CN105693669A

CN105693669A - Antidiabetic compound and preparation method and application thereof

Info

Publication number: CN105693669A
Application number: CN201510996750.3A
Authority: CN
Inventors: 聂丽娟; 李响敏
Original assignee: Nanchang University
Current assignee: Nanchang University
Priority date: 2015-12-28
Filing date: 2015-12-28
Publication date: 2016-06-22

Abstract

The invention discloses an antidiabetic compound and a preparation method and application thereof, and belongs to the technical field of medicine. The chemical structure of the compound is shown as a formula (I) (please see the formula in the description), wherein R is selected from i-Pr, Cl and COCH2Cl. According to the antidiabetic compound and the preparation method and application thereof, 2-chloro-5-bromobenzoic acid and D-gluconolactone are taken as starting raw materials, and three Dapagliflozin derivatives are finally obtained through reacting; the optimal reaction condition of different positioning groups is determined according to the reaction conditions of a Friede-Crafts alkylation reaction of the different positioning groups; in addition, a novel stereoisomerism splitting method is applied, therefore, the reaction conditions are optimized, the reaction cost is greatly lowered, the yield is increased, the used raw materials are cheap and easy to obtain, and the wide applicability is achieved.

Description

A kind of antidiabetic compound and its production and use

Technical field

The present invention relates to pharmaceutical technology field, particularly relate to a kind of antidiabetic compound and its production and use。

Background technology

Diabetes are a series of Clinical syndromes caused by a kind of absolute because of internal insulin or relative deficiency, and research shows that it not only has very close association with gene, but also also closely related with daily life custom。But the Major Clinical disease of diabetes shows as polydipsia more, polyuria, polyphagia body weight but decline (" three-many-one-little "), and containing glucose (should not contain glucose in normal urine) etc., various clinical disease in blood sugar content height, urine。

Diabetes can cause multiple complications, if diabetes patient does not obtain the effective treatment, will cause some acute complicationses, such as non-ketone hyperosmolar coma disease, hypoglycemia, ketoacidosis etc.。If be in a bad way, long-term complications such as chronic renal failure (i.e. diabetic nephropathy will be caused, patient's main cause of carrying out hemodialysis), cardiovascular and cerebrovascular disease, retinopathy (i.e. diabetic ophthalmopathy is the blind principal disease of non-aged adult), neuropathy and microangiopathies etc.。Wherein, microangiopathies may result in patient wound to be difficult to heal, if foot has the wound being difficult to heal, likely can cause gangrene (being namely commonly called as " diabetic foot "), causes that patient must amputation。

Dapagliflozin is the medicine of a kind of new oral treatment type 2 diabetes mellitus, has become as the focus of people's research with its good drug effect, less toxic and side effects。In numerous transformation research, it has been found that terminal phenyl rings is transformed, is easier to obtain the good new drug of drug effect。So recent years, people be devoted to always on research terminal phenyl rings transformation。

Summary of the invention

It is an object of the invention to provide a kind of antidiabetic compound and preparation method thereof。

The present invention adopts the following technical scheme that

Shown in the chemical constitution of the antidiabetic compound of the present invention such as formula (I):

Wherein, R is i-Pr, Cl and COCH₂Cl。

Preferred substituents R is i-Pr, and chemical constitution is as follows:

The antidiabetic compound of the present invention also includes formula (I) compound pharmaceutically acceptable salt, hydrate, solvate, its optical isomer or its prodrug。

The synthetic route of the antidiabetic compound of the present invention 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:

The synthetic route of compound 5 is as follows:

Step a11:

Step a12:

Step a13:

The synthetic route of compound 7 is as follows:

Specifically comprising the following steps that of the preparation method of the antidiabetic compound of the present invention

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。

The concrete synthesis step of 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。

The concrete synthesis step of 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。

The compound of the present invention may be used for preparation treatment diabetes medicament。

Present invention additionally comprises a kind of pharmaceutical composition treating diabetes, containing, for example the compound described in formula (I) in described compositions。

The positive effect of the present invention is as follows:

The present invention, with 2-chlorine 5-bromobenzoic acid and D-Glucose lactone for initiation material, through reaction, has finally given three kinds of Dapagliflozin derivants, has passed through¹HNMR、¹³CNMR and MS determines the structure of gained compound; and determine the fusing point of these compounds; the reaction condition of the friedel-crafts acylation of difference seeking group of the present invention; determine they optimum reaction conditions, also used a kind of stereomeric method of novel fractionation, optimize reaction condition; it is substantially reduced reaction cost; improve productivity, and the raw material used is cheap and easy to get, has wide applicability。Dapagliflozin and derivant thereof have good drug effect。

Detailed description of the invention

The specific embodiment of the present invention is further elucidated below:

Embodiment 1

The synthesis of the chloro-5-bromo-benzoyl chloride 2 of 2-

Take 2-chloro-5-bromobenzoic acid 0.59g (2.51mmol) in 15mL there-necked flask, add the anhydrous methylene chloride of 5ml, reaction bulb is placed in frozen water, stir ten minutes。Then, the oxalyl chloride of dropping 0.31ml (3.00mmol), reacts overnight under room temperature。After reaction terminates, solvent evaporated, obtain 0.62g (2.46mmol) yellow solution thing (2), productivity is 98.13%。

The synthesis of bromo-(4-the isopropyl phenyl)-benzophenone 4a of the chloro-5-of 2-

Take compound (2) 0.50g (1.98mmol) and put in round-bottomed flask, be sequentially added into the anhydrous methylene chloride of 5ml and the isopropylbenzene of 0.30g (2.51mmol)。Reaction bulb is put in cryosel bath, stir ten minutes。Weigh 0.4g (3.00mmol) 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 add 10ml frozen water in reactant liquor, isolate organic facies and aqueous phase after half an hour。The HCl of organic facies 10ml1N washs three times, then with saturated NaHCO₃Solution is washed till neutrality, then with 10ml saturated common salt water washing three times, finally uses anhydrous MgSO₄Dry。Then filter, concentrate to obtain brown-red solid, silica gel column chromatography (chromatographic silica gel, 200-300 order；Eluant, V_{Petroleum ether}/V_{Ethyl acetate}=1:60) purification, obtain 0.633g white solid, productivity is 95.32%。M.p.83～85 DEG C；¹HNMR (500MHz, CDCl₃), δ 7.73 (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-MSm/z337.1 (value of calculation 335.9) ([M+H]⁺)。

The synthesis of bromo-(4-the isopropyl phenyl)-phenylmethane 5a of the chloro-5-of 2-

Compound (4a) 0.50g (1.52mmol) is dissolved in the trifluoroacetic acid of 3ml, then the triethyl silicane of 0.50ml (4.31mmol) is dripped, a droplet trifluoromethanesulfonic acid of dropping after stirring ten minutes under room temperature, then heat to backflow, stopping after reaction 3h, concentrated by reactant liquor, its residue is dissolved in 5ml ethyl acetate, wash three times with 10ml, then with saturated NaHCO₃Solution is washed till neutrality, finally uses anhydrous MgSO₄It is dried overnight。Filtering, concentrate to obtain thick product, carry out recrystallization with methanol and obtain 0.46g white solid, productivity is 93.15%。

M.p.39～40 DEG C；¹HNMR (400MHz, CDCl₃), δ 7.28～7.21 (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)。

The protection reaction of D-Glucose lactone 7

Weigh D-Glucose lactone (6) 1.00g (5.61mmol) and put in 25mL round-bottomed flask, add anhydrous tetrahydro furan and the 5mlN-methyl morpholine of 10ml, stirring is cooled to-5 DEG C, then the trim,ethylchlorosilane of 5ml (38.93mmol) is dripped, it is warmed up to 35 DEG C of reaction 5h, stopped reaction after stirring 15min, is initially charged the toluene of 15ml when 0 DEG C to reactant liquor, the rear water adding 25ml, period temperature does not exceed 10 DEG C。Stratification, organic facies is successively with the saturated NaH of 20ml₂PO₄With 20ml saturated common salt water washing, then use anhydrous MgSO₄It is dried overnight。Filtering, recycling design, residue is dissolved in the toluene of 15ml, then solvent is thoroughly evaporated off, obtain 2.51g yellow viscous liquid (7), productivity is 96.45%。

The synthesis of (3R, 4S, 5R, 6S)-2-[3-(4-isopropyl phenyl)-4-chlorphenyl]-2-methoxyl group-6-methylol tetrahydrochysene-2H-pyrans-3,4,5-triol 8a

Weigh Compound (5a) 0.50g (1.59mmol) puts in (THF:toluene=1:2) solution of 7.5ml。Under the protection of nitrogen, stirring is cooled to-78 DEG C, is then added dropwise over the n-Buli [1.91mmol (2.5Ninhexane)] of 0.8ml。At this temperature, stir 30min, then the toluene solution of (7) 0.89g (1.92mmol) and 2.5ml is added gradually in reactant liquor, at-78 DEG C of stirring reaction 3h。

The saturated NH of 5ml is added to reactant liquor₄Cl cancellation is reacted, and separates organic facies and aqueous phase。Aqueous phase 10ml toluene extracts three times, merges the concentration of organic facies vacuum。Residue is dissolved in the methanol of 10ml, is cooled to 0 DEG C, add 0.18g (1.6mmol) p-methyl benzenesulfonic acid, be warmed up to 15 DEG C of stirring reactions, overnight。Reaction is cooled to 0 DEG C after terminating, and adds the saturated NaHCO of 10ml₃Solution washing, stratification, aqueous phase 10ml extraction into ethyl acetate three times, merge organic facies, and with 20ml saturated common salt water washing three times, use anhydrous MgSO afterwards₄It is dried overnight。Filtering, vacuum concentrates, and obtains white solid, then uses V_{Ethyl acetate}/V_{Petroleum ether}=1:5 mixed solvent recrystallization obtains 0.51g white solid, and productivity is 73.25%。M.p.80～83 DEG C；¹HNMR (500MHz, CDCl₃), δ 7.36 (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-CH₂), 3.86 (d, J=11Hz, 1H, CH), 3.81 (s, 2H, CH₂), 3.57～3.50 (m, 2H, CH-CH), 3.19 (d, J=12Hz, 1H, CH), 2.91 (s, 3H, CH₃-O), 2.8～32.79 (m, 1H, CH-CH₃), 1.19 (d, J=8.5Hz, 6H, CH₃) .ESI-MSm/z405.1 (value of calculation 436.17) ([M-CH₃-O]⁺). because the methoxyl group in compound 8 is easy to leave away, so mass spectra peak is shown as 405.1。

The synthesis of (3R, 4S, 5R, 6S)-2-[3-(4-isopropyl phenyl)-4-chlorphenyl]-6-methylol tetrahydrochysene-2H-pyrans-3,4,5-triol 9a

Compound (8a) 0.50g (1.15mmol) is dissolved in 8ml (V_Acetonitrile∶V_{Dichloromethane}=1:1) in solution; it is cooled to-15 DEG C; stirring 10min; the triethyl silicane of dropping 0.35ml (2.20mmol); maintain temperature stirring 30min; being added dropwise over the boron trifluoride ether solution of 0.20ml (1.59mmol) under the protection of nitrogen, temperature controls between-10 DEG C-15 DEG C, reacts 5h。Stopped reaction, adds the saturated NaHCO of 5ml to reactant liquor₃Solution, separates organic facies and aqueous phase, with 10ml extraction into ethyl acetate aqueous phase, merges organic facies, with 10ml saturated common salt water washing, uses anhydrous MgSO₄It is dried overnight。Filtering, concentration obtains white solid, through silica gel column chromatography (chromatographic silica gel, 200-300 order；Eluant, V_Chloroform/V_Methanol=10:1) purification obtains white solid 0.38g, and productivity is 82.13%, m.p.75～78 DEG C。

The synthesis of (3R, 4S, 5R, 6S)-β-2-[3-(4-isopropyl phenyl)-4-chlorphenyl]-6-methylol tetrahydrochysene-2H-pyrans-3,4,5-triol-L-PROLINE 10a

In 10ml reaction bulb, it is sequentially added into the L-PROLINE of the compound (9a) of 0.38g (0.93mmol), 0.43g (3.73mmol), 3ml (V_Ethanol/V_Water=14:1) mixed liquor, heating to backflow, reaction 1h after, it is cooled to 60 DEG C gradually, has white solid to generate, then at the normal hexane slowly dripping 3ml, after stirring 3h, naturally cool to room temperature, be filtrated to get white solid, wash three times with the normal hexane of 30ml, dry in vacuum drying oven at 100 DEG C, obtaining 0.42g white solid, productivity is 70.45%, m.p.162～164 DEG C。

The synthesis of (3R, 4S, 5R, 6S)-β-2-[3-(4-isopropyl phenyl)-4-chlorphenyl]-6-methylol tetrahydrochysene-2H-pyrans-3,4,5-triol 11

0.42g (0.66mmol) compound (10a) is dissolved in the ethyl acetate of 5ml and the water of 5ml, heating is to refluxing, after becoming clarification until solution, separate organic facies and aqueous phase immediately while hot, aqueous phase 10ml extraction into ethyl acetate three times, merge organic facies, with 20ml saturated common salt water washing three times, use anhydrous MgSO₄It is dried overnight, filters, concentration, silica gel column chromatography (chromatographic silica gel, 200-300 order；Eluant, V_Chloroform/V_Methanol=10:1) purification obtains white solid 0.24g, and for target product (11), productivity is 91.35%。M.p.75～77 DEG C；¹HNMR (400MHz, CDCl₃), δ 7.23 (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-CH₂-CH), 3.66 (s, 2H, CH₂), 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-CH₃), 1.14 (d, J=6.8Hz, 6H, CH₃).¹³CNMR (100MHz, CDCl₃) δ 146.87,138.98,136.88,136.48,134.45,130.62,129.77,128.66,126.55,126.39,81.14,79.26,77.23,76.81,74.84,70.22,62.10,38.79,33.64,30.92,23.99；ESI-MSm/z405 (value of calculation 406) ([M-H]^-)。

Embodiment 2

The synthesis of bromo-(4-the chlorphenyl)-benzophenone 4b of the chloro-5-of 2-

Weighing the aluminum trichloride (anhydrous) of 0.35g (2.63mmol), put in the round-bottomed flask of 25ml, add the anhydrous chlorobenzene of 10ml, be warming up to 50 DEG C, stirring makes aluminum chloride all dissolve。Then it is added dropwise over the mixed liquor of 0.50g (1.99mmol) compound (2) and 3ml anhydrous chlorobenzene, is warming up to boiling, react 4h。Stopped reaction, is cooled to 0 DEG C, adds 10ml frozen water, isolate organic facies and aqueous phase after half an hour in reactant liquor。The HCl of organic facies 10ml1N washs three times, then with saturated NaHCO₃Solution is washed till neutrality, then with 10ml saturated common salt water washing three times, finally uses anhydrous MgSO₄Dry。Then filter, concentrate to obtain brown-red solid, silica gel column chromatography (chromatographic silica gel, 200-300 order；Eluant, V_{Petroleum ether}/V_{Ethyl acetate}=60:1) purification, obtain 0.61g white solid, productivity is 93.56%。M.p.78～80 DEG C；¹HNMR (500MHz, CDCl₃), δ 7.75 (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)。

The synthesis of bromo-(4-the chlorphenyl)-phenylmethane 5b of the chloro-5-of 2-

Compound (4b) 0.50g (1.52mmol) is dissolved in the trifluoroacetic acid of 3ml, then the triethyl silicane of 0.50ml (3.14mmol) is dripped, drip a trifluoromethanesulfonic acid after stirring 30min under room temperature, then heat to backflow, react 3h。Stopped reaction, concentration of reaction solution, then residue is dissolved in 5ml ethyl acetate, washes three times with 10ml, then with saturated NaHCO₃Solution is washed till neutrality, finally uses anhydrous MgSO₄It is dried overnight；Filtering, concentrate to obtain thick product, carry out recrystallization with methanol and obtain 0.44g white solid, productivity is 91.60%。M.p.40～41 DEG C；¹HNMR (400MHz, CDCl₃), δ 7.31～7.22 (m, 5H, Ar-H), 7.34 (d, J=8Hz, 2H, Ar-H), 4.01 (s, 2H, CH₂)。

The synthesis of (3R, 4S, 5R, 6S)-2-[3-(4-chlorphenyl)-4-chlorphenyl]-2-methoxyl group-6-methylol tetrahydrochysene-2H-pyrans-3,4,5-triol 8b

Weigh Compound (5b) 0.50g (1.58mmol) puts into (V of 7.5ml_THF:V_toluene=1:2) in solution。Stirring is cooled to-78 DEG C, is then added dropwise over the n-Buli [1.91mmol (2.5Ninhexane)] of 0.8ml。Stir 30min at this temperature, then the mixed solution of (7b) 0.89g (1.92mmol) and 2.5ml toluene is slowly added in reactant liquor, at-78 DEG C of stirring reaction 3h。The saturated NaHCO of 5ml is added to reactant liquor₃Cancellation is reacted, and separates organic facies and aqueous phase。Aqueous phase 10ml toluene extracts three times, combining methylbenzene phase, and vacuum concentrates, and is dissolved in the methanol of 10ml by residue, is cooled back to 0 DEG C, adds 0.18g (1.6mmol) p-methyl benzenesulfonic acid, is warmed up to 15 DEG C, and stirring reaction is overnight。After having reacted, it is cooled to 0 DEG C, adds the saturated NaHCO of 10ml₃Solution washing, separates organic facies and aqueous phase, with 10ml extraction into ethyl acetate aqueous phase three times, merges organic facies, with 20ml saturated common salt water washing three times, after use anhydrous Na₂SO₄It is dried overnight。Filtering, vacuum concentrates, silica gel column chromatography (chromatographic silica gel, 200-300 order；Eluant, V_Chloroform/V_Methanol=10:1), obtain 0.48g yellow solid, productivity is 70.81%。M.p.69～72 DEG C；¹HNMR (400MHz, CDCl₃), δ 7.33 (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-CH₂-CH), 3.8 (m, 2H, CH₂), 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, CH₃-O)；ESI-MSm/z451.0 ([M+Na]⁺)。

The synthesis of (3R, 4S, 5R, 6S)-2-[3-(4-chlorphenyl)-4-chlorphenyl]-6-methylol tetrahydrochysene-2H-pyrans-3,4,5-triol 9b

The compound (8b) of 0.50g (1.16mmol) is dissolved in 8ml (V_Acetonitrile∶V_{Dichloromethane}=1:1) solution in; it is cooled to-15 DEG C; the triethyl silicane of dropping 0.40ml (2.51mmol); at this temperature after stirring 30min; the boron trifluoride ether solution of 0.20ml (1.59mmol) it is added dropwise under the protection of nitrogen; temperature controls between-10 DEG C-15 DEG C, reacts 5h。Stopped reaction, adds the saturated NaHCO of 5ml to reactant liquor₃Solution, separates organic facies and aqueous phase, with 10ml extraction into ethyl acetate aqueous phase, merges organic facies, with 10ml saturated common salt water washing, uses anhydrous Na₂SO₄It is dried overnight, filters, silica gel column chromatography (chromatographic silica gel, 200-300 order；Eluant, V_Chloroform/V_Methanol=10:1) white solid 0.37g productivity be 80.14%。M.p.75～77 DEG C。

The synthesis of (3R, 4S, 5R, 6S)-β-2-[3-(4-chlorphenyl)-4-chlorphenyl]-6-methylol tetrahydrochysene-2H-pyrans-3,4,5-triol-L-PROLINE 10b

The compound (9b) of 0.37g (0.93mmol) being put in the flask of 10ml, the L-PROLINE weighing 0.43g (3.73mmol) adds in reaction bulb, adds 3ml (V_Ethanol/V_Water=14:1) mixed liquor, heating, to backflow, after reaction 1h, is cooled to 60 DEG C gradually, White Flocculus is had to generate, after stirring 3h, slowly it is cooled to room temperature, is filtrated to get white solid, wash three times with the normal hexane of 30ml, drying in 100 DEG C of vacuum drying ovens, obtain 0.41g white solid, productivity is 70.20%。M.p.1581～61 DEG C。

The synthesis of (3R, 4S, 5R, 6S)-β-2-[3-(4-chlorphenyl)-4-chlorphenyl]-6-methylol tetrahydrochysene-2H-pyrans-3,4,5-triol 12

0.41g (0.65mmol) compound (10b) is dissolved in the ethyl acetate of 5ml and the water of 5ml, heating is to refluxing, after becoming clarification until solution, separate organic facies and aqueous phase immediately while hot, the extraction into ethyl acetate of aqueous phase 10ml three times, mixing organic facies, with 20ml saturated common salt water washing three times, uses anhydrous Na₂SO₄It is dried overnight, filters, concentration, silica gel column chromatography (chromatographic silica gel, 200-300 order；Eluant, V_Chloroform/V_Methanol=10:1) obtain target product (12) white solid 0.25g, productivity is 96.63%。M.p.74～76 DEG C；¹HNMR (400MHz, CDCl₃), δ 7.26 (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-CH₂-CH), 3.68 (s, 2H, CH₂), 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).¹³CNMR (100MHz, CDCl₃) δ 138.18,137.64,137.12,134.34,132.08,130.63,130.10,129.83,128.61,126.65,81.06,79.39,77.99,77.24,74.70,769.92,61.81,38.54,30.92；ESI-MSm/z421 (value of calculation 398) ([M+Na]⁺)。

Embodiment 3

The synthesis of the bromo-benzophenone 4c of the chloro-5-of 2-

0.50g (1.99mmol) compound (2) compound is mixed with the anhydrous methylene chloride of 10ml, then the anhydrous benzene of 0.20g (2.56mmol) is dripped, it is cooled to 0 DEG C, weigh the aluminum trichloride (anhydrous) of 0.35g (2.63mmol), being dividedly in some parts in reactant liquor, temperature does not exceed 5 DEG C, after stirring 30min, it is warming up to room temperature, reacts 4h。Stopped reaction, is cooled to 0 DEG C, adds 10ml frozen water in reactant liquor, after reacting half an hour, separates organic facies and aqueous phase。The HCl of organic facies 10ml1N washs three times, then with saturated NaHCO₃Solution is washed till neutrality, then with 10ml saturated common salt water washing three times, finally uses anhydrous MgSO₄Dewater。Then filter, concentrate to obtain brown-red solid, silica gel column chromatography (chromatographic silica gel, 200-300 order；Eluant, petrol ether/ethyl acetate=1:60) purification, obtain 0.55g white solid, productivity is 94.00%。

M.p.86～87 DEG C；¹HNMR (500MHz, CDCl₃), δ 8.12 (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=7Hz, 3H, Ar-H), 7.34 (d, J=8.5Hz, 1H, Ar-H)。

The synthesis of the bromo-phenylmethane 5c of the chloro-5-of 2-

Compound (4c) 0.50g (1.70mmol) is dissolved in the trifluoroacetic acid of 3ml, then the triethyl silicane of 0.50ml (3.14mmol) is dripped, a droplet trifluoromethanesulfonic acid of dropping after stirring ten minutes under room temperature, then heats to backflow, reacts 3h。Stopped reaction, concentration of reaction solution, then residue is dissolved in 5ml ethyl acetate, washes three times with 10ml, then with saturated NaHCO₃Solution is washed till neutrality, finally uses anhydrous MgSO₄It is dried overnight, filters, concentrate to obtain thick product, silica gel column chromatography (chromatographic silica gel, 200-300 order；Eluant, V_{Petroleum ether}/V_{Ethyl acetate}=50:1) purification, obtain 0.42g colourless oil liquid, productivity is 88.23%。¹HNMR (500MHz, CDCl₃), δ 7.23～7.13 (m, 6H, Ar-H), 7.09 (d, J=7Hz, 2H, Ar-H), 3.96 (s, 2H, CH₂)。

The synthesis of (3R, 4S, 5R, 6S)-2-[3-(4-phenyl)-4-chlorphenyl]-2-methoxyl group-6-methylol tetrahydrochysene-2H-pyrans-3,4,5-triol 8c

Weigh Compound (5c) 0.40g (1.42mmol) puts into (V of 7.5ml_THF:V_toluene=1:2) in solution。Under the protection of nitrogen, stirring is cooled to-78 DEG C, is then added dropwise over the n-Buli [1.91mmol (2.5Ninhexane)] of 0.8ml。At this temperature, after stirring 30min, the mixed solution of (7) 0.89g (1.92mmol) and 2.5ml toluene is added gradually in reactant liquor, at-78 DEG C of stirring reaction 3h。The saturated NH of 5ml is added to reactant liquor₄Cl cancellation is reacted, and separates organic facies and aqueous phase。Aqueous phase 10ml toluene extracts three times, merges organic facies, and vacuum concentrates, and is dissolved in the methanol of 10ml by residue。It is cooled to 0 DEG C, adds 0.18g (1.6mmol) p-methyl benzenesulfonic acid, be warmed up to 25 DEG C of stirring reactions overnight。After having reacted, it is cooled to 0 DEG C, adds the saturated NaHCO of 10ml₃Solution washing, separates organic facies and aqueous phase, with 10ml extraction into ethyl acetate aqueous phase three times, merges organic facies, with 20ml saturated common salt water washing three times, uses anhydrous MgSO afterwards₄It is dried overnight。Filtering, vacuum concentrates, and obtains white solid (V_{Ethyl acetate}/V_{Petroleum ether}=1:7) mixed solvent recrystallization, obtain 0.36g white solid, productivity is 64.34%。

M.p.77～79 DEG C；¹HNMR (400MHz, MEOD), δ 7.38 (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, CH₂), 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=1.6Hz, 2H, O-CH₂), 3.10 (s, 3H, CH₃-O)；ESI-MSm/z417.0 (value of calculation 394) ([M+Na]⁺)。

The synthesis of (3R, 4S, 5R, 6S)-2-[3-(4-phenyl)-4-chlorphenyl]-6-methylol tetrahydrochysene-2H-pyrans-3,4,5-triol 9c

The compound (8c) of 0.36g (0.91mmol) is dissolved in 8mlV_Acetonitrile:V_{Dichloromethane}In the solution of=1:1; it is cooled to-15 DEG C; stirring 10min; the triethyl silicane of dropping 0.30ml (1.88mmol); stir 1h at this temperature; then being added dropwise over the boron trifluoride ether solution of 0.15ml (1.19mmol) under the protection of nitrogen, temperature controls between-10 DEG C-15 DEG C, reacts 5h。Stopped reaction, adds the saturated NaHCO of 5ml to reactant liquor₃Solution, separates organic facies and aqueous phase, with 10ml extraction into ethyl acetate aqueous phase, merges organic facies, with 10ml saturated common salt water washing, uses anhydrous MgSO₄Being dried overnight, filter, concentration obtains white solid, silica gel column chromatography (chromatographic silica gel, 200-300 order；Eluant, V_Chloroform/V_Methanol=12:1) white solid 0.28g productivity be 84.29%。M.p.75～77 DEG C。

The synthesis of (3R, 4S, 5R, 6S)-β-2-[3-(4-phenyl)-4-chlorphenyl]-6-methylol tetrahydrochysene-2H-pyrans-3,4,5-triol-L-PROLINE 10c

The compound (9c) of 0.28g (0.77mmol) is put in the flask of 10ml, be subsequently adding the L-PROLINE of 0.35g (3.04mmol), add 3ml (V_Ethanol/V_Water=14:1) mixed liquor, heating to backflow, react 1h, it is cooled to 60 DEG C gradually, white solid is had to generate, then at the normal hexane slowly dripping 3ml, after stirring 3h, naturally cool to room temperature, it is filtrated to get white solid, washs three times with the normal hexane of 30ml, dry in 100 DEG C of vacuum drying ovens, obtaining 0.33g white solid, productivity is 72.15%。M.p.182～184 DEG C；。

The synthesis of (3R, 4S, 5R, 6S)-β-2-[3-(4-chlorphenyl)-4-chlorphenyl]-6-methylol tetrahydrochysene-2H-pyrans-3,4,5-triol 14

0.33g (0.55mmol) compound (10c) is dissolved in the ethyl acetate of 5ml and the water of 5ml, heating is to refluxing, after becoming clarification until solution, separate organic facies and aqueous phase immediately while hot, aqueous phase 10ml extraction into ethyl acetate three times, mixing organic facies, with 20ml saturated common salt water washing three times, uses anhydrous Na₂SO₄It is dried overnight, filters, concentration, silica gel column chromatography (chromatographic silica gel, 200-300 order；Eluant, V_Chloroform/V_Methanol=12:1) obtain white solid 0.19g, productivity is 94.90%。M.p.75～76 DEG C；¹HNMR (400MHz, MEOD), δ 7.21～7.03 (m, 8H, Ar-H), 4.00 (d, J=4.8Hz, 1H, CH), 3.94 (s, 2H, CH₂), 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-MSm/z387.0 (value of calculation 364) ([M+Na]⁺).

The synthesis of (3R, 4S, 5R, 6S)-β-2-[3-(4-phenyl)-4-chlorphenyl]-6-methyl acetate base tetrahydrochysene-2H-pyrans-3,4,5-triacetate 15:

0.19g (0.52mmol) compound (14) is dissolved in the pyridine of 5ml, and is cooled to 0 DEG C, then drip the acetic anhydride of 0.2ml (2.11mmol), react overnight under room temperature。Add the water of 1ml to reactant liquor, continue reaction 1h, then turn off reaction, with the dichloromethane extraction reactant liquor of 5ml, the water washing of organic facies 30ml three times, use anhydrous MgSO₄It is dried overnight, filters, concentration, carry out recrystallization with petroleum ether, obtain 0.24g white solid, productivity is 86.53%。M.p.134～135 DEG C；¹HNMR (400MHz, CDCl₃), δ 7.31 (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-CH₂), 4.08 (d, J=10.8Hz, 2H, CH₂), 3.99 (d, J=10.8Hz, 1H, CH), 3.74～3.70 (m, 1H, CH), 2.00 (d, J=10.8Hz, 6H, CH₃), 1.91 (s, 3H, CH₃), 1.61 (s, 3H, CH₃) ESI-MSm/z553.0 (value of calculation 530.9) ([M+Na]⁺)。

The synthesis of (3R, 4S, 5R, 6S)-β-2-[3-(4-chloracetyl phenyl)-4-chlorphenyl]-6-methyl acetate base tetrahydrochysene-2H-pyrans-3,4,5-triacetate 16

The compound (15) of 0.24g (0.45mmol) is dissolved in the anhydrous methylene chloride of 5ml, again 0.06g (0.45mmol) aluminum trichloride (anhydrous) is joined in reactant liquor, it is warming up to 30 DEG C, after treating that aluminum chloride all dissolves, it is added dropwise over the chloracetyl chloride of 0.04ml (0.53mmol), is warming up to backflow, react 2h, then add the aluminum trichloride (anhydrous) of 0.03g (0.23mmol) again to reactant liquor, react 2h。Stopped reaction, adds 10ml frozen water to reactant liquor, reacts 30min, separates organic facies and aqueous phase。The HCl of organic facies 10ml1N washs three times, then with saturated NaHCO₃Solution is washed till neutrality, then with 10ml saturated common salt water washing three times, finally uses anhydrous MgSO₄Dewater。Then filter, concentrate to obtain white solid, silica gel column chromatography (chromatographic silica gel, 200-300 order；Eluant, V_{Petroleum ether}/V_{Ethyl acetate}=30:1) purification, obtain 0.18g white solid, productivity is 65.79%。M.p.149～151 DEG C；¹HNMR (500MHz, CDCl₃), δ 7.82 (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, CH₂-Cl), 4.28 (d, J=6.5Hz, 2H, O-CH₂), 4.22～4.18 (m, 1H, CH), 4.08 (s, 2H, CH₂), 3.76～3.73 (m, 1H, CH), 1.98 (d, J=9Hz, 6H, CH₃), 1.92 (s, 3H, CH₃), 1.66 (s, 3H, CH₃) ESI-MSm/z631.0 (value of calculation 608.1) ([M+Na]⁺)。

The synthesis of (3R, 4S, 5R, 6S)-β-2-[3-(4-chloracetyl phenyl)-4-chlorphenyl]-6-methylol tetrahydrochysene-2H-pyrans-3,4,5-triol 13

The compound (16) of 0.18g (0.30mmol) is dissolved in the absolute methanol of 5ml, adds the Feldalat NM of 0.02g (0.37mmol), react overnight under room temperature。Stopped reaction, concentration of reaction solution。Silica gel column chromatography (chromatographic silica gel, 200-300 order；Eluant, V_Chloroform/V_Methanol=15:1) obtain desired product as white solid (13) 0.12g, productivity is 90.91%。M.p.77～79 DEG C；¹HNMR (500MHz, CDCl₃), δ 7.25 (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, CH₂-Cl), 3.97～3.91 (m, 3H, O-CH₂-CH), 3.68 (s, 2H, CH₂), 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).¹³CNMR (100MHz, CDCl₃) δ 190.01,138.28,137.66,137.09,134.30,132.06,130.63,130.10,129.85,128.59,126.63,81.05,79.40,78.01,77.02,74.68,69.91,61.83,44.81,38.53,30.91；ESI-MSm/z440 (value of calculation 440) ([M+Na]⁺)。

Embodiment 4

In the present invention, the internal hypoglycemic activity of compound can pass through to use mensuration system measurement as described below。

Normal mouse oral glucose tolerance test (OGTT)

10 week old Kunming kind cleaning grade mices, body weight 18～22g, male, it is randomly divided into 11 groups, blank group (blank solvent), positive drug control group 1 (Dapagliflozin:1.5mg/kg (3.7 μm of ol/kg)), test-compound group (3.7 μm of ol/kg), often group 8。

Before experiment, mice fasting can't help water 12 hours, and the equal oral administration gavage administration of each group, docking takes blood, measures blood glucose value (being designated as-30min)。Then 11 groups of mice gavages respectively give blank solvent, Dapagliflozin and test-compound, measure blood glucose value after 30min and be designated as 0min, the glucose solution that concentration is 3g/10ml is given immediately afterwards by 10ml/kg gavage, and in 15,30,45,60,120min measure blood glucose value (mmol/L)。Result is following table such as。

Table 1: after normal mouse single-dose 2h blood glucose value change (N=8)

Note: * P≤0.05, * * P≤0.01 is Student ' the st assay relative to blank group。

Normal mouse oral glucose tolerance test shows, all test-compounds all have certain hypoglycemic effect, and wherein compound 11,12 and 13 can be obviously improved the carbohydrate tolerance of normal mouse, and internal hypoglycemic activity is suitable with Dapagliflozin, even better, show the hypoglycemic activity of excellence。

In the present invention, the activity of the internal promotion glucose in urine of compound can be passed through to use mensuration system measurement as described below。

Before experiment, mice fasting can't help water 12 hours, the equal oral administration gavage administration of each group, measures glucose in urine (being designated as-30min)。

Then 11 groups of mice gavages respectively give blank solvent, Dapagliflozin and test-compound, measure urine sugar value and are designated as 0min, give, by 10ml/kg gavage, the glucose solution that concentration is 3g/10ml immediately afterwards after 30min, and in 15,30,45,60,120min measure urine sugar value。

The mensuration of urine sugar value is to immerse in urine by Tes-Tape band, and drenched (about 1-2 second kind) takes out afterwards；Reagent paper is taken out to remove unnecessary urine along container edge；Within the 30-60 second, observe reagent paper band color and compare with color board, recording result。

Result judges: (reagent paper is represented testing result by light blue to brownish red change) light blue indicates without glucose in urine, represents by "-"；Brownish red indicates glucose in urine, deeper "+" number the more, in urine, concentration of glucose is more high。Result is following table such as。

Table 2: the urine sugar value change of 2h after normal mouse single-dose

Note :-: there is no glucose in urine；±: 100mg/dL；+: 250mg/dL；

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

Normal mouse urine glucose test shows, all test-compounds all have certain glucose in urine effect, and wherein compound 11,12 and 13 can be obviously promoted glucose in urine discharge, it was shown that it has good SGLT2 inhibitory activity, and the effect of compound 11 is best。

The foregoing is only presently preferred embodiments of the present invention, not in order to limit the present invention, all any amendment, equivalent replacement and improvement etc. made within the spirit and principles in the present invention, should be included within protection scope of the present invention。

Claims

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:

Step b:

Step c:

Step d:

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:

Step a12:

Step a13:

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

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。