependent diabetes) or various diabetes-related diseases (including insulin resistance disease and obesity).

Background technique

Approximately 100 million people worldwide suffer from type 2 diabetes, characterized by hyperglycemia due to excess hepatic glucose production and peripheral insulin resistance. Hyperglycemia is considered a major risk factor for the development of diabetic complications and may be directly related to impaired insulin secretion in advanced type II diabetes. Normalization of insulin can therefore be expected to improve blood glucose in type 2 diabetic patients. Most of the existing diabetes drugs are insulin secretory drugs or insulin sensitizers, such as sulfonylureas, glinides, thiazolidinediones, and metformin, which have potential side effects, such as easy to cause weight gain , hypoglycemia, lactic acidosis, etc. Therefore, there is an urgent need to develop novel, safe and effective antidiabetic drugs with a mechanism of action.

In the kidney, glucose is freely filtered from the glomerulus (approximately 180 g/day), but is almost reabsorbed by active transport in the proximal convoluted tubule. Two of the sodium-glucose transporters play an important role in glucose reabsorption, namely SGLT-1 and SGLT-2, and the role of SGLT-2 is particularly prominent. SGLT-2 is a transmembrane protein specifically expressed only in the S1 section of the proximal tubule. One of its most important physiological functions is to absorb sugar in the blood flowing through the renal tubule, accounting for 90% of the reabsorption. SGLT-2 Transported at a sodium-glucose ratio of 1:1, SGLT-2 inhibitors can inhibit the absorption of blood sugar in the renal tubules and excrete a large amount of sugar from the urine. SGLT-1 is mainly expressed in the distal convoluted tubule, accounting for 10% of reabsorption, and SGLT-1 is transported at the ratio of sodium-glucose 2:1. SGLT-1 has also been found in the gut and other tissues. These transporters function through the Na+/ATPase pump and are transferred back into the blood via the glucose transporter 2 (GLUT2). This suggests that the most likely drug target to develop is the SGLT-2 transporter, both because of its absolute reabsorption of glucose and because it is only expressed in the kidney. The feasibility of this approach has also been confirmed in the research on familial nephropathy and urine sugar. The urine sugar in familial nephropathy mainly manifests as variable urine sugar (about 10-120g/day), but the patients are generally in good condition, and no adverse long-term negative effects on health have been found. This benign glycosuria 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 induction of glycosuria. Evidence has shown that an important clinical advantage of SGLT-2 inhibitors is that they are less likely to cause hypoglycemia. Inhibition of SGLT-1 can cause sugar-galactose malabsorption syndrome, which can lead to dehydration, and there is evidence that SGLT-1 inhibitors will delay the absorption of carbohydrates, which will cause gastrointestinal symptoms that individuals cannot tolerate. Selecting a high SGLT-2 inhibitor will not block the role of SGLT-1 in transporting and absorbing glucose in the intestine, so it is not easy to cause gastrointestinal symptoms. In addition, SGLT-1 is also highly expressed in human myocardial tissue, and its blockade may cause new cardiac function or organic lesions. Therefore, the development of compounds with high selectivity for SGLT-2 is of great significance for the study of drugs for the treatment of diabetes.

SGLT-2 inhibitors treat hyperglycemia by acting on SGLT-2 transporters to inhibit renal glucose reabsorption, which provides a new way for the treatment of diabetes. Although this pathway does not directly contribute to the pathophysiology of type 2 diabetes, lowering blood glucose by increasing renal glucose excretion would cause a net energy deficit, promote weight loss and indirectly improve obesity symptoms. Studies have found that the combination of these drugs with existing hypoglycemic drugs or insulin has a lower risk of hypoglycemia and has the potential to reduce body weight. This type of drug does not depend on the function of β-cells and insulin resistance. Therefore, while SGLT-2 inhibitors are effective for general diabetic patients, they are also effective for diabetic patients who have failed treatment with biguanides and DPP-4 inhibitors. Very good curative effect. Therefore, such drugs can also be used in combination with hypoglycemic drugs such as biguanides and DPP-4 inhibitors in the future.

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

The applicant also disclosed a series of C-glycoside SGLT-2 inhibitor compounds in patent WO2013/000275A1, wherein compound 4 has better inhibitory effect and better selectivity on SGLT-2, and its structural formula is

This compound is a mixture of stereoisomers having an asymmetric center, and multiple optical isomers exist. Considering that many chiral mixture drugs in the prior art have potential problems such as easy to produce unknown toxic and side effects, reduced drug efficacy and difficulty in quality control, it will greatly increase the risk of research and development, and optically pure stereoisomers have more advantages than chiral mixtures. The advantages of safer, lower probability of toxic side effects, better stability and easier quality control, and optically pure stereoisomers also have potential improvements in pharmacodynamics, pharmacokinetics and toxicology Therefore, the development of a single stereoisomer with high selectivity, fast onset, high efficiency, safety, and good stability for SGLT-2 is of great significance for subsequent drug development and quality control in drug production after marketing .

Contents of the invention

Technical scheme of the present invention is as follows:

1. Stereoisomer compounds of compounds represented by formula (I) or pharmaceutically acceptable salts thereof, selected from formulas (II), (III), (IV) and (V):

Its name is (2S,3R,4R,5S,6R)-2-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-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]hexan-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]hexan-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]hexan-3-yl)oxy) Benzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

2. The present invention further claims to protect the preparation method of the compound of formula (II) described in the above 1, the reaction scheme of the preparation method is:

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, benzyl Oxymethyl group, trimethylsilylethyl group, etc., preferably trimethylsilyl group.

making process:

Formula b, namely (1R, 3r, 5S)-bicyclo[3.1.0]hexane-3-yl methanesulfonate, is dissolved in an organic solvent (the organic solvent can be selected from N-methylpyrrolidone, N , N-dimethylformamide, tetrahydrofuran, dioxane and acetonitrile, preferably N-methylpyrrolidone), add formula a, control the temperature and react at 0°C to 70°C to prepare formula c, formula c with Formula d-1 is obtained by reaction, formula d-1 is deprotected to obtain formula d-2, formula d-2 is reacted at a temperature ranging from -78°C to 30°C to generate formula e, and formula e is purified to obtain formula (II) compound.

Purification of the above formula e to obtain the compound of formula (II) can adopt the following purification methods, but not limited to the following methods.

Purification method: Formula e is subjected to hydroxyl protection reaction to generate formula f, and formula f is subjected to deprotection reaction to generate formula (II) compound.

Among them, 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 compound of formula (II) of the present invention can be synthesized by the methods described in the above schemes and/or other techniques known to those of ordinary skill in the art, but not limited to the above methods.

3. The present invention further claims to protect the preparation method of the compound of formula (III) described in the above 1, the reaction scheme of the preparation method is:

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, benzyl Oxymethyl group, trimethylsilylethyl group, etc., preferably trimethylsilyl group.

making process:

Formula a is dissolved in an organic solvent (the organic solvent can be selected from toluene, N,N-dimethylformamide, tetrahydrofuran, dioxane and acetonitrile, preferably toluene), and formula b is added to control the temperature at 0 ℃ to 70 ℃ under the conditions of reaction, the preparation of formula c', formula c' and Reaction to obtain formula d'-1, formula d'-1 is deprotected to obtain formula d'-2, formula d'-2 is reacted at a temperature ranging from -78°C to 30°C to form formula e', formula e' undergoes Purification affords the compound of formula (III).

Purification of the above formula e' to obtain the compound of formula (III) can adopt the following purification methods, but not limited to the following methods.

Purification method: carry out hydroxyl protection reaction of formula e' to generate formula f', and carry out deprotection reaction of formula f' to generate compound of formula (III).

Among them, 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 compound of formula (III) of the present invention can be synthesized by the methods described in the above schemes and/or other techniques known to those of ordinary skill in the art, but not limited to the above methods.

4. The present invention further claims to protect the intermediate of the compound of formula (II) as shown below,

5. The present invention further claims to protect the intermediate of the compound of formula (II) as shown below,

Wherein, X represents bromine or iodine.

6. The present invention further claims to protect the intermediate of the compound of formula (III) as shown below,

7. The present invention further claims the intermediate of the compound of formula (III) as shown below,

Wherein, X represents bromine or iodine.

The "pharmaceutically acceptable salt" includes alkali metal salts, such as sodium salts, potassium salts, lithium salts, etc.; alkaline earth metal salts, such as calcium salts, magnesium salts, etc.; other metal salts, such as aluminum salts, iron salts, Zinc salt, copper salt, nickel salt, cobalt salt, etc.; inorganic alkali salt, such as ammonium salt; organic alkali salt, such as tert-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, N'-dibenzylethylenediamine salt , chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, piperazine salt, tetramethylamine salt, tris(hydroxymethyl)aminomethane salt, etc. ; Hydrohalides, such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, etc.; inorganic acid salts, such as nitrates, perchlorates, sulfates, phosphates, etc.; lower alkane sulfonates Acid salts, such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, etc.; arylsulfonate, such as benzenesulfonate, p-benzenesulfonate, etc.; organic acid salts, such as acetate, Malate, fumarate, succinate, citrate, tartrate, oxalate, maleate, etc.; amino acid salts, such as glycinate, trimethylglycinate, arginine, ornithine salt, glutamate, aspartate, etc.

The present invention also claims a pharmaceutical composition comprising the compound of formula (II) and/or formula (III) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers and/or diluents of the present invention, which can be prepared into any pharmaceutically acceptable dosage form. Oral, parenteral, rectal or pulmonary administration to patients in need thereof. For oral administration, it can be made into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc. When making oral preparations, suitable fillers, binders, disintegrants, lubricants and the like can be added. For parenteral administration, it can be made into injections, including injection liquid, sterile powder for injection and concentrated solution for injection. When making injections, it can be produced by conventional methods in the existing pharmaceutical field. When preparing injections, no additives can be added, and suitable additives can also be added according to the properties of the medicine. For rectal administration, it can be made into suppositories and the like. For pulmonary administration, it can be made into inhalants or sprays. Each unit preparation contains 0.005g to 10g of the compound represented by the formula (I) in a physiologically effective amount, which can be 0.005g, 0.01g, 0.05g, 0.1g, 0.125g, 0.2g, 0.25g, 0.3g, 0.4 g, 0.5g, 0.6g, 0.75g, 1g, 1.25g, 1.5g, 1.75g, 2g, 2.5g, 3g, 4g, 5g, 10g, etc.

The present invention further claims the pharmaceutical composition of the compound of formula (II) and/or formula (III) or its pharmaceutically acceptable salt and other pharmaceutically active ingredients of the present invention, and said other pharmaceutically active ingredients can be a or multiple hypoglycemic drugs, and the hypoglycemic drugs are selected from the group consisting of sitagliptin phosphate, vildagliptin, saxagliptin, alogliptin benzoate, linagliptin, tige Gliptin, Gemigliptin, Metformin, Phenformin, Exenatide or Liraglutide, etc.

The present invention also claims the use of the compounds of formula (II) and/or formula (III) or pharmaceutically acceptable salts thereof in the preparation of 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 resistance disease and obesity.

The present invention further claims a method for treating and/or preventing various diabetes (including insulin-dependent diabetes and non-insulin-dependent diabetes) or various diabetes-related diseases (including insulin resistance disease and obesity), the method comprising giving Mammals including humans are administered an effective dose of the compound of formula (II) and/or formula (III) of the present invention or a pharmaceutically acceptable salt thereof.

The compounds of the present invention have the following characteristics:

(1) The compound of the present invention has high selectivity to SGLT-2, and can be safely used to treat and/or prevent diabetes in various mammals (including humans) and various diseases caused by diabetes.

(2) The compound of the present invention has high-efficiency inhibitory effect on SGLT-2 and significant hypoglycemic effect, and has quick onset, less toxic and side effects, and high safety.

(3) The compound of the present invention exhibits good physical and chemical properties, high purity, good stability, easy quality control, and is suitable for large-scale industrial production.

4. Specific implementation

For convenience, well-known abbreviations used in the present invention include but are not limited to:

Me: methyl;

Et: ethyl;

Ms: methylsulfonyl;

Ac: acetyl;

TBS: tert-butyldimethylsilyl;

THF: Tetrahydrofuran;

DMAP: 4-dimethylaminopyridine;

DIPEA: N,N-Diisopropylethylamine;

n-BuLi: n-butyllithium;

TMS: trimethylsilyl group.

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

The beneficial effects of the compounds of the present invention are further described below through pharmacological experiments, but it should not be understood that the compounds of the present invention only have the following beneficial effects.

Experimental Example 1 The in vitro activity test of the compound of the present invention

Test product: the compound of formula (II), formula (III), formula (IV) and formula (V) of the present invention, its chemical name and preparation method are shown in the preparation examples of each compound.

Control drug 1: compound 4 in patent WO2013/000275A1, self-made (refer to patent WO2013/000275A1 for the preparation method), and its structural formula is as follows:

Compound 4 is the compound of formula (I).

The meanings represented by the abbreviations of the following experiments are as follows:

NMG N-methylglucosamine (N-methyl-glucosamine)

KRH Krebs-Ringer-Henseleit

Experimental method: Transfect the human SGLT-2 and SGLT-1 sequences into Chinese hamster ovary cells for stable expression, and inhibit the cells from [ ¹⁴ C]-labeled-R-methyl-D-glucopyranoside (AMG) Sodium-dependent absorption, the half-inhibitory concentration IC50 was measured, and the activity was determined.

Buffer A (KRH-Na ⁺ ): 120mM NaCl, 4.7mM KCl, 1.2mM MgCl ₂ , 2.2mM CaCl ₂ , 10mM HEPES (PH7.4with1mM Tris).

Buffer A-(KRH-NMG): 120 mM NMG, 4.7 mM KCl, 1.2 mM MgCl ₂ , 2.2 mM CaCl ₂ , 10 mM HEPES (PH74 with 1 mM Tris).

Buffer D: 120mM NaCl, 4.7mM KCl, 1.2mM MgCl ₂ , 2.2mM CaCl ₂ , 10mM HEPES, 0.5mM phlorizin (PH7.4with 1mM Tris).

Experimental method: The sequences of human SGLT-2 and SGLT-1 are stably expressed on CHO cells, and the cells are cultured on a 96-well plate for 12 hours, with KRH-Na ⁺ (Buffer A) or KRH-NMG (Buffer A-) 200 μL/well buffer solution, washed 3 times. Add 100 μL/well of buffer solution containing Buffer A or Buffer A-plus [ ¹⁴ C]-AMG (10 μCi/mL) and incubate at 37° C. for 1 hour. Then, 100 μL of ice-precooled buffer solution (Buffer D) was added to stop the test, and washed 5 times. Then add 20 μL/well of ice-precooled bacteriolysis buffer (100 mM NaOH) solution, centrifuge at 600 rpm for 5 minutes, and 80 μL/well of Microscint40 solution, centrifuge at 600 rpm for 5 minutes. Finally, the radioactivity of [ ¹⁴ C]-AMG was detected by MicroBeta Trilux (purchased from PerkinElmer) by scintillation counting method, and the half inhibitory concentration IC50 was calculated.

Experimental results and conclusions:

Table 1 The inhibitory effect evaluation result of compound of the present invention

It can be seen from Table 1 that the compound of formula (II) of the present invention has better inhibitory effect and better selectivity on SGLT-2, and shows obvious advantages compared with the control drug 1.

Experimental Example 2 Pharmacokinetics experiment in rats of compounds of the present invention

Test animals: 6-8 week old male SD rats (purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.), 3 rats/compound, body weight 200-240g.

Test product: the compound of formula (II) of the present invention, its chemical name and preparation method are shown in Example 1 below.

Control drug 1: compound 4 in patent WO2013/000275A1, self-made (refer to patent WO2013/000275A1 for the preparation method), and its structural formula is as follows:

Compound 4 is the compound of formula (I).

Control drug 2: compound 22 in patent WO2013/000275A1, self-made (refer to patent WO2013/000275A1 for the preparation method), and its structural formula is as follows:

Compound 22.

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

experimental method:

See Table 2 for the administration method of intragastric administration (PO)

Rat PK (pharmacokinetics) administration method of table 2 compound

Blood collection: 0.17 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours, 30 hours, 48 hours, 54 hours, 72 hours, take about 200 μL whole blood at each time point, at low temperature High-speed centrifuge (5415R, Eppendorf) was centrifuged at 4°C at 8000 rpm for 6 minutes to separate the plasma, and the plasma was stored in a -80°C refrigerator.

Plasma sample analysis: Precisely pipette 20 μL of plasma, add 600 μl of internal standard MTBE (methyl tert-butyl ether) solution (including internal standard dapagliflozin 25 ng/mL), vortex at 1500 rpm for 10 min, and centrifuge for 5 min (12000 rpm), 400 μL supernatant was taken, blown dry with nitrogen, reconstituted with 200 μL reconstitution solution (acetonitrile:water=7:3), vortexed for 10 min, and analyzed by LC-MS/MS (API4000, Aplplied Biosystems).

Rat PK (pharmacokinetics) evaluation result (PO) of table 3 compound

T _1/2 stands for half-life

Tmax represents the peak time of the drug in plasma

Cmax represents the peak plasma drug concentration

AUC _last represents the area under the drug-time curve 0→t

AUC _inf represents the area under the drug-time curve 0→∞

Conclusion: From the experimental results in Table 3, it can be seen that the peak time of the compound of formula (II) of the present invention in the blood concentration of rats is shorter, the onset of effect is rapid, and compared with contrast drug 1 and contrast drug 2, the exposure is higher , has a significant difference, indicating that the compound of formula (II) of the present invention has obvious progress.

The above-mentioned content of the present invention will be further described in detail through specific implementation in the form of examples below. However, it should not be construed that the scope of the above-mentioned subject matter of the present invention is limited to the following examples.

In the examples, the raw material compounds used are commercially available, obtained from Alfa Aisha (Tianjin) Chemical Co., Ltd., Sinopharm Chemical Reagent Co., Ltd., Tianjin Fuyu Fine Chemical Co., Ltd., Shanghai Bangcheng Chemical Co., Ltd. Company, Tianjin Guangcheng Chemical Reagent Co., Ltd., Tianjin Guangfu Fine Chemical Co., Ltd., Tianjin Kemiou Chemical Reagent Co., Ltd. and other companies.

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

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

Suspend 5-bromo-2-chlorobenzoic acid (270g, 1.15mol) in dichloromethane (2700mL), add N,N-dimethylformamide (1mL), add dropwise oxalyl chloride (288mL , 3.46mol). After the dropwise addition, move to 20°C to react for 3 hours, the reaction liquid becomes clear, TLC (thin layer chromatography) shows that the reaction is complete, and the product is obtained by rotary evaporation at 30-35°C, which is directly used in the next reaction.

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

Under nitrogen protection, anhydrous aluminum trichloride (155 g, 1.16 mol) was suspended in dichloromethane (2050 mL), at -5°C, anisole (125 mL, 1.15 mol) was added in one go, and after stirring for 20 min, A dichloromethane solution (300 mL) of 5-bromo-2-chlorobenzoyl chloride was added dropwise, and reacted at -5°C for 3 h. TLC showed that the reaction was complete, poured into 2N hydrochloric acid, and separated layers. The organic phase was taken, washed twice with saturated sodium bicarbonate solution, and then washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and rotary evaporated to obtain a solid. Add ethanol (150 mL) and wash with slurry for 30 min, filter, and dry the filter cake to obtain the product (265 g, yield 71%).

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

Dissolve (5-bromo-2-chlorophenyl)(4-methoxyphenyl)methanone (265 g, 0.81 mol) in dichloromethane (515 mL) and acetonitrile (1030 mL), and add triethylsilane ( 352 mL, 2.22 mol). Under nitrogen protection, boron trifluoride diethyl ether (273 mL, 2.22 mol) was added dropwise at 0°C. After the dropwise addition was completed, stir for 20 min and move to room temperature for 2 h. TLC showed that the reaction was complete, and methyl tert-butyl ether (1.5L) and saturated sodium bicarbonate solution (1.5L) were added, and after stirring for 30min, the organic phase was separated, washed four times with saturated sodium bicarbonate solution, saturated sodium chloride The solution was washed once, dried over anhydrous sodium sulfate, and rotary evaporated to obtain an oily product. Ethanol was added, stirred at room temperature for 30 minutes, and stirred in an ice bath for 30 minutes. A large amount of solid precipitated, filtered, and the filter cake was dried to obtain the product (226 g, yield 89%).

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

Under the protection of nitrogen and protected from light, 4-bromo-1-chloro-2-(4-methoxybenzyl)benzene (226g, 0.73mol) was dissolved in dichloromethane (2240mL), and slowly A solution of boron tribromide (357 g, 1.42 mol) in dichloromethane (1416 mL) was added dropwise. After the dropwise addition was completed, it was moved to room temperature for 2h. TLC showed that the reaction was complete, and water was slowly added dropwise under ice-water bath conditions, the dichloromethane phase was taken, and the remaining water phase was extracted twice with dichloromethane (1L), and the combined organic phase was washed twice with water and once with saturated sodium chloride solution , dried over anhydrous sodium sulfate, and rotary evaporated to obtain the product (210 g, yield 97%).

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

At 0°C, diethylzinc (7.16L, 7.14mol) was added dropwise into dichloromethane (9L), and after the addition was complete, when there was no white smoke in the bottle, trifluoroacetic acid (816g, 7.16mol) in dichloromethane solution (1L). After the dropwise addition was completed, after stirring for 30 min, a dichloromethane solution (1 L) of diiodomethane (1918 g, 7.14 mol) was added dropwise. After the dropwise addition was completed and stirred for 30 min, a dichloromethane solution (800 mL) of cyclopentane-3-en-1-ol (200 g, 2.38 mol) was added dropwise, and after the dropwise addition was completed, the mixture was raised to room temperature for 30 min. TLC showed that the reaction was complete. Pour it into saturated ammonium chloride, stir for 10 minutes, and separate the liquids. Take the aqueous phase and extract it once with dichloromethane (2L). Take the organic phase and wash it with saturated sodium sulfite, saturated sodium bicarbonate, and saturated sodium chloride. After washing and drying over anhydrous sodium sulfate, the residue was subjected to column chromatography to obtain the product (112 g, yield 48%).

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

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

(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]hexan-3-yl methanesulfonate (138g, 0.78mol) was dissolved in N-methylpyrrolidone (2.1L), and 4-( 5-bromo-2-chlorobenzyl)phenol (210 g, 0.71 mol), cesium carbonate (462 g, 1.42 mol), benzyltriethylammonium chloride (5.46 g, 24 mmol). After stirring at room temperature for 10 min, it was moved to 50° C. to react overnight. TLC showed that the reaction was complete. After adding water, extract twice with a mixed solution of petroleum ether and methyl tert-butyl ether (petroleum ether: methyl tert-butyl ether = 1: 1), combine the organic phases, and wash with saturated sodium bicarbonate The solution was washed twice, washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, and rotary evaporated, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate = 50: 1) to obtain the product (135 g, yield 50%) .

Molecular formula: C ₁₉ H ₁₈ BrClO Molecular weight: 377.71

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 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) (3R, 4S, 5R, 6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetra Preparation of Hydrogen-2H-pyran-2-one

Suspend (D)-(+)-glucono-1,5-lactone (85g, 0.47mol) in THF (tetrahydrofuran) (932mL), add N-methylmorpholine (405mL, 4.78mol), nitrogen Under protection, the temperature was lowered to -5 °C, TMSCl (trimethylsilyl chloride) (360 mL, 4.78 mol) was added dropwise, stirred at room temperature for 1 h, stirred at 35 °C for 5 hours, and kept stirring at 25 °C overnight, and the reaction was detected by TLC. Add toluene (200mL), add water (1L) dropwise under an ice-water bath, take the organic phase, wash once with sodium dihydrogen phosphate, once with water, once with saturated sodium chloride solution, dry and concentrate to obtain the product (218g, yield 100%) .

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

Under nitrogen protection, (1R, 3s, 5S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)bicyclo[3.1.0]hexane (135g, 0.358mol) was dissolved in In tetrahydrofuran (813 mL) and toluene (813 mL), after cooling down to -78°C, n-butyllithium (194 mL, 0.465 mol) was added dropwise, and after the addition was complete, stirred for 2 h. Extract the reaction solution with a syringe and add to (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) solution, after stirring for 1h, add methylsulfonic acid (44.9mL, 2.15mol) in methanol (1.2 L) The solution was stirred at -78°C for 1 h, then raised to room temperature and reacted overnight. TLC detects that the reaction is complete, quenched by adding saturated sodium bicarbonate solution, extracted with ethyl acetate (2L), takes the organic phase and washes it with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and rotary evaporated to give the product (173g, produced rate 98%).

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

At -78°C under nitrogen protection, (3R, 4S, 5S, 6R)-2-(3-(4-(((1R, 3s, 5S)-bicyclo[3.1.0]hexane-3 -yl)oxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (173g, 0.352 mol) and triethylsilane (180mL, 1.05mol) were dissolved in dichloromethane (2L), and boron trifluoride ether (134mL, 1.05mol) was slowly added dropwise. Raised to room temperature for 1h. HPLC detects that the reaction is complete, drips saturated sodium bicarbonate solution, extracts with ethyl acetate (1L), washes the organic phase with water and saturated sodium chloride solution, drys over anhydrous sodium sulfate, and rotary evaporates to obtain the product (143g, yield 88% ).

(11)(2R,3R,4R,5S,6S)-2-(Acetoxymethyl)-6-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0] Preparation of Hexan-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]hexan-3-yl)oxy)benzyl)- 4-Chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (143g, 0.311mol) was dissolved in dichloromethane (720mL), and pyridine (252mL , 3.11mol) and DMAP (4-dimethylaminopyridine) (1.9g, 15.6mmol), then acetic anhydride (292mL, 3.11mol) was added dropwise in an ice-water bath, and stirred at room temperature for 3h. Add water to quench the reaction, extract with ethyl acetate (1.5L), take the organic layer, wash with dilute hydrochloric acid three times, wash with saturated sodium bicarbonate once, wash with water, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, rotary evaporate, and the residue The product (81 g, yield 42%) was obtained by recrystallization from ethanol.

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

(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 (81 g, 0.129 mol) was dissolved in tetrahydrofuran (313 mL) Lithium hydroxide monohydrate (6.32 g, 150 mmol) was added to a mixed solvent of , methanol (470 mL) and water (156 mL), and stirred overnight at room temperature. TLC showed that the reaction was complete, and the solvent was removed by rotary evaporation, dissolved by adding ethyl acetate (400mL), the organic phase was washed with saturated aqueous sodium chloride solution, _KHSO4 aqueous solution, and water twice, dried over anhydrous sodium sulfate, rotary evaporated, and the residue was washed with C18 The final product (54.2 g, 91% yield) was prepared by reverse phase preparative chromatography.

Molecular formula: C ₂₅ H ₂₉ ClO ₆ Molecular weight: 460.95 LC-MS (m/z): 478.3[M+NH ₄ ] ⁺

¹ H-NMR (400MHz, MeOD) δ: 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]hexan-3-yl) oxy ) benzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (formula (III) compound) preparation

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

The 4-(5-bromo-2-chlorobenzyl)phenol (29.7g, 0.10mol) prepared according to the method of Example 1 (1)-(4) was dissolved in toluene (450mL), and the hydrogen Sodium (8g, 0.20mol), water (27mL), (1R, 3r, 5S)-bicyclo[3.1.0]hexan-3-yl prepared according to the method of Example 1 (5)-(6) Mesylate (17.6 g, 0.10 mol), benzyltriethylammonium chloride (1.05 g, 4.61 mmol). Reaction at 70°C for 2h. TLC showed that the reaction was complete, 500 mL of ethyl acetate was added for extraction, the organic phase was dried, and the solvent was removed by rotary evaporation. The residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate=50:1) to obtain the product (10.1 g, yield 27% ).

Molecular formula: C ₁₉ H ₁₈ BrClO Molecular weight: 377.71

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 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) (3R, 4S, 5S, 6R)-2-(3-(4-(((1R, 3r, 5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl Preparation of )-4-chlorophenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol

Dissolve (1R,3r,5S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)bicyclo[3.1.0]hexane (1.5 g, 3.97 mmol) in tetrahydrofuran (100 mL ), cooled to -78°C under nitrogen protection. Add n-butyllithium (2 mL, 4.8 mmol) dropwise, and stir at -78°C for 1 h after the addition is complete. (3R, 4S, 5R, 6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro -2H-pyran-2-one (3.0 g, 6.4 mmol) in toluene (25 mL) was reacted at -78°C for 1 h. A solution of methanesulfonic acid (3.8 g, 39.6 mmol) in methanol (50 mL) was added, kept at -78°C for 0.5 h, and then reacted at room temperature for 18 h. Quench the reaction solution with saturated aqueous sodium bicarbonate (100 mL), then extract with ethyl acetate (100 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, take the filtrate and concentrate under reduced pressure to remove the solvent to obtain the product (1.5 g, 77% yield).

(3)(3R,4R,5S,6R)-2-(3-(4-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl Preparation of )-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]hexan-3-yl)oxy)benzyl) -4-chlorophenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1.40 g, 2.86 mmol) was dissolved in dichloromethane ( 40mL) and acetonitrile (40mL), add triethylsilane (1.0g, 8.6mmol), under stirring at room temperature, dropwise add boron trifluoride diethyl ether (1.2g, 8.45mmol), after adding, react at room temperature 16h.Add saturated aqueous sodium bicarbonate solution (100mL) to the reaction system, then add ethyl acetate (100mL×3) for extraction, combine the organic phases, dry with anhydrous sodium sulfate, filter, take the filtrate and concentrate under reduced pressure to remove the solvent to obtain Crude product (1.0 g, 76% yield).

(4) (2R, 3R, 4R, 5S, 6S)-2-(acetoxymethyl)-6-(3-(4-((1R,3r,5S)-bicyclo[3.1.0]hexyl Preparation of alk-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]hexan-3-yl)oxy)benzyl) -4-Chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (1.0 g, 2.2 mmol) was dissolved in dichloromethane (40 mL) and pyridine was added (1.76mL) and DMAP (13mg), add acetic anhydride (2.07mL) dropwise under ice-bath conditions, stir at room temperature for 3h, add water (10mL) to quench the reaction, and separate the layers to obtain an organic phase, and the aqueous phase is washed with ethyl acetate (50mL ×2) extraction, combined organic phases, dried over anhydrous sodium sulfate, and silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain the product (400 mg, yield 29%).

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

Molecular formula: C ₂₅ H ₂₉ ClO ₆ Molecular weight: 460.95

¹ H-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 Base) benzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (formula (Ⅳ) compound)

(1) (3R, 4S, 5S, 6R)-2-(3-(4-(((1R,3s, 5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl Preparation of )-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 (5 g, 13.3 mmol) was dissolved in THF (100 mL) , cooled to -78°C under nitrogen protection. n-BuLi (6.7 mL, 15.8 mmol) was added dropwise, and the reaction was stirred at -78°C for 1 hour after the dropwise addition. (3R, 4S, 5R, 6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro- 2H-pyran-2-one (10 g, 21.4 mmol) was dissolved in toluene (50 mL), then added dropwise to the reaction system, and kept at -78°C for 1 hour. Add methanesulfonic acid (12.7 g, 132 mmol) dissolved in methanol (60 mL) and react at room temperature for 18 hours. The reaction solution was quenched with saturated aqueous sodium bicarbonate (100 mL), then extracted with ethyl acetate (100 mL×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 obtain the product (4.5 g, yield 69%).

(2)(3R,4R,5S,6R)-2-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)benzyl Preparation of )-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 (4g, 8.16mmol) was dissolved in dichloromethane (30mL) Add triethylsilane (2.86g, 24.6mmol) to a mixed solution of acetonitrile (30mL), add boron trifluoride ether (3.43g, 24.2mmol) dropwise under stirring at room temperature, and react at room temperature for 16 hours after the addition. Add saturated aqueous sodium bicarbonate solution (50mL) to the reaction system, then add ethyl acetate (50mL×3) for extraction, combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to remove the solvent. The product was purified by silica gel column chromatography (dichloromethane:methanol=10:1) (2 mg, yield 53%).

(3)(2R,3R,4R,5S,6R)-2-(Acetoxymethyl)-6-(3-(4-(((1R,3s,5S)-bicyclo[3.1.0] Preparation of Hexan-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]hexan-3-yl)oxy)benzyl)- 4-Chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (1.0 g, 2.17 mmol) was dissolved in dichloromethane (20 mL), N was added, N-Diisopropylethylamine (2.8 g, 21.7 mmol), acetic anhydride (2.2 g, 21.7 mmol) and a catalytic amount of 4-dimethylaminopyridine (25 mg). Stir at room temperature for 2 h, wash the reaction mixture with 1N hydrochloric acid (15 mL), separate the layers to obtain an organic phase, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to remove the solvent. ester=5:1) to obtain the product (0.55 g, yield 40%).

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

Molecular formula: C ₂₅ H ₂₉ ClO ₆ Molecular weight: 460.95

¹ H-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 Base) benzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (formula (V) compound)

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

2-Chloro-5-iodobenzoic acid (10.0 g, 35.5 mmol) was suspended in dichloromethane (200 mL), N, N-dimethylformamide (0.05 mL) was added, and oxalyl chloride ( 11.3g, 89.0mmol), after the dropwise addition was completed, it was raised to room temperature and stirred for 4 hours. The resulting clear solution was rotary evaporated to remove the solvent to obtain the product (10.7 g, yield 100%), which was directly 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 (4.2 g, 38.9 mmol) in dichloromethane (50 mL) was added dropwise. After the dropwise addition was completed, the mixture was raised to room temperature and stirred for 3 hours. Pour the reaction solution into ice water to quench, add 3mol/L hydrochloric acid, separate the layers, extract the aqueous phase with dichloromethane (150mL×2), combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and reduce Concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=0~1:100) to obtain the product (12.0 g, yield 91%).

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

Dissolve (2-chloro-5-iodophenyl)(4-methoxyphenyl)methanone (12.0 g, 32.2 mmol) and triethylsilane (9.86 g, 84.8 mmol) in acetonitrile (200 mL), Boron trifluoride etherate (13.7 g, 96.5 mmol) was added at 0°C. After the dropwise addition, the temperature was raised to 70°C and stirred for 3 hours. Cooled to room temperature, quenched by adding saturated sodium bicarbonate solution, extracted with ethyl acetate (200mL×3), combined the organic phases, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (Ethyl acetate:petroleum ether=0～1:100) was purified to obtain the product (10.0 g, yield 87%).

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

Dissolve 1-chloro-4-iodo-2-(4-methoxybenzyl)benzene (10.0g, 27.9mmol) in dichloromethane (150mL), cool in an ice-water bath, add boron tribromide (21g , 83.7mmol), after the dropwise addition was completed, it was raised to room temperature and stirred for 3 hours. Add saturated sodium bicarbonate solution to quench, separate the layers, extract the aqueous phase with dichloromethane (150mL×2), combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and pass the crude product through a silica gel column The product was purified by chromatography (ethyl acetate:petroleum ether=0~1:20) (8.5 g, yield 88%).

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

Dissolve 4-(2-chloro-5-iodobenzyl)phenol (8.5g, 24.7mmol) and triethylamine (5.0g, 49.5mmol) in dichloromethane (200mL), and add tert-butyl Chlorodimethylsilane (5.6g, 37.1mmol) and 4-(dimethylamino)pyridine (305mg, 2.5mmol) were added and stirred at room temperature for 18 hours. Add water (100mL), separate the layers, extract the aqueous phase with dichloromethane (100mL×2), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and the crude product is subjected to silica gel column chromatography (ethyl acetate ester:petroleum ether=0～1:100) to obtain the product (10.0g, yield 88%).

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

Dissolve (4-(2-chloro-5-iodobenzyl)phenyloxy)tert-butyldimethylsilane (10.0 g, 21.8 mmol) in a mixed solution of anhydrous tetrahydrofuran (80 mL) and toluene (80 mL) , cooled to -78°C, slowly added n-butyllithium (2.4mol/L n-hexane solution) (13.6mL, 32.6mmol) dropwise, reacted at -78°C for 2 hours, raised the temperature to -60°C, dissolved (3R , 4S, 5R, 6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyridine A solution of pyran-2-one (15.3 g, 32.7 mmol) in toluene (60 mL) was added to the reaction solution at one time, and reacted at -60°C for 2 hours. A methanol (50 mL) solution in which methanesulfonic acid (14.6 g, 152.1 mmol) was dissolved was added dropwise. After the dropwise addition was completed, the reaction was stirred at room temperature for 17 hours. Add saturated sodium bicarbonate solution to quench, separate the layers, extract the aqueous phase with ethyl acetate (200mL×3), combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product (9.0g ), used directly in the next step without purification.

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

(3R, 4S, 5S, 6R)-2-(3-(4-((tert-butyldimethylsilyl)oxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl )-2-methoxytetrahydro-2H-pyran-3,4,5-triol crude product (9.0g) was dissolved in tetrahydrofuran (70mL), and tetrabutylammonium fluoride trihydrate (22.1g, 70mmol ), stirred at room temperature for 2 hours, concentrated under reduced pressure, added ethyl acetate (400mL) and water (200mL), separated, the organic phase was washed with water (200mL×3) successively, washed with saturated sodium chloride solution, anhydrous sodium sulfate It was dried and concentrated under reduced pressure to obtain the crude product (6.5 g), which was directly used in the next reaction without purification.

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

(3R, 4S, 5S, 6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyridine Crude furan-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 added dropwise at 0°C Boron trifluoride diethyl ether complex (5.6 g, 39.5 mmol), after the dropwise addition, was raised to room temperature and stirred for 16 hours. Quenched by adding saturated sodium bicarbonate solution, extracted with ethyl acetate (250mL×3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (methanol: Dichloromethane=0～1:15) was purified to obtain the product (3.8g, 3-step yield 46%).

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

(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]hexane-3-yl methanesulfonate (3.5g, 20mmol) were suspended in toluene (100mL) and water (10mL), sequentially added sodium hydroxide (1.0g, 25mmol) and benzyltriethylammonium chloride (114mg, 0.5mmol), heated to 80 ° C for 16 hours, cooled to room temperature, added water (50mL), The liquid was separated, the aqueous phase was extracted with ethyl acetate (50mL×3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (5.0g), which was directly used in the next step without purification. step response.

(10)(2R,3R,4R,5S,6R)-2-(Acetoxymethyl)-6-(3-(4-(((1R,3r,5S)-bicyclo[3.1.0] Preparation of Hexan-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]hexan-3-yl)oxy)benzyl)- 4-Chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol crude product (5.0g) was dissolved in dichloromethane (50mL), and pyridine (7.9g , 100mmol) and 4-(dimethylamino)pyridine (122mg, 1mmol), added acetic anhydride (10.2g, 100mmol) under ice-cooling, raised to room temperature, stirred for 4 hours, added water, extracted with ethyl acetate (150mL×3 ), the organic phases were combined, washed successively with 1mol/L hydrochloric acid (150mL × 3), washed with saturated sodium bicarbonate solution (150mL), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was passed through a silica gel column Purification by chromatography (ethyl acetate:petroleum ether=0~1:4) gave the product (350 mg, 5.6% yield over 2 steps).

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

(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 water, methanol and In a mixed solvent of tetrahydrofuran (1:2:2) (25mL), add LiOH·H ₂ O (118mg, 2.8mmol), stir at room temperature for 16 hours, concentrate under reduced pressure, add water (20mL), extract with ethyl acetate (30mL ×3), the organic phases were 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 (methanol:dichloromethane=0～1:15) to obtain the product (140mg, Yield 54.7%).

Molecular formula: C ₂₅ H ₂₉ ClO ₆ Molecular weight: 460.95

¹ H-NMR (400MHz, MeOD) δ: 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. compound shown in formula (II)：

Its entitled (2S, 3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3s, 5S)-two ring [3.1.0] hexane -3- base) epoxide) Benzyl) -4- chlorphenyl) -6- (methylol) tetrahydrochysene -2H- pyrans -3,4,5- triol.

2. the preparation method of the formula described in claim 1 (II) compound, the method includes, and formula b is dissolved in organic solvent, Addition formula a, controls temperature react under the conditions of 0 DEG C to 70 DEG C, prepares formula c, formula c andReaction obtains formula D-1, the reaction of formula d-1 obtains formula d-2, formula d-2 is reacted under -78 DEG C to 30 DEG C range of condition of temperature production e, and formula e is passed through Purifying obtains formula (II) compound,

Wherein, X represents fluorine, chlorine, bromine or iodine,

G representation hydroxy protection group, selected from TMS, triethyl silyl, benzyl, to methoxy-benzyl, to nitrobenzyl Base, pivaloyl group, pi-allyl, methoxyl methyl, benzyloxymethyl or trimethylsilyl ethyl.

3. the preparation method of the formula described in claim 2 (II) compound, wherein said G is selected from TMS.

4. the preparation method of the formula described in claim 2 (II) compound, wherein said organic solvent is selected from N- crassitude Ketone, N,N-dimethylformamide, oxolane, dioxane and acetonitrile.

5. the preparation method of the formula described in claim 4 (II) compound, wherein said organic solvent is selected from N- crassitude Ketone.

6. the preparation method of the formula described in claim 2 (II) compound, formula e purifies the purification process obtaining formula (II) compound For：Formula e is carried out hydroxyl protection reaction production f, formula f carries out deprotection reaction production (II) compound,

Wherein, G' representation hydroxy protection group, selected from acetyl group, TMS, triethyl silyl, benzyl, to methoxyl group Benzyl, to nitrobenzyl, pivaloyl group, pi-allyl, methoxyl methyl, benzyloxymethyl, trimethylsilyl ethyl, propiono, different Bytyry or benzoyl.

7. the preparation method of the formula described in claim 6 (II) compound, wherein said G' be selected from acetyl group, pivaloyl group, Propiono, isobutyryl or benzoyl.

8. the intermediate of formula as follows (II) compound,

9. include the medicine group of formula (II) compound described in claim 1 and one or more pharmaceutical carrier and/or diluent Compound, is pharmaceutically acceptable arbitrary formulation.

10. pharmaceutical composition as claimed in claim 9, also includes one or more hypoglycemic medicine, and described hypoglycemic medicine selects From phosphoric acid Xi Gelieting, vildagliptin, BMS-477118, SYR-322, Li Gelieting, for Ge Lieting, Jimmy Ge Lieting, Melbine, insoral, Yi Xina peptide or Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37].

Formula (II) compound described in 11. claims 1 is as the white inhibitor of sodium glucose co-transporter 2 in preparation treatment And/or the application in the medicine of prevention diabetes or diabetes related diseases.

12. formula (II) compounds as claimed in claim 11 are controlled in preparation as the white inhibitor of sodium glucose co-transporter 2 Treat and/or prevent the application in diabetes or the medicine of diabetes related diseases, described diabetes are selected from insulin-dependent Diabetes and Non-Insulin Dependent Diabetes Mellitus.

13. formula (II) compounds as claimed in claim 11 are controlled in preparation as the white inhibitor of sodium glucose co-transporter 2 Treat and/or prevent the application in diabetes or the medicine of diabetes related diseases, described diabetes related diseases are selected from insulin Resistance disease and obesity.