CN104327027B - One class novel C aryl glucoside SGLT2 inhibitor - Google Patents

Abstract

A class of novel C-aryl glucoside SGLT2 inhibitors, the present invention relates to the field of medicine related to diabetes, in particular to a novel C-aryl glucoside derivative shown in general formula (I), its preparation method, combination Drugs and their application in the preparation of hypoglycemic drugs. The C-aryl glucoside derivatives have extremely excellent excretion effect of uric acid and hypoglycemic activity in vivo, and a compound with an in vivo hypoglycemic activity comparable to or even better than that of dapagliflozin is screened out, which can be used for prevention or treatment diabetes.

Description

A Novel C-Aryl Glucoside SGLT2 Inhibitor

technical field

The invention relates to the field of pharmacology related to diabetes, in particular to a new type 2 sodium-glucose transporter (SGLT2) inhibitor containing a polyaryl glucoside structure that has a therapeutic effect on diabetes. The invention also discloses its preparation The method, the pharmaceutical composition with the compounds as active components, and their application in the preparation of hypoglycemic drugs.

Background technique

At present, there are about 370 million diabetic patients in the world, most of whom are type 2 (ie non-insulin dependent) diabetic patients. Traditional drugs for the treatment of diabetes mainly include insulin, metformin, sulfonylureas, thiazolidinedione and α-glucosidase inhibitors. In recent years, new drugs for the treatment of diabetes include glucagon-like peptide 1 (GLP-1) agonists, dipeptidyl peptidase-IV (DPP-IV) inhibitors, etc. These drugs have good therapeutic effects, but there are safety problems in the long-term treatment of diabetes, such as: liver toxicity, weight gain and hypoglycemia and many other problems.

Sodium-glucose transporter type 2 (SGLT2) is a new target discovered in recent years that can be used to develop hypoglycemic drugs. SGLT2 is mainly distributed in the kidney, and its function is to reabsorb glucose that enters the renal tubules through glomerular filtration. Maintain the balance of glucose concentration in the blood. Inhibiting the activity of SGLT2 can effectively reduce the reabsorption of glucose in the kidney, increase the concentration of urine glucose, and lower blood glucose. Since this hypoglycemic mechanism does not depend on insulin and can be used in combination with other hypoglycemic drugs, SGLT2 inhibitors are promising hypoglycemic drugs.

Although a series of compounds targeting SGLT2 inhibition, such as dapagliflozin, canagliflozin, and Ipragliflozin, have been disclosed, it is still necessary to develop compounds with better efficacy, pharmacokinetic properties, and higher safety for the treatment of diabetes. After continuous efforts, this The invention discloses an SGLT2 inhibitor with a novel structure of general formula (I) that can effectively reduce plasma glucose levels, and unexpectedly finds that the compound with this type of structure exhibits excellent SGLT2 inhibitory effect and good hypoglycemic activity in vivo, And from them, the compounds whose hypoglycemic activity in vivo is equal to or even better than that of dapagliflozin are screened out, which has broad development prospects.

Contents of the invention

The object of the present invention is to provide a new class of compounds of general formula (I) and pharmaceutically acceptable esters thereof with pharmaceutical value. It inhibits the function of SGLT2 and can be used to prepare new diabetes drugs.

It is also an object of the present invention to provide processes for the preparation of compounds of general formula (I).

Another object of the present invention is to provide a pharmaceutical preparation containing the compound of general formula (I) as an active ingredient.

Detailed invention content is as follows:

The present invention has synthesized a series of compounds of general formula (I):

in,

R ¹ and R ² are respectively selected from: H, F, Cl, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, -O-aryl, -OC _1-5 -aryl, cycloalkyl ;

Or R1 and R2 form ^{a cycloalkyl} group together with the carbon atoms they are attached to or have 1-4 substituted or unsubstituted 5-12 members selected from N, O, S, SO and/or _SO2 heteroatoms aromatic heterocycle;

Wherein, the cycloalkyl group, aryl group, and aromatic heterocycle can be further substituted by one or more substituents, and the substituents include halogen atoms, hydroxyl groups, alkyl groups, alkoxy groups substituted by halogen atoms, substituted Or unsubstituted aryl or aralkyl.

The following compounds of general formula (I) are preferred:

Wherein R ¹ is preferably selected from: C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy;

R ² is preferably selected from: F, Cl, C ₁ -C ₅ alkyl;

Or R ¹ and R ² together with the carbon atoms they are attached to form a 5-12 membered substituted or unsubstituted aromatic heterocyclic ring with _1-4 heteroatoms selected from N, O, S, SO and/or SO ;

Wherein, the aromatic heterocycle can be further substituted by one or more substituents, the substituents include halogen atoms, hydroxyl, alkyl, alkoxy or alkoxy substituted by halogen atoms, substituted or unsubstituted aryl or aralkyl groups.

Preferably:

Wherein R is selected from ^: methoxy, ethoxy, propoxy;

R ^{is selected from:} F, Cl, methyl, ethyl;

Or R ¹ and R ² form a 5-membered substituted or unsubstituted aromatic heterocyclic ring with one oxygen atom together with the carbon atoms they are connected to;

More preferred compounds of general formula (I) and pharmaceutically acceptable esters of the present invention are shown in the following table:

The compound of general formula (I) of the present invention is synthesized through the following steps:

As shown in Scheme 1, at -78°C, the compound of formula II is treated with n-butyllithium in a mixed solvent of tetrahydrofuran/toluene, and then lactone III is added. After the reaction is complete, methanesulfonic acid and methanol solution are added, and stirred overnight at room temperature to obtain The compound of formula IV; the preparation of lactone III refers to literature R. Benhaddous, S. Czemecki et al., Carbohydr. Res., 1994, 260, 243-250.

At -20°C, the compound of formula IV can be prepared by reducing the compound of formula IV with triethylsilane and boron trifluoride ether in acetonitrile/dichloromethane mixed solvent. , and recrystallized and resolved to prepare the compound of formula VI, and then hydrolyzed by LiOH in tetrahydrofuran, methanol and water mixed solvent to obtain the compound of formula I; wherein R ¹ is preferably selected from: methoxy, ethoxy, propoxy; R ² Preferably selected from: F, Cl, methyl, ethyl; or R ¹ and R ² together with the carbon atoms they are connected to form a 5-membered substituted or unsubstituted aromatic heterocyclic ring with 1 oxygen atom.

The preparation method of general formula II compound is:

As shown in Scheme 2, phenol was dissolved in DMF, and potassium carbonate was added to react at room temperature to obtain compound 2, which was acylated with 2-chloro-5-bromobenzoic acid Friedel-Crafts acylation under ice bath to obtain compound 3. Boron fluoride ethyl ether was reduced at room temperature to obtain compound 4, which was dissolved in trifluoroacetic acid, and hexatropine was added in batches to reflux to obtain compound 5, which was cyclized with potassium carbonate to obtain compound 6, which was dissolved in tetrahydrofuran with sodium borohydride, methanol Compound 7 was obtained by reduction, and compound II-a was synthesized via Williams ether; wherein, R is selected from: C ₁ ~C ₅ alkyl, C ₁ ~C ₅ alkoxy, -O-aryl, -OC _1-5 - aryl, substituted or unsubstituted cycloalkyl; II-a is a compound of general formula II.

As shown in Scheme 3, the Friedel-Crafts acylation reaction of 2-chloro-5-bromobenzoic acid and compound 8 under the action of aluminum trichloride gave compound 9, and the reduction of compound 9 under the action of triethylsilane and boron trifluoride ether II-b; wherein R ¹ is preferably selected from: methoxy, ethoxy, propoxy; R ² is preferably selected from: F, Cl, methyl, ethyl; or R ¹ and R ² are connected to the carbon atom together form a 5-membered substituted or unsubstituted aromatic heterocyclic ring with one oxygen atom; II-b is a compound with general formula II.

The pharmaceutically acceptable esters of the compound of general formula (I) of the present invention include the pharmaceutically acceptable esters of the 6-O hydroxyl group of the glucose fragment in the molecule and the acetyl, formyl, methoxycarbonyl and ethoxycarbonyl groups. ; Can be prepared by the method shown in the following formula:

Compound I is treated with one equivalent of R ³ COCl, and esterified at the 6-O position of the glucose fragment of Compound I to obtain the corresponding ester; wherein, R ³ is selected from Me, Et, MeO and EtO, etc. pharmaceutically acceptable groups, preferably MeO and EtO.

The present invention also includes pharmaceutical preparations, which contain the compound of general formula (I) or its ester or a pharmaceutically acceptable carrier as an active agent. The above-mentioned pharmaceutically acceptable carrier refers to the conventional drug carrier in the field of pharmacy, and refers to one or more inert, non-toxic solid or liquid fillers, diluents, auxiliary agents, etc., which do not reversely interact with active compounds or patients. take effect.

The dosage forms of the composition of the present invention can be commonly used dosage forms in pharmacy such as tablets, capsules, pills, and soft capsules.

Tablets and capsules for oral use contain conventional excipients such as fillers, diluents, lubricants, dispersants and binders.

Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to well-known methods in the field of pharmacy.

Dosages of the above active agents will vary from formulation to formulation.

In general, the amounts that have proven to be advantageous are about 0.01-200 mg per kilogram, preferably 0.1-100 mg/kg, of the compound of formula (I) administered per kilogram per 24 hours; if necessary , administered in the form of several single doses.

However, it is also possible, if necessary, to deviate from the above-mentioned dosages, i.e. it depends on the type and body weight of the subject to be treated, the individual's behavior towards the drug, the nature and severity of the disease, the type of formulation and administration, and the time of administration. and interval.

The in vivo hypoglycemic activity of the compounds of the present invention can be determined by using the assay system described below.

Oral glucose tolerance test (OGTT) in normal mice

10-week-old Kunming clean-grade mice, weighing 18-22g, male, were randomly divided into 11 groups, blank control group (blank vehicle), positive drug control group 1 (Dapagliflozin: 1.5mg/kg (3.7μmol/kg)) , positive drug control group 2 (metformin: 100 mg/kg), test compound group (3.7 μmol/kg), 8 rats in each group.

Before the experiment, the mice were fasted without food and water for 12 hours, and each group was administered orally by gavage, and the blood was collected from the tail to measure the blood sugar level (denoted as -30min). Then 11 groups of mice were given blank solvent, Dapagliflozin, metformin and test compound by intragastric administration respectively, measured blood glucose value after 30min and recorded it as 0min, and then immediately administered a glucose solution with a concentration of 3g/10ml by intragastric administration of 10ml/kg, and at 15 , 30, 45, 60, 120min to measure the blood glucose value (mmol/L). The results are shown in the table below.

Table 1: Changes in blood glucose level 2h after a single administration in normal mice ( n=8).

Note: *P≤0.05, **P≤0.01 are the results of Student’s t test relative to the blank control group.

Oral glucose tolerance test in normal mice showed that all the compounds tested had certain hypoglycemic effects, among which compounds I-1 and I-5 could significantly improve the glucose tolerance of normal mice, and their in vivo hypoglycemic activity was comparable to that of Dapagliflozin, or even better than that of Dapagliflozin. Well, exhibited an excellent hypoglycemic effect.

The in vivo glycosuria-promoting activity of the compounds of the present invention can be determined by using the assay system described below.

10-week-old Kunming clean-grade mice, weighing 18-22g, male, were randomly divided into 11 groups, blank control group (blank vehicle), positive drug control group 1 (Dapagliflozin: 1.5mg/kg (3.7μmol/kg)) , positive drug control group 2 (metformin: 100 mg/kg), test compound group (3.7 μmol/kg), 8 rats in each group.

Before the experiment, the mice were fasted without food and water for 12 hours, and each group was administered orally by gavage, and the urine sugar was measured (denoted as -30min). Then 11 groups of mice were given blank vehicle, Dapagliflozin, metformin and the test compound by intragastric administration respectively, and the urine glucose value was measured as 0min after 30 minutes, and then the glucose solution with a concentration of 3g/10ml was given by intragastric administration immediately after 10ml/kg, and at 15, 30, 45, 60, 120min to measure the urine sugar value.

The urine sugar value is measured by immersing the urine sugar test strip into the urine, taking it out after soaking (about 1-2 seconds); taking out the test paper along the edge of the container to remove excess urine; observing the color of the test strip within 30-60 seconds And compare it with the color guide to measure the result. Judgment of results: (the test paper changes from light blue to brown red to indicate the test result) light blue means no urine sugar, which is indicated by "-"; brown red means urine sugar, the darker the more "+" signs, the glucose concentration in urine higher. The results are shown in the table below.

Table 2: Changes in urine glucose value of normal mice 2 hours after a single administration.

Note: -: No urine sugar; ±: 100mg/dL; +: 250mg/dL

++: 500mg/dL +++: 1000mg/dL++++: 2000mg/dL

The urine sugar test in normal mice showed that all the tested compounds had a certain effect on urine sugar, among which compounds I-1, I-5 and I-8 could significantly promote the excretion of urine sugar, indicating that they had better SGLT2 inhibitory activity.

detailed description

The present invention will be further described below in conjunction with embodiment. It should be noted that the following examples are only for illustration, but not for limiting the present invention. Various changes made by those skilled in the art according to the teaching of the present invention shall be within the scope of protection required by the claims of the present application.

Example 1

(5-Bromo-2-chlorophenyl)(4-ethoxy-3-fluorophenyl)methanone (IIa-1)

In a 100ml single-necked bottle equipped with a calcium chloride drying tube, 2-chloro-5-bromobenzoic acid (5.0g, 21.23mmol) was suspended in 20ml of dichloromethane, and oxalyl chloride (5.49ml, 63.69mmol) was added dropwise under stirring , after dropping, catalyze with a drop of DMF, react at room temperature for 3 hours, distill off the solvent and excess oxalyl chloride under reduced pressure, dissolve the residue in 25ml of dichloromethane, cool to about -10°C in an ice-salt bath, and add AlCl ₃ ( 3.40g, 24.98mmol), after adding, stir evenly until the reaction solution changes from yellow-green to yellow thick liquid, start to drop 2-fluorophenetole (2.84g, 20.84mmol), control the internal temperature below 0°C, dropwise, The reaction was completed at 0°C for about 45 minutes, poured into cold 1N hydrochloric acid (100ml), stirred until the reddish-brown reaction solution became nearly colorless, extracted with dichloromethane (25ml×3), and the organic phase was washed with 1N NaOH (30ml× 1) Washing, washing with saturated brine (50ml×2), drying over anhydrous sodium sulfate, filtering, distilling off the solvent under reduced pressure, and recrystallizing the residual solid with ethanol to obtain 5.3g of colorless columnar crystals, melting point: 136-138°C, collected Rate: 72.0%.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 7.80-7.76 (m, 2H, Ar-H), 7.63-7.55 (m, 2H, Ar-H), 7.46-7.43 (m, 1H, Ar-H ), 7.32-7.27 (m, 1H, Ar-H), 4.22 (q, J=6.96Hz, 2H, CH ₃ CH ₂ -O), 1.38 (t, J=6.95Hz, 3H, CH ₃ CH ₂ - O).

(5-Bromo-2-chlorophenyl)(4-ethoxy-3-chlorophenyl)methanone (IIa-2)

The synthesis method is the same as IIa-1, using 2-chlorophenetole as raw material to obtain colorless crystal IIa-2 (4.7g), melting point: 126-128°C, yield: 82.2%.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 7.80-7.76 (m, 3H, Ar-H), 7.63-7.55 (m, 2H, Ar-H), 7.30 (d, J=8.58Hz, 1H, Ar-H), 4.25 (q, J= 6.97Hz , 2H, _CH3CH2O ), 1.39 (t, J=6.95Hz, _3H , CH3CH2 _- O ₎ .

(5-Bromo-2-chlorophenyl)(4-ethoxy-3-methylphenyl)methanone (IIa-3)

The synthesis method is the same as IIa-1, using 2-methylphenetole as raw material to obtain colorless crystal IIa-3 (5.6g), melting point: 93-95°C, yield: 76.1%.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 7.77-7.70 (m, 2H, Ar-H), 7.60-7.47 (m, 3H, Ar-H), 7.05 (d, J=8.64Hz, 1H, Ar-H), 4.15(q, J=6.94Hz, 2H, CH3CH2 _- O), 2.18(s, 3H, Ar-CH3 _{) ,} 1.39(t, J=6.95Hz, _3H , CH3CH ₂ -O).

(5-Bromo-2-chlorophenyl)(2-dibenzofuran)methanone (IIa-4)

The synthesis method is the same as that of IIa-1, using dioxyfluorene as the raw material to obtain colorless columnar crystal IIa-4 (4.9g), melting point: 169-171°C, yield: 83.5%.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 8.63 (d, J=1.32Hz, 1H, Ar-H), 8.32 (d, J=7.41Hz, 1H, Ar-H), 7.93-7.75(m , 5H, Ar-H), 7.60 (d, J=8.46Hz, 2H, Ar-H), 7.47-7.42 (m, 1H, Ar-H).

Among them, IIa-1 to IIa-4 are compounds having the general formula 9.

Example 2

4-Bromo-1-chloro-2-(4-ethoxy-3-fluorobenzyl)benzene (II-1)

In a 100ml single-neck bottle equipped with anhydrous calcium chloride drying tube, the raw material IIa-1 (5.3g, 15.0mmol) was dissolved in a mixed solvent of 20ml of dichloromethane and 20ml of acetonitrile, cooled to about -5°C in an ice-salt bath, Add Et ₃ SiH (5.3ml, 33.0mmol) dropwise under stirring, and then add BF ₃ ·Et ₂ O (3.8ml, 30.0mmol) dropwise after stirring evenly. Add 2N NaOH dropwise to the reaction solution under cooling in an ice-water bath to adjust the pH of the solution to about 8-9, dilute with water, extract with dichloromethane (25ml×3), wash the organic phase with 1N hydrochloric acid (30ml×2), and wash with saturated salt Wash with water (40ml×1), dry over anhydrous sodium sulfate, filter, evaporate the solvent under reduced pressure, and purify the residue by column chromatography to obtain 5.1g of colorless oily liquid, yield: 97.3%.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 7.56 (d, J=2.16Hz, 1H, Ar-H), 7.48-7.38 (m, 2H, Ar-H), 7.10-7.04 (m, 2H, Ar-H), 6.95(d, J=8.37Hz, 1H, ArH), 4.05(q, J=6.97Hz, 2H, CH ₃ CH ₂ -O), 3.99(s, 2H, Ar- CH ₂ -Ar ), 1.33 (t, J = 6.97 Hz, _3H , CH3CH2 _- O).

4-Bromo-1-chloro-2-(4-ethoxy-3-chlorobenzyl)benzene (II-2)

The synthesis method is the same as that of II-1, and a colorless oily substance is obtained by using IIa-2 as a raw material, and the yield is 93.7%.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 7.58 (d, J=2.19Hz, 1H, Ar-H), 7.48-7.44 (m, 2H, Ar-H), 7.28 (d, J=1.80Hz , 1H, Ar-H), 7.13-7.04 (m, 2H, Ar-H), 4.06 (q, J=6.96Hz, 2H, CH ₃ CH ₂ -O), 3.99 (s, 2H, Ar- CH ₂ -Ar), 1.33 (t, J = 6.96 Hz, _3H , CH3CH2 _- O).

4-Bromo-1-chloro-2-(3-methyl-4-ethoxybenzyl)benzene (II-3)

The synthesis method is the same as that of II-1, and a colorless oily substance is obtained by using IIa-3 as a raw material, and the yield is 95.6%.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 7.48-7.37 (m, 3H, Ar-H), 6.98-6.81 (m, 3H, Ar-H), 3.96 (q, J=6.95Hz, 2H, CH ₃ CH ₂ -O), 3.93 (s, 3H, Ar- CH ₃ ), 2.10 (s, 2H, Ar- CH ₂ -Ar), 1.31 (t, J=6.95Hz, 3H, CH ₃ CH ₂ - O).

2-(5-Bromo-2-chlorobenzyl)dibenzofuran (II-4)

The synthesis method is the same as II-1, using IIa-4 as the raw material to obtain colorless columnar crystals, melting point: 102-104°C, yield: 83.2%.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 8.12 (d, J=7.32 Hz, 1H, Ar-H), 8.01 (s, 1H, Ar-H), 7.70-7.59 (m, 3H, Ar-H) H), 7.54-7.36 (m, 5H, Ar-H), 4.23 (s, 2H, Ar- CH2 _- Ar).

Among them, II-1 to II-4 are compounds having the general formula II-b.

Example 3

Ethyl 2-(4-(2-chloro-5-bromobenzoyl)phenoxy)acetate (3)

In a 100ml round bottom flask, phenol (5.0g, 53.1mmol) and ethyl chloroacetate (6.7mL, 63.8mmol) were dissolved in 40mL of DMF, potassium carbonate (22.0g, 159.4mmol) was added in one portion while stirring, and stirred at room temperature for 3h. Add saturated sodium chloride solution to the reaction solution until potassium carbonate dissolves, extract with ethyl acetate (40ml×3), wash the organic phase with water (30ml×2), wash with 1N sodium hydroxide (20ml×2), and wash with saturated saline (25ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure to obtain 0.86g of light yellow liquid.

In a 100ml single-necked bottle equipped with anhydrous calcium chloride drying tube, 2-chloro-5-bromobenzoic acid (5g, 21.2mmol) was suspended in 40mL of dry dichloromethane, a drop of DMF was added to catalyze, and 10mL of dry dichloromethane was slowly added dropwise. Oxalyl chloride (7.3 mL, 131.4 mmol) dissolved in methyl chloride was added and stirred at room temperature for 3 h after dropping. Stirring was stopped, and the solvent and excess oxalyl chloride were distilled off under reduced pressure to obtain a yellow oil. Dissolve the yellow oil in 40 mL of dry dichloromethane, cool in an ice bath to 0°C, add AlCl ₃ (8.5g, 63.7mmol) in batches to keep the internal temperature below 5°C, after the addition is complete, stir evenly and then slowly add dropwise Dry ethyl 2-phenoxyacetate (3.8g, 21.2mmol) dissolved in dichloromethane, stir at 0°C for 5h after dropping, stop stirring, pour the reaction solution into ice water (100ml), stir for 15min, dichloromethane Extraction (40ml×3), the organic phase was washed with 1N hydrochloric acid (20ml×2), washed with saturated brine (25ml×2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting solid was recrystallized from ethanol to obtain 4.7g of white crystals, melting point: 78-79°C, yield: 55.6%.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 7.78(t, J=4.92Hz, 2H, Ar-H), 7.68(d, J=8.7Hz, 2H, Ar-H), 7.55(d, J =8.37Hz, 1H, Ar-H), 7.08(d, J=8.73Hz, 2H, Ar-H), 4.92(s, 2H, O- CH2 _- CO), 4.17(q, J=7.08Hz, 2H, -COO CH ₂ -), 1.21 (t, 3H, J = 7.08 Hz, -CH ₂ CH ₃ ).

Example 4

Ethyl 2-(4-(2-chloro-5-bromobenzyl)phenoxy)acetate (4)

Compound 3 (4g, 10.0mmol) was dissolved in 20mL of dry dichloromethane and 20mL of dry acetonitrile, Et ₃ SiH (6.0mL, 37.4mmol) was added, cooled to 0°C with ice water, and 5ml of dry dichloromethane was slowly added dropwise Dissolved BF ₃ ·Et ₂ O (5.0 mL, 39.5 mmol), stirred at room temperature for 12 h after addition. Add 20mL of 1N potassium hydroxide solution to the reaction solution, stir for 15min, extract with ethyl acetate (30ml×3), wash with 1N sodium hydroxide (15ml×2), wash with saturated brine (20ml×2), anhydrous sodium sulfate It was dried, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 2.8 g of a colorless oily liquid with a yield of 72.5%.

¹ HNMR (300 MHz, CDCl ₃ ) δ: 7.30 (m, 3H), 7.11 (d, J=8.62Hz, 2H), 6.97 (d, J=8.63Hz, 2H), 4.60 (s, 2H), 4.30 ( q, J=7.12Hz, 2H), 3.99(s, 2H), 1.29(t, J=7.13Hz, 3H).

Example 5

Ethyl 2-(4-(2-chloro-5-bromobenzyl)-2-formylphenoxy)acetate (5)

Under ice-cooling, urotropine (1g, 6.26mmol) was mixed with 10ml of trifluoroacetic acid, compound 4 (2g, 5.20mmol) was added to the above mixture, the reaction solution was light red, heated to reflux in an oil bath for about 1h, stop Stir, pour into ice water after cooling to room temperature, stir, alkalinize carefully with sodium carbonate to pH 8-9, extract with ethyl acetate (20ml×3), wash the organic phase with saturated brine (20ml×2), without Dry over sodium sulfate, filter, and distill the filtrate to remove the solvent under reduced pressure to obtain a yellow oil, which is purified by column chromatography to obtain 0.6 g of white flaky crystals, melting point: 68-70°C, yield: 23.4%.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 10.39(s, 1H, CHO), 7.64(d, J=2.25Hz, 1H, Ar- H ), 7.51(d, J=7.98Hz, 1H , Ar-H), 7.48(t, J=3.12Hz, 2H, Ar-H), 7.41(d, J=8.52Hz, 1H, Ar-H), 7.13(d, J=8.43Hz, 1H, Ar -H), 4.96(s, 2H, O- CH2 _- CO), 4.19(q, J=7.10Hz, 2H, -COOCH2-), 4.05(s, 2H, Ar-CH2 _- Ar ₎ , 1.21 (t, J = 7.10 Hz, _3H , -CH2CH3 ₎ .

Example 6

Ethyl 5-(5-bromo-2-chlorobenzyl)benzofuran-2-carboxylate (6)

Compound 5 (2.0g, 4.9mmol) was dissolved in 10ml of DMF, anhydrous potassium carbonate (0.9g, 6.3mmol) was added, heated at 92-94°C and stirred for 4h, after the reaction was complete, it was poured into ice-cold saturated saline (30ml) , extracted with ethyl acetate (20ml×3), the organic phase was washed successively with 1N hydrochloric acid (20ml×1), washed with saturated brine (25ml×2), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain 1.6g White solid, melting point: 115-117°C, yield: 80.8%.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 7.72(s, 1H, Ar-H), 7.67(d, J=8.61Hz, 1H, Ar-H), 7.62(d, J=2.22Hz, 1H , Ar-H), 7.58(s, 1H, Ar-H), 7.47(d, J=2.31Hz, 1H, Ar-H), 7.42(m, 2H, Ar-H), 4.36(q, J= 7.10 Hz, 2H, -COO CH ₂ -), 4.18 (s, 2H, Ar- CH ₂ -Ar), 1.32 (t, J = 7.10 Hz, 3H, -CH ₂ CH ₃ ).

Example 7

5-(5-Bromo-2-chlorobenzyl)benzofuran-2-methanol (7)

In a 50ml single-neck bottle equipped with anhydrous calcium chloride drying tube, compound 6 (0.54g, 1.37mmol) was dissolved in 5mlTHF, placed in an ice-water bath and cooled to about 0°C, and NaBH4 (0.11g, 2.74mmol) was added in batches , after the addition, stir evenly and heat to reflux, add 0.5ml of methanol drop by drop, the reaction violently produces a large number of bubbles, after the dropwise reflux reaction for 0.5h, after the reaction is completed, pour into ice water, stir, ethyl acetate (20ml×3) After extraction, the organic phase was washed with saturated brine (25ml×2), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain 0.47g of white solid, melting point: 98-100°C, yield 97.5%.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 7.54(d, J=2.13Hz, 1H, Ar-H), 7.47(d, 1H, Ar-H), 7.44(d, J=2.31Hz, 1H , Ar-H), 7.42(s, 1H, Ar-H), 7.40(m, J=1.96Hz, 1H, Ar-H), 7.13(m, 1H, Ar-H), 6.70(s, 1H, Ar-H), 5.48(t, J=5.82Hz, 1H, OH), 4.54(d, J=5.61Hz, 2H, Ar- CH2 _- O), 4.13(s, 2H, Ar- CH2 _- Ar ).

Example 8

5-(5-Bromo-2-chlorobenzyl)-2-ethoxymethylbenzofuran (II-5)

Under ice-cooling, NaH (0.15g, 3.13mmol) was added to a THF (5ml) solution of compound 7 (0.5g, 1.4mmol), the ice bath was removed, and stirred at room temperature until the reaction solution had no bubbles (about 1h). Add a catalytic amount of TBAB, add bromoethane (0.17g, 1.57mmol) dropwise, raise the temperature and reflux for 1h after the dropwise completion, pour into ice water, extract with ethyl acetate (25ml×3), and saturated saline (25ml×2) Wash, dry over anhydrous sodium sulfate, filter, evaporate the solvent under reduced pressure to obtain 0.53 g of yellow oil II-5, yield 80.1%.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 7.51(d, J=2.07Hz, 1H, Ar-H), 7.47(d, 1H, Ar-H), 7.44(d, J=2.07Hz, 1H , Ar-H), 7.42(s, 1H, Ar-H), 7.40(m, 1H, Ar-H), 7.13(m, 1H, Ar-H), 6.78(s, 1H, Ar-H), 4.51(s, 2H, Ar- CH2 _- O), 4.10(s, 2H, Ar _- CH2 _- Ar), 3.48(q, J=6.99Hz, 2H, OCH2CH3 ₎ , 1.10(t, J = 7.00 Hz, _3H , _OCH2CH3 ).

5-(5-Bromo-2-chlorobenzyl)-2-benzyloxymethylbenzofuran (II-6)

The synthesis method is the same as II-5, and the raw material used is benzyl bromide to obtain 2 g of white solid, melting point: 74-76°C, yield: 96.3%.

¹ H NMR (300MHz, CDCl ₃ ) δ: 7.43 (d, J=8.43Hz, 1H, Ar-H), 7.31 (s, 1H, Ar-H), 7.27-7.20 (m, 8H, Ar-H) , 7.11-7.08(m, 1H, Ar-H), 6.64(s, 1H, Ar-H), 4.63(s, 2H, Ar- CH ₂ -O), 4.62(s, 2H, Ph- CH ₂ - O), 4.13 (s, 2H, Ar- CH2 _- Ar).

5-(5-Bromo-2-chlorobenzyl)-2-(2-tetrahydrofuranmethoxymethyl)benzofuran (II-7)

The synthesis method is the same as II-5, colorless oily liquid 1.5g, yield: 80.2%.

¹ H NMR (300MHz, CDCl ₃ ) δ: 7.41 (d, J=8.43Hz, 1H, Ar-H), 7.33 (s, 1H, Ar-H), 7.30-7.22 (m, 3H, Ar-H) , 7.11-7.08(m, 1H, Ar-H), 6.63(s, 1H, Ar-H), 4.67(s, 2H, Ar- CH ₂ -O), 4.12(s, 2H, Ar- CH ₂ - Ar), 4.10-4.06 (m, 1H, O CH CH ₂ CH ₂ ), 3.92-3.75 (m, 2H, O CH ₂ CHO), 3.58-3.50 (m, 2H, O CH ₂ CH ₂ ), 1.96- _{1.58 (} m, 4H , CHCH2CH2CH2 ₎ .

Among them, II-5 to II-7 are compounds having the general formula II-a.

Example 9

4-Chloro-3-(4-ethoxy-3-fluorobenzyl)phen-1-yl-α/β-D-methoxyglucopyranoside (IV-1)

In a 100ml three-necked flask equipped with a thermometer at -100°C and a rubber stopper, compound II-1 (0.54g, 1.42mmol) was dissolved in 5mL of dry tetrahydrofuran and 5mL of dry toluene, protected by nitrogen, cooled to -78°C, and slowly added n-butyl Base Lithium (1.04mL, 1.56mmol, 1.6M), reacted at -78°C for 0.5h after the addition was completed, then slowly added dropwise 5mL trimethylchlorosilane-protected gluconolactone (1g, 2.13mmol) dissolved in anhydrous toluene, After the addition, react at -78°C for 3 hours, then add 0.3 mL of methanesulfonic acid dissolved in 2 mL of methanol, and then raise to room temperature and react for 16 hours. After the reaction, add saturated sodium bicarbonate dropwise to the reaction solution until no bubbles emerge. , extracted with ethyl acetate (50mL×3), combined the organic phases, washed successively with saturated sodium bicarbonate solution (25mL×2), washed with saturated brine (25mL×2), dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure The solvent was removed to obtain a yellow oil, which was separated and purified by column chromatography (dichloromethane:methanol=30:1) to obtain 0.3 g of a white solid (a mixture of two configurations), melting point: 60-62°C, yield: 42.9%.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 7.52-7.40 (m, 3H, Ar-H), 7.05-6.88 (m, 3H, Ar-H), 4.99 (d, J=5.46Hz, 2H, -O CH ₂ -), 4.54 (t, J=5.68Hz, 1H, -O CH -), 4.07-3.99 (m, 5H, Ar- CH ₂ -Ar, -O CH -, -O CH ₂ CH ₃ ), 3.73-3.68 (m, 1H, -O CH -), 3.49-3.42 (m, 1H, -O CH ), 3.31-3.08 (m, 4H, -OH ), 2.92 (s, 3H, -O CH ₃ ), 1.31 (t, J = 6.96 Hz, 3H, -OCH ₂ CH ₃ ).

Example 10

4-Chloro-3-(4-ethoxy-3-fluorobenzyl)phen-1-yl-β-D-2,3,4,6,-tetra-O-acetylglucopyranoside (VI -1)

Compound IV-1 (0.3g, 0.61mmol) was dissolved in 5mL of dichloromethane and 5mL of acetonitrile, Et3SiH (0.27mL, 1.71mmol) was added, cooled to -15°C, and BF ₃ ·Et diluted with dichloromethane was slowly added dropwise ₂ O (0.11 mL, 0.85 mmol), react overnight at -10°C after dropping. After the reaction, add saturated sodium bicarbonate to the reaction solution until no bubbles emerge, extract with ethyl acetate, combine the organic phases, wash with saturated brine (20mL×2), dry over anhydrous sodium sulfate, and filter with suction to obtain 0.2 g of yellow solid. The above crude product (0.2g, 0.43mmol) was dissolved in 5ml of dichloromethane, followed by adding pyridine (0.42mL, 4.32mmol), acetic anhydride (0.5mL, 4.32mmol) and a catalytic amount of DMAP under ice-cooling. Reaction 2h. After the reaction was completed, 20ml of water was added to the reaction liquid, extracted with dichloromethane (30mL×3), the combined organic phases were washed with 1N hydrochloric acid (20mL×2), saturated brine (20mL×2), and anhydrous Na ₂ SO _4. Dry, filter with suction, and evaporate the solvent under reduced pressure. The resulting solid is recrystallized from ethanol to obtain 0.18 g of white powdery solid, melting point: 132-134° C., yield: 48.9%.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 7.44-7.25(m, 3H, Ar-H), 7.08-6.89(m, 3H, Ar-H), 5.35(t, J=9.48Hz, 1H, -O CH- ), 5.07 (t, J=9.45Hz, 1H, -O CH- ), 4.96 (t, J=9.64Hz, 1H, -O CH- ), 4.66 (d, J=9.69Hz, 1H , -O- CH- Ar), 4.10-3.98 (m, 7H, Ar- CH ₂ -Ar, -O CH -, -O CH ₂ -, -O CH ₂ CH ₃ ), 2.01 (s, 3H, CH ₃ CO), 1.99 (s, 3H, CH ₃ CO), 1.92 (s, 3H, CH ₃ CO), 1.70 (s, 3H, CH ₃ CO), 1.31 (t, J=6.96Hz, 3H, -OCH _2CH3 ) _.

Example 11

4-Chloro-3-(4-ethoxy-3-fluorobenzyl)phen-1-yl-β-D-glucopyranoside (I-1)

Compound VI-1 (0.18g, 0.30mmol) was dissolved in 4mL of tetrahydrofuran, 6mL of methanol and 2mL of water, added with hydrated lithium hydroxide (0.07g, 1.7mmol), and reacted overnight at room temperature. After the reaction was completed, it was concentrated under reduced pressure, and the residual liquid was 30ml of ethyl acetate was dissolved, washed with 5% potassium bisulfate solution (10mL×2), saturated brine (15mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a colorless oil. Chromatographic separation and purification (dichloromethane:methanol=30:1) gave 0.1 g of white solid, melting point: 66-68°C, yield: 76.9%.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 7.39-7.35 (m, 2H, Ar-H), 7.27-7.23 (m, 1H, Ar-H), 7.07-6.98 (m, 2H, Ar-H ), 6.94-6.91 (m, 1H, Ar-H), 4.96 (d, J=5.53Hz, 2H, -O CH ₂ -), 4.84 (d, J=5.67Hz, 1H, -O CH Ar), 4.50 (t, J=5.68Hz, 1H, -O CH -), 4.08-3.99 (m, 5H, Ar- CH ₂ -Ar, -O CH -, -O CH ₂ CH ₃ ), 3.73-3.68 (m , 1H, -O CH -), 3.49-3.42 (m, 1H, -O CH ), 3.31-3.08 (m, 4H, -OH ), 1.31 (t, J=6.96Hz, 3H, -OCH ₂ CH ₃ );

¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 153.0, 149.8, 139.7, 137.1, 131.8, 130.8, 128.6, 127.5, 124.5, 116.1, 115.8, 114.8, 81.1, 80.6, 78.2, 74.6, 70.2, 64.2, 61.3 , 59.7, 37.4, 14.5;

MS (ESI, m/z): 449.8 [M+Na] ⁺ .

Example 12

4-Chloro-3-(4-ethoxy-3-chlorobenzyl)phen-1-yl-β-D-glucopyranoside (I-2)

The synthesis method is the same as that of I-1 to obtain 0.30 g of white solid, melting point: 78-79° C., yield: 91.3%.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 7.36 (d, J=8.19Hz, 1H, Ar-H), 7.31-7.30 (m, 1H, Ar-H), 7.25-7.21 (m, 1H, Ar-H), 6.97-6.92(m, 2H, Ar-H), 6.80(d, J=8.28Hz, 1H, Ar-H), 4.96(d, J=5.48Hz, 2H, -O CH ₂ - ), 4.83(d, J=5.55Hz, 1H, -O- CH _- Ar), 4.50(t, J=5.68Hz, 1H, -OCH- ), 4.06-3.92(m, 5H, ArCH2Ar , -O CH -, -O CH ₂ CH ₃ ), 3.73-3.68 (m, 1H, -O CH -), 3.49-3.43 (m, 1H, -O CH ), 3.30-3.07 (m, 4H, - OH ), 1.30 (t, J=6.93Hz, 3H, -OCH ₂ CH ₃ );

¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 152.1, 139.7, 137.1, 132.6, 131.8, 130.8, 129.7, 128.7, 128.2, 127.5, 121.0, 113.7, 81.1, 80.6, 78.2, 74.6, 70.2, 64.2, 61.3 , 37.2, 14.5;

MS (ESI, m/z): 466.3 [M+Na] ⁺ .

Example 13

4-Chloro-3-(4-ethoxy-3-methylbenzyl)phen-1-yl-β-D-glucopyranoside (I-3)

The synthesis method is the same as I-1, white solid 0.31g, melting point 75-76°C, yield: 90.2%.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 7.39-7.36 (m, 2H, Ar-H), 7.27-7.22 (m, 2H, Ar-H), 7.11-7.01 (m, 2H, Ar-H ), 4.96 (d, J=5.66Hz, 2H, -O CH ₂ -), 4.84 (d, J=5.55Hz, 1H, -O- CH -Ar), 4.44 (t, J=5.60Hz, 1H, -O CH -), 4.06-3.99 (m, 5H, Ar- CH ₂ -Ar, -O CH -, -O CH ₂ CH ₃ ), 3.73-3.68 (m, 1H, -O CH -), 3.47- 3.44 (m, 1H, -O CH ), 3.23-3.11 (m, 4H, -OH ), 2.09 (s, 3H, Ar CH ₃ ), 1.32 (t, J=6.94Hz, 3H, -OCH ₂ CH ₃ );

¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 154.9, 139.5, 137.8, 131.8, 130.8, 130.7, 130.6, 128.6, 127.1, 126.8, 125.4, 111.1, 81.1, 80.6, 78.2, 74.6, 70.2, 63.0, 61.3 , 37.6, 16.0, 14.7;

MS (ESI, m/z): 445.9 [M+Na] ⁺ .

Example 14

4-Chloro-3-(dibenzofuran-2-methyl)phen-1-yl-β-D-glucopyranoside (I-4)

The synthesis method is the same as that of I-1 to obtain 0.45 g of white solid with a melting point of 88-90° C. and a yield of 95.7%.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 8.10 (d, J=7.53Hz, 1H, Ar-H), 7.96 (s, 1H, Ar-H), 7.69-7.60 (m, 3H, Ar- H), 7.53-7.25 (m, 5H, Ar-H), 4.94 (d, J = 5.72Hz, 2H, -O CH ₂ ), 4.85 (d, J = 5.67Hz, 1H, -O CH Ar), 4.43 (t, J=5.76Hz, 1H, -O CH ), 4.23 (s, 2H, Ar CH ₂ Ar), 4.02-3.99 (m, 1H, -O CH -), 3.71-3.66 (m, 1H, -O CH ), 3.47-3.42 (m, 1H, -O CH ), 3.26-3.08 (m, 4H, -OH );

¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 155.7, 154.0, 139.7, 137.5, 134.3, 131.9, 130.9, 128.7, 128.1, 127.5, 127.4, 123.5, 123.4, 122.9, 121.0, 120.8, 111.5, 111 , 80.6, 78.2, 74.7, 70.2, 61.3, 38.3;

MS (ESI, m/z): 477.8 [M+Na] ⁺ .

Example 15

4-Chloro-3-(2-ethoxymethylbenzofuran-5-methyl)phen-1-yl-β-D-glucopyranoside (I-5)

The synthesis method is the same as that of I-1 to obtain 0.11 g of white solid, melting point: 64-65°C, yield: 80.9%.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 7.48 (d, J=8.49Hz, 1H, Ar-H), 7.40-7.36 (m, 3H, Ar-H), 7.26-7.23 (m, 1H, Ar-H), 7.17-7.13(m, 1H, Ar-H), 6.81(s, 1H, Ar-H), 4.95(d, J=5.64Hz, 2H, -O CH ₂ ), 4.84(d, J=5.64Hz, 1H, -O- CH -Ar), 4.53(s, 2H, Ar -CH- O), 4.44(t, J=5.62Hz, 1H, -OCH ), 4.14(s, 2H, Ar- CH ₂ -Ar), 4.01-3.98 (m, 3H, -O CH -, -O CH ₂ ), 3.72-3.66 (m, 1H, -O CH ), 3.54-3.40 (m, 3H, -O CH , O CH ₂ CH ₃ ), 3.26-3.10 (m, 4H, -OH ), 1.12 (t, J=6.99Hz, 3H, CH ₃ );

¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 154.9, 153.1, 137.7, 134.1, 131.9, 130.9, 128.6, 127.8, 127.3, 125.2, 120.7, 110.8, 105.5, 81.1, 80.6, 78.2, 75.6, 73.6, 7 , 70.2, 69.4, 38.3, 14.2;

MS (ESI, m/z): 485.9 [M+Na] ⁺ .

Example 16

4-Chloro-3-(2-benzyloxymethylbenzofuran-5-methyl)phen-1-yl-β-D-glucopyranoside (I-6)

The synthesis method was the same as that of I-1, and 0.23 g of white solid was obtained, with a melting point of 57-58° C. and a yield of 87.1%.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 7.49 (d, J=8.43Hz, 1H, Ar-H), 7.31 (s, 1H, Ar-H), 7.27-7.20 (m, 8H, Ar- H), 7.11-7.08 (d, J=8.37Hz, 1H, Ar-H), 6.64 (s, 1H, Ar-H), 4.98 (d, J=5.52Hz, 2H, -O CH ₂ -), 4.87(d, J=5.52Hz, 1H, -O- CH -Ar), 4.62(s, 2H, Ar- CH2 _- O), 4.55(s, 2H, Ph- CH2 _- O), 4.46(t , J=5.22Hz, HOCH ₂ CH- O), 4.14(s, 2H, Ar- CH ₂ -Ar), 4.01(t, J=7.32Hz, 1H, -O CH- ), 3.71(t, J= 6.3Hz, 1H, -OCH- ), 3.38(t, J=4.5Hz, 1H, -OCH ), 3.26-3.16(m, 4H, -OH );

¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 154.7, 153.2, 139.7, 137.8, 137.7, 134.1, 131.1, 130.9, 128.7, 128.2, 127.8, 127.6, 127.5, 127.3, 125.3, 120.8, 110.8, 105. , 80.6, 78.2, 74.6, 71.3, 70.2, 63.9, 61.3, 59.7, 38.3;

MS (ESI, m/z): 548.1 [M+Na] ⁺ .

Example 17

4-Chloro-3-(2-(2-tetrahydrofuranmethoxymethyl)benzofuran-5-methyl)phen-1-yl-β-D-glucopyranoside (I-7)

The synthesis method is the same as that of I-1 to obtain 0.19 g of white solid with a melting point of 52-54° C. and a yield of 77.2%.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 7.47 (d, J=8.34Hz, 1H, Ar-H), 7.38-7.16 (m, 5H, Ar-H), 6.82 (d, J=8.36Hz , 1H, Ar-H), 4.58 (d, J = 5.43Hz, 2H, -O CH ₂ ), 4.48 (d, J = 6.52Hz, 1H, -O- CH -Ar), 4.23 (s, 2H, Ar -CH- O), 4.08(s, 2H, Ar- CH2 _- Ar), 4.01-3.92 (m, 2H, CH2CH _- O), 3.82-3.69(m, 3H, _OCH2CHO ,- O CH ), 3.60-3.5 (m, 3H, -O CH -, -O CH ₂ ), 3.43 (t, J=4.50Hz, 1H, -O CH ), 3.28-3.19 (m, 4H, -OH ) , 1.98-1.76 (m, 4H, CH CH ₂ CH ₂ CH ₂ );

¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 154.9, 153.1, 137.7, 134.1, 131.9, 130.9, 128.6, 127.8, 127.3, 125.2, 120.7, 110.8, 105.5, 78.2, 77.1, 74.6, 72.3, 74.2, 69. , 67.2, 64.7, 61.3, 59.7, 38.3, 27.6, 25.1;

MS (ESI, m/z): 541.9 [M+Na] ⁺ .

Example 18

4-Chloro-3-(4-ethoxy-3-fluorobenzyl)phen-1-yl-6-O-methoxycarbonyl-β-D-glucopyranoside (I-8)

Compound I-1 (0.5g, 1.20mmol), triethylamine (0.11g, 1.20mmol) were dissolved in 20ml of dichloromethane, cooled in an ice-water bath, 0.11g of ethyl chloroformate was added dropwise, and the mixture was left at room temperature Stir overnight, quench the reaction system with 30ml of saturated brine, extract with ethyl acetate (20mL×3), combine the organic phases, wash with saturated brine (10mL×2), dry over anhydrous sodium sulfate, suction filter, evaporate under reduced pressure solvent, and the resulting residue was purified by column chromatography to obtain the pure product I-8, 0.4 g of colorless crystals, and the yield was 68.7%.

MS (ESI, m/z): 485.9 [M+H] ⁺ .

Example 19

Tablets containing active agent I-1:

Sieve the active ingredient, pregelatinized starch and microcrystalline cellulose, mix well, add polyvinylpyrrolidone solution, mix, make soft material, sieve, make wet granules, dry at 50-60°C, and carboxymethyl starch Sodium salt, magnesium stearate and talcum powder are sieved and added to the above granules and compressed into tablets.

It has been verified that the above composition also has a good effect of promoting urine sugar excretion and in vivo hypoglycemic activity.

Claims (3)

1. The compound is selected from: 4-Chloro-3-[2-ethoxymethylbenzofuran-5-methyl]phen-1-yl-β-D-glucopyranoside; 4-Chloro-3-[2-benzyloxymethylbenzofuran-5-methyl]phen-1-yl-β-D-glucopyranoside; 4-Chloro-3-[2-(2-tetrahydrofuranmethoxymethyl)benzofuran-5-methyl]phen-1-yl-β-D-glucopyranoside. 2. The application of the compound defined in claim 1 in the preparation of drugs for the prevention or treatment of diabetes. 3. A pharmaceutical composition comprising the compound as defined in claim 1 and a suitable carrier or excipient.