CN105693669A - Antidiabetic compound and preparation method and application thereof - Google Patents

Abstract

The invention discloses an antidiabetic compound, its preparation method and application, and belongs to the technical field of medicine. The chemical structure of described compound is as shown in formula (I): Wherein, R is i-Pr, Cl and COCH ₂ Cl. The present invention takes 2-chloro-5-bromobenzoic acid and D-gluconolactone as starting materials, and finally obtains three kinds of Dapagliflozin derivatives through reaction, and the reaction conditions of the Friedel-Crafts acylation reaction of different positioning groups in the present invention, The best reaction conditions for them were determined, and a new method of resolving stereoisomerism was used to optimize the reaction conditions, which greatly reduced the reaction cost and increased the yield, and the raw materials used were cheap and easy to obtain, and had a wide range of applications. sex.

Description

A kind of antidiabetic compound and its preparation method and application

technical field

The invention relates to the technical field of medicine, in particular to an antidiabetic compound and its preparation method and application.

Background technique

Diabetes is a series of clinical syndromes caused by absolute or relative insufficiency of insulin in the body. Studies have shown that it is not only closely related to genetics, but also closely related to daily life habits. The main clinical symptoms of diabetes are polydipsia, polyuria, polyphagia but weight loss ("three more and one less"), high blood sugar level, and glucose in urine (normal urine should not contain glucose), etc. , a variety of clinical conditions.

Diabetes can cause a variety of complications. If diabetics are not treated effectively, it will cause some acute complications, such as non-ketone hyperosmolar coma, hypoglycemia, ketoacidosis, etc. If the condition is serious, it will lead to long-term complications such as: chronic renal failure (that is, diabetic nephropathy, which is the main reason for patients to undergo hemodialysis), cardiovascular and cerebrovascular diseases, and retinopathy (that is, diabetic eye disease, which is the main cause of blindness in non-aged adults) ), neuropathy, and microvascular disease. Among them, microvascular lesions may make it difficult for the patient's wound to heal. If there is a wound that is difficult to heal on the foot, it may cause gangrene (commonly known as "diabetic foot"), causing the patient to have to amputate.

Dapagliflozin is a new oral drug for the treatment of type 2 diabetes. It has become a research hotspot because of its good efficacy and less toxic side effects. In numerous transformation studies, people found that it is easier to obtain new drugs with better efficacy by modifying the terminal benzene ring. So in recent years, people have been working on the modification of the terminal benzene ring.

Contents of the invention

The object of the present invention is to provide an antidiabetic compound and its preparation method.

The present invention adopts following technical scheme:

The chemical structure of the antidiabetic compound of the present invention is shown in formula (I):

Wherein, R is i-Pr, Cl and COCH ₂ Cl.

The preferred substituent R is i-Pr, and the chemical structure is as follows:

The antidiabetic compounds of the present invention also include pharmaceutically acceptable salts, hydrates, solvates, optical isomers or prodrugs of the compound of formula (I).

The synthetic route of antidiabetic compound of the present invention is as follows:

Step a, Compound 5 and Compound 7 are combined to obtain Compound 8:

Step b, compound 8 is obtained compound 9:

Step c, compound 9 is obtained compound 10:

Step d, compound 10 is obtained formula (I) compound:

The synthetic route of compound 5 is as follows:

Step a11:

Step a12:

Step a13:

The synthetic route of compound 7 is as follows:

The concrete steps of the preparation method of antidiabetic compound of the present invention are as follows:

Step a:

According to the molar ratio of compound 5, n-Buli, compound 7 and p-toluenesulfonic acid as 1:1.2:1.2:1, weigh compound 5 into the mixed solution of THF:toluene=1:2, under the protection of nitrogen , stirred and cooled to -78°C, then added n-Buli dropwise, at this temperature, stirred for 30min, then gradually added compound 7 and toluene solution to the reaction solution, stirred at -78°C for 3h, added to the reaction solution Quench the reaction with saturated NH ₄ Cl, separate the organic phase and the aqueous phase, extract the aqueous phase with toluene three times, combine the organic phases and concentrate in vacuo, dissolve the residue in methanol, cool to 0°C, add p-toluenesulfonic acid, and heat up to 15°C Stir the reaction overnight, after the reaction, cool to 0°C, add saturated NaHCO ₃ solution to wash, stand to separate layers, extract, and concentrate in vacuo to obtain compound 8;

Step b:

According to the molar ratio of compound 8, triethylsilane and boron trifluoride ether solution as 1:2:1.4, dissolve compound 8 in V _acetonitrile : V _{dichloromethane} = 1:1 solution, cool to -15°C, Stir for 10 minutes, add triethylsilane dropwise, maintain the temperature and stir for 30 minutes, add boron trifluoride ether solution dropwise under the protection of nitrogen, control the temperature between -10°C and -15°C, react for 5 hours, stop the reaction, Compound 9 is obtained;

stepc:

According to the molar ratio of compound 9 and L-proline as 1:4, add the mixture of compound 9, L-proline and V _ethanol /V _water = 14:1 into the reactor, heat to reflux, and react for 1h After that, it was gradually cooled to 60°C, and a white solid was formed, then slowly added n-hexane dropwise, stirred for 3 hours, cooled naturally to room temperature, filtered to obtain a white solid, washed three times with n-hexane, and placed in a vacuum oven at 100°C Dry to obtain compound 10;

Step d:

Dissolve compound 10 in ethyl acetate and water, heat to reflux until the solution becomes clear, immediately separate the organic phase and the aqueous phase while hot, dry the organic phase overnight, filter, concentrate, and obtain formula (I) by silica gel column chromatography compound.

The specific synthetic steps of compound 5 are as follows:

Step a11:

According to the molar ratio of 2-chloro-5-bromobenzoic acid and oxalyl chloride as 1:1.2, take 2-chloro-5-bromobenzoic acid in a three-necked flask, add anhydrous dichloromethane, and place the reaction bottle in ice water. Stir for ten minutes, then add oxalyl chloride dropwise, and react overnight at room temperature. After the reaction is completed, evaporate the solvent to dryness to obtain compound 2;

Step a12:

According to the molar ratio of compound ₂ , cumene and anhydrous AlCl3 being 1:1.3:1.5, take compound 2 and put it into a round bottom flask, add anhydrous dichloromethane and cumene successively, and put the reaction bottle in ice In the salt bath, stir for ten minutes, weigh anhydrous AlCl ₃ , add to the reaction solution in batches, the temperature should not exceed -4°C, stir and react at 5°C for 4 hours, then add ice water to the reaction solution, after half an hour The organic phase and the aqueous phase were separated, and the organic phase was washed three times with 1N HCl, then washed with saturated _NaHCO3 solution until neutral, then washed three times with saturated brine, and finally dried with anhydrous _MgSO4 , then filtered, concentrated and purified Compound 4 is obtained;

Step a13:

According to the molar ratio of compound 4 and triethylsilane as 1:2.8, compound 4 was dissolved in trifluoroacetic acid, then triethylsilane was added dropwise, after stirring at room temperature for ten minutes, a drop of trifluoromethanesulfonic acid was added dropwise, and then The temperature was raised to reflux, the reaction was stopped after 3h, the reaction solution was concentrated, the residue was dissolved in ethyl acetate, washed _three times with water, then washed with saturated NaHCO solution until neutral, finally dried overnight with anhydrous _MgSO , filtered, Compound 5 was obtained by concentration and purification.

The specific synthetic steps of compound 7 are as follows:

According to the molar ratio of D-gluconolactone and trimethylchlorosilane as 1:7, weigh D-gluconolactone and put it into a round bottom flask, add anhydrous tetrahydrofuran and N-methylmorpholine, stir and cool to - 5°C, then add trimethylchlorosilane dropwise, stir for 15 minutes, then raise the temperature to 35°C for 5 hours, stop the reaction, add toluene to the reaction solution at 0°C, then add water, the temperature should not exceed 10°C during this period, let it stand and separate layer, and the organic phase was washed successively with saturated NaH ₂ PO ₄ and saturated brine, then dried overnight with anhydrous MgSO ₄ , filtered, the solvent was recovered, the residue was dissolved in toluene, and the solvent was evaporated completely to obtain compound 7.

The compound of the present invention can be used to prepare medicines for treating diabetes.

The present invention also includes a pharmaceutical composition for treating diabetes, which contains the compound as described in formula (I).

The positive effects of the present invention are as follows:

The present invention uses 2-chloro-5-bromobenzoic acid and D-gluconolactone as starting materials, and finally obtains three kinds of Dapagliflozin derivatives through reaction, and determines the structure of the obtained compound by ¹ HNMR, ¹³ CNMR and MS, and The fusing points of these compounds have been measured, the reaction conditions of the Friedel-Crafts acylation reaction of different positioning groups in the present invention have determined their optimal reaction conditions, and a new method for splitting stereoisomerism has also been used to optimize the reaction conditions. The reaction cost is reduced, the yield is increased, and the raw materials used are cheap and easy to obtain, and have wide applicability. Dapagliflozin and its derivatives have good efficacy.

detailed description

Further set forth the specific embodiment of the present invention below:

Example 1

Synthesis of 2-chloro-5-bromobenzoyl chloride 2

Take 0.59g (2.51mmol) of 2-chloro-5-bromobenzoic acid in a 15mL three-necked flask, add 5ml of anhydrous dichloromethane, place the reaction flask in ice water, and stir for ten minutes. Then, 0.31 ml (3.00 mmol) of oxalyl chloride was added dropwise, and reacted overnight at room temperature. After the reaction, the solvent was evaporated to dryness to obtain 0.62 g (2.46 mmol) of yellow solution (2), with a yield of 98.13%.

Synthesis of 2-chloro-5-bromo-(4-isopropylphenyl)-benzophenone 4a

Put 0.50 g (1.98 mmol) of compound (2) into a round-bottomed flask, and add 5 ml of anhydrous dichloromethane and 0.30 g (2.51 mmol) of cumene successively. Place the reaction vial in an ice-salt bath and stir for ten minutes. Weigh 0.4g (3.00mmol) of anhydrous AlCl ₃ , add it to the reaction solution in batches, and the temperature should not exceed -4°C. The reaction was stirred at 5° C. for 4 hours, then 10 ml of ice water was added to the reaction solution, and the organic phase and the aqueous phase were separated after half an hour. The organic phase was washed three times with 10 ml of 1N HCl, then washed with saturated NaHCO ₃ solution until neutral, then washed three times with 10 ml of saturated brine, and finally dried with anhydrous MgSO ₄ . Then filter and concentrate to obtain a brownish-red solid, which was purified by silica gel column chromatography (chromatographic silica gel, 200-300 mesh; eluent, V _{petroleum ether} /V _{ethyl acetate} =1:60) to obtain 0.633 g of a white solid. is 95.32%. mp83～85℃ ^; 1HNMR (500MHz, CDCl ₃ ), δ7.73(d, J=8.5Hz, 2H, Ar-H), 7.55～7.53(m, 1H, Ar-H), 7.48(d, J =2Hz, 1H, Ar-H), 7.33(d, J=8.5Hz, 3H, Ar-H), 3.01～2.95(m, 1H, CH), 1.28(d, J=7.0Hz, 6H, CH- _CH3 ). ESI-MS m/z 337.1 (calcd. 335.9) ([M+H] ⁺ ).

Synthesis of 2-chloro-5-bromo-(4-isopropylphenyl)-benzenemethane 5a

Dissolve 0.50 g (1.52 mmol) of compound (4a) in 3 ml of trifluoroacetic acid, then add dropwise 0.50 ml (4.31 mmol) of triethylsilane, stir at room temperature for ten minutes, then add a drop of trifluoromethanesulfonic acid, Then the temperature was raised to reflux, the reaction was stopped after 3h, the reaction solution was concentrated, the residue was dissolved in 5ml ethyl acetate, washed _three times with 10ml water, then washed with saturated NaHCO solution until neutral, and finally dried overnight with anhydrous _MgSO . Filter and concentrate to obtain a crude product, which is recrystallized with methanol to obtain 0.46 g of a white solid with a yield of 93.15%.

mp39～40℃; ¹ HNMR (400MHz, CDCl ₃ ), δ7.28～7.21(m, 3H, Ar-H), 7.17(d, J=8Hz, 2H, Ar-H), 7.11(d, J= 7.6Hz, 2H, Ar-H), 4.02(s, 1H, _CH2 ), 2.91~2.85(m, 1H, CH), 1.28(d, J=6.8Hz, 6H, CH- _CH3 ).

Protection reaction of D-gluconolactone 7

Weigh 1.00 g (5.61 mmol) of D-gluconolactone (6) and put it into a 25 mL round bottom flask, add 10 ml of anhydrous tetrahydrofuran and 5 ml of N-methylmorpholine, stir and cool to -5 ° C, then dropwise add 5 ml ( 38.93mmol) of trimethylchlorosilane, stirred for 15min, heated to 35°C for 5h, stopped the reaction, first added 15ml of toluene to the reaction solution at 0°C, and then added 25ml of water, during which the temperature should not exceed 10°C. The layers were left standing, and the organic phase was washed successively with 20 ml of saturated NaH ₂ PO ₄ and 20 ml of saturated brine, and then dried overnight with anhydrous MgSO ₄ . After filtration, the solvent was recovered, the residue was dissolved in 15ml of toluene, and the solvent was evaporated thoroughly to obtain 2.51g of yellow viscous liquid (7), with a yield of 96.45%.

(3R,4S,5R,6S)-2-[3-(4-Isopropylphenyl)-4-chlorophenyl]-2-methoxy-6-hydroxymethyltetrahydro-2H-pyran Synthesis of -3,4,5-triol 8a

Weigh 0.50 g (1.59 mmol) of compound (5a) into 7.5 ml (THF:toluene=1:2) solution. Under the protection of nitrogen, it was stirred and cooled to -78°C, and then 0.8ml of n-Buli [1.91mmol (2.5Ninhexane)] was added dropwise. Stir at this temperature for 30 min, then gradually add (7) 0.89 g (1.92 mmol) and 2.5 ml of toluene solution into the reaction solution, and stir for 3 h at -78°C.

5 ml of saturated NH ₄ Cl was added to the reaction solution to quench the reaction, and the organic phase and the aqueous phase were separated. The aqueous phase was extracted three times with 10 ml of toluene, and the combined organic phases were concentrated in vacuo. Dissolve the residue in 10ml of methanol, cool to 0°C, add 0.18g (1.6mmol) p-toluenesulfonic acid, raise the temperature to 15°C and stir the reaction overnight. After the reaction, cool to 0°C, add 10ml of saturated NaHCO ₃ solution to wash, stand to separate the layers, extract the aqueous phase with 10ml of ethyl acetate three times, combine the organic phases, and wash with 20ml of saturated brine three times, and then wash with anhydrous MgSO ₄ Let dry overnight. Filtration and vacuum concentration gave a white solid, which was recrystallized from a mixed solvent of V _{ethyl acetate} /V _{petroleum ether} = 1:5 to obtain 0.51 g of a white solid with a yield of 73.25%. mp80～83℃; ¹ HNMR (500MHz, CDCl ₃ ), δ7.36(s, 1H, Ar-H), 7.29～7.23(m, 2H, Ar-H), 7.07(dd, J=10.5, 15.5Hz ,, 4H, Ar-H), 4.07～3.98(m, 2H, O-CH ₂ ), 3.86(d, J=11Hz, 1H, CH), 3.81(s, 2H, CH ₂ ), 3.57～3.50( m, 2H, CH-CH), 3.19 (d, J=12Hz, 1H, CH), 2.91 (s, 3H, CH ₃ -O), 2.8～32.79 (m, 1H, CH-CH ₃ ), 1.19 ( d, J=8.5Hz, 6H, CH ₃ ). ESI-MSm/z 405.1 (calculated value 436.17) ([M-CH ₃ -O] ⁺ ). Because the methoxy group in compound 8 is easy to leave, So the mass spectrum peak shows up as 405.1.

(3R,4S,5R,6S)-2-[3-(4-Isopropylphenyl)-4-chlorophenyl]-6-hydroxymethyltetrahydro-2H-pyran-3,4,5 - Synthesis of Triol 9a

Dissolve 0.50 g (1.15 mmol) of compound (8a) in 8 ml (V _acetonitrile : V _{dichloromethane} = 1:1) solution, cool to -15 °C, stir for 10 min, add dropwise 0.35 ml (2.20 mmol) of triethyl Under the protection of nitrogen, 0.20ml (1.59mmol) of boron trifluoride ether solution was added dropwise, the temperature was controlled between -10°C and -15°C, and the reaction was carried out for 5h. Stop the reaction, add ₅ ml of saturated NaHCO solution to the reaction solution, separate the organic phase and the aqueous phase, extract the aqueous phase with 10 ml of ethyl acetate, combine the organic phases, wash with ₁₀ ml of saturated brine, and dry overnight with anhydrous MgSO . Filtration and concentration gave a white solid, which was purified by silica gel column chromatography (chromatographic silica gel, 200-300 mesh; eluent, V _chloroform /V _methanol = 10:1) to give 0.38 g of a white solid with a yield of 82.13%, mp75 ~78°C.

(3R,4S,5R,6S)-β-2-[3-(4-Isopropylphenyl)-4-chlorophenyl]-6-hydroxymethyltetrahydro-2H-pyran-3,4 , Synthesis of 5-triol-L-proline 10a

In the 10ml reaction bottle, add the compound (9a) of 0.38g (0.93mmol), the L-proline of 0.43g (3.73mmol), the mixed solution of 3ml (V _ethanol /V _water =14:1), heat To reflux, after reacting for 1 hour, gradually cool down to 60°C, a white solid is formed, then slowly add 3ml of n-hexane dropwise, after stirring for 3h, naturally cool to room temperature, filter to obtain a white solid, wash three times with 30ml of n-hexane , dried in a vacuum oven at 100°C to obtain 0.42g of a white solid with a yield of 70.45%, mp 162-164°C.

(3R,4S,5R,6S)-β-2-[3-(4-Isopropylphenyl)-4-chlorophenyl]-6-hydroxymethyltetrahydro-2H-pyran-3,4 , Synthesis of 5-triol 11

Dissolve 0.42g (0.66mmol) of compound (10a) in 5ml of ethyl acetate and 5ml of water, heat to reflux until the solution becomes clear, immediately separate the organic phase and the aqueous phase while hot, and use 10ml of ethyl acetate for the aqueous phase The ester was extracted three times, the organic phases were combined, washed _three times with 20ml saturated brine, dried overnight with anhydrous MgSO, filtered, concentrated, silica gel column chromatography (chromatographic silica gel, 200-300 mesh; eluent, V _chloroform /V _Methanol =10:1) to obtain 0.24 g of white solid, which is the target product (11), with a yield of 91.35%. mp75～77℃; ¹ HNMR (400MHz, CDCl ₃ ), δ7.23(d, J=8.4Hz,, 1H, Ar-H), 7.16(s, 1H, Ar-H), 7.11(d, J= 8.4Hz, 1H, Ar-H), 7.04(dd, J=8, 16.8Hz, 4H, Ar-H), 4.013～.89(m, 3H, O-CH ₂ -CH), 3.66(s , 2H, CH ₂ ), 3.58(t, J=8.8Hz, 1H, CH), 3.47(t, J=8.2Hz, 1H, CH), 3.36(t, J=8.8Hz, 1H, CH), 3.19 (d, J=8.8Hz, 1H, CH), 2.80～2.71 (m, 1H, CH-CH ₃ ), 1.14 (d, J=6.8Hz, 6H, CH ₃ ). ¹³ CNMR (100MHz, CDCl ₃ ) δ146.87，138.98，136.88，136.48，134.45，130.62，129.77，128.66，126.55，126.39，81.14，79.26，77.23，76.81，74.84，70.22，62.10，38.79，33.64，30.92，23.99；ESI-MSm/z405( Calculated 406) ([MH] ⁻ ).

Example 2

Synthesis of 2-chloro-5-bromo-(4-chlorophenyl)-benzophenone 4b

Weigh 0.35g (2.63mmol) of anhydrous aluminum trichloride, put it into a 25ml round bottom flask, add 10ml of anhydrous chlorobenzene, heat up to 50°C, and stir to dissolve all the aluminum trichloride. Then, a mixture of 0.50 g (1.99 mmol) of compound (2) and 3 ml of anhydrous chlorobenzene was added dropwise, heated to boiling, and reacted for 4 h. Stop the reaction, cool to 0°C, add 10ml of ice water to the reaction solution, and separate the organic phase and the aqueous phase after half an hour. The organic phase was washed three times with 10 ml of 1N HCl, then washed with saturated NaHCO ₃ solution until neutral, then washed three times with 10 ml of saturated brine, and finally dried with anhydrous MgSO ₄ . Then filter and concentrate to obtain a brownish-red solid, which was purified by silica gel column chromatography (chromatographic silica gel, 200-300 mesh; eluent, V _{petroleum ether} /V _{ethyl acetate} =60:1) to obtain 0.61 g of a white solid. is 93.56%. mp78～80℃; ¹ HNMR (500MHz, CDCl ₃ ), δ7.75(d, J=8.5Hz, 2H, Ar-H), 7.58(d, J=11Hz, 1H, Ar-H), 7.50(m , 3H, Ar-H), 7.34 (d, J=9Hz, 1H, Ar-H).

Synthesis of 2-chloro-5-bromo-(4-chlorophenyl)-benzenemethane 5b

Compound (4b) 0.50g (1.52mmol) was dissolved in 3ml of trifluoroacetic acid, then 0.50ml (3.14mmol) of triethylsilane was added dropwise, stirred at room temperature for 30min, and then a drop of trifluoromethanesulfonic acid was added dropwise, then Warm up to reflux and react for 3h. Stop the reaction, concentrate the reaction solution, then dissolve the residue in 5ml of ethyl acetate, wash three times with 10ml of water, then wash with saturated _NaHCO3 solution until neutral, and finally dry overnight with anhydrous _MgSO4 ; filter and concentrate to obtain the crude product , recrystallized with methanol to obtain 0.44 g of white solid, with a yield of 91.60%. mp40～41℃; ¹ HNMR (400MHz, CDCl ₃ ), δ7.31～7.22(m, 5H, Ar-H), 7.34(d, J=8Hz, 2H, Ar-H), 4.01(s, 2H, _CH2 ).

(3R,4S,5R,6S)-2-[3-(4-Chlorophenyl)-4-chlorophenyl]-2-methoxy-6-hydroxymethyltetrahydro-2H-pyran-3 , Synthesis of 4,5-triol 8b

Weigh 0.50 g (1.58 mmol) of compound (5b) into 7.5 ml of (V _THF :V _toluene =1:2) solution. Stir and cool to -78°C, then add 0.8ml of n-Buli [1.91mmol (2.5Ninhexane)] dropwise. Stir at this temperature for 30 min, then slowly add a mixed solution of (7b) 0.89 g (1.92 mmol) and 2.5 ml of toluene into the reaction solution, and stir at -78°C for 3 h. Add 5 ml of saturated NaHCO ₃ to the reaction solution to quench the reaction, and separate the organic and aqueous phases. Extract the water phase with 10ml of toluene three times, combine the toluene phases, concentrate in vacuo, dissolve the residue in 10ml of methanol, then cool to 0°C, add 0.18g (1.6mmol) p-toluenesulfonic acid, heat up to 15°C, and stir overnight . After the reaction, cool to 0°C, add 10ml of saturated NaHCO ₃ solution to wash, separate the organic phase and the aqueous phase, extract the aqueous phase with 10ml of ethyl acetate three times, combine the organic phases, wash with 20ml of saturated saline three times, and then wash with anhydrous _Na2SO4 dried overnight _. Filtration, vacuum concentration, and silica gel column chromatography (chromatographic silica gel, 200-300 mesh; eluent, V _chloroform /V _methanol = 10:1) gave 0.48 g of a yellow solid with a yield of 70.81%. mp69～72℃; ¹ HNMR (400MHz, CDCl ₃ ), δ7.33(s, 1H, Ar-H), 7.26(d, J=2.4Hz, 2H, Ar-H), 7.18(d, J=8Hz , 2H, Ar-H), 7.05 (d, J=8.4Hz, 2H, Ar-H), 4.04～3.95 (m, 3H, O-CH ₂ -CH), 3.8 (m, 2H, CH ₂ ), 3.57～3.50(t, J=9.2Hz, 1H, CH), 3.53(t, J=9.6Hz, 1H, CH), 3.20(d, J=9.6Hz, 1H, CH), 2.90(s, 3H, CH ₃ —O); ESI-MS m/z 451.0 ([M+Na] ⁺ ).

(3R,4S,5R,6S)-2-[3-(4-Chlorophenyl)-4-chlorophenyl]-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-tri Synthesis of Alcohol 9b

Dissolve 0.50 g (1.16 mmol) of compound (8b) in 8 ml (V _acetonitrile : V _{dichloromethane} = 1:1), cool to -15 ° C, dropwise add 0.40 ml (2.51 mmol) of triethyl After silane was stirred at this temperature for 30 minutes, 0.20ml (1.59mmol) of boron trifluoride ether solution was added dropwise under the protection of nitrogen, the temperature was controlled between -10°C and -15°C, and the reaction was carried out for 5h. Stop the reaction, add 5ml of saturated _NaHCO3 solution to the reaction solution, separate the organic phase and the aqueous phase, extract the aqueous phase with 10ml of ethyl acetate, combine the organic phases, wash with _10ml of saturated brine, and dry overnight with anhydrous _Na2SO4 , filtered, and silica gel column chromatography (chromatographic silica gel, 200-300 mesh; eluent, V _chloroform /V _methanol = 10:1) gave 0.37 g of a white solid with a yield of 80.14%. mp75～77℃.

(3R,4S,5R,6S)-β-2-[3-(4-Chlorophenyl)-4-chlorophenyl]-6-hydroxymethyltetrahydro-2H-pyran-3,4,5 - Synthesis of triol-L-proline 10b

The compound (9b) of 0.37g (0.93mmol) is put into the flask of 10ml, the L-proline that takes 0.43g (3.73mmol) is added in the reaction flask, then add 3ml (V _ethanol /V _water =14: 1) The mixed solution was heated to reflux. After reacting for 1 hour, it was gradually cooled to 60°C, and white flocs were formed. After stirring for 3 hours, it was slowly cooled to room temperature, filtered to obtain a white solid, and washed three times with 30ml of n-hexane. Dry in a vacuum oven at 100°C to obtain 0.41 g of white solid with a yield of 70.20%. mp1581～61℃.

(3R,4S,5R,6S)-β-2-[3-(4-Chlorophenyl)-4-chlorophenyl]-6-hydroxymethyltetrahydro-2H-pyran-3,4,5 - Synthesis of Triol 12

Dissolve 0.41g (0.65mmol) of compound (10b) in 5ml of ethyl acetate and 5ml of water, heat to reflux until the solution becomes clear, immediately separate the organic phase and the aqueous phase while hot, and use 10ml of acetic acid for the aqueous phase Extracted three times with ethyl ester, mixed organic phase, washed _three times with 20ml saturated brine, dried overnight with anhydrous _Na2SO4 , filtered, concentrated, silica gel column chromatography (chromatographic silica gel, 200-300 mesh; eluent, V _Chloroform /V _methanol =10:1) to obtain 0.25 g of the target product (12) as a white solid with a yield of 96.63%. mp74～76℃; ¹ HNMR (400MHz, CDCl ₃ ), δ7.26(d, J=6Hz,, 1H, Ar-H), 7.14(t, J=6Hz, 4H, Ar-H), 7.00(d , J=8Hz, 2H, Ar-H), 3.97～3.91(m, 3H, O-CH ₂ -CH), 3.68(s, 2H, CH ₂ ), 3.60(t, J=8.8Hz, 1H, CH ), 3.50(t, J=8.2Hz, 1H, CH), 3.37(t, J=8.8Hz, 1H, CH), 3.23(d, J=8.8Hz, 1H, CH). ¹³ CNMR (100MHz, CDCl ₃ ) δ138.18, 137.64, 137.12, 134.34, 132.08, 130.63, 130.10, 129.83, 128.61, 126.65, 81.06, 79.39, 77.99, 77.24, 74.70, 769.92, 61.81, 126.65, 77.24, 74.70, 769.92, 61.81, 38.524, 30. 398) ([M+Na] ⁺ ).

Example 3

Synthesis of 2-chloro-5-bromo-benzophenone 4c

Mix 0.50g (1.99mmol) of compound (2) with 10ml of anhydrous dichloromethane, then dropwise add 0.20g (2.56mmol) of anhydrous benzene, cool to 0°C, and weigh 0.35g (2.63mmol) of Add anhydrous aluminum trichloride to the reaction liquid in batches, the temperature should not exceed 5°C, stir for 30 minutes, then raise the temperature to room temperature, and react for 4 hours. Stop the reaction, cool to 0° C., add 10 ml of ice water to the reaction liquid, react for half an hour, separate the organic phase and the aqueous phase. The organic phase was washed three times with 10 ml 1N HCl, then washed with saturated NaHCO ₃ solution until neutral, then washed three times with 10 ml saturated brine, and finally dehydrated with anhydrous MgSO ₄ . Then filter and concentrate to obtain a brown-red solid, which was purified by silica gel column chromatography (chromatographic silica gel, 200-300 mesh; eluent, petroleum ether/ethyl acetate=1:60) to obtain 0.55 g of a white solid with a yield of 94.00 %.

mp86～87℃ ^; 1HNMR (500MHz, CDCl ₃ ), δ8.12(d, J=3Hz, 2H, Ar-H), 7.80～7.64(m, 1H, Ar-H), 7.63～7.59(m, 1H, Ar-H), 7.58 (t, J=7 Hz, 3H, Ar-H), 7.34 (d, J=8.5 Hz, 1H, Ar-H).

Synthesis of 2-chloro-5-bromo-benzenemethane 5c

Dissolve 0.50 g (1.70 mmol) of compound (4c) in 3 ml of trifluoroacetic acid, then add dropwise 0.50 ml (3.14 mmol) of triethylsilane, stir at room temperature for ten minutes, then add dropwise a drop of trifluoromethanesulfonic acid, Then it was heated to reflux and reacted for 3h. Stop the reaction, concentrate the reaction solution, then dissolve the residue in 5ml of ethyl acetate, wash three times with 10ml of water, then wash with saturated _NaHCO3 solution until neutral, finally dry with anhydrous _MgSO4 overnight, filter, and concentrate to obtain the crude product , purified by silica gel column chromatography (chromatographic silica gel, 200-300 mesh; eluent, V _{petroleum ether} /V _{ethyl acetate} = 50:1) to obtain 0.42 g of a colorless oily liquid with a yield of 88.23%. ¹ HNMR (500MHz, CDCl ₃ ), δ7.23～7.13 (m, 6H, Ar-H), 7.09 (d, J=7Hz, 2H, Ar-H), 3.96 (s, 2H, CH ₂ ).

(3R,4S,5R,6S)-2-[3-(4-Phenyl)-4-chlorophenyl]-2-methoxy-6-hydroxymethyltetrahydro-2H-pyran-3, Synthesis of 4,5-triol 8c

Weigh 0.40 g (1.42 mmol) of compound (5c) into 7.5 ml of (V _THF :V _toluene =1:2) solution. Under the protection of nitrogen, it was stirred and cooled to -78°C, and then 0.8ml of n-Buli [1.91mmol (2.5Ninhexane)] was added dropwise. At this temperature, after stirring for 30 min, a mixed solution of (7) 0.89 g (1.92 mmol) and 2.5 ml of toluene was gradually added to the reaction liquid, and the reaction was stirred at -78° C. for 3 h. 5 ml of saturated NH ₄ Cl was added to the reaction solution to quench the reaction, and the organic phase and the aqueous phase were separated. The aqueous phase was extracted three times with 10 ml of toluene, the combined organic phases were concentrated in vacuo, and the residue was dissolved in 10 ml of methanol. Cool to 0°C, add 0.18g (1.6mmol) p-toluenesulfonic acid, heat up to 25°C and stir to react overnight. After the reaction, cool to 0°C, add 10ml of saturated NaHCO ₃ solution to wash, separate the organic phase and the aqueous phase, extract the aqueous phase with 10ml of ethyl acetate three times, combine the organic phases, wash with 20ml of saturated saline three times, and then wash with anhydrous MgSO ₄ dried overnight. Filtration and vacuum concentration gave a white solid, which was recrystallized with a mixed solvent (V _{ethyl acetate} /V _{petroleum ether} =1:7) to obtain 0.36 g of a white solid with a yield of 64.34%.

mp77～79℃; ¹ HNMR (400MHz, MEOD), δ7.38(d, J=6.4Hz, 1H, Ar-H), 7.25～7.11(m, 7H, Ar-H), 4.11(d, J= 2.4Hz, 1H, CH), 4.04(s, 2H, CH ₂ ), 3.79(t, J=3Hz, 1H, CH), 3.75(t, J=2.4Hz, 1H, CH), 3.61～3.55(m , 1H, CH), 3.29 (d, J = 1.6 Hz, 2H, O-CH ₂ ), 3.10 (s, 3H, CH ₃ -O); ESI-MS m/z 417.0 (calculated 394) ([M +Na] ⁺ ).

(3R,4S,5R,6S)-2-[3-(4-Phenyl)-4-chlorophenyl]-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol Synthesis of 9c

Dissolve 0.36g (0.91mmol) of compound (8c) in 8ml of V _acetonitrile :V _{dichloromethane} = 1:1 solution, cool to -15°C, stir for 10min, add dropwise 0.30ml (1.88mmol) of triethyl Silane, stirred at this temperature for 1h, then added dropwise 0.15ml (1.19mmol) of boron trifluoride ether solution under the protection of nitrogen, the temperature was controlled between -10°C--15°C, and reacted for 5h. Stop the reaction, add ₅ ml of saturated NaHCO solution to the reaction solution, separate the organic phase and the aqueous phase, extract the aqueous phase with 10 ml of ethyl acetate, combine the organic phases, wash with ₁₀ ml of saturated brine, dry overnight with anhydrous MgSO, and filter , concentrated to obtain a white solid, silica gel column chromatography (chromatographic silica gel, 200-300 mesh; eluent, V _chloroform /V _methanol = 12:1) to obtain a white solid 0.28 g with a yield of 84.29%. mp75～77℃.

(3R,4S,5R,6S)-β-2-[3-(4-Phenyl)-4-chlorophenyl]-6-hydroxymethyltetrahydro-2H-pyran-3,4,5- Synthesis of Triol-L-Proline 10c

Put 0.28g (0.77mmol) of compound (9c) into a 10ml flask, then add 0.35g (3.04mmol) of L-proline, then add 3ml (V _ethanol /V _water = 14:1) for mixing liquid, heated to reflux, reacted for 1h, gradually cooled to 60°C, a white solid was formed, then slowly added dropwise 3ml of n-hexane, stirred for 3h, cooled naturally to room temperature, filtered to obtain a white solid, and washed with 30ml of n-hexane Washed three times and dried in a vacuum oven at 100°C to obtain 0.33 g of white solid with a yield of 72.15%. mp182～184℃;.

(3R,4S,5R,6S)-β-2-[3-(4-Chlorophenyl)-4-chlorophenyl]-6-hydroxymethyltetrahydro-2H-pyran-3,4,5 -Synthesis of Triol 14

Dissolve 0.33g (0.55mmol) of compound (10c) in 5ml of ethyl acetate and 5ml of water, heat to reflux until the solution becomes clear, immediately separate the organic phase and the aqueous phase while hot, and use 10ml of ethyl acetate for the aqueous phase The ester was extracted three times, the organic phase was mixed, washed _three times with 20ml saturated brine, dried overnight with anhydrous _Na2SO4 , filtered, concentrated, silica gel column chromatography (chromatographic silica gel, 200-300 mesh; eluent, V _chloroform /V _Methanol =12:1) to obtain 0.19 g of white solid with a yield of 94.90%. mp75～76℃; ¹ HNMR (400MHz, MEOD), δ7.21～7.03(m, 8H, Ar-H), 4.00(d, J=4.8Hz, 1H, CH), 3.94(s, 2H, CH ₂ ), 3.78(t, J=4.8Hz, 1H, CH), 3.60～3.56(m, 1H, CH), 3.33(t, J=5.2Hz, 1H, CH), 3.29(t, J=4.8Hz, 1H, CH), 3.20 (d, J=4.8Hz, 2H, O- _CH2 ). ESI-MS m/z 387.0 (calcd. 364) ([M+Na] ⁺ ).

(3R,4S,5R,6S)-β-2-[3-(4-Phenyl)-4-chlorophenyl]-6-acetoxymethyltetrahydro-2H-pyran-3,4,5 - Synthesis of triacetate 15:

0.19g (0.52mmol) of compound (14) was dissolved in 5ml of pyridine, and cooled to 0°C, then 0.2ml (2.11mmol) of acetic anhydride was added dropwise, and reacted overnight at room temperature. Add 1ml of water to the reaction solution, continue the reaction for 1h, then stop the reaction, extract the reaction solution with 5ml of dichloromethane, wash the organic phase _three times with 30ml of water, dry overnight with anhydrous MgSO , filter, concentrate, and wash with petroleum ether Recrystallization was carried out to obtain 0.24 g of white solid with a yield of 86.53%. mp134～135°C; ¹ HNMR (400MHz, CDCl ₃ ), δ7.31 (d, J=8.5Hz, 1H, Ar-H), 7.22 (dd, J=2.8, 8.5Hz, 2H, Ar-H), 7.15(dd, J=2.8, 7.6Hz, 2H, Ar-H), 7.09(d, J=7.2Hz, 2H, Ar-H), 7.02(d, J=1.6Hz, 1H, Ar-H), 5.23(t, J=9.6Hz, 1H, CH), 5.15(t, J=9.6Hz, 1H, CH), 5.00(t, J=9.6Hz, 1H, CH), 4.25～4.17(m, 2H, O-CH ₂ ), 4.08(d, J=10.8Hz, 2H, CH ₂ ), 3.99(d, J=10.8Hz, 1H, CH), 3.74～3.70(m, 1H, CH), 2.00(d, J=10.8Hz, 6H, CH ₃ ), 1.91 (s, 3H, CH ₃ ), 1.61 (s, 3H, CH ₃ ) ESI-MS m/z 553.0 (calculated 530.9) ([M+Na] ⁺ ) .

(3R,4S,5R,6S)-β-2-[3-(4-Chloroacetylphenyl)-4-chlorophenyl]-6-acetoxymethyltetrahydro-2H-pyran-3, Synthesis of 4,5-triacetate 16

Dissolve 0.24g (0.45mmol) of compound (15) in 5ml of anhydrous dichloromethane, then add 0.06g (0.45mmol) of anhydrous aluminum trichloride to the reaction solution, heat up to 30°C, and wait for three After the aluminum chloride is completely dissolved, add 0.04ml (0.53mmol) of chloroacetyl chloride dropwise, heat up to reflux, react for 2h, then add 0.03g (0.23mmol) of anhydrous aluminum trichloride to the reaction solution, and react for 2h . Stop the reaction, add 10ml of ice water to the reaction solution, react for 30min, and separate the organic phase and the aqueous phase. The organic phase was washed three times with 10 ml 1N HCl, then washed with saturated NaHCO ₃ solution until neutral, then washed three times with 10 ml saturated brine, and finally dehydrated with anhydrous MgSO ₄ . Then filter and concentrate to obtain a white solid, which is purified by silica gel column chromatography (chromatographic silica gel, 200-300 mesh; eluent, V _{petroleum ether} /V _{ethyl acetate} =30:1) to obtain 0.18 g of a white solid, and the yield is 65.79%. mp149～151℃; ¹ HNMR (500MHz, CDCl ₃ ), δ7.82(d, J=8.5Hz, 2H, Ar-H), 7.31(d, J=8Hz, 1H, Ar-H), 7.21(d , J=8Hz, 2H, Ar-H), 7.15～7.10(m, 2H, Ar-H), 5.25(t, J=9.5Hz, 1H, CH), 5.15(t, J=10Hz, 1H, CH ), 5.02(t, J=10Hz, 1H, CH), 4.62(s, 2H, CH ₂ -Cl), 4.28(d, J=6.5Hz, 2H, O-CH ₂ ), 4.22～4.18(m, 1H, CH), 4.08 (s, 2H, CH ₂ ), 3.76～3.73 (m, 1H, CH), 1.98 (d, J=9Hz, 6H, CH ₃ ), 1.92 (s, 3H, CH ₃ ), 1.66 (s, 3H, _CH3 ) ESI-MS m/z 631.0 (calcd. 608.1) ([M+Na] ⁺ ).

(3R,4S,5R,6S)-β-2-[3-(4-Chloroacetylphenyl)-4-chlorophenyl]-6-hydroxymethyltetrahydro-2H-pyran-3,4 , Synthesis of 5-triol 13

Dissolve 0.18g (0.30mmol) of compound (16) in 5ml of anhydrous methanol, add 0.02g (0.37mmol) of sodium methoxide, and react overnight at room temperature. The reaction was stopped, and the reaction solution was concentrated. Silica gel column chromatography (chromatographic silica gel, 200-300 mesh; eluent, V _chloroform /V _methanol = 15:1) gave 0.12 g of the target product (13) as a white solid, with a yield of 90.91%. mp77～79℃; ¹ HNMR (500MHz, CDCl ₃ ), δ7.25 (d, J=7.5Hz,, 1H, Ar-H), 7.12 (t, J=7.5Hz, 4H, Ar-H), 7.00 (d, J=10Hz, 2H, Ar-H), 4.49 (s, 2H, CH ₂ -Cl), 3.97~3.91 (m, 3H, O-CH ₂ -CH), 3.68 (s, 2H, CH ₂ ), 3.58(t, J=11Hz, 1H, CH), 3.48(t, J=11Hz, 1H, CH), 3.34(t, J=11Hz, 1H, CH), 3.22(d, J=11Hz, 1H , CH). ¹³ CNMR (100MHz, CDCl ₃ ) δ190.01, 138.28, 137.66, 137.09, 134.30, 132.06, 130.63, 130.10, 129.85, 128.59, 126.63, 81.05, 79.40, 78.01, 747.02, 69 44.81, 38.53, 30.91; ESI-MS m/z 440 (calcd. 440) ([M+Na] ⁺ ).

Example 4

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)) , 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, and the test compound by intragastric administration respectively. After 30 minutes, the blood glucose value was measured as 0min, and then immediately after that, the glucose solution with a concentration of 3g/10ml was given by intragastric administration of 10ml/kg, and at 15, Blood glucose (mmol/L) was measured at 30, 45, 60, and 120 minutes. 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 st test relative to the blank control group.

Oral glucose tolerance test in normal mice showed that all the tested compounds had a certain hypoglycemic effect, among which compounds 11, 12 and 13 could significantly improve the glucose tolerance of normal mice, and the hypoglycemic activity in vivo was comparable to that of Dapagliflozin, or even better, Exhibits 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)) , 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 and the test compound by intragastric administration respectively, and the urine sugar value was measured as 0min after 30 minutes, and immediately after that, the glucose solution with a concentration of 3g/10ml was given by intragastric administration of 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 strip 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.

Result judgment: (the test paper changes from light blue to brown red to indicate the test result) light blue means no urine sugar, which is represented 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 in 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 11, 12 and 13 could significantly promote the excretion of urine sugar, indicating that they had better SGLT2 inhibitory activity, and the effect of compound 11 was the best. it is good.

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements and improvements made within the spirit and principles of the present invention should be included in the protection of the present invention. within range.

Claims (10)

1. an antidiabetic compound, it is characterised in that: shown in the chemical constitution of described compound such as formula (I):

Wherein, R is i-Pr, Cl and COCH₂Cl。

2. antidiabetic compound as claimed in claim 1, it is characterised in that: also include this change

Compound pharmaceutically acceptable salt, hydrate, solvate, its optical isomer or its prodrug。

3. the method preparing compound as claimed in claim 1, it is characterised in that: described side

The synthetic route of method is as follows:

Step a, obtains compound 8 by compound 5 and compound 7:

Step b, obtains compound 9 by compound 8:

Step c, obtains compound 10 by compound 9:

Step d, obtains formula (I) compound by compound 10:

4. preparation method as claimed in claim 3, it is characterised in that: the synthetic route of compound 5 is as follows:

Step a11:

Step a12:

Step a13:

5. preparation method as claimed in claim 3, it is characterised in that: the synthetic route of compound 7 is as follows:

6. preparation method as claimed in claim 3, it is characterised in that: specifically comprising the following steps that of described method

Step a:

It is 1:1.2:1.2:1 by the mol ratio of compound 5, n-Buli, compound 7 and p-methyl benzenesulfonic acid; Weigh Compound 5 is put in the mixed solution of THF:toluene=1:2; under the protection of nitrogen; stirring is cooled to-78 DEG C, is then added dropwise over n-Buli, at this temperature; stirring 30min; then compound 7 and toluene solution are added gradually in reactant liquor, at-78 DEG C of stirring reaction 3h, add saturated NH to reactant liquor₄Cl cancellation is reacted, and separates organic facies and aqueous phase, and aqueous phase toluene extracts three times, merges the concentration of organic facies vacuum, residue is dissolved in methanol, is cooled to 0 DEG C, add p-methyl benzenesulfonic acid, be warmed up to 15 DEG C of stirring reactions, overnight, reaction is cooled to 0 DEG C, adds saturated NaHCO after terminating₃Solution washing, stratification, extract, vacuum concentrates, and obtains compound 8；

Step b:

It is 1:2:1.4 by the mol ratio of compound 8, triethyl silicane and boron trifluoride ether solution, compound 8 is dissolved in V_Acetonitrile: V_{Dichloromethane}In=1:1 solution, it is cooled to-15 DEG C, stirs 10min, drip triethyl silicane; maintaining temperature stirring 30min, the boron trifluoride ether solution being added dropwise under the protection of nitrogen, temperature controls between-10 DEG C～-15 DEG C; reaction 5h, stopped reaction, obtain compound 9；

Step c:

It is 1:4 by the mol ratio of compound 9 and L-PROLINE, reactor will add compound 9, L-PROLINE and V_Ethanol/V_WaterThe mixed liquor of=14:1, heating, to backflow, after reaction 1h, is cooled to 60 DEG C gradually, white solid is had to generate, then slowly drip normal hexane, after stirring 3h, naturally cool to room temperature, it is filtrated to get white solid, wash three times with normal hexane, dry in vacuum drying oven at 100 DEG C, obtain compound 10；

Step d:

Compound 10 being dissolved in ethyl acetate and water, heating is to backflow, after becoming clarification until solution, separates organic facies and aqueous phase immediately while hot, and organic facies is dried overnight, and filters, and concentration, silica gel column chromatography obtains formula (I) compound。

7. preparation method as claimed in claim 4, it is characterised in that: the concrete synthesis step of described compound 5 is as follows:

Step a11:

It is 1:1.2 by the mol ratio of the chloro-5-bromobenzoic acid of 2-and oxalyl chloride, takes the chloro-5-bromobenzoic acid of 2-in there-necked flask, add anhydrous methylene chloride, reaction bulb is placed in frozen water, stir ten minutes, then, drip oxalyl chloride, react under room temperature overnight, after reaction terminates, solvent evaporated, obtain compound 2；

Step a12:

By compound 2, isopropylbenzene and anhydrous AlCl₃Mol ratio be 1:1.3:1.5, take compound 2 and put in round-bottomed flask, be sequentially added into anhydrous methylene chloride and isopropylbenzene, reaction bulb is put into cryosel bath in, stir ten minutes, weigh anhydrous AlCl₃, it is dividedly in some parts in reactant liquor, temperature does not exceed-4 DEG C, stirring reaction 4 hours at 5 DEG C, then adds frozen water in reactant liquor, isolates organic facies and aqueous phase after half an hour, and the HCl of organic facies 1N washs three times, then with saturated NaHCO₃Solution is washed till neutrality, then with saturated common salt water washing three times, finally uses anhydrous MgSO₄Dry, then filtration, concentrating and purifying obtain compound 4；

Step a13:

It is 1:2.8 by the mol ratio of compound 4 and triethyl silicane, compound 4 is dissolved in trifluoroacetic acid, then triethyl silicane is dripped, a droplet trifluoromethanesulfonic acid of dropping after stirring ten minutes under room temperature, then heats to backflow, stops after reaction 3h, reactant liquor is concentrated, its residue is dissolved in ethyl acetate, washes with water three times, then with saturated NaHCO₃Solution is washed till neutrality, finally uses anhydrous MgSO₄It is dried overnight, filters, concentrate and purify and obtain compound 5。

8. preparation method as claimed in claim 5, it is characterised in that: the concrete synthesis step of described compound 7 is as follows:

It is 1:7 by the mol ratio of D-Glucose lactone and trim,ethylchlorosilane, weighing D-Glucose lactone and put in round-bottomed flask, add anhydrous tetrahydro furan and N-methylmorpholine, stirring is cooled to-5 DEG C, then trim,ethylchlorosilane is dripped, it is warmed up to 35 DEG C of reaction 5h, stopped reaction after stirring 15min, is initially charged toluene when 0 DEG C to reactant liquor, rear addition water, period temperature does not exceed 10 DEG C, stratification, and organic facies uses saturated NaH successively₂PO₄With saturated common salt water washing, then use anhydrous MgSO₄It is dried overnight, filters, recycling design, residue is dissolved in toluene, then solvent is thoroughly evaporated off, obtain compound 7。

9. compound as claimed in claim 1 or 2 is for preparing the purposes for the treatment of diabetes medicament。

10. the pharmaceutical composition treating diabetes, it is characterised in that: containing, for example the compound described in claim 1 or 2 in described compositions。